RARE DISEASE
Hereditary ATTR amyloidosis
Hereditary ATTR amyloidosis
Hereditary ATTR amyloidosis
Synonyms: ATTRv amyloidosis, Familial TTR-related amyloidosis, Familial transthyretin-related amyloidosis, Hereditary TTR amyloid polyneuropathy, Hereditary TTR amyloidosis, Hereditary transthyretin amyloid polyneuropathy, hATTR
Synonyms: ATTRv amyloidosis, Familial TTR-related amyloidosis, Familial transthyretin-related amyloidosis, Hereditary TTR amyloid polyneuropathy, Hereditary TTR amyloidosis, Hereditary transthyretin amyloid polyneuropathy, hATTR
Synonyms: ATTRv amyloidosis, Familial TTR-related amyloidosis, Familial transthyretin-related amyloidosis, Hereditary TTR amyloid polyneuropathy, Hereditary TTR amyloidosis, Hereditary transthyretin amyloid polyneuropathy, hATTR
Drug discovery
29
drugs
With orphan designations
Overview
Hereditary ATTR (hATTR) amyloidosis is a progressive, multisystem disorder caused by autosomal dominant mutations in the TTR gene, leading to misfolded transthyretin protein aggregates that form amyloid deposits in nerves, heart, and other organs. Symptoms include sensorimotor neuropathy, cardiomyopathy, and autonomic dysfunction. Diagnosis relies on genetic testing, tissue biopsy (Congo red staining), and cardiac scintigraphy. Early intervention with disease-modifying therapies is critical to slow progression [1][4][12].
Population
Global prevalence ≈50,000, with >150 pathogenic TTR variants [1][7][19].
Higher incidence in endemic regions (e.g., 1:538 in northern Portugal); V122I mutation prevalent in 1:25 Black individuals [2][6][16].
Median age of onset varies: 30–50s for neuropathic forms, later for cardiac phenotypes [4][6].
Burden
Diagnostic delay: ~6 years due to nonspecific symptoms mimicking common conditions (e.g., diabetic neuropathy) [7][15].
High morbidity: Progressive disability (wheelchair dependence in 5–15 years), heart failure, and mortality within 3–12 years post-symptom onset [4][7][12].
Economic impact: Annual US healthcare costs ≥$60,000/patient, driven by hospitalizations and advanced therapies [5][14].
Categories: rare cardiac diseases, rare genetic diseases, rare systemic and rheumatological diseases, rare transplant-related disorders
Research Papers
1,149 drug discovery papers about Hereditary ATTR amyloidosis, with 3 first-in-class and 20 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,149 drug discovery papers about Hereditary ATTR amyloidosis, with 3 first-in-class and 20 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2025-12-26 | Predictors of poor prognosis in a large cohort of patients with hereditary cardiac transthyretin amyloidosis.
Hereditary transthyretin amyloidosis (hATTR) is a rare, multisystemic, autosomal dominant disease. Cardiac involvement worsens prognosis. We aimed to characterize Spanish patients with hATTR cardiac amyloidosis (hATTR-CA) and to identify predictors of poor prognosis. We conducted a retrospective, multicenter study in 39 Spanish hospitals, including adults with genetically confirmed hATTR and cardiac involvement (January 2000-September 2022). Independent predictors of poor prognosis (death, heart transplantation, heart failure, or cardiovascular hospitalization) were identified using multivariate logistic regression. Data were also collected on clinical and genetic characteristics, management patterns, and event-free survival. A total of 442 patients were included (67.6% male; median age at diagnosis, 65 years). Fifteen TTR variants were identified, with p.Val30Met being the most frequent (64.9%). The most common extracardiac manifestation was neuropathy (64.6%). At baseline, most patients were in New York Heart Association class I-II, with progressive worsening during follow-up. Overall, 48.9% of patients were hospitalized, and 21.9% died; 25.3% of deaths were heart failure-related. Five-year event-free survival was 80.2% from symptom onset and 66.9% from diagnosis. Disease-specific treatments (tafamidis, patisiran, inotersen, or liver transplant) were associated with improved survival (P <.001). In an exploratory analysis stratified by diagnosis before vs after 2018, event-free survival did not differ significantly (HR, 1.04; 95%CI, 0.63-1.72; P=.88). Independent predictors of poor prognosis included New York Heart Association class II-IV, lower left ventricular ejection fraction, elevated N-terminal pro-B-type natriuretic peptide, and the presence of neurological involvement. This national cohort-the largest reported to date-highlights the clinical and genetic heterogeneity of hATTR -CA in Spain. Early diagnosis and disease-specific therapies are essential to improving prognosis.
