RARE DISEASE
Alpha-1-antitrypsin deficiency
Alpha-1-antitrypsin deficiency
Alpha-1-antitrypsin deficiency
Synonyms: Alpha-1-proteinase inhibitor deficiency, Alpha1-antitrypsin deficiency
Synonyms: Alpha-1-proteinase inhibitor deficiency, Alpha1-antitrypsin deficiency
Synonyms: Alpha-1-proteinase inhibitor deficiency, Alpha1-antitrypsin deficiency
Drug discovery
42
drugs
With orphan designations
Overview
Alpha-1-antitrypsin deficiency (AATD) is an autosomal codominant genetic disorder caused by mutations in the SERPINA1 gene, leading to reduced levels/functionality of alpha-1 antitrypsin (AAT). This deficiency results in unopposed neutrophil elastase activity, causing early-onset emphysema (often misdiagnosed as COPD) and liver disease (cirrhosis, hepatocellular carcinoma). Smoking accelerates pulmonary damage. Diagnosis involves serum AAT quantification and genotyping. Management includes smoking cessation, augmentation therapy, and liver/lung transplantation for advanced disease [1][2][16].
Population
Prevalence: 1 in 1,500–3,500 individuals of European ancestry; severe deficiency (Pi*ZZ genotype) affects 70,000–100,000 in the US, with >90% undiagnosed [1][12]
Highest risk: Northern European and Iberian descent; rare in Asian populations [1][7]
Carriers (Pi*MZ/MS) have variable risk of lung/liver disease, especially with smoking [2][12]
Burden
Mortality: 4.7x higher vs general population; pediatric liver disease carries 33.8x mortality risk [9][14]
Morbidity: 32% develop COPD, 21% emphysema, 12% bronchiectasis; 10–15% develop cirrhosis [12][19]
Socioeconomic impact: High healthcare costs, frequent exacerbations requiring hospitalization (~1.5/year), and caregiver stress due to progressive disability [4][5][19]
Therapies
Augmentation therapy: Weekly IV AAT infusions (Prolastin-C®, Aralast NP™, Zemaira®) to slow emphysema progression [3][16][18]
COPD management: Bronchodilators, inhaled corticosteroids, pulmonary rehabilitation, and oxygen therapy [8][18]
Liver transplant: Curative for liver failure; investigational approaches include gene therapy and hepatocyte transplantation [8][16]
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare renal diseases, rare respiratory diseases, rare transplant-related disorders
Research Papers
1,034 drug discovery papers about Alpha-1-antitrypsin deficiency, with 1 first-in-class and 33 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,034 drug discovery papers about Alpha-1-antitrypsin deficiency, with 1 first-in-class and 33 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-08 | p62/SQSTM1-KEAP1 complex prevents clearance of ubiquitinated Z alpha-1 antitrypsin and aggravates liver proteotoxicity.
Liver disease in Alpha-1 antitrypsin deficiency (AATD) is caused by the toxic accumulation of mutant Z alpha-1 antitrypsin (Z-AAT) within the endoplasmic reticulum (ER) of hepatocytes. Livers from PiZ transgenic mice expressing the human Z-AAT and AATD patients were both found to have increased p62/SQSTM1, a multifunctional protein involved in protein homeostasis, consistent with previous reports. However, whether p62/SQSTM1 is a marker of Z-AAT globules or plays an active role in Z-AAT proteostasis is unclear. The goal of this study was to elucidate the involvement of p62/SQSTM1 in the formation of Z-AAT globules that are responsible for liver injury in AATD. In the present study, we found that p62/SQSTM1 decorated ubiquitin-positive, Periodic-Acid Shiff-diastase-resistant Z-AAT globules and interacted with Z-AAT at the ER-cytosol interface. Genetic ablation of p62/SQSTM1 in PiZ mice (PiZ;p62-/-) led to marked reduction in hepatic Z-AAT globules and polymers, and decreased serum Z-AAT, highlighting a central role for p62/SQSTM1 in disease pathogenesis. Moreover, hepatocyte-specific somatic deletion of the ubiquitin-association (UBA) domain of p62/SQSTM1 reduced Z-AAT aggregation. Furthermore, KEAP1 was identified as a binding partner of p62/SQSTM1-Z-AAT complex, leading to nuclear translocation and activation of NRF2. Inhibition of KEAP1-p62/SQSTM1 interaction reduced the abundance of p62 and phosphorylated p62, decreased intracellular Z-AAT, and redistributed NRF2 to the cytoplasm. In conclusion, this study identifies p62/SQSTM1 as a regulator of Z-AAT proteostasis and link Z-AAT/p62 accumulation to KEAP1 sequestration and NRF2 pathway activation in liver disease due to Z-AAT.
2026-05-04 | Adaptive Regulation of mTOR Activity by AMPK, Akt, and ATF6 Pathways in Pi*Z Alpha-1 Antitrypsin Deficient Hepatocytes.
Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by intracellular retention of mutant Z (Pi*Z) alpha-1 antitrypsin (AAT) within hepatocytes, resulting in progressive liver disease. Currently, no approved pharmacological therapies exist for AATD-associated hepatic injury. Emerging preclinical evidence indicates that inhibition of mammalian target of rapamycin (mTOR) ameliorates liver pathology in AATD; however, the status of mTOR activity and its regulatory mechanisms under Pi*Z AAT-induced cellular stress remains incompletely understood. In this study, we investigated alterations in mTOR signaling and its upstream regulatory pathways using a gene-edited human hepatocyte model harboring the Pi*Z mutation (Huh7.5Z cells) and a Pi*Z AAT transgenic mouse model. Attenuation of mTORC1 activity was observed in both cellular and murine Pi*Z models. In vitro analyses demonstrated activation of AMP-activated protein kinase (AMPKα), a key inhibitory regulator of mTORC1, accompanied by paradoxical activation of Akt and the unfolded protein response (UPR) branch ATF6α. Pharmacological inhibition of mTOR significantly reduced intracellular Pi*Z AAT accumulation, alleviated ER stress, and suppressed apoptotic signaling through enhancement of autophagy. These findings reveal that hepatocytes adapt to Pi*Z AAT-induced stress through coordinated regulation of mTOR by AMPK, Akt, and ATF6α pathways. This study provides mechanistic insight into metabolic and stress-response signaling in AATD and identifies mTOR modulation as a promising therapeutic strategy for AATD-associated liver disease.
2026-05-01 | D108-18 Sex Hormones and Inflammatory Proteins Impact Disease Heterogeneity in Alpha-1 Antitrypsin Deficiency-Associated COPD
Abstract Background Chronic Obstructive Pulmonary Disease (COPD) associated with Alpha-1 Antitrypsin Deficiency (AATD) exhibits sex differences in onset and progression, with males experiencing higher COPD risk and more rapid lung function decline. Sex hormones modulate immune responses, but the roles of sex hormones and inflammatory proteins in sex-specific COPD heterogeneity remain unclear. We hypothesized that distinct profiles of sex hormones and inflammatory mediators in males and females contribute to COPD differences in AATD, and aimed to identify sex-specific predictors of lung function by integrating systemic inflammatory protein and sex hormone profiling. Methods We analyzed 398 adults (221 females, 177 males) with severe AATD (PiZZ genotype) from the Alpha-1 Antitrypsin Genetic Modifiers Study. Plasma inflammatory proteins were measured via the Olink Explore 384 Inflammation panel. Serum sex hormone levels (SHBG, total/free testosterone, dihydrotestosterone, estradiol, estrone) were measured in a subset of 145 participants. Linear regression assessed associations between protein/hormone levels and COPD status, FEV1, and FEV1/FVC, adjusting for age and smoking history, using sex-stratified and sex-interaction models. Interactions between sex hormones and proteins in predicting lung function were also tested. Results Proteomic analysis revealed sex-specific inflammatory signatures that were associated with lung function among individuals with AATD. In females, eight proteins were significantly associated with FEV1/FVC ratio (FDR < 0.05), while in males, seventeen proteins were identified, with only one shared protein marker (AGER) across both sexes, highlighting divergent molecular markers of lung function by sex. To assess the impact of circulating sex hormones, we tested for the interaction between sex hormones and proteins on lung function at FDR<0.05. In females, higher estradiol levels were positively associated with ITM2A abundance, and their interaction predicted better lung function, suggesting a potential protective and modulatory role for estradiol in females with AATD. Conversely, in males, elevated testosterone levels were negatively associated with the inflammatory proteins ENPP5, OMD, and MEPE, and the interactions between testosterone and these markers predicted reduced lung function. Conclusion Our study identified sex-specific inflammatory proteins that are associated with lung function in AATD-associated COPD, with some of these associations influenced by sex hormones. Estradiol appears protective in females, while higher testosterone in males is linked to reduced lung function through its interaction with key inflammatory proteins. These findings highlight the role of sex hormones and systemic inflammatory markers in lung function, underscoring the need for sex- and hormone-informed approaches in the management and therapeutic targeting of AATD-associated COPD. This abstract is funded by: Alpha-1 Foundation
2026-05-01 | C46-16 Alpha-1 Antitrypsin Deficiency and Sarcoidosis: A Strange Duo
Abstract Alpha-1-Antitrypsin (AAT) deficiency and sarcoidosis are two rare systemic diseases frequently leading to pulmonary involvement. The first one, frequently underdiagnosed and with a broad clinical spectrum, consists of an imbalance between neutrophil elastase and its counterpart, AAT, a protein made to avoid health tissue damage; the latter provokes a chronic inflammation in the form of non-necrotizing epithelioid granulomas in response to unknown triggers. We still don’t know so much about the implications of an eventual coexistence of these diseases. Our case is about R.F., a white woman in her 50s with asthma-like symptoms after a viral illness, fatigue and multiple arthralgias associated with stiffness. Never smoker, profession hair stylist, mild obese recently diagnosed with type 2 diabetes and atopic, she denied any familiar or personal respiratory history. A serum electrophoresis showed a decrease in alpha-1 band, thus she underwent a genetic analysis leading to diagnosis of “Pi*MZ” (heterozigosis mutation) AATD. Serum levels of AAT was 80 mg/dL, in presence of normal CRP (C reactive protein); a mild increase in AST (aspartate transaminase) and ALT (alanine transaminase) was seen. Respiratory functional tests were normal; a metacholine challenge test was positive at 4th diluition (377 mcg); abdominal ultrasound showed hepatic steatosis. A chest CT scan showed diffuse mediastinal lymphadenopathy and multiple parenchimal micronodules, so we performed an EBUS-TBNA (endobronchial ultrasound-guided transbronchial needle aspiration) and a bronchoalveolar lavage, coherent with pulmonary sarcoidosis. We prescribed as-needed asthma therapy and dietotherapy as well, in order to counteract obesity pro-inflammatory Th1 milieu, strong independent risk factor for sarcoidosis also represented in AATD patients with normal lung function. We chose not to start systemic steroid therapy yet, avoiding a potential glycometabolic imbalance since, until proven otherwise (ophtalmological and cardiovascular evaluations still need to be carried out), actual organ involvement seems to be mild. Further hepatological assessments will be necessary, given a major risk of liver disease in presence of multiple known risk factors (sarcoidosis, AATD, but also metabolic syndrome). On AATD side, at time of writing this patient doesn’t need an augmentation therapy, but what about her prognosis? Further research is needed to better comprehend if AATD patients could be prone to bigger clinical instability in presence of sarcoidosis inflammatory booster, hence deeper organ reshaping and faster functional worsening; should we start earlier anti-inflammatory treatment despite of organ involvement, and/or an earlier augmentation therapy despite of AAT blood amounts? This abstract is funded by: None
2026-03-17 | SAHA increases chaperone expression and reduces Z-alpha-1-antitrypsin polymers in a patient specific iPSC-based liver model for alpha-1-antitrypsin deficiency
Summary The most severe phenotype of alpha-1-antitrypsin deficiency (AATD) is caused by the Z-mutation within the SERPINA1 gene. The Glu342Lys substitution causes misfolding and polymerisation of the alpha-1-antitrypsin (AAT) protein, its accumulation in the ER and increases the susceptibility of hepatocytes towards ER-stress. Here, we present an induced pluripotent stem cell (iPSC)-based hepatic model to study AATD. We demonstrate that iPSCs from AATD patients differentiate equally well to hepatocyte-like cells (HLCs) as control iPSCs. We detected ZAAT polymers in patient-derived HLCs which could be reduced by SAHA or CBZ treatment. Transcriptome analyses revealed major differences in metabolism and signalling between control and AATD HLCs and indicated increased stress levels affecting intracellular organelles. Importantly, the transcriptomes of control and patient-derived cells separated into distinct clusters with respect to the expression of Heat-shock protein (HSP) encoding genes. SAHA treatment increased expression of various HSPs which might contribute towards reduced ZAAT polymers.