2025-10-01 | S6462 Gastric Transthyretin Amyloidosis: A Unique Case of Gastric Outlet Obstruction and Gastroparesis
Introduction: Gastric transthyretin amyloidosis (ATTR) affects the interstitial cells of Cajal, which are pivotal for gastric motility. The rare complications include gastroparesis secondary to autonomic neuropathy and gastric outlet obstruction (GOO) due to pyloric stenosis from fibril deposits. The exact incidence and prevalence of the disease with these complications are currently unknown. We present a unique case of hereditary ATTR complicated with recurrent GOO and gastroparesis requiring a gastric simulator. Case Description/Methods: An 80-year-old woman with a past medical history of hereditary transthyretin cardiac amyloidosis presented with persistent nausea and vomiting. The admission vital signs were stable, with a benign physical examination, and labs were pertinent for hypokalemia and hyperchloremic metabolic alkalosis. She received antiemetics without any relief. Subsequently, the computed tomography (CT) abdomen revealed thickened gastric folds. This prompted an esophagogastroduodenoscopy (EGD), which revealed retained food in the stomach, raising concerns for gastroparesis. The pyloric junction was stenosed and required balloon catheter dilation. The EGD biopsy showed amyloid deposits in the gastric wall, positive for Congo red stain. Immunohistochemistry detected ATTR. After the EGD, her symptoms initially improved, and on discharge, she continued Tafamidis and Eplontersen. Three months later, she was hospitalized again with persistent vomiting, not responding to any antiemetics. She required a repeat EGD with pyloric dilation. Following a multidisciplinary team approach, a joint decision was made to place a gastric simulator for refractory vomiting. After this intervention, her symptoms improved significantly, and she closely followed up with the gastroenterologist. Discussion: Gastrointestinal symptoms in ATTR are often nonspecific, making diagnosis challenging; therefore, a high clinical suspicion is warranted to establish a definitive diagnosis promptly. The mainstay treatments for gastric ATTR are disease-modifying therapies (TTR stabilizers and gene silencing). Moreover, a gastric simulator is used as a last resort for patients with gastric ATTR complicated with gastroparesis who haven't responded to other treatments. Due to the rare co-occurring complications and underreported incidence, we aim to raise awareness and strongly advocate for the need for large, multi-center, prospective studies to capture the impact of gastric ATTR and its burden on the US healthcare system.
2025-07-07 | Uncovering cell type-specific phenotypes using a novel human in vitro model of transthyretin amyloid cardiomyopathy.
Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the misfolding of transthyretin (TTR), fibrillogenesis, and progressive amyloid fibril deposition in the myocardium, leading to cardiac dysfunction with dismal prognosis. In ATTR-CM, either destabilizing mutations (variant TTR, ATTRv) or ageing-associated processes (wild-type TTR, ATTRwt) lead to the formation of TTR amyloid fibrils. Due to a lack of representative disease models, ATTR-CM disease mechanisms are largely unknown, thereby limiting disease understanding and therapeutic discovery. Here, we report a novel in vitro ATTR-CM model which uncovers cell type-specific disease phenotypes by exposing the three major human cardiac cell types to TTR fibrils, thereby providing novel insights into the cellular mechanisms of ATTR-CM disease. Human recombinant TTR proteins (WT, V122I, V30M) and respective fibrils were generated and characterized using Thioflavin T, Amytracker, Congo red and dot blot analyses. Seeding human induced pluripotent stem cell-derived-cardiomyocytes (hiPSC-CMs) and endothelial cells (ECs) on TTR fibrils resulted in reduced cell viability. Confocal microscopy revealed extracellular localization of TTR fibrils to hiPSC-CMs, leading to sarcomere disruption, altered calcium handling and disrupted electromechanical coupling, while ECs showed a reduced migration capacity with aberrant cell morphology. hiPSC-fibroblasts (hiPSC-FBs) were largely unaffected by TTR fibrils, presenting normal viability, but showing enhanced localization with TTR fibrils. Our model shows that WT and variant TTR fibrils lead to cell type-specific phenotypes, providing novel insights into the underlying cellular disease mechanisms of ATTR-CM, thereby facilitating the identification of novel therapeutic targets and biomarkers.
2025-06-21 | 40 years of CEPARM: transforming amyloidosis related to transthyretin from neglect to recognition.
Variant transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTRv-CM), formerly known as familial amyloidotic polyneuropathy (FAP), is a severe, progressive disorder caused by mutations in the transthyretin (TTR) gene. Historically, FAP was considered a neglected disease due to its rarity and the limited understanding of its pathophysiology, which led to minimal research funding and few therapeutic options. The present article explores the transformative role of Centro de Paramiloidose Antônio Rodrigues de Mello (CEPARM), established in 1984, in elevating the status of FAP through significant advancements in research and treatment. Although CEPARM was not the sole catalyst for this shift, its contributions in liver transplantation, the development of pharmacological therapies, and holistic patient care have substantially improved the recognition and management of FAP. The article also examines CEPARM's impact on patient care, the ongoing challenges, and ethical considerations within the field.
2023-05-30 | A rare pathogenic variant identified in a heart transplant recipient with hereditary transthyretin amyloidosis: a case report.
Hereditary transthyretin (ATTRv) amyloidosis is a rare and complex genetic disorder that can lead to life-threatening cardiac amyloidosis and rapid disease progression. Early diagnosis and treatment with disease-modifying drugs can improve patient outcomes; however, heart transplantation may be necessary in some patients. We present the unique case of a 65-year-old Korean woman diagnosed with ATTRv amyloidosis after experiencing progressive neurological symptoms, followed by heart failure. Despite the absence of significant symptoms of heart failure, subsequent screening revealed cardiac amyloid infiltration, which caused left ventricular hypertrophy and rapid disease progression. The patient underwent successful heart transplantation, and subsequent genetic testing revealed a pathogenic variant, NM_000371.3:c.425T>C (p.Val142Ala), which affects both the nerves and heart and has not been previously reported in Korea. Our report underscores the potential benefits of heart transplantation in managing advanced ATTRv amyloidosis and emphasizes the need for continued research on the genetic heterogeneity of the disease. Clinicians should consider ATTRv amyloidosis in the differential diagnosis of patients presenting with neurological symptoms and heart failure, particularly in those with a family history of the disease.
small molecules
2026-09-30 | Clinical Benefit of the Transthyretin Stabiliser Tafamidis in Hereditary Transthyretin Amyloid Cardiomyopathy: A Case Report.
This case report aims to illustrate the critical importance of a standardized diagnostic approach and genotype-specific therapy in hereditary transthyretin amyloid cardiomyopathy (ATTR-CM). It highlights the clinical challenge of diagnosing ATTR-CM amidst complex comorbidities and addresses the evidence gap regarding the long-term efficacy of tafamidis for the rare and aggressive p.Val40Ile (protein-level substitution of valine to isoleucine at codon 40) mutation. A 72-year-old East Asian man with multiple comorbidities presented with refractory heart failure. Key clinical clues included the classic "red flag" of electrocardiogram (ECG)-echocardiogram discordance (low voltage with ventricular hypertrophy). Genetic testing identified the pathogenic p.Val40Ile transthyretin (TTR) mutation. The diagnosis was confirmed non-invasively via cardiac magnetic resonance (CMR) and technetium-99m pyrophosphate scintigraphy. Following the initiation of tafamidis, the patient's symptoms significantly improved. Over a two-year follow-up period, he sustained clinical stability with a marked reduction in heart failure-related hospitalizations. This report provides detailed case-based evidence supporting the long-term efficacy of tafamidis in stabilizing disease and improving prognosis for patients with ATTR-CM harboring the p.Val40Ile mutation. It underscores the value of timely diagnosis, genetic subtyping, and access to targeted therapy in altering the clinical course of this aggressive genotype.
2026-08-30 | Gastric amyloid pathology and mucosal denervation in ATTRv amyloidosis: insights from patients, mice, and gut microenvironment profiles.
Hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN) frequently presents with gastrointestinal autonomic dysfunction, but its underlying pathology remains unclear. We examined gastric mucosal amyloid deposition and innervation using conventional endoscopic biopsies in ATTRv-PN patients and a human TTR (hTTR A117S) knock-in mouse model. Clinical assessments, gut microbiota, metabolomics, and neurite growth assays were integrated. Among 33 patients, 84.8% showed TTR(+) amyloid deposition in gastric mucosa. Gastric mucosal innervation density (GMID) was significantly reduced in all gastric regions compared with controls and was similarly decreased in hTTR(A117S) mice. Lower GMID correlated with gastroparesis and reflux symptom severity. Integrated analyses revealed positive associations between GMID, four microbial genera, and histidine levels. Both microbiota-derived principal components and histidine independently correlated with GMID. Histidine also promoted neurite growth in vitro. Endoscopic biopsy enables assessment of both gastric amyloid pathology and mucosal innervation in ATTRv-PN. Reduced GMID is closely associated with gastrointestinal symptoms, microbiota alterations, and metabolomic changes, providing insights into disease mechanisms and potential biomarkers of autonomic gastrointestinal dysfunction.