proteins
2026-05-01 | A22-21 Comprehensive Lipidomic Profiling of Bronchoalveolar Lavage Fluid (BALF) in Alpha-1 Antitrypsin Deficiency (AATD)
Abstract Rationale Inflammation and metabolic dysfunction of the alveolar space - particularly lipid species - has been linked to Chronic Obstructive Pulmonary Disease (COPD) pathogenesis. Similar metabolic disruption has been reported in Alpha-1 Antitrypsin Deficiency (AATD), however little is known about defective cellular metabolism in the lung. Given the disturbed lipid metabolism reported in the AATD liver, detailed lipidomic profiling of the lung is warranted. Here we aim to characterize the lipidomic profile of AATD bronchoalveolar lavage fluid (BALF) to define the pathogenic changes in lipid metabolism specific to AATD. Methods BALF was collected from the right upper lobe of AATD patients (ZZ and ZZ with augmentation [ZZ-aug]) and healthy controls (MM) with and without COPD using an optimized protocol (Herron et al., Thorax, 2025). Lipids were extracted in isopropanol, dried and reconstituted with 0.5μg/mL EquiSPLASH® LIPIDOMIX®. Samples were analyzed on a Waters ACQUITY™ Premier UPLC System with an ACQUITY™ Premier CSH C18 column (1.7µm, 2.1x100mm) and Xevo™ G3 QToF mass spectrometer. Pooled QC samples and blanks were included, and results were analyzed using MetaboAnalyst, ProgenesisQI, and Lipostar2. Results Fifty-one samples were included in the positive mode (ESI+) analysis; 7 MM, 14 MM-COPD, 8 ZZ, 15 ZZ-COPD, and 7 ZZ-aug. Initial analyses detected 17,005 chromatographic peaks, and after QC and blank removal 442 lipid features were included in the analysis. Of these, 194 were differentially expressed between the five groups. PCA analysis showed that the MM-COPD group clustered separately from all others, suggesting ZZ-COPD lungs are not as strongly affected by lipid dysregulation. Interestingly, ZZ-aug patients clustered closer to healthy ZZ patients than ZZ-COPD, suggesting that augmentation therapy corrects this minor lipid metabolism dysregulation. Preliminary, in-silico identification suggests that triglycerides and ceramides are the most affected lipid classes, and further characterization is underway. Different normalization strategies are also being trialed to improve intergroup variability. Conclusions Lipidomic differences can be seen in MM-COPD and AATD BALF, with minimal differences between the different AATD phenotypes. Additional experiments (Oil-Red O staining, flow cytometry, Seahorse mitochondrial profiling) are underway to further probe the role of lipid metabolism in AATD. This abstract is funded by: Alpha-1 Foundation
2026-04-06 | Pulmonary Function Decline in Alpha-1 Antitrypsin Deficiency: A Systematic Review and Meta-Analysis.
Limited data exist on pulmonary function decline in patients with alpha-1 antitrypsin deficiency (AATD)-associated lung and/or liver disease. This study aimed to conduct a systematic literature review (SLR) and meta-analysis of pulmonary function decline and associated risk factors, clinical outcomes, and health-related quality of life (HRQoL) in patients with AATD-associated lung and/or liver disease. Following PRISMA guidelines, studies were identified from MEDLINE/Embase (2003-2023) using Population, Intervention, Comparison, Outcomes, and Study criteria; key congresses were hand-searched (2021-2023). For each publication, two independent reviewers determined eligibility for inclusion and quality was assessed using relevant JBI tools. Meta-analyses were conducted on select outcomes that were deemed appropriate. Overall, 77 publications were included in the SLR and 32 reported pulmonary function decline in patients with AATD-associated lung and/or liver disease. Eight publications that evaluated forced expiratory volume in 1 second (FEV1) in mL, five that evaluated FEV1% predicted and four that evaluated HRQoL (as measured by St. George's Respiratory Questionnaire [SGRQ]) were deemed eligible for meta-analysis. In patients with AATD-associated lung disease, based on the random effects model, annualized change (95% confidence interval) in FEV1 was -39.1 (-45.2, -32.9) mL/year and -1.1 (-1.2, -0.9) %/year, and there was a slight worsening in SGRQ score (1.3 [0.6, 1.9] points/year). Data in patients with AATD-associated liver disease with or without comorbid lung disease were too limited to calculate an annualized rate of decline in pulmonary function or SGRQ. This comprehensive SLR and meta-analysis provides an estimate for annual pulmonary function decline in patients with AATD-associated lung disease and highlights an evidence gap in patients with AATD-associated liver disease with or without comorbid lung disease. Further insights into risk factors or potential biomarkers of pulmonary function decline may support clinical strategies for optimizing treatment.
2026-04-01 | Alpha-1 Antitrypsin Deficiency Alleles in Non-Cirrhotic Hepatocellular Carcinoma: Insights from a Multicenter French Cohort
Background & Aims: Patients with Alpha-1 Antitrypsin Deficiency (AATD) have a 20to 50-fold higher risk of developing primary liver cancer (PLC), such as hepatocellular carcinoma (HCC), in both cirrhotic and non-cirrhotic livers, highlighting AATD as a potential oncogenic factor.In this exploratory study, we aimed to describe the frequency and characteristics of AATD alleles in patients with HCC arising in noncirrhotic livers. Methods:The two most common pathogenic AATD variants, the Z (SERPINA1 p.Glu366Lys) and S (SERPINA1 p.Glu264Val) alleles, were identified using a multiplex digital PCR system in a French cohort of 91 patients who developed HCC in a noncirrhotic liver and without major liver risk factors, including alcohol consumption, viral hepatitis, or metabolic-associated steatohepatitis. Results:We found that 22.83% (21/91) of patients with HCC carried at least one S or Z allele of SERPINA1, a prevalence that was higher than in the general French population (16.9%) and in the UK population with PLC (12%).The distribution of genotypes was heterozygous for the M and S alleles (18/21), heterozygous for the M and Z alleles (2/21), and homozygous for the S allele (1/21).Interestingly, AAT globules were observed in non-tumoral liver tissue in 7 cases (37%), including individuals heterozygous for the M and S alleles and the individual homozygous for the S allele Conclusion:Our study provides descriptive data on the presence of S and Z variants of SERPINA1 in patients with HCC arising in non-cirrhotic livers, highlighting their potential relevance for further investigation.
2026-03-27 | Alpha-1 Antitrypsin Deficiency Beyond COPD and Emphysema: A Narrative Review.
Background/Objectives: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder classically associated with emphysema and COPD. However, emerging evidence indicates that its clinical spectrum extends to airway-predominant diseases such as bronchiectasis and asthma, where protease-antiprotease imbalance and neutrophilic inflammation may drive tissue injury. This narrative review aims to synthesize current evidence on the relationship between AATD and airway diseases beyond emphysema, focusing on epidemiological patterns, underlying mechanisms, diagnostic strategies, and therapeutic implications. Methods: A narrative synthesis of the literature was performed, integrating data from registries, with observational and translational studies addressing the prevalence, pathobiology, and therapeutic implications of AATD in bronchiectasis, asthma, and severe asthma. Epidemiologic and mechanistic insights were analyzed to identify overlapping pathways and evidence gaps. Results: Evidence supports a non-negligible prevalence of bronchiectasis and asthma among AATD individuals, particularly in severe or heterozygous genotypes. Neutrophil elastase overactivity, impaired mucociliary clearance, and chronic neutrophilic inflammation emerge as shared mechanisms promoting bronchial remodeling and airflow limitation. In asthma, AATD appears linked to T2-low, steroid-resistant phenotypes and persistent obstruction, whereas in severe asthma cohorts, up to 20% may carry non-PiMM SERPINA 1 variants. No randomized trials have evaluated augmentation therapy and standardized screening algorithms are lacking. Conclusions: AATD represents a systemic disorder with clinically relevant airway manifestations beyond COPD and emphysema. Targeted testing should be considered in patients with idiopathic bronchiectasis or severe asthma. Future genotype-stratified, prospective studies are required to clarify causality, define biomarkers of disease activity, and evaluate the potential role of anti-protease-based therapeutic strategies.
2026-03-26 | Severe α1-Antitrypsin Deficiency and Increased Risk of Gastrointestinal Diseases.
To determine whether the genetic disorder severe α1-antitrypsin deficiency, which has a known association with increased risk for development of lung and liver diseases, is also associated with increased risk for development of gastrointestinal diseases. We conducted a national, longitudinal, registry-based study of individuals with severe α1-antitrypsin deficiency (phenotype PiZZ; n=1561) and controls (n=5964) who were part of Swedish population-based cohorts between January 1,1991, through January 1, 2015. Data on gastrointestinal diseases (Crohn disease, ulcerative colitis, noninfectious gastroenteritis, and diverticular disease encompassing symptomatic diverticulosis and its complications), hospitalizations, and mortality were obtained by cross-linkage with national registries. Risk factors for development of gastrointestinal diseases were analyzed using Cox proportional hazards models and Fine-Gray regression models, adjusted for baseline age, sex, smoking status, the presence of chronic obstructive pulmonary disease, and liver diseases. During a median follow-up of 10 years (IQR, 11 years) for the whole study population, the incidence rate of any gastrointestinal disease per 1000 person-years was 10.6 (95% CI, 9.0 to 12.4) for the individuals with the PiZZ phenotype and 3.6 (95% CI, 3.2 to 4.1) for the controls, with an adjusted hazard ratio (aHR) of 2.7 (95% CI, 2.1 to 3.4). Individuals with PiZZ had an increased risk of Crohn disease (aHR, 4.1; 95% CI, 2.0 to 8.4), ulcerative colitis (aHR, 4.6; 95% CI, 2.4 to 8.6), noninfectious gastroenteritis (aHR, 2.6; 95% CI, 1.3 to 5.2), and diverticular disease (aHR, 2.1; 95% CI, 1.5 to 2.9). Individuals with PiZZ have an increased risk for development of gastrointestinal diseases (Crohn disease, ulcerative colitis, noninfectious gastroenteritis, and diverticular disease encompassing symptomatic diverticulosis and its complications), as compared with the general population.
gene therapies
2026-07-29 | From one-size-fits-all to on-demand: personalized crispr gene editing for rare genetic liver diseases.
Rare genetic liver diseases collectively affect millions of individuals worldwide and encompass a heterogeneous group of monogenic disorders including Wilson disease, alpha-1 antitrypsin deficiency, glycogen storage diseases, urea cycle disorders, progressive familial intrahepatic cholestasis, and acute hepatic porphyrias. While conventional management relies on dietary modification, pharmacotherapy, and ultimately liver transplantation, the advent of clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has opened transformative therapeutic avenues. This review provides a comprehensive and critical appraisal of the current landscape of CRISPR-based therapies for genetic liver diseases, from preclinical proof-of-concept studies to landmark clinical trials. We examine the evolution from conventional Cas9 nuclease-mediated editing to precision tools including base editors and prime editors, which enable single-nucleotide corrections without inducing double-strand DNA breaks. The role of lipid nanoparticle delivery systems in achieving efficient hepatocyte-targeted delivery is discussed, alongside emerging challenges in pediatric dosing and immunogenicity. We highlight the paradigm shift toward personalized, patient-specific CRISPR therapies, exemplified by the first-in-human bespoke gene editing treatment delivered in 2025. Competing nucleic acid technologies, including RNA interference and antisense oligonucleotides, are compared in terms of durability, safety, and cost-effectiveness. Finally, we critically evaluate the evolving regulatory landscape and propose a priority framework for selecting genetic liver diseases most amenable to CRISPR-based correction. This review underscores that CRISPR gene editing is transitioning from experimental promise to clinical reality for genetic liver diseases, with personalized approaches poised to redefine the treatment paradigm.
2026-05-20 | Optimization of Alpha-1 Antitrypsin Expression from Adeno-Associated Virus Vectors.
Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder caused by mutations in SERPINA1 that result in insufficient circulating alpha-1 antitrypsin (AAT) and progressive lung and liver diseases. Adeno-associated virus (AAV)-mediated gene therapy offers the potential for durable AAT expression; however, achieving therapeutic serum concentrations (≥11 µM) at clinically acceptable vector doses remains a major challenge. Here, we evaluated multiple AAV vector design strategies to enhance AAT expression and increase vector potency, thereby reducing the required dose to levels below those associated with severe adverse events. Using AAV1- and AAV8-based platforms, we compared promoter and enhancer configurations, codon optimization of the SERPINA1 transgene, single-stranded versus self-complementary vector genomes, alternative polyadenylation signals, and an engineered oxidation-resistant AAT variant. Across mouse and ferret models, the chicken β-actin expression cassette consistently produced higher AAT levels than a liver-specific promoter variant despite comparable vector biodistribution, reflecting superior intrinsic transcriptional activity or an important contribution. Codon optimization did not enhance expression and, in some cases, modestly reduced AAT levels. Self-complementary AAV vectors exhibited reduced overall expression due to required promoter truncation, yielding lower transgene output than full-length single-stranded constructs. Modifications to polyadenylation signals or enhancer combinations did not improve expression. An oxidation-resistant AAT variant resulted in lower circulating levels but may retain therapeutic potential through enhanced functional stability. Collectively, these findings demonstrate that promoter strength and cassette architecture are dominant determinants of AAV-AAT potency and that full-length, single-stranded vectors with robust regulatory elements provide the highest expression. This work defines key parameters governing AAT expression in vivo and provides a foundation for next-generation AAV designs aimed at achieving therapeutic efficacy at safer, lower vector doses for the treatment of AATD.
2026-01-27 | Advances in Precision Editing Therapies for Alpha-1 Antitrypsin Deficiency.
Genome and RNA editing modalities have revolutionized precision gene therapy, offering a safer alternative to traditional gene replacement approaches. Alpha-1 antitrypsin deficiency (AATD) is a compelling model for precision medicine because the disease mechanism is well defined-mutations in a single gene are responsible for both liver and lung pathology. In this review, we summarize the current preclinical and clinical efforts for AATD, with an emphasis on genome and RNA editing strategies.
2025-09-22 | Alpha 1-antitrypsin deficiency and chronic liver disease in adults: Molecular basis and clinical aspects
Alpha 1-antitrypsin deficiency (A1ATD) is a codominant genetic disorder primarily caused by PiZ mutations in the serpin family A member 1 (SERPINA1) gene. A1ATD is typically associated with the early-onset lung emphysema. However, the misfolding and accumulation of alpha 1-antitrypsin (A1AT) in hepatocytes can also lead to chronic liver disease (CLD). This perspective paper discusses the genetic and molecular factors, the epidemiological features, and clinico-pathological spectrum of A1ATD-related CLD in adults. Emphasis is given to steatosis, cirrhosis, and primary liver cancer, the risks of which critically depend on the PiZ genotype. We discuss the diagnostic strategy, including non-invasive assessment of liver fibrosis. While augmentation therapy plays a role in treating the pulmonary manifestations of A1ATD, this approach carries no benefit for the liver, and early detection is critical to slow the progression of CLD. New approaches comprise gene-editing, innovative pharmacological chaperones, and personalized medicine that target the underlying protein misfolding defect. Enhancing early diagnosis and refining precision treatment strategies promise to significantly improve clinical outcomes.
2025-03-24 | The Role of Gene Therapy as an Emerging Treatment Strategy for Alpha-1 Antitrypsin Deficiency-Associated Lung Disease: A Systematic Review.
Monogenetic disease alpha-1 antitrypsin deficiency (AATD) is the leading cause of emphysema, which is a major life-limiting chronic obstructive pulmonary disease (COPD). The current standard of care for severely affected individuals with lung disease is the periodic intravenous infusion of human AAT protein to restore circulating AAT levels to a protective level, known as augmentation therapy. We did a systematic review to see the effect of gene therapy as a potential therapeutic option for AATD-related lung diseases. MEDLINE (via PubMed), SCOPUS, Web of Science, Cochrane Library, and EMBASE have been searched following PICO (Population, Intervention, Comparison, Outcome) criteria. After duplication removal, abstract and title screening, full-text screening was done by two individual reviewers. Then, the data were extracted, tabulated, and analyzed. A total of 1094 articles were found in the primary search. After a comprehensive review following strict inclusion and exclusion criteria, 14 articles have been included in the review. Evidence shows the response of gene therapy depends on multiple factors, e.g., what vector is used, route of therapy administration, duration of therapy, etc. The AAV8-CASI-luc vector, delivered intratracheally (IT), achieved sustained lung transgene expression for at least 52 weeks, but 29% of mice had persistent expression up to 72 weeks, providing therapeutic AAT protein levels, reducing experimental emphysema severity in mice. Intratracheal AAV8 in mice showed the highest AAT expression in the lung, outperforming AAV9, AAV5, AAV2, and AAV2 capsid mutants, providing long-term expression up to 4 months. Intrapleural administration of AAV5-hA1AT achieved higher lung and serum A1AT levels than intramuscular delivery, with AAV5 yielding 10 times higher levels than AAV2. Gene therapy using viral vectors has a potential role in producing AAT protein, which can be beneficial for AATD-related lung diseases. Human trials are necessary to establish the effectiveness and safety of gene therapy. In conclusion, while initial studies are encouraging, more research is needed to confirm the role of gene therapy.
oligonucleotides
2026-06-01 | B101-10 RNA Editing for the Treatment of Alpha-1 Antitrypsin Deficiency (AATD)
Abstract Rationale Severe AATD is commonly caused by homozygous mutations in the SERPINA1 gene (Pi*ZZ), resulting in misfolded Z-AAT protein in the liver and offering decreased protection for the lung against neutrophil elastase. Current standard of care focuses on augmenting serum AAT levels through weekly infusions of human plasma-purified AAT to maintain serum levels above a putative protective threshold (11 µM). Liver disease is not addressed by this intervention. WVE-006, an investigational N-Acetylgalactosamine-conjugated RNA editing oligonucleotide, is designed to recruit endogenous ADAR enzymes to edit SERPINA1 mRNA in hepatocytes, replacing Z-AAT with M-AAT synthesis. This approach aims to increase serum M-AAT levels while reducing Z-AAT, preserve endogenous regulation of AAT expression, and address both lung and liver manifestations of severe AATD. Methods RestorAATion-2 (NCT06405633) is an ongoing phase 1b/2a clinical trial evaluating the safety, tolerability, pharmacodynamics, and pharmacokinetics of single- and multiple-ascending doses of WVE-006 (200, 400, 600 mg; n = 8 per cohort) in individuals with a ZZ genotype. Participants received a single subcutaneous dose of WVE-006 with a 12-week observation period, followed by biweekly (200 mg) or monthly doses (400, 600 mg) for 12 weeks, with a subsequent 12-week observation period. Serum levels of M-AAT, Z-AAT and total (M + Z) AAT were measured by LC-MS/MS assays, while functional AAT levels were assessed by a neutrophil elastase inhibition assay. Results In the 200 mg multidose cohort, mean maximum serum M-AAT levels reached 7.2 μM in ZZ individuals, corresponding to 64.4% of total serum AAT (11.9 μM). Increases in functional AAT activity were consistent with M-AAT production and were accompanied by 60.3% decrease in Z-AAT protein. In the 200 and 400 mg single dose cohorts, M-AAT levels increased to 4.8 μM and 5.3 μM, respectively. During the 200 mg single dose phase, one participant experienced an acute-phase response due to a kidney stone, during which total serum AAT levels reached 20.6 μM. WVE-006 has been generally safe and well tolerated; all adverse events have been mild to moderate, with no serious adverse events. Conclusions These data, which show production of M-AAT, lowering of Z-AAT protein, and endogenous upregulation of AAT protein in individuals with a ZZ genotype during stress provide proof-of-concept for the first RNA editing therapy to enter clinical testing. This abstract is funded by: Wave Life Sciences
2026-05-01 | B76-07 Overproduction of Muc5b Impairs the Mucociliary Transport in Alpha 1 Antitrypsin Deficiency
Abstract Rationale Alpha-1-antitrypsin deficiency (AATD) is a genetic risk factor that accelerates the onset of chronic obstructive pulmonary disease in smokers, impairing mucociliary clearance (MCC). AATD disrupts the protease-antiprotease balance, promoting epithelial injury and mucus overproduction through cytokine and neutrophil elastase (NE) driven feedback, thereby worsening small airway obstruction. Mechanisms by which NE in AATD contributes to mucus stasis in the small airways are unknown. Here, we hypothesize that Muc5b overexpression contributes to the differentiation of club cells to goblet cells in AATD by enhanced NE activity. To investigate the role of Muc5b in AATD-related mucociliary dysfunction, we examined its association in human and ferret bronchial epithelial cells (BECs) exposed to cigarette smoke extract (CSE), following targeted Muc5b inhibition and treatment with CSE, NE, or both. Methods First, we performed single-cell RNA-sequencing (scRNA-seq) of primary BECs derived from an AATD patient treated with 1% CSE vs. vehicle control. To determine whether uncontrolled NE activity in AATD worsens CSE-induced mucociliary dysfunction via Muc5B regulation, we silenced MUC5B using siRNA and treated cells with NE, CSE, or both. Knockdown was confirmed by RT-PCR and immunofluorescence (IF), and MCC was assessed using micro-optical coherence tomography (µOCT) imaging. Ongoing experiments involve Muc5B overexpression using CRISPR activation with a lentiviral dCas9-VPR system. Gene expression is being evaluated by IF and Western blotting to determine whether Muc5b knockdown or overexpression influences MCC in AATD and potentiates the effects of CSE. Cytokine will also be measured for the inflammatory response. Results scRNA-seq and IF exhibited an increased Muc5B-positive goblet cell population following CSE exposure compared to vehicle controls. Primary HBE treated with NE upregulated Muc5b (1.8 fold, p = 0.01), and the effect was further enhanced by CSE treatment after NE treatment (2.4 fold, p = 0.01). μOCT analysis of CSE-exposed AATD-derived HBEs demonstrated a decline in MCT following CSE treatment (15% reduction; p = 0.001, N = 3). A further decrease in MCT was observed with combined NE (1μM) and 1% CSE treatment vs vehicle (20% reduction, p = 0.001), indicating an enhanced impairment of mucociliary function. Further, intervention with Muc5b-specific siRNA reduced expression of Muc5b (90%, p = 0.001, N = 3). Neither CSE, NE, nor a combination induced Muc5b expression with Muc5b knockdown. Conclusion We demonstrate that Muc5b overproduction worsens MCT in AATD by NE and exacerbates the effect of smoke exposure; the effect can be attenuated by siRNA Muc5b knockdown. Findings identify Muc5b as a potential therapeutic target for mitigating AATD-associated airway obstruction. This abstract is funded by: Alpha 1 foundation, American lung association, ATS, DREAM council, CF foundation
2025-11-03 | Alpha-1 antitrypsin deficiency: genetics, clinical manifestations, AI prognostics, and advanced imaging in liver disease.
Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder caused by mutations in the SERPINA1 gene, resulting in reduced or dysfunctional alpha-1 antitrypsin (AAT) protein. This deficiency leads to progressive lung and liver diseases, including emphysema, chronic obstructive pulmonary disease, and cirrhosis. Despite its clinical significance, AATD remains underdiagnosed, delaying treatment. This review explores the molecular mechanisms of AATD, emphasizing Z-variant AAT protein accumulation in hepatocytes and excessive protease activity in the lungs. Advancements in imaging modalities - such as computed tomography, magnetic resonance imaging (MRI), dark-field radiography, and hyperpolarized MRI - enhance early diagnosis and disease monitoring. Novel therapies are reshaping AATD management, including small interfering RNA therapies (fazirsiran, belcesiran), gene-editing techniques (CRISPR-Cas9), regenerative approaches, autophagy-enhancing drugs, proteostasis regulators, aerosolized AAT, and artificial intelligence (AI) for real-time disease tracking via wearable devices. The integration of AI, advanced imaging, and emerging therapies represents a paradigm shift in AATD diagnosis and treatment. This review highlights the need for a multidisciplinary approach, early intervention, and personalized medicine to improve outcomes in both pulmonary and hepatic complications.
2025-04-14 | Alpha-1 antitrypsin deficiency-associated liver disease: From understudied disorder to the poster child of genetic medicine.
Alpha-1 antitrypsin deficiency (AATD) constitutes an inborn disorder arising due to mutations in alpha-1 antitrypsin (AAT), a secreted protease inhibitor produced primarily in hepatocytes. It leads to diminished serum AAT levels, and this loss-of-function predisposes to chronic obstructive pulmonary disease and lung emphysema. The characteristic Pi*Z mutation results in hepatic Z-AAT accumulation. In its homozygous form (Pi*ZZ genotype), it is responsible for the majority of severe AATD cases and can cause both pediatric and adult liver disease, while the heterozygous form (Pi*MZ) is considered a disease modifier that becomes apparent primarily in the presence of other comorbidities or risk factors. In the current review, we collate conditions associated with AATD, introduce typical AAT variants, and discuss our understanding of disease pathogenesis. We present both cross-sectional and longitudinal data informing about the natural disease history and noninvasive tools that can be used for disease stratification as well as a basis for disease monitoring. Given that AATD-associated liver disease is highly heterogeneous, we discuss the risk factors affecting disease progression. While the loss-of-function lung disease is treated by weekly intravenous administration of purified AAT, recombinant modified AAT and oral protease inhibitors are currently in clinical trials. Among the liver candidates, small interfering RNA fazirsiran efficiently suppresses AAT production and is currently in phase 3 clinical trial, while several other genetic approaches, such as RNA editing, are at earlier stages. In summary, AATD represents a systemic disorder increasingly seen in the hepatologic routine and requiring thorough interdisciplinary care, since the currently ongoing clinical trials often address only one of the organs it affects.
2025-04-04 | Improved RNA base editing with guide RNAs mimicking highly edited endogenous ADAR substrates.