2026-08-26 | Hereditary ATTR amyloidosis with prominent central nervous system involvement associated with the p.Arg54Gly (Arg34Gly) substitution
Hereditary ATTR amyloidosis (ATTRv amyloidosis) is a multisystem disorder caused by pathogenic variants in the TTR gene, which encodes transthyretin, a tetrameric protein that transports thyroxine ...
2026-08-12 | Differential Effects of Tafamidis on Cardiac Remodelling in Transthyretin Amyloid Cardiomyopathy: Evidence From Contemporary Imaging Data.
Tafamidis is the only approved disease-modifying therapy for transthyretin amyloid cardiomyopathy (ATTR-CM) in Australia. Although its clinical efficacy is established, its effects on cardiac remodelling assessed by contemporary multimodality imaging remain incompletely defined. MEDLINE, Embase and Cochrane databases were systematically searched from 2000 to 2025. Observational studies evaluating tafamidis-treated versus untreated/control patients that reported serial TTE, CMR or bone-tracer scintigraphy measurements were eligible. Change-from-baseline values were used to derive measures. Outcomes were pooled as standardised mean differences (SMDs) with 95% confidence intervals using random-effects modelling. A two-sided p < 0.05 was considered statistically significant. Over a mean follow-up of 16 months, tafamidis was associated with significant improvements in left atrial reservoir strain (LASr) (SMD +0.58, 95% CI +0.27 to +0.89; p < 0.001; I2 = 0) on TTE and right ventricular ejection fraction (RVEF) (SMD +0.51, 95% CI +0.16 to +0.86; p = 0.004; I2 = 0) on CMR. A reduction in left atrial volume index (LAVi) was observed (SMD -0.24, 95% CI -0.46 to -0.02; p = 0.034; I2 = 0) on TTE. No consistent effects were seen for LV parameters including LVEF, LV-GLS, LV mass index, wall thickness, diastolic indices, pulmonary pressures, tissue characterisation markers (native T1, ECV), or H/CL ratio, despite trends toward benefit in some. Tafamidis demonstrates selective remodelling effects in ATTR-CM, with the most benefits noted in left atrial function and RV systolic performance, rather than LV structural or functional parameters. Imaging parameters such as LASr, LAVi, and RVEF may serve as sensitive endpoints of therapeutic response in future clinical trials, offering mechanistic insights beyond conventional LV metrics. PROSPERO CRD420251145891.
2026-08-04 | Efficacy and tolerability of sodium-glucose cotransporter-2 inhibitors in transthyretin amyloid cardiomyopathy: A systematic review and stratified meta-analysis.
Although disease-modifying therapies have changed the management of transthyretin amyloid cardiomyopathy (ATTR-CM), supportive heart failure care remains crucial. Patients with ATTR-CM were excluded or underrepresented in randomized trials of sodium-glucose cotransporter-2 inhibitors (SGLT2i), leaving their role in this population uncertain. We performed a systematic review and stratified meta-analysis evaluating their efficacy, safety, and tolerability. PubMed/MEDLINE, Scopus, and the Cochrane Library/CENTRAL were searched up to 1 May 2026. The primary endpoint was ATTR-specific HR-based all-cause mortality. For studies enrolling both ATTR and AL amyloidosis, only separable ATTR subcohort estimates were extracted for the primary synthesis; AL estimates were excluded. Risk of bias was assessed using ROBINS-I and certainty of evidence using GRADE. Eighteen studies were included, comprising 12,039 SGLT2i-treated patients and 12,016 comparator patients across all analytic domains, although possible database overlap should be considered. The primary ATTR-specific HR-based synthesis showed an association between SGLT2i therapy and lower all-cause mortality (HR 0.65, 95% CI 0.56-0.76; I²=37.5%; 8 studies). HF-related events were directionally favourable but non-definitive (HR 0.73, 95% CI 0.50-1.06; I²=73.2%; 5 studies). Composite mortality/HF-related outcomes were associated with a lower risk (HR 0.69, 95% CI 0.55-0.85; I²=3.1%; 3 studies). Arrhythmic outcomes were only exploratory. SGLT2i therapy appeared well tolerated, with low pooled rates of definite discontinuation (6.9%), genitourinary events (4.7%), and AKI/renal adverse events (2.3%). Current non-randomized ATTR-specific evidence suggests that SGLT2i therapy in ATTR-CM/ATTR-HF is associated with lower all-cause mortality and acceptable safety and tolerability. Certainty remains low because of observational design, endpoint heterogeneity, heterogeneous background disease-modifying therapy, potential database overlap, and lack of patient-level amyloidosis subtype/stage stratification. Dedicated randomized trials are needed.
proteins
2025-08-06 | Cardiovascular and brain effects of liraglutide in transthyretin amyloidosis (ATTR) mice models.
Aim: The effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in hereditary transthyretin amyloidosis (ATTRv) remain uncertain. This study aims to investigate whether liraglutide interacts with transthyretin protein (TTR) and thereby exerts therapeutic effects for ATTRv. Methods: High throughput screening was conducted to characterize the drug targets of liraglutide, and microscale thermophoresis was used to observe direct binding of liraglutide to TTR. Humanized RBP4/TTR (normal)and RBP4/TTRVal50Met (ATTRv) mice were constructed, and treated with liraglutide (0.3mg/kg/d) or placebo for 28 days. Fasting plasma glucose, intraperitoneal glucose tolerance test (IPGTT), and plasma brain natriuretic peptide (BNP) were measured. Brain and cardiac tissues were processed with western blot, enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (PCR), and pathological staining to evaluate the lesion status in corresponding organs. Results: Liraglutide exhibited high affinity and direct combination ability to TTR. In ATTRv mice, liraglutide significantly decreased the contents of TTR protein in brain compared with placebo. However, the cardiovascular prognosis measurements including heart failure (plasma BNP concentrations), cardiac fibrosis (the relative expression levels of Cola1 and TGFβ1 in cardiac tissues), and pathological changes (right ventricular collagen percentage, ventricular septum thickness, left ventricular wall thickness, and left ventricular internal diameter) were statistically comparable between mice receiving liraglutide and placebo treatment. Conclusion: Liraglutide could decrease the deposition of TTR in brain tissues, while it did not improve cardiovascular outcomes in ATTRv mice compared to placebo. More researches regarding the mechanisms and therapeutic effects of GLP-1RAs to ATTRv are still required.
2024-07-28 | Identification of the interfacial regions in misfolded transthyretin oligomers.
Misfolding and aggregation of transthyretin (TTR) is associated with numerous ATTR amyloidosis. TTR aggregates extracted from ATTR patients consist of not only full-length TTR, but also N-terminally truncated TTR fragments that can be produced by proteolytic cleavage, suggesting the presence of multiple misfolding pathways. Here, we report mechanistic studies of an early stage of TTR aggregation to probe the oligomerization process for the full-length as well as N-terminally truncated TTR. Our kinetic analyses using size exclusion chromatography revealed that amyloidogenic monomers dissociated from wild-type (WT) as well as pathogenic variants (V30M and L55P) form misfolded dimers, which self-assemble into oligomers, precursors of fibril formation. Dimeric interfaces in the full-length misfolded oligomers were investigated by examining the effect of single-point mutations on the two β-strands (F and H). The single-point mutations on the two β-strands (E92P on strand F and T119W on strand H) inhibited the dimerization of misfolded monomers, while the TTR variants can still form native dimers through the same F and H strands. These results suggest that the two strands are involved in intermolecular associations for both native and misfolded dimers, but detailed intermolecular interactions are different in the two forms of dimers. In the presence of a proteolytic enzyme, TTR aggregation is greatly accelerated. The two mutations on the two β-strands, however, inhibited TTR aggregation even in the presence of a proteolytic enzyme, trypsin. These results suggest that the two β-strands (F and H) play a critical role in aggregation of the N-terminally truncated TTR as well.
2022-05-25 | The effect of mutation on an aggregation-prone protein: An in vivo, in vitro, and in silico analysis
Aggregation of initially stably structured proteins is involved in more than 20 human amyloid diseases. Despite intense research, however, how this class of proteins assembles into amyloid fibrils remains poorly understood, principally because of the complex effects of amino acid substitutions on protein stability, solubility, and aggregation propensity. We address this question using β 2 -microglobulin (β 2 m) as a model system, focusing on D76N-β 2 m that is involved in hereditary amyloidosis. This amino acid substitution causes the aggregation-resilient wild-type protein to become highly aggregation prone in vitro, although the mechanism by which this occurs remained elusive. Here, we identify the residues key to protecting β 2 m from aggregation by coupling aggregation with antibiotic resistance in E. coli using a tripartite β-lactamase assay (TPBLA). By performing saturation mutagenesis at three different sites (D53X-, D76X-, and D98X-β 2 m) we show that residue 76 has a unique ability to drive β 2 m aggregation in vivo and in vitro. Using a randomly mutated D76N-β 2 m variant library, we show that all of the mutations found to improve protein behavior involve residues in a single aggregation-prone region (APR) (residues 60 to 66). Surprisingly, no correlation was found between protein stability and protein aggregation rate or yield, with several mutations in the APR decreasing aggregation without affecting stability. Together, the results demonstrate the power of the TPBLA to develop proteins that are resilient to aggregation and suggest a model for D76N-β 2 m aggregation involving the formation of long-range couplings between the APR and Asn76 in a nonnative state.