Adenosine deaminase acting on RNA (ADAR)-mediated RNA base editing offers a safer alternative to genome editing for specific clinical applications because of nonpermanent editing of targets. Current guide RNA (gRNA) designs feature a fully complementary specificity domain with an A-C mismatch at the targeted adenosine. However, perfectly matched dsRNA is not the most effective ADAR substrate. Here we introduce MIRROR (mimicking inverted repeats to recruit ADARs using engineered oligoribonucleotides), an approach that implements structural motifs derived from highly edited inverted Alu repeats in human tissues to enable rational gRNA design for ADAR recruitment. We demonstrated that MIRROR is applicable to both short chemically synthesized gRNAs with modifications and long biologically generated gRNAs and surpasses current state-of-the-art approaches in both gRNA forms. It enhances editing efficiency by up to 5.7-fold in multiple human cell types and primary hepatocytes from an alpha-1 antitrypsin deficiency mouse model. Our findings improve programmable RNA editing in vitro and in vivo by rational design through the screening of highly edited natural substrate mimics.
other
2026-05-01 | C33-29 Not All Cough in Alpha-1 Antitrypsin Deficiency Is Emphysema: A Case of Eosinophilic Asthma
Abstract Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder that predisposes to early-onset emphysema and bronchiectasis through protease-antiprotease imbalance and neutrophil-driven inflammation. Although asthma and atopy occur more frequently in AATD, eosinophilic asthma is rarely documented. This case highlights a patient with genetically confirmed severe AATD whose chronic cough stemmed not from emphysema, but from eosinophilic asthma. A 39-year-old nonsmoking woman with Raynaud’s disease and recurrent sinusitis presented with a two-year history of chronic cough and intermittent dyspnea. She had required multiple short courses of oral corticosteroids with transient relief. Spirometry was normal (FEV₁ 97% predicted, FEV₁/FVC 89%), and DLCO was preserved (85% predicted). High-resolution CT revealed mild lower-lobe bronchiectasis without emphysema. Serum alpha-1 antitrypsin was <25 mg/dL, and genotyping confirmed a homozygous ZZ mutation. Peripheral eosinophilia (1.5 × 109/L; 21%) and bronchoalveolar lavage showing 43% eosinophils confirmed type-2 airway inflammation. All bacterial and fungal cultures, including Aspergillus precipitins, were negative. She was treated with inhaled budesonide/formoterol for airway inflammation and intranasal ipratropium for postnasal-drip-related symptoms, with partial improvement. Persistent cough and elevated eosinophils prompted initiation of Mepolizumab 100 mg subcutaneously every 4 weeks per ATS/ERS severe-asthma guidance. Over three months she reported improved symptom control and reduced cough frequency, allowing consideration of inhaled corticosteroid step-down. Lung function remained normal. In the absence of emphysema or fixed obstruction, augmentation therapy for AATD was not indicated. Emphysema is the hallmark pulmonary manifestation of ZZ AATD, affecting most adults, whereas asthma occurs in a minority. This patient’s normal spirometry, preserved diffusion, and eosinophilic airway inflammation were consistent with eosinophilic asthma coexisting with but mechanistically distinct from AATD. The two processes represent different inflammatory pathways - neutrophilic tissue injury versus IL-5-driven eosinophilic inflammation - but can intersect clinically. Management should follow severe-asthma protocols, with high-dose inhaled corticosteroid-LABA therapy and biologic add-on (anti-IL-5 or anti-IL-4Rα) for persistent eosinophilia. The clinical response suggests that biologic therapy remains effective in the setting of AATD. Patients require dual monitoring: spirometry and DLCO for AATD progression, and eosinophil counts and symptom assessment for asthma control. Not every cough in AATD signals emphysema progression. Recognizing eosinophilic asthma as a coexisting, treatable inflammatory phenotype allows targeted therapy and improved control while maintaining vigilance for longterm AATD related complications. This abstract is funded by: None
2025-12-02 | Resolution of the circulating pathogenic phenotype of alpha-1 antitrypsin deficiency following liver transplantation
Abstract Alpha-1 antitrypsin is a member of the serpin family of protease inhibitors and normally found in monomeric form at high concentration in the circulation. Certain pathogenic variants of this protein self-assemble into flexible chains (polymers) that undergo toxic accumulation in the liver, underlying the development of liver disease, and a corresponding functional deficiency in circulation results in a susceptibility to chronic damage to the lungs and thereby COPD. A proportion of these polymers are detectable in the circulation. This study aimed to provide data on the dynamics of AAT monomers and polymers in the circulation after correction of a deficiency state by liver transplantation. The evolution of the circulating AAT phenotype was characterised quantitatively over time by analysis of blood samples taken pre- and post-liver transplant from three PiZZ AAT deficiency patients, using a panel of conformer-specific monoclonal antibodies and a novel ELISA with enhanced sensitivity for AAT polymers. Circulating wild-type M AAT was found to increase with a half-time of 29-39 h, attaining a clinically-defined putative ‘protective’ threshold level within 24-50 h post-transplant. Baseline circulating polymer levels ranged from 5-35 μg/mL with a half-time clearance of 3-12 h following transplant, and levels were indistinguishable from reference wild-type plasma 22 months post-surgery. The glycosylation profile and disappearance of detectable circulating polymers of AAT were consistent with their origin in, and canonical secretion by, the liver. To our knowledge this is the first post-transplant evaluation of the hybrid conformational profile of endogenous and donor tissue-derived AAT.
2025-05-01 | Long Term Effectiveness of Bronchoscopic Lung Volume Reduction in COPD Patients With Alpha-1 Antitrypsin Deficiency
Abstract Introduction: Chronic Obstructive Pulmonary Disease (COPD) causes breathlessness through dynamic hyperinflation. Bronchoscopic lung volume reduction (BLVR) has been shown to reduce hyperinflation, improve lung function, symptoms and quality of life in COPD patients. Several studies have suggested these benefits extend to COPD patients with Alpha-1 antitrypsin deficiency (AATD). Improvements have been shown in the short and intermediate term. The persistence of these benefits into the long term are questionable. Our analysis presents and compares intermediate and long-term outcomes following BLVR for a group of COPD patients with AATD. Methods: We conducted a retrospective, single-center chart review of 238 patients who underwent BLVR at our large quaternary care institution between August 2018 and April 2024. Chart review revealed 14 patients with documented AATD within this group. Baseline characteristics including demographics, modified medical research council (mMRC) dyspnea scale, BODE index and pulmonary function testing (PFT) prior to BLVR were recorded. Lung function data was then collected from PFTs performed at a mean of 7 (SD±1.95) and 12.43 (SD±5.47) months following the BLVR procedure. Post-BLVR data was compared to baseline data and analyzed using Wilcoxon signed rank test for statistical significance. Outcomes were compared between the 7-month and 12-month group using a single variance t-test. Results: Following BLVR, 7 patients (50%) experienced an increase in forced expiratory volume in one second (FEV1) greater than 15% at both 7 months and 12 months. The median improvement in FEV1 was 111mL (IQR 0.05 – 0.24) which equated to 13.94% (IQR 7.53 – 25.01) at 7 months and 110mL (IQR 0.04 – 0.23) which equated to 15.38% (IQR 5.87 – 30.09) at 12 months. Statistically significant improvements were also demonstrated in residual volume (RV), total lung capacity (TLC), RV/TLC ratio indicating improvements in hyperinflation. Single variance t-test analysis showed no statistically significant differences between the 7 month and 12-month outcomes. Conclusion: BLVR represents a promising therapeutic approach for COPD patients with concomitant AATD. Our findings suggest improvements in pulmonary dynamics that persist into the intermediate and long-term. This study contributes valuable insights to the growing body of evidence demonstrating benefits to BLVR in patients with COPD and AATD.
2025-05-01 | Evaluating the Role of Eosinophils in Alpha-1 Antitrypsin Deficiency
Abstract Rational: Alpha-1 antitrypsin deficiency (AATD) is a condition which results in reduced plasma and lung AAT levels. The most common allele associated with AATD is the Z allele. Z homozygous individuals have an increased risk of developing early onset COPD. Type 2 inflammation is a pathway modulated by type 2 cytokines such as IL-13 and IL-5. Recent studies have identified a subset of COPD patients with elevated type 2 inflammation who respond better to inhaled corticosteroids and other novel interventions. Since IL-13 and IL-5 are involved in eosinophil maturation, high blood eosinophils can indicate type 2 inflammation in COPD. However, less is known about type 2 inflammation in AATD, hence the objective of this project was to identify if AATD is associated with elevated eosinophil counts. Methods: Patients were identified from the Irish national Alpha-1 registry and reviewed in a national AATD clinic. Each patient underwent clinical assessment including routine bloods, to evaluate eosinophils and spirometry. COPD diagnosis was defined by clinical review, pulmonary function tests and CT of thorax. Results: Overall 106 patients with AATD were included, 79% were ZZ and 9.5% of these were receiving augmentation therapy. A significant negative correlation between eosinophil count and FEV1 in AATD patients was found (p=0.038). Additionally, there was a significant positive correlation between age and eosinophil count among AATD patients, (p=0.03). Similarly, in ZZ patients and ZZ patients not receiving augmentation therapy there were significant negative correlations between eosinophil count and FEV1 (N=84, p=0.016 and N=76, p=0.011 respectively). Additionally, significant positive correlation between eosinophil count and age was found in these groups (N=84, p=0.007 and N=76, p=0.006 respectively). The median eosinophil count in the general population was previously described as 130/µL (1). Our study found an elevated median eosinophil count in AATD individuals of 170/µL. Diagnosis of COPD or history of ever smoking was associated with higher median eosinophil counts compared to no COPD diagnosis and never smokers respectively however these were not significant at the numbers tested. Conclusions: Further research is needed to identify if targeting type 2 inflammation in AATD patients with high eosinophils would be an effective therapeutic option. Future work will involve evaluation of type 2 cytokines in correlation with eosinophil counts. Reference:1. Hartl S, Breyer M-K, Burghuber OC, Ofenheimer A, Schrott A, Urban MH, et al. Blood eosinophil count in the general population: typical values and potential confounders. European Respiratory Journal. 2020;55(5).
2025-03-06 | Bacterial colonisation doubles the risk of exacerbation in alpha-1 antitrypsin deficiency.
Pulmonary exacerbations in alpha-1 antitrypsin deficiency (AATD) are associated with worse disease outcomes, including accelerated lung function decline. As with non-deficient COPD, subjects with AATD are predisposed to bacterial colonisation of the lower respiratory tract, a known risk factor for exacerbations. Despite this, the extent to which colonising bacteria contribute to exacerbations remains relatively unexplored. Sputum samples were collected longitudinally from AATD subjects, when clinically stable and during exacerbations, and were processed for quantitative culture to identify bacterial pathogens. Using contemporaneous clinical data, a post-hoc analysis was performed to calculate the odds of an exacerbation in the presence of recognised, potentially pathogenic bacteria (PPB) of the lower respiratory tract. 324 sputum samples were collected from 29 patients with AATD plus radiological evidence of bronchiectasis and 671 samples from 62 patients without bronchiectasis (AATD alone). Both groups contained patients with AATD-associated lung disease (emphysema and chronic bronchitis). At least half of the samples (55.5 %) from AATD alone were positive for a PPB and almost three quarters (72.8 %) of those with bronchiectasis. Presence of a Pseudomonas species, Staphylococcus aureus or Moraxella catarrhalis during stable state disease were all significantly associated with increased likelihood of a subsequent exacerbation (OR: 1.89, p = 0.0013; 1.98, 0.0022; 1.98, 0.0047; 2.19, 0.0047, respectively), independent of age, sex, disease severity (FEV1 impairment), smoking status and presence or absence of bronchiectasis. Disease progression in AATD is variable and identification of traits which may contribute may prove influential. Here, we report that bacterial colonisation is an important predictor of exacerbation in AATD, likely attributed to the associated levels of increased inflammation. Thereby, this may represent a sub cohort of patients that could benefit from additional, targeted therapy.
small molecules
2026-08-08 | p62/SQSTM1-KEAP1 complex prevents clearance of ubiquitinated Z alpha-1 antitrypsin and aggravates liver proteotoxicity.
Liver disease in Alpha-1 antitrypsin deficiency (AATD) is caused by the toxic accumulation of mutant Z alpha-1 antitrypsin (Z-AAT) within the endoplasmic reticulum (ER) of hepatocytes. Livers from PiZ transgenic mice expressing the human Z-AAT and AATD patients were both found to have increased p62/SQSTM1, a multifunctional protein involved in protein homeostasis, consistent with previous reports. However, whether p62/SQSTM1 is a marker of Z-AAT globules or plays an active role in Z-AAT proteostasis is unclear. The goal of this study was to elucidate the involvement of p62/SQSTM1 in the formation of Z-AAT globules that are responsible for liver injury in AATD. In the present study, we found that p62/SQSTM1 decorated ubiquitin-positive, Periodic-Acid Shiff-diastase-resistant Z-AAT globules and interacted with Z-AAT at the ER-cytosol interface. Genetic ablation of p62/SQSTM1 in PiZ mice (PiZ;p62-/-) led to marked reduction in hepatic Z-AAT globules and polymers, and decreased serum Z-AAT, highlighting a central role for p62/SQSTM1 in disease pathogenesis. Moreover, hepatocyte-specific somatic deletion of the ubiquitin-association (UBA) domain of p62/SQSTM1 reduced Z-AAT aggregation. Furthermore, KEAP1 was identified as a binding partner of p62/SQSTM1-Z-AAT complex, leading to nuclear translocation and activation of NRF2. Inhibition of KEAP1-p62/SQSTM1 interaction reduced the abundance of p62 and phosphorylated p62, decreased intracellular Z-AAT, and redistributed NRF2 to the cytoplasm. In conclusion, this study identifies p62/SQSTM1 as a regulator of Z-AAT proteostasis and link Z-AAT/p62 accumulation to KEAP1 sequestration and NRF2 pathway activation in liver disease due to Z-AAT.
2026-05-04 | Adaptive Regulation of mTOR Activity by AMPK, Akt, and ATF6 Pathways in Pi*Z Alpha-1 Antitrypsin Deficient Hepatocytes.
Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by intracellular retention of mutant Z (Pi*Z) alpha-1 antitrypsin (AAT) within hepatocytes, resulting in progressive liver disease. Currently, no approved pharmacological therapies exist for AATD-associated hepatic injury. Emerging preclinical evidence indicates that inhibition of mammalian target of rapamycin (mTOR) ameliorates liver pathology in AATD; however, the status of mTOR activity and its regulatory mechanisms under Pi*Z AAT-induced cellular stress remains incompletely understood. In this study, we investigated alterations in mTOR signaling and its upstream regulatory pathways using a gene-edited human hepatocyte model harboring the Pi*Z mutation (Huh7.5Z cells) and a Pi*Z AAT transgenic mouse model. Attenuation of mTORC1 activity was observed in both cellular and murine Pi*Z models. In vitro analyses demonstrated activation of AMP-activated protein kinase (AMPKα), a key inhibitory regulator of mTORC1, accompanied by paradoxical activation of Akt and the unfolded protein response (UPR) branch ATF6α. Pharmacological inhibition of mTOR significantly reduced intracellular Pi*Z AAT accumulation, alleviated ER stress, and suppressed apoptotic signaling through enhancement of autophagy. These findings reveal that hepatocytes adapt to Pi*Z AAT-induced stress through coordinated regulation of mTOR by AMPK, Akt, and ATF6α pathways. This study provides mechanistic insight into metabolic and stress-response signaling in AATD and identifies mTOR modulation as a promising therapeutic strategy for AATD-associated liver disease.
2026-05-01 | D108-18 Sex Hormones and Inflammatory Proteins Impact Disease Heterogeneity in Alpha-1 Antitrypsin Deficiency-Associated COPD
Abstract Background Chronic Obstructive Pulmonary Disease (COPD) associated with Alpha-1 Antitrypsin Deficiency (AATD) exhibits sex differences in onset and progression, with males experiencing higher COPD risk and more rapid lung function decline. Sex hormones modulate immune responses, but the roles of sex hormones and inflammatory proteins in sex-specific COPD heterogeneity remain unclear. We hypothesized that distinct profiles of sex hormones and inflammatory mediators in males and females contribute to COPD differences in AATD, and aimed to identify sex-specific predictors of lung function by integrating systemic inflammatory protein and sex hormone profiling. Methods We analyzed 398 adults (221 females, 177 males) with severe AATD (PiZZ genotype) from the Alpha-1 Antitrypsin Genetic Modifiers Study. Plasma inflammatory proteins were measured via the Olink Explore 384 Inflammation panel. Serum sex hormone levels (SHBG, total/free testosterone, dihydrotestosterone, estradiol, estrone) were measured in a subset of 145 participants. Linear regression assessed associations between protein/hormone levels and COPD status, FEV1, and FEV1/FVC, adjusting for age and smoking history, using sex-stratified and sex-interaction models. Interactions between sex hormones and proteins in predicting lung function were also tested. Results Proteomic analysis revealed sex-specific inflammatory signatures that were associated with lung function among individuals with AATD. In females, eight proteins were significantly associated with FEV1/FVC ratio (FDR < 0.05), while in males, seventeen proteins were identified, with only one shared protein marker (AGER) across both sexes, highlighting divergent molecular markers of lung function by sex. To assess the impact of circulating sex hormones, we tested for the interaction between sex hormones and proteins on lung function at FDR<0.05. In females, higher estradiol levels were positively associated with ITM2A abundance, and their interaction predicted better lung function, suggesting a potential protective and modulatory role for estradiol in females with AATD. Conversely, in males, elevated testosterone levels were negatively associated with the inflammatory proteins ENPP5, OMD, and MEPE, and the interactions between testosterone and these markers predicted reduced lung function. Conclusion Our study identified sex-specific inflammatory proteins that are associated with lung function in AATD-associated COPD, with some of these associations influenced by sex hormones. Estradiol appears protective in females, while higher testosterone in males is linked to reduced lung function through its interaction with key inflammatory proteins. These findings highlight the role of sex hormones and systemic inflammatory markers in lung function, underscoring the need for sex- and hormone-informed approaches in the management and therapeutic targeting of AATD-associated COPD. This abstract is funded by: Alpha-1 Foundation
2026-05-01 | C46-16 Alpha-1 Antitrypsin Deficiency and Sarcoidosis: A Strange Duo
Abstract Alpha-1-Antitrypsin (AAT) deficiency and sarcoidosis are two rare systemic diseases frequently leading to pulmonary involvement. The first one, frequently underdiagnosed and with a broad clinical spectrum, consists of an imbalance between neutrophil elastase and its counterpart, AAT, a protein made to avoid health tissue damage; the latter provokes a chronic inflammation in the form of non-necrotizing epithelioid granulomas in response to unknown triggers. We still don’t know so much about the implications of an eventual coexistence of these diseases. Our case is about R.F., a white woman in her 50s with asthma-like symptoms after a viral illness, fatigue and multiple arthralgias associated with stiffness. Never smoker, profession hair stylist, mild obese recently diagnosed with type 2 diabetes and atopic, she denied any familiar or personal respiratory history. A serum electrophoresis showed a decrease in alpha-1 band, thus she underwent a genetic analysis leading to diagnosis of “Pi*MZ” (heterozigosis mutation) AATD. Serum levels of AAT was 80 mg/dL, in presence of normal CRP (C reactive protein); a mild increase in AST (aspartate transaminase) and ALT (alanine transaminase) was seen. Respiratory functional tests were normal; a metacholine challenge test was positive at 4th diluition (377 mcg); abdominal ultrasound showed hepatic steatosis. A chest CT scan showed diffuse mediastinal lymphadenopathy and multiple parenchimal micronodules, so we performed an EBUS-TBNA (endobronchial ultrasound-guided transbronchial needle aspiration) and a bronchoalveolar lavage, coherent with pulmonary sarcoidosis. We prescribed as-needed asthma therapy and dietotherapy as well, in order to counteract obesity pro-inflammatory Th1 milieu, strong independent risk factor for sarcoidosis also represented in AATD patients with normal lung function. We chose not to start systemic steroid therapy yet, avoiding a potential glycometabolic imbalance since, until proven otherwise (ophtalmological and cardiovascular evaluations still need to be carried out), actual organ involvement seems to be mild. Further hepatological assessments will be necessary, given a major risk of liver disease in presence of multiple known risk factors (sarcoidosis, AATD, but also metabolic syndrome). On AATD side, at time of writing this patient doesn’t need an augmentation therapy, but what about her prognosis? Further research is needed to better comprehend if AATD patients could be prone to bigger clinical instability in presence of sarcoidosis inflammatory booster, hence deeper organ reshaping and faster functional worsening; should we start earlier anti-inflammatory treatment despite of organ involvement, and/or an earlier augmentation therapy despite of AAT blood amounts? This abstract is funded by: None
2026-03-17 | SAHA increases chaperone expression and reduces Z-alpha-1-antitrypsin polymers in a patient specific iPSC-based liver model for alpha-1-antitrypsin deficiency
Summary The most severe phenotype of alpha-1-antitrypsin deficiency (AATD) is caused by the Z-mutation within the SERPINA1 gene. The Glu342Lys substitution causes misfolding and polymerisation of the alpha-1-antitrypsin (AAT) protein, its accumulation in the ER and increases the susceptibility of hepatocytes towards ER-stress. Here, we present an induced pluripotent stem cell (iPSC)-based hepatic model to study AATD. We demonstrate that iPSCs from AATD patients differentiate equally well to hepatocyte-like cells (HLCs) as control iPSCs. We detected ZAAT polymers in patient-derived HLCs which could be reduced by SAHA or CBZ treatment. Transcriptome analyses revealed major differences in metabolism and signalling between control and AATD HLCs and indicated increased stress levels affecting intracellular organelles. Importantly, the transcriptomes of control and patient-derived cells separated into distinct clusters with respect to the expression of Heat-shock protein (HSP) encoding genes. SAHA treatment increased expression of various HSPs which might contribute towards reduced ZAAT polymers.
proteins
2026-05-01 | A22-21 Comprehensive Lipidomic Profiling of Bronchoalveolar Lavage Fluid (BALF) in Alpha-1 Antitrypsin Deficiency (AATD)
Abstract Rationale Inflammation and metabolic dysfunction of the alveolar space - particularly lipid species - has been linked to Chronic Obstructive Pulmonary Disease (COPD) pathogenesis. Similar metabolic disruption has been reported in Alpha-1 Antitrypsin Deficiency (AATD), however little is known about defective cellular metabolism in the lung. Given the disturbed lipid metabolism reported in the AATD liver, detailed lipidomic profiling of the lung is warranted. Here we aim to characterize the lipidomic profile of AATD bronchoalveolar lavage fluid (BALF) to define the pathogenic changes in lipid metabolism specific to AATD. Methods BALF was collected from the right upper lobe of AATD patients (ZZ and ZZ with augmentation [ZZ-aug]) and healthy controls (MM) with and without COPD using an optimized protocol (Herron et al., Thorax, 2025). Lipids were extracted in isopropanol, dried and reconstituted with 0.5μg/mL EquiSPLASH® LIPIDOMIX®. Samples were analyzed on a Waters ACQUITY™ Premier UPLC System with an ACQUITY™ Premier CSH C18 column (1.7µm, 2.1x100mm) and Xevo™ G3 QToF mass spectrometer. Pooled QC samples and blanks were included, and results were analyzed using MetaboAnalyst, ProgenesisQI, and Lipostar2. Results Fifty-one samples were included in the positive mode (ESI+) analysis; 7 MM, 14 MM-COPD, 8 ZZ, 15 ZZ-COPD, and 7 ZZ-aug. Initial analyses detected 17,005 chromatographic peaks, and after QC and blank removal 442 lipid features were included in the analysis. Of these, 194 were differentially expressed between the five groups. PCA analysis showed that the MM-COPD group clustered separately from all others, suggesting ZZ-COPD lungs are not as strongly affected by lipid dysregulation. Interestingly, ZZ-aug patients clustered closer to healthy ZZ patients than ZZ-COPD, suggesting that augmentation therapy corrects this minor lipid metabolism dysregulation. Preliminary, in-silico identification suggests that triglycerides and ceramides are the most affected lipid classes, and further characterization is underway. Different normalization strategies are also being trialed to improve intergroup variability. Conclusions Lipidomic differences can be seen in MM-COPD and AATD BALF, with minimal differences between the different AATD phenotypes. Additional experiments (Oil-Red O staining, flow cytometry, Seahorse mitochondrial profiling) are underway to further probe the role of lipid metabolism in AATD. This abstract is funded by: Alpha-1 Foundation
2026-04-06 | Pulmonary Function Decline in Alpha-1 Antitrypsin Deficiency: A Systematic Review and Meta-Analysis.
Limited data exist on pulmonary function decline in patients with alpha-1 antitrypsin deficiency (AATD)-associated lung and/or liver disease. This study aimed to conduct a systematic literature review (SLR) and meta-analysis of pulmonary function decline and associated risk factors, clinical outcomes, and health-related quality of life (HRQoL) in patients with AATD-associated lung and/or liver disease. Following PRISMA guidelines, studies were identified from MEDLINE/Embase (2003-2023) using Population, Intervention, Comparison, Outcomes, and Study criteria; key congresses were hand-searched (2021-2023). For each publication, two independent reviewers determined eligibility for inclusion and quality was assessed using relevant JBI tools. Meta-analyses were conducted on select outcomes that were deemed appropriate. Overall, 77 publications were included in the SLR and 32 reported pulmonary function decline in patients with AATD-associated lung and/or liver disease. Eight publications that evaluated forced expiratory volume in 1 second (FEV1) in mL, five that evaluated FEV1% predicted and four that evaluated HRQoL (as measured by St. George's Respiratory Questionnaire [SGRQ]) were deemed eligible for meta-analysis. In patients with AATD-associated lung disease, based on the random effects model, annualized change (95% confidence interval) in FEV1 was -39.1 (-45.2, -32.9) mL/year and -1.1 (-1.2, -0.9) %/year, and there was a slight worsening in SGRQ score (1.3 [0.6, 1.9] points/year). Data in patients with AATD-associated liver disease with or without comorbid lung disease were too limited to calculate an annualized rate of decline in pulmonary function or SGRQ. This comprehensive SLR and meta-analysis provides an estimate for annual pulmonary function decline in patients with AATD-associated lung disease and highlights an evidence gap in patients with AATD-associated liver disease with or without comorbid lung disease. Further insights into risk factors or potential biomarkers of pulmonary function decline may support clinical strategies for optimizing treatment.
2026-04-01 | Alpha-1 Antitrypsin Deficiency Alleles in Non-Cirrhotic Hepatocellular Carcinoma: Insights from a Multicenter French Cohort
Background & Aims: Patients with Alpha-1 Antitrypsin Deficiency (AATD) have a 20to 50-fold higher risk of developing primary liver cancer (PLC), such as hepatocellular carcinoma (HCC), in both cirrhotic and non-cirrhotic livers, highlighting AATD as a potential oncogenic factor.In this exploratory study, we aimed to describe the frequency and characteristics of AATD alleles in patients with HCC arising in noncirrhotic livers. Methods:The two most common pathogenic AATD variants, the Z (SERPINA1 p.Glu366Lys) and S (SERPINA1 p.Glu264Val) alleles, were identified using a multiplex digital PCR system in a French cohort of 91 patients who developed HCC in a noncirrhotic liver and without major liver risk factors, including alcohol consumption, viral hepatitis, or metabolic-associated steatohepatitis. Results:We found that 22.83% (21/91) of patients with HCC carried at least one S or Z allele of SERPINA1, a prevalence that was higher than in the general French population (16.9%) and in the UK population with PLC (12%).The distribution of genotypes was heterozygous for the M and S alleles (18/21), heterozygous for the M and Z alleles (2/21), and homozygous for the S allele (1/21).Interestingly, AAT globules were observed in non-tumoral liver tissue in 7 cases (37%), including individuals heterozygous for the M and S alleles and the individual homozygous for the S allele Conclusion:Our study provides descriptive data on the presence of S and Z variants of SERPINA1 in patients with HCC arising in non-cirrhotic livers, highlighting their potential relevance for further investigation.