2022-04-06 | Amyloid seeding as a disease mechanism and treatment target in transthyretin cardiac amyloidosis
Transthyretin (TTR) is a tetrameric transport protein mainly synthesized by the liver and choroid plexus. ATTR amyloidosis is characterized by the misfolding of TTR monomers and their accumulation within tissues as amyloid fibres. Current therapeutic options rely on the blockade of TTR production, TTR stabilization to maintain the native structure of TTR, amyloid degradation, or induction of amyloid removal from tissues. "Amyloid seeds" are defined as small fibril fragments that induce amyloid precursors to assume a structure rich in β-sheets, thus promoting fibrillogenesis. Amyloid seeds are important to promote the amplification and spread of amyloid deposits. Further studies are needed to better understand the molecular structure of ATTR seeds (i.e. the characteristics of the most amyloidogenic species), and the conditions that promote the formation and multiplication of seeds in vivo. The pathological cascade may begin months to years before symptom onset, suggesting that seeds in tissues might potentially be used as biomarkers for the early disease stages. Inhibition of amyloid aggregation by anti-seeding peptides may represent a disease mechanism and treatment target in ATTR amyloidosis, with an additional benefit over current therapies.
2021-08-31 | In Vitro and In Vivo Effects of SerpinA1 on the Modulation of Transthyretin Proteolysis
Transthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo.
gene therapies
2026-09-25 | Transthyretin Amyloidosis: From Mechanisms to Treatment
Transthyretin amyloidosis (ATTR) is a progressive systemic disorder driven by the misfolding of transthyretin (TTR) proteins and their deposition as amyloid fibrils. It manifests as hereditary ATTR (ATTRv), caused by pathogenic variants, and wild-type ATTR (ATTRwt), linked primarily to aging. These deposits preferentially affect the myocardium and peripheral nerves, producing severe cardiomyopathy and polyneuropathy. The amyloidogenic cascade is initiated by the dissociation of TTR tetramers into misfolded monomers that aggregate into insoluble fibrils. Historically, treatment was limited to supportive care or organ transplantation; however, it has been transformed by TTR stabilizers, RNA interference (RNAi) agents, and antisense oligonucleotides (ASOs). More recently, CRISPR-Cas9 genome editing has emerged as a potential single-dose strategy for durable TTR suppression. In parallel, anti-fibril therapies, including amyloid-depleting monoclonal antibodies designed to clear existing tissue deposits, are being developed as a complementary disease-modifying strategy. This review delineates the molecular mechanisms of amyloidogenesis and evaluates current clinical management strategies. Recent advances in noninvasive diagnostics and targeted molecular therapies, enabled by precision medicine, have markedly improved disease management and clinical outcomes.
2026-08-31 | Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN): integrating epidemiological insights with diagnostic and therapeutic progress
Abstract Background Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a progressive, fatal multisystem disorder characterized by significant genotypic and geographic heterogeneity. Despite recent therapeutic breakthroughs, overlapping clinical features frequently lead to misdiagnosis and delayed intervention. Methods A comprehensive narrative review of the literature was conducted to synthesize recent advancements in the epidemiology, diagnostic workflows, and therapeutic landscape of ATTRv-PN, with an emphasis on clinical translation and multidisciplinary management. Results The epidemiological profile of ATTRv-PN highlights region-specific variant distributions (e.g., p.Val50Met, p.Ala117Ser). The diagnostic paradigm has shifted towards prioritizing early genetic testing and minimally invasive biopsies, complemented by emerging serum biomarkers like neurofilament light chain (NfL) and advanced neuroimaging. Therapeutically, the landscape has been transformed by disease-modifying therapies (DMTs). Gene-silencing agents (siRNAs and ASOs) and TTR stabilizers have demonstrated robust efficacy in halting neuropathy progression. Furthermore, novel modalities, including amyloid-depleting monoclonal antibodies and in vivo CRISPR/Cas9 gene-editing therapies, show unprecedented promise in ongoing clinical trials. Conclusions ATTRv-PN has entered an era of precision medicine. Overcoming diagnostic delays through “red-flag” recognition and routine genetic screening is imperative. Early, stage-adapted initiation of DMTs within a multidisciplinary care framework is crucial for optimizing long-term patient outcomes.
2026-07-15 | Disease-Modifying Therapies for Hereditary Transthyretin Amyloidosis with Polyneuropathy: Current Status and Future Perspectives
Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is an autosomal dominant disorder caused by pathogenic variants in the transthyretin (TTR) gene resulting in progressive sensorimotor neuropathy, autonomic dysfunction, and effects on other organs, particularly the heart. Historically, treatment options have been limited to liver transplantation and symptomatic management, and the disease was associated with poor prognosis and progressive disability. However, over the past decade, the therapeutic landscape has been transformed by the development of disease-modifying therapies that target the underlying pathophysiology of TTR amyloid formation. These therapies include TTR stabilizers, such as tafamidis, diflunisal, and acoramidis, as well as RNA-silencing agents, such as patisiran, vutrisiran, inotersen, and eplontersen, which reduce hepatic production of TTR and slow disease progression. Clinical trials of RNA interference therapies have demonstrated significant improvements in neuropathy impairment scores, quality of life, and functional outcomes, with acceptable safety profiles and sustained long-term benefits. Emerging gene-editing approaches, including CRISPR-based therapies like NTLA-2001, may provide a one-time treatment and long-term disease control, representing a promising future direction for managing ATTRv-PN. Despite these advances, important challenges remain. These include high treatment costs, limited global accessibility, uncertainty regarding optimal treatment selection and sequencing, and the need for long-term real-world, patient-centered outcome data. This review summarizes current disease-modifying therapies for ATTRv-PN, compares their mechanisms and clinical evidence, and discusses unmet needs and future research directions, with the aim of providing a practical and comprehensive overview for clinicians treating patients with ATTRv-PN.
2026-01-02 | Targeting transthyretin by one Cas9 variant with superfidelity and broad compatibility.
Amyloid transthyretin (ATTR) amyloidosis is a fatal disease caused by the accumulation of misfolded transthyretin proteins. Although knocking down the TTR gene by CRISPR-Cas9 represents a promising strategy for treating ATTR amyloidosis, its efficiency and safety remain to be further investigated. Here, we report a systematic investigation of SpCas9-based TTR editing. Besides the target site, wild-type SpCas9 and the reported variants induced extensive off-target edits. To improve the fidelity, we performed structural analysis and designed a series of SpCas9 variants. Studies demonstrated that SpCas9-Mut5 is an ultrahigh-fidelity variant, which induces extremely low levels of off-target edits and translocations without substantial impairment of on-target editing activity. SpCas9-Mut5 is compatible with the adenine base editor (ABE) system, markedly reducing off-target edits and narrowing the editing window. In conclusion, our study suggests that SpCas9-Mut5 is an excellent candidate for TTR gene editing. Besides ATTR amyloidosis, SpCas9-Mut5 and its derivative ABE could be widely used in the treatment of other diseases.
2025-09-26 | Nexiguran Ziclumeran Gene Editing in Hereditary ATTR with Polyneuropathy.
Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare, multisystem, progressive, debilitating, and fatal disease characterized by tissue deposition of misfolded transthyretin (TTR) in peripheral nerves. Nexiguran ziclumeran (nex-z) is an investigational in vivo therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) that is designed to reduce serum TTR levels through selective inactivation of TTR in the liver. In this phase 1, open-label study, we administered one infusion of nex-z to patients with ATTRv-PN. Primary objectives included assessment of the safety and pharmacodynamics of nex-z. Secondary end points included changes in the familial amyloid polyneuropathy stage, polyneuropathy disability score, serum neurofilament light chain (NfL) level, modified body-mass index (modified BMI, defined as the conventional BMI [weight in kilograms divided by square of height in meters] multiplied by the albumin level in grams per liter), and modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment). A total of 36 patients received nex-z; the mean follow-up was 27 months. The mean percent change from baseline in the serum TTR level was -90% at day 28, which was sustained through month 24 (-92%). Treatment-related adverse events included transient infusion-related reactions (in 21 patients), decreased thyroxine level without hypothyroidism or elevated thyrotropin level (in 8), and headache (in 4). One participant died from cardiac amyloidosis, and one withdrew owing to progressive decline in motor function. Serious adverse events were reported in 11 patients. At month 24, the familial amyloid polyneuropathy stage and polyneuropathy disability score remained stable in 29 and 27 patients, respectively; improved in 2 and 5, respectively; and worsened in 2 and 2, respectively. The mean change in the serum NfL level was -9.0 pg per milliliter, and the change in the modified BMI was 24.7. The mean change from baseline in the mNIS+7 was -8.5. A single administration of nex-z in patients with ATTRv-PN was associated with rapid, deep, and durable reductions in serum TTR levels. The results support further investigation of nex-z to treat ATTRv-PN. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).
other
2026-07-09 | Guidelines for the management of hereditary ATTR amyloidosis 2026.