2026-03-27 | Alpha-1 Antitrypsin Deficiency Beyond COPD and Emphysema: A Narrative Review.
Background/Objectives: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder classically associated with emphysema and COPD. However, emerging evidence indicates that its clinical spectrum extends to airway-predominant diseases such as bronchiectasis and asthma, where protease-antiprotease imbalance and neutrophilic inflammation may drive tissue injury. This narrative review aims to synthesize current evidence on the relationship between AATD and airway diseases beyond emphysema, focusing on epidemiological patterns, underlying mechanisms, diagnostic strategies, and therapeutic implications. Methods: A narrative synthesis of the literature was performed, integrating data from registries, with observational and translational studies addressing the prevalence, pathobiology, and therapeutic implications of AATD in bronchiectasis, asthma, and severe asthma. Epidemiologic and mechanistic insights were analyzed to identify overlapping pathways and evidence gaps. Results: Evidence supports a non-negligible prevalence of bronchiectasis and asthma among AATD individuals, particularly in severe or heterozygous genotypes. Neutrophil elastase overactivity, impaired mucociliary clearance, and chronic neutrophilic inflammation emerge as shared mechanisms promoting bronchial remodeling and airflow limitation. In asthma, AATD appears linked to T2-low, steroid-resistant phenotypes and persistent obstruction, whereas in severe asthma cohorts, up to 20% may carry non-PiMM SERPINA 1 variants. No randomized trials have evaluated augmentation therapy and standardized screening algorithms are lacking. Conclusions: AATD represents a systemic disorder with clinically relevant airway manifestations beyond COPD and emphysema. Targeted testing should be considered in patients with idiopathic bronchiectasis or severe asthma. Future genotype-stratified, prospective studies are required to clarify causality, define biomarkers of disease activity, and evaluate the potential role of anti-protease-based therapeutic strategies.
2026-03-26 | Severe α1-Antitrypsin Deficiency and Increased Risk of Gastrointestinal Diseases.
To determine whether the genetic disorder severe α1-antitrypsin deficiency, which has a known association with increased risk for development of lung and liver diseases, is also associated with increased risk for development of gastrointestinal diseases. We conducted a national, longitudinal, registry-based study of individuals with severe α1-antitrypsin deficiency (phenotype PiZZ; n=1561) and controls (n=5964) who were part of Swedish population-based cohorts between January 1,1991, through January 1, 2015. Data on gastrointestinal diseases (Crohn disease, ulcerative colitis, noninfectious gastroenteritis, and diverticular disease encompassing symptomatic diverticulosis and its complications), hospitalizations, and mortality were obtained by cross-linkage with national registries. Risk factors for development of gastrointestinal diseases were analyzed using Cox proportional hazards models and Fine-Gray regression models, adjusted for baseline age, sex, smoking status, the presence of chronic obstructive pulmonary disease, and liver diseases. During a median follow-up of 10 years (IQR, 11 years) for the whole study population, the incidence rate of any gastrointestinal disease per 1000 person-years was 10.6 (95% CI, 9.0 to 12.4) for the individuals with the PiZZ phenotype and 3.6 (95% CI, 3.2 to 4.1) for the controls, with an adjusted hazard ratio (aHR) of 2.7 (95% CI, 2.1 to 3.4). Individuals with PiZZ had an increased risk of Crohn disease (aHR, 4.1; 95% CI, 2.0 to 8.4), ulcerative colitis (aHR, 4.6; 95% CI, 2.4 to 8.6), noninfectious gastroenteritis (aHR, 2.6; 95% CI, 1.3 to 5.2), and diverticular disease (aHR, 2.1; 95% CI, 1.5 to 2.9). Individuals with PiZZ have an increased risk for development of gastrointestinal diseases (Crohn disease, ulcerative colitis, noninfectious gastroenteritis, and diverticular disease encompassing symptomatic diverticulosis and its complications), as compared with the general population.
gene therapies
2026-07-29 | From one-size-fits-all to on-demand: personalized crispr gene editing for rare genetic liver diseases.
Rare genetic liver diseases collectively affect millions of individuals worldwide and encompass a heterogeneous group of monogenic disorders including Wilson disease, alpha-1 antitrypsin deficiency, glycogen storage diseases, urea cycle disorders, progressive familial intrahepatic cholestasis, and acute hepatic porphyrias. While conventional management relies on dietary modification, pharmacotherapy, and ultimately liver transplantation, the advent of clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has opened transformative therapeutic avenues. This review provides a comprehensive and critical appraisal of the current landscape of CRISPR-based therapies for genetic liver diseases, from preclinical proof-of-concept studies to landmark clinical trials. We examine the evolution from conventional Cas9 nuclease-mediated editing to precision tools including base editors and prime editors, which enable single-nucleotide corrections without inducing double-strand DNA breaks. The role of lipid nanoparticle delivery systems in achieving efficient hepatocyte-targeted delivery is discussed, alongside emerging challenges in pediatric dosing and immunogenicity. We highlight the paradigm shift toward personalized, patient-specific CRISPR therapies, exemplified by the first-in-human bespoke gene editing treatment delivered in 2025. Competing nucleic acid technologies, including RNA interference and antisense oligonucleotides, are compared in terms of durability, safety, and cost-effectiveness. Finally, we critically evaluate the evolving regulatory landscape and propose a priority framework for selecting genetic liver diseases most amenable to CRISPR-based correction. This review underscores that CRISPR gene editing is transitioning from experimental promise to clinical reality for genetic liver diseases, with personalized approaches poised to redefine the treatment paradigm.
2026-05-20 | Optimization of Alpha-1 Antitrypsin Expression from Adeno-Associated Virus Vectors.
Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder caused by mutations in SERPINA1 that result in insufficient circulating alpha-1 antitrypsin (AAT) and progressive lung and liver diseases. Adeno-associated virus (AAV)-mediated gene therapy offers the potential for durable AAT expression; however, achieving therapeutic serum concentrations (≥11 µM) at clinically acceptable vector doses remains a major challenge. Here, we evaluated multiple AAV vector design strategies to enhance AAT expression and increase vector potency, thereby reducing the required dose to levels below those associated with severe adverse events. Using AAV1- and AAV8-based platforms, we compared promoter and enhancer configurations, codon optimization of the SERPINA1 transgene, single-stranded versus self-complementary vector genomes, alternative polyadenylation signals, and an engineered oxidation-resistant AAT variant. Across mouse and ferret models, the chicken β-actin expression cassette consistently produced higher AAT levels than a liver-specific promoter variant despite comparable vector biodistribution, reflecting superior intrinsic transcriptional activity or an important contribution. Codon optimization did not enhance expression and, in some cases, modestly reduced AAT levels. Self-complementary AAV vectors exhibited reduced overall expression due to required promoter truncation, yielding lower transgene output than full-length single-stranded constructs. Modifications to polyadenylation signals or enhancer combinations did not improve expression. An oxidation-resistant AAT variant resulted in lower circulating levels but may retain therapeutic potential through enhanced functional stability. Collectively, these findings demonstrate that promoter strength and cassette architecture are dominant determinants of AAV-AAT potency and that full-length, single-stranded vectors with robust regulatory elements provide the highest expression. This work defines key parameters governing AAT expression in vivo and provides a foundation for next-generation AAV designs aimed at achieving therapeutic efficacy at safer, lower vector doses for the treatment of AATD.
2026-01-27 | Advances in Precision Editing Therapies for Alpha-1 Antitrypsin Deficiency.
Genome and RNA editing modalities have revolutionized precision gene therapy, offering a safer alternative to traditional gene replacement approaches. Alpha-1 antitrypsin deficiency (AATD) is a compelling model for precision medicine because the disease mechanism is well defined-mutations in a single gene are responsible for both liver and lung pathology. In this review, we summarize the current preclinical and clinical efforts for AATD, with an emphasis on genome and RNA editing strategies.
2025-09-22 | Alpha 1-antitrypsin deficiency and chronic liver disease in adults: Molecular basis and clinical aspects
Alpha 1-antitrypsin deficiency (A1ATD) is a codominant genetic disorder primarily caused by PiZ mutations in the serpin family A member 1 (SERPINA1) gene. A1ATD is typically associated with the early-onset lung emphysema. However, the misfolding and accumulation of alpha 1-antitrypsin (A1AT) in hepatocytes can also lead to chronic liver disease (CLD). This perspective paper discusses the genetic and molecular factors, the epidemiological features, and clinico-pathological spectrum of A1ATD-related CLD in adults. Emphasis is given to steatosis, cirrhosis, and primary liver cancer, the risks of which critically depend on the PiZ genotype. We discuss the diagnostic strategy, including non-invasive assessment of liver fibrosis. While augmentation therapy plays a role in treating the pulmonary manifestations of A1ATD, this approach carries no benefit for the liver, and early detection is critical to slow the progression of CLD. New approaches comprise gene-editing, innovative pharmacological chaperones, and personalized medicine that target the underlying protein misfolding defect. Enhancing early diagnosis and refining precision treatment strategies promise to significantly improve clinical outcomes.
2025-03-24 | The Role of Gene Therapy as an Emerging Treatment Strategy for Alpha-1 Antitrypsin Deficiency-Associated Lung Disease: A Systematic Review.
Monogenetic disease alpha-1 antitrypsin deficiency (AATD) is the leading cause of emphysema, which is a major life-limiting chronic obstructive pulmonary disease (COPD). The current standard of care for severely affected individuals with lung disease is the periodic intravenous infusion of human AAT protein to restore circulating AAT levels to a protective level, known as augmentation therapy. We did a systematic review to see the effect of gene therapy as a potential therapeutic option for AATD-related lung diseases. MEDLINE (via PubMed), SCOPUS, Web of Science, Cochrane Library, and EMBASE have been searched following PICO (Population, Intervention, Comparison, Outcome) criteria. After duplication removal, abstract and title screening, full-text screening was done by two individual reviewers. Then, the data were extracted, tabulated, and analyzed. A total of 1094 articles were found in the primary search. After a comprehensive review following strict inclusion and exclusion criteria, 14 articles have been included in the review. Evidence shows the response of gene therapy depends on multiple factors, e.g., what vector is used, route of therapy administration, duration of therapy, etc. The AAV8-CASI-luc vector, delivered intratracheally (IT), achieved sustained lung transgene expression for at least 52 weeks, but 29% of mice had persistent expression up to 72 weeks, providing therapeutic AAT protein levels, reducing experimental emphysema severity in mice. Intratracheal AAV8 in mice showed the highest AAT expression in the lung, outperforming AAV9, AAV5, AAV2, and AAV2 capsid mutants, providing long-term expression up to 4 months. Intrapleural administration of AAV5-hA1AT achieved higher lung and serum A1AT levels than intramuscular delivery, with AAV5 yielding 10 times higher levels than AAV2. Gene therapy using viral vectors has a potential role in producing AAT protein, which can be beneficial for AATD-related lung diseases. Human trials are necessary to establish the effectiveness and safety of gene therapy. In conclusion, while initial studies are encouraging, more research is needed to confirm the role of gene therapy.
oligonucleotides
2026-06-01 | B101-10 RNA Editing for the Treatment of Alpha-1 Antitrypsin Deficiency (AATD)
Abstract Rationale Severe AATD is commonly caused by homozygous mutations in the SERPINA1 gene (Pi*ZZ), resulting in misfolded Z-AAT protein in the liver and offering decreased protection for the lung against neutrophil elastase. Current standard of care focuses on augmenting serum AAT levels through weekly infusions of human plasma-purified AAT to maintain serum levels above a putative protective threshold (11 µM). Liver disease is not addressed by this intervention. WVE-006, an investigational N-Acetylgalactosamine-conjugated RNA editing oligonucleotide, is designed to recruit endogenous ADAR enzymes to edit SERPINA1 mRNA in hepatocytes, replacing Z-AAT with M-AAT synthesis. This approach aims to increase serum M-AAT levels while reducing Z-AAT, preserve endogenous regulation of AAT expression, and address both lung and liver manifestations of severe AATD. Methods RestorAATion-2 (NCT06405633) is an ongoing phase 1b/2a clinical trial evaluating the safety, tolerability, pharmacodynamics, and pharmacokinetics of single- and multiple-ascending doses of WVE-006 (200, 400, 600 mg; n = 8 per cohort) in individuals with a ZZ genotype. Participants received a single subcutaneous dose of WVE-006 with a 12-week observation period, followed by biweekly (200 mg) or monthly doses (400, 600 mg) for 12 weeks, with a subsequent 12-week observation period. Serum levels of M-AAT, Z-AAT and total (M + Z) AAT were measured by LC-MS/MS assays, while functional AAT levels were assessed by a neutrophil elastase inhibition assay. Results In the 200 mg multidose cohort, mean maximum serum M-AAT levels reached 7.2 μM in ZZ individuals, corresponding to 64.4% of total serum AAT (11.9 μM). Increases in functional AAT activity were consistent with M-AAT production and were accompanied by 60.3% decrease in Z-AAT protein. In the 200 and 400 mg single dose cohorts, M-AAT levels increased to 4.8 μM and 5.3 μM, respectively. During the 200 mg single dose phase, one participant experienced an acute-phase response due to a kidney stone, during which total serum AAT levels reached 20.6 μM. WVE-006 has been generally safe and well tolerated; all adverse events have been mild to moderate, with no serious adverse events. Conclusions These data, which show production of M-AAT, lowering of Z-AAT protein, and endogenous upregulation of AAT protein in individuals with a ZZ genotype during stress provide proof-of-concept for the first RNA editing therapy to enter clinical testing. This abstract is funded by: Wave Life Sciences
2026-05-01 | B76-07 Overproduction of Muc5b Impairs the Mucociliary Transport in Alpha 1 Antitrypsin Deficiency
Abstract Rationale Alpha-1-antitrypsin deficiency (AATD) is a genetic risk factor that accelerates the onset of chronic obstructive pulmonary disease in smokers, impairing mucociliary clearance (MCC). AATD disrupts the protease-antiprotease balance, promoting epithelial injury and mucus overproduction through cytokine and neutrophil elastase (NE) driven feedback, thereby worsening small airway obstruction. Mechanisms by which NE in AATD contributes to mucus stasis in the small airways are unknown. Here, we hypothesize that Muc5b overexpression contributes to the differentiation of club cells to goblet cells in AATD by enhanced NE activity. To investigate the role of Muc5b in AATD-related mucociliary dysfunction, we examined its association in human and ferret bronchial epithelial cells (BECs) exposed to cigarette smoke extract (CSE), following targeted Muc5b inhibition and treatment with CSE, NE, or both. Methods First, we performed single-cell RNA-sequencing (scRNA-seq) of primary BECs derived from an AATD patient treated with 1% CSE vs. vehicle control. To determine whether uncontrolled NE activity in AATD worsens CSE-induced mucociliary dysfunction via Muc5B regulation, we silenced MUC5B using siRNA and treated cells with NE, CSE, or both. Knockdown was confirmed by RT-PCR and immunofluorescence (IF), and MCC was assessed using micro-optical coherence tomography (µOCT) imaging. Ongoing experiments involve Muc5B overexpression using CRISPR activation with a lentiviral dCas9-VPR system. Gene expression is being evaluated by IF and Western blotting to determine whether Muc5b knockdown or overexpression influences MCC in AATD and potentiates the effects of CSE. Cytokine will also be measured for the inflammatory response. Results scRNA-seq and IF exhibited an increased Muc5B-positive goblet cell population following CSE exposure compared to vehicle controls. Primary HBE treated with NE upregulated Muc5b (1.8 fold, p = 0.01), and the effect was further enhanced by CSE treatment after NE treatment (2.4 fold, p = 0.01). μOCT analysis of CSE-exposed AATD-derived HBEs demonstrated a decline in MCT following CSE treatment (15% reduction; p = 0.001, N = 3). A further decrease in MCT was observed with combined NE (1μM) and 1% CSE treatment vs vehicle (20% reduction, p = 0.001), indicating an enhanced impairment of mucociliary function. Further, intervention with Muc5b-specific siRNA reduced expression of Muc5b (90%, p = 0.001, N = 3). Neither CSE, NE, nor a combination induced Muc5b expression with Muc5b knockdown. Conclusion We demonstrate that Muc5b overproduction worsens MCT in AATD by NE and exacerbates the effect of smoke exposure; the effect can be attenuated by siRNA Muc5b knockdown. Findings identify Muc5b as a potential therapeutic target for mitigating AATD-associated airway obstruction. This abstract is funded by: Alpha 1 foundation, American lung association, ATS, DREAM council, CF foundation
2025-11-03 | Alpha-1 antitrypsin deficiency: genetics, clinical manifestations, AI prognostics, and advanced imaging in liver disease.
Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder caused by mutations in the SERPINA1 gene, resulting in reduced or dysfunctional alpha-1 antitrypsin (AAT) protein. This deficiency leads to progressive lung and liver diseases, including emphysema, chronic obstructive pulmonary disease, and cirrhosis. Despite its clinical significance, AATD remains underdiagnosed, delaying treatment. This review explores the molecular mechanisms of AATD, emphasizing Z-variant AAT protein accumulation in hepatocytes and excessive protease activity in the lungs. Advancements in imaging modalities - such as computed tomography, magnetic resonance imaging (MRI), dark-field radiography, and hyperpolarized MRI - enhance early diagnosis and disease monitoring. Novel therapies are reshaping AATD management, including small interfering RNA therapies (fazirsiran, belcesiran), gene-editing techniques (CRISPR-Cas9), regenerative approaches, autophagy-enhancing drugs, proteostasis regulators, aerosolized AAT, and artificial intelligence (AI) for real-time disease tracking via wearable devices. The integration of AI, advanced imaging, and emerging therapies represents a paradigm shift in AATD diagnosis and treatment. This review highlights the need for a multidisciplinary approach, early intervention, and personalized medicine to improve outcomes in both pulmonary and hepatic complications.
2025-04-14 | Alpha-1 antitrypsin deficiency-associated liver disease: From understudied disorder to the poster child of genetic medicine.
Alpha-1 antitrypsin deficiency (AATD) constitutes an inborn disorder arising due to mutations in alpha-1 antitrypsin (AAT), a secreted protease inhibitor produced primarily in hepatocytes. It leads to diminished serum AAT levels, and this loss-of-function predisposes to chronic obstructive pulmonary disease and lung emphysema. The characteristic Pi*Z mutation results in hepatic Z-AAT accumulation. In its homozygous form (Pi*ZZ genotype), it is responsible for the majority of severe AATD cases and can cause both pediatric and adult liver disease, while the heterozygous form (Pi*MZ) is considered a disease modifier that becomes apparent primarily in the presence of other comorbidities or risk factors. In the current review, we collate conditions associated with AATD, introduce typical AAT variants, and discuss our understanding of disease pathogenesis. We present both cross-sectional and longitudinal data informing about the natural disease history and noninvasive tools that can be used for disease stratification as well as a basis for disease monitoring. Given that AATD-associated liver disease is highly heterogeneous, we discuss the risk factors affecting disease progression. While the loss-of-function lung disease is treated by weekly intravenous administration of purified AAT, recombinant modified AAT and oral protease inhibitors are currently in clinical trials. Among the liver candidates, small interfering RNA fazirsiran efficiently suppresses AAT production and is currently in phase 3 clinical trial, while several other genetic approaches, such as RNA editing, are at earlier stages. In summary, AATD represents a systemic disorder increasingly seen in the hepatologic routine and requiring thorough interdisciplinary care, since the currently ongoing clinical trials often address only one of the organs it affects.
2025-04-04 | Improved RNA base editing with guide RNAs mimicking highly edited endogenous ADAR substrates.
Adenosine deaminase acting on RNA (ADAR)-mediated RNA base editing offers a safer alternative to genome editing for specific clinical applications because of nonpermanent editing of targets. Current guide RNA (gRNA) designs feature a fully complementary specificity domain with an A-C mismatch at the targeted adenosine. However, perfectly matched dsRNA is not the most effective ADAR substrate. Here we introduce MIRROR (mimicking inverted repeats to recruit ADARs using engineered oligoribonucleotides), an approach that implements structural motifs derived from highly edited inverted Alu repeats in human tissues to enable rational gRNA design for ADAR recruitment. We demonstrated that MIRROR is applicable to both short chemically synthesized gRNAs with modifications and long biologically generated gRNAs and surpasses current state-of-the-art approaches in both gRNA forms. It enhances editing efficiency by up to 5.7-fold in multiple human cell types and primary hepatocytes from an alpha-1 antitrypsin deficiency mouse model. Our findings improve programmable RNA editing in vitro and in vivo by rational design through the screening of highly edited natural substrate mimics.
other
2026-05-01 | C33-29 Not All Cough in Alpha-1 Antitrypsin Deficiency Is Emphysema: A Case of Eosinophilic Asthma
Abstract Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder that predisposes to early-onset emphysema and bronchiectasis through protease-antiprotease imbalance and neutrophil-driven inflammation. Although asthma and atopy occur more frequently in AATD, eosinophilic asthma is rarely documented. This case highlights a patient with genetically confirmed severe AATD whose chronic cough stemmed not from emphysema, but from eosinophilic asthma. A 39-year-old nonsmoking woman with Raynaud’s disease and recurrent sinusitis presented with a two-year history of chronic cough and intermittent dyspnea. She had required multiple short courses of oral corticosteroids with transient relief. Spirometry was normal (FEV₁ 97% predicted, FEV₁/FVC 89%), and DLCO was preserved (85% predicted). High-resolution CT revealed mild lower-lobe bronchiectasis without emphysema. Serum alpha-1 antitrypsin was <25 mg/dL, and genotyping confirmed a homozygous ZZ mutation. Peripheral eosinophilia (1.5 × 109/L; 21%) and bronchoalveolar lavage showing 43% eosinophils confirmed type-2 airway inflammation. All bacterial and fungal cultures, including Aspergillus precipitins, were negative. She was treated with inhaled budesonide/formoterol for airway inflammation and intranasal ipratropium for postnasal-drip-related symptoms, with partial improvement. Persistent cough and elevated eosinophils prompted initiation of Mepolizumab 100 mg subcutaneously every 4 weeks per ATS/ERS severe-asthma guidance. Over three months she reported improved symptom control and reduced cough frequency, allowing consideration of inhaled corticosteroid step-down. Lung function remained normal. In the absence of emphysema or fixed obstruction, augmentation therapy for AATD was not indicated. Emphysema is the hallmark pulmonary manifestation of ZZ AATD, affecting most adults, whereas asthma occurs in a minority. This patient’s normal spirometry, preserved diffusion, and eosinophilic airway inflammation were consistent with eosinophilic asthma coexisting with but mechanistically distinct from AATD. The two processes represent different inflammatory pathways - neutrophilic tissue injury versus IL-5-driven eosinophilic inflammation - but can intersect clinically. Management should follow severe-asthma protocols, with high-dose inhaled corticosteroid-LABA therapy and biologic add-on (anti-IL-5 or anti-IL-4Rα) for persistent eosinophilia. The clinical response suggests that biologic therapy remains effective in the setting of AATD. Patients require dual monitoring: spirometry and DLCO for AATD progression, and eosinophil counts and symptom assessment for asthma control. Not every cough in AATD signals emphysema progression. Recognizing eosinophilic asthma as a coexisting, treatable inflammatory phenotype allows targeted therapy and improved control while maintaining vigilance for longterm AATD related complications. This abstract is funded by: None
2025-12-02 | Resolution of the circulating pathogenic phenotype of alpha-1 antitrypsin deficiency following liver transplantation
Abstract Alpha-1 antitrypsin is a member of the serpin family of protease inhibitors and normally found in monomeric form at high concentration in the circulation. Certain pathogenic variants of this protein self-assemble into flexible chains (polymers) that undergo toxic accumulation in the liver, underlying the development of liver disease, and a corresponding functional deficiency in circulation results in a susceptibility to chronic damage to the lungs and thereby COPD. A proportion of these polymers are detectable in the circulation. This study aimed to provide data on the dynamics of AAT monomers and polymers in the circulation after correction of a deficiency state by liver transplantation. The evolution of the circulating AAT phenotype was characterised quantitatively over time by analysis of blood samples taken pre- and post-liver transplant from three PiZZ AAT deficiency patients, using a panel of conformer-specific monoclonal antibodies and a novel ELISA with enhanced sensitivity for AAT polymers. Circulating wild-type M AAT was found to increase with a half-time of 29-39 h, attaining a clinically-defined putative ‘protective’ threshold level within 24-50 h post-transplant. Baseline circulating polymer levels ranged from 5-35 μg/mL with a half-time clearance of 3-12 h following transplant, and levels were indistinguishable from reference wild-type plasma 22 months post-surgery. The glycosylation profile and disappearance of detectable circulating polymers of AAT were consistent with their origin in, and canonical secretion by, the liver. To our knowledge this is the first post-transplant evaluation of the hybrid conformational profile of endogenous and donor tissue-derived AAT.
2025-05-01 | Long Term Effectiveness of Bronchoscopic Lung Volume Reduction in COPD Patients With Alpha-1 Antitrypsin Deficiency
Abstract Introduction: Chronic Obstructive Pulmonary Disease (COPD) causes breathlessness through dynamic hyperinflation. Bronchoscopic lung volume reduction (BLVR) has been shown to reduce hyperinflation, improve lung function, symptoms and quality of life in COPD patients. Several studies have suggested these benefits extend to COPD patients with Alpha-1 antitrypsin deficiency (AATD). Improvements have been shown in the short and intermediate term. The persistence of these benefits into the long term are questionable. Our analysis presents and compares intermediate and long-term outcomes following BLVR for a group of COPD patients with AATD. Methods: We conducted a retrospective, single-center chart review of 238 patients who underwent BLVR at our large quaternary care institution between August 2018 and April 2024. Chart review revealed 14 patients with documented AATD within this group. Baseline characteristics including demographics, modified medical research council (mMRC) dyspnea scale, BODE index and pulmonary function testing (PFT) prior to BLVR were recorded. Lung function data was then collected from PFTs performed at a mean of 7 (SD±1.95) and 12.43 (SD±5.47) months following the BLVR procedure. Post-BLVR data was compared to baseline data and analyzed using Wilcoxon signed rank test for statistical significance. Outcomes were compared between the 7-month and 12-month group using a single variance t-test. Results: Following BLVR, 7 patients (50%) experienced an increase in forced expiratory volume in one second (FEV1) greater than 15% at both 7 months and 12 months. The median improvement in FEV1 was 111mL (IQR 0.05 – 0.24) which equated to 13.94% (IQR 7.53 – 25.01) at 7 months and 110mL (IQR 0.04 – 0.23) which equated to 15.38% (IQR 5.87 – 30.09) at 12 months. Statistically significant improvements were also demonstrated in residual volume (RV), total lung capacity (TLC), RV/TLC ratio indicating improvements in hyperinflation. Single variance t-test analysis showed no statistically significant differences between the 7 month and 12-month outcomes. Conclusion: BLVR represents a promising therapeutic approach for COPD patients with concomitant AATD. Our findings suggest improvements in pulmonary dynamics that persist into the intermediate and long-term. This study contributes valuable insights to the growing body of evidence demonstrating benefits to BLVR in patients with COPD and AATD.
2025-05-01 | Evaluating the Role of Eosinophils in Alpha-1 Antitrypsin Deficiency
Abstract Rational: Alpha-1 antitrypsin deficiency (AATD) is a condition which results in reduced plasma and lung AAT levels. The most common allele associated with AATD is the Z allele. Z homozygous individuals have an increased risk of developing early onset COPD. Type 2 inflammation is a pathway modulated by type 2 cytokines such as IL-13 and IL-5. Recent studies have identified a subset of COPD patients with elevated type 2 inflammation who respond better to inhaled corticosteroids and other novel interventions. Since IL-13 and IL-5 are involved in eosinophil maturation, high blood eosinophils can indicate type 2 inflammation in COPD. However, less is known about type 2 inflammation in AATD, hence the objective of this project was to identify if AATD is associated with elevated eosinophil counts. Methods: Patients were identified from the Irish national Alpha-1 registry and reviewed in a national AATD clinic. Each patient underwent clinical assessment including routine bloods, to evaluate eosinophils and spirometry. COPD diagnosis was defined by clinical review, pulmonary function tests and CT of thorax. Results: Overall 106 patients with AATD were included, 79% were ZZ and 9.5% of these were receiving augmentation therapy. A significant negative correlation between eosinophil count and FEV1 in AATD patients was found (p=0.038). Additionally, there was a significant positive correlation between age and eosinophil count among AATD patients, (p=0.03). Similarly, in ZZ patients and ZZ patients not receiving augmentation therapy there were significant negative correlations between eosinophil count and FEV1 (N=84, p=0.016 and N=76, p=0.011 respectively). Additionally, significant positive correlation between eosinophil count and age was found in these groups (N=84, p=0.007 and N=76, p=0.006 respectively). The median eosinophil count in the general population was previously described as 130/µL (1). Our study found an elevated median eosinophil count in AATD individuals of 170/µL. Diagnosis of COPD or history of ever smoking was associated with higher median eosinophil counts compared to no COPD diagnosis and never smokers respectively however these were not significant at the numbers tested. Conclusions: Further research is needed to identify if targeting type 2 inflammation in AATD patients with high eosinophils would be an effective therapeutic option. Future work will involve evaluation of type 2 cytokines in correlation with eosinophil counts. Reference:1. Hartl S, Breyer M-K, Burghuber OC, Ofenheimer A, Schrott A, Urban MH, et al. Blood eosinophil count in the general population: typical values and potential confounders. European Respiratory Journal. 2020;55(5).
2025-03-06 | Bacterial colonisation doubles the risk of exacerbation in alpha-1 antitrypsin deficiency.
Pulmonary exacerbations in alpha-1 antitrypsin deficiency (AATD) are associated with worse disease outcomes, including accelerated lung function decline. As with non-deficient COPD, subjects with AATD are predisposed to bacterial colonisation of the lower respiratory tract, a known risk factor for exacerbations. Despite this, the extent to which colonising bacteria contribute to exacerbations remains relatively unexplored. Sputum samples were collected longitudinally from AATD subjects, when clinically stable and during exacerbations, and were processed for quantitative culture to identify bacterial pathogens. Using contemporaneous clinical data, a post-hoc analysis was performed to calculate the odds of an exacerbation in the presence of recognised, potentially pathogenic bacteria (PPB) of the lower respiratory tract. 324 sputum samples were collected from 29 patients with AATD plus radiological evidence of bronchiectasis and 671 samples from 62 patients without bronchiectasis (AATD alone). Both groups contained patients with AATD-associated lung disease (emphysema and chronic bronchitis). At least half of the samples (55.5 %) from AATD alone were positive for a PPB and almost three quarters (72.8 %) of those with bronchiectasis. Presence of a Pseudomonas species, Staphylococcus aureus or Moraxella catarrhalis during stable state disease were all significantly associated with increased likelihood of a subsequent exacerbation (OR: 1.89, p = 0.0013; 1.98, 0.0022; 1.98, 0.0047; 2.19, 0.0047, respectively), independent of age, sex, disease severity (FEV1 impairment), smoking status and presence or absence of bronchiectasis. Disease progression in AATD is variable and identification of traits which may contribute may prove influential. Here, we report that bacterial colonisation is an important predictor of exacerbation in AATD, likely attributed to the associated levels of increased inflammation. Thereby, this may represent a sub cohort of patients that could benefit from additional, targeted therapy.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
42 orphan drug designations for Alpha-1-antitrypsin deficiency, including 1 approved therapy.
42 orphan drug designations for Alpha-1-antitrypsin deficiency, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Guide RNA against the human SERPINA1 gene, mRNA encoding a CRISPR-associated endonuclease Cas9 against the human SERPINA1 gene | gene editing enzymes | EMA | 2026-07-24 | — | Voisin Consulting Life Sciences |
Efdoralprin alfa | proteins | EMA | 2025-12-09 | — | Sanofi B.V. |
RNA editing antisense oligonucleotide (ASO) | oligonucleotides | FDA | 2025-11-19 | — | AIRNA Corporation |
in vivo target-primed reverse transcription genome editing product consisting of two chemically modified RNA drug substances: a messenger RNA, and a template guide RNA formulated in a lipid nanoparticle delivery vehicle comprised of 4 lipids to target the pathogenic PiZ allele in the SERPINA1 gene | RNAs | FDA | 2025-11-06 | — | Tessera Therapeutics, Inc. |
RNA editing antisense oligonucleotide against the Z mutation of the human SERPINA1 mRNA transcript, sodium salt | oligonucleotides | EMA | 2025-08-22 | — | Parexel International (IRL) Limited |
a lipid nanoparticle-based therapy consisting of a guide RNA that targets the SERPINA1-c.1096G>A allele and a messenger RNA that encodes an ABE protein | gene editing enzymes | FDA | 2025-05-28 | — | Beam Therapeutics |
lipid nanoparticles containing base editor CRISPR-Cas9 messenger RNA (mRNA) and a single guide RNA (sgRNA) targeting SERPINA1 gene | gene editing enzymes | FDA | 2025-04-09 | — | Yoltech Therapeutics Co., Ltd |
RNA editing antisense oligonucleotide (ASO) KB100967 directed at the Z mutation of the human SERPINA1 mRNA transcript, encapsulated in a lipid nanoparticle | oligonucleotides | FDA | 2025-03-12 | — | Korro Bio, Inc. |
Alvelestat | small molecules | EMA | 2025-01-16 | — | Mereo BioPharma Europe B.V. |
N-[(1R)-1-[(S)-(2-Chloro-3-fluorophenyl)hydroxymethyl]butyl]-7-fluoro-2,3-dihydro-2-oxo-1H-indole-4-carboxamide | small molecules | EMA | 2024-07-25 | — | BioMarin International Limited |
oxoindoline carboxamide compound | small molecules | FDA | 2023-12-12 | — | BioMarin Pharmaceutical Inc. |
A replication-defective, non-integrating herpes simplex virus type 1-based vector engineered to express full-length, functional human alpha-1 antitrypsin | gene therapies | FDA | 2023-09-01 | — | Krystal Biotech, Inc. |
IgG4 Fc linked recombinant human AAT (alpha-1 antitrypsin) | proteins | FDA | 2022-03-02 | — | Sanofi Aventis US. LLC (A Sanofi Company) |
Alvelestat | small molecules | FDA | 2021-10-25 | — | Mereo Biopharma 4 Limited |
CHO cell line produced human Alpha-1 Antitrypsin (CHO-AAT) protein | proteins | FDA | 2020-10-19 | — | Caravella Biopharma SA |
a synthetic double-stranded RNA oligonucleotide conjugated to N-acetyl-D-galactosamine aminosugar residues | oligonucleotides | FDA | 2020-03-16 | — | Dicerna Pharmaceuticals, Inc. |
Recombinant human alpha-1 antitrypsin from Oryza sativa | proteins | FDA | 2020-02-19 | — | Wuhan Healthgen Biotechnology Corporation |
Belcesiran | RNAs | EMA | 2019-12-16 | — | Novo Nordisk A/S |
N-acetylgalactosamine-conjugated synthetic double-stranded oligomer specific to serpin family A member 1 gene | oligonucleotides | EMA | 2018-07-31 | — | Takeda Pharma A/S |
double stranded oligomer ADS-001 RNA interference-based liver targeted therapeutic | oligonucleotides | FDA | 2018-02-14 | — | Takeda Development Center Americas, Inc. |
three-dimensional bioprinted therapeutic liver tissue | cell therapies | FDA | 2017-12-21 | — | Organovo Inc. |
hyaluronic acid | small molecules | FDA | 2017-01-18 | — | Gerard M. Turino, MD |
Double-stranded oligomer specific to the SERPINA1 gene and containing a cholesterol-conjugated acyclic nucleobase analogue [API-AAT (AD00370)] | oligonucleotides | EMA | 2016-01-11 | — | Pharma Gateway AB |
double stranded oligomer AD00370 RNA interference-based liver targeted therapeutic | RNAs | FDA | 2015-06-09 | — | Arrowhead Research Corporation |
Cyclo[L-alanyl-L-seryl-L-isoleucyl-L-prolyl-L-prolyl-L-glutaminyl-L-lysyl-L-tyrosyl-D-prolyl-L-prolyl-(2S)-2-aminodecanoyl-L-alpha-glutamyl-L-threonyl] acetate salt | peptides | EMA | 2013-03-20 | — | Santhera Pharmaceuticals (Deutschland) GmbH |
alpha1 proteinase inhibitor (human) | proteins | FDA | 2010-01-29 | — | Grifols Therapeutics, Inc. |
Alpha-1 proteinase inhibitor (inhalation use) | proteins | EMA | 2008-06-03 | — | Grifols Deutschland GmbH |
Recombinant adeno-associated viral vector containing human alpha-1 antitrypsin gene | gene therapies | EMA | 2007-03-20 | — | Propharma Group The Netherlands B.V. |
Human alfa-1-proteinase inhibitor | proteins | EMA | 2006-02-16 | — | Octapharma (IP) Limited |
Alpha1-Proteinase Inhibitor (Human) | proteins | FDA | 2004-12-22 | — | Kamada Ltd. |
Alpha-1 antitrypsin (inhalation use) | proteins | EMA | 2004-11-16 | — | Kamada Ireland Limited |
recombinant adeno-associated virus alpha 1-antitrypsin vector | gene therapies | FDA | 2003-01-27 | — | University of Massachusetts Medical School |
Human alpha1-proteinase inhibitor, recombinant | proteins | EMA | 2002-04-30 | — | Aptiv Solutions (UK) Limited |
hyaluronic acid | small molecules | FDA | 2002-03-19 | — | CoTherix |
recombinant human alpha-1 antitrypsin (rAAT) | proteins | FDA | 2001-08-28 | — | AiroMedica LLC |
Human Alpha1-Proteinase Inhibitor (respiratory use) | proteins | EMA | 2001-07-09 | — | CSL Behring GmbH |
Human alpha1-proteinase inhibitor, recombinant | proteins | EMA | 2001-05-30 | — | Grifols Deutschland GmbH |
Alpha1-proteinase inhibitor (human) | proteins | FDA | 1999-11-24 | — | CSL Behring L.L.C. |
Transgenic human alpha 1 antitrypsin | gene therapies | FDA | 1999-05-19 | — | PPL Therapeutics (Scotland) Limited |
Recombinant secretory leucocyte protease inhibitor | proteins | FDA | 1991-03-29 | — | Amgen Inc. |
Alpha1-proteinase inhibitor (human) [Prolastin] | proteins | FDA | 1984-12-07 | 1987-12-02 | Bayer Corporation |
Alpha-1-antitrypsin (recombinant DNA Origin) | proteins | FDA | 1984-01-01 | — | Chiron Corporation |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.