The pathogenesis of hereditary ATTR (ATTRv) amyloidosis has been elucidated, and disease-modifying drugs with multiple mechanisms of action are used clinically. The International Society of Amyloidosis (ISA) guidelines strongly recommend treating ATTRv amyloidosis patients with transthyretin (TTR) tetramer stabilizers or TTR gene silencers (e.g. small-interfering RNA, antisense oligonucleotide). Tafamidis and vutrisiran are indicated for both polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTR-CM), patisiran, eplontersen and diflunisal are for ATTRv-PN only, and acoramidis is for ATTR-CM only. Eligibility for treatment varies by country and is heterogeneous. These disease-modifying drugs are most effective before significant end-organ dysfunction has ensued, making early diagnosis of ATTRv amyloidosis essential. With multiple treatment options existing, it is important to accumulate evidence regarding treatment selection, switching and combination therapy. The currently available disease-modifying therapeutics have a limited effect on central nervous system (CNS) and ocular manifestations since they target either blood circulating TTR from the liver or ATTR amyloid fibrils misfolding in the blood and depositing in systemic (non-CNS, non-ocular) tissues. Development of disease-modifying therapies for CNS and ocular ATTR amyloidosis is an urgent unmet medical need.
2026-04-06 | Transthyretin stabilizer therapy increases naturally-occurring antibodies in ATTR cardiomyopathy.
Amyloid transthyretin cardiomyopathy (ATTR-CM) results from extracellular deposition of misfolded transthyretin (TTR), causing progressive heart failure. Naturally-occurring antibodies (nAbs) targeting misfolded proteins exist in neurodegenerative disease, but their presence in ATTR-CM is unknown. The objective of this study is to determine whether nAbs against TTR (nAbsTTR) exist in humans and whether they are influenced by disease or its treatment. Serum from healthy donors, umbilical cord blood (UCB), and patients with ATTR-CM - both untreated and receiving TTR-stabilizing therapy - was analyzed for nAbsTTR using immunoassays, blotting, and binding studies. Functional activity was evaluated in a fibril formation assay. nAbsTTR binding both native and amyloid TTR (ATTR) with high affinity (KD 30 nM/7 nM) were detected in healthy serum and UCB. NAbsTTR levels were significantly altered in ATTR-CM compared to controls: nAbsTTR (IgG) were higher while nAbsTTR (IgM) were lower. nAbsTTR of both subtypes significantly increased by 22% (p ≤ 0.05) in patients receiving TTR-stabilizing therapy. In vitro, nAbsTTR suppressed TTR fibril aggregation. Naturally-occurring TTR-targeting antibodies are present from birth, modulated by disease and therapy, and inhibit fibril formation. These findings reveal an unrecognized immune mechanism with potential relevance for ATTR-CM pathogenesis and treatment.
2026-01-01 | Clinical and economic impact of inotersen for the treatment of hereditary transthyretin amyloidosis (ATTRv) in adults: a systematic review.
This registration corresponds to a completed systematic review, registered retrospectively for transparency. Background. Hereditary transthyretin amyloidosis (ATTRv) is a rare disease caused by the deposition of transthyretin-derived amyloid fibrils in tissues such as the heart, peripheral nerves and liver, leading to organ dysfunction. Inotersen is an antisense oligonucleotide developed for its treatment. Objective. To systematically review the existing literature on the efficacy, safety and economic impact of inotersen in the treatment of adults diagnosed with ATTR. Methods. The review was conducted in accordance with the methodological guidelines of the Cochrane Collaboration and reported following the PRISMA recommendations. Two research questions were defined (clinical and economic). Clinical question — Population: adults with familial transthyretin amyloidosis and stage 1 or 2 polyneuropathy (Coutinho classification); Intervention: inotersen (Tegsedi, ISIS 420915) 300 mg subcutaneously once weekly; Comparator: best available supportive therapy or placebo; Outcomes: quality of life, mortality, reduction of disease-associated symptoms, incidence of adverse and serious adverse events, and thrombocytopenia; Study design: randomized controlled trials. Economic question — Population: adults with familial transthyretin amyloidosis and stage 1 or 2 polyneuropathy (Coutinho); Outcomes: cost-effectiveness (ICER; QALY/DALY), direct and indirect costs, budget impact and cost of illness, from a health-system/payer perspective. Information sources. MEDLINE, EMBASE, SciELO and CENTRAL (Cochrane) were searched. Risk of bias and certainty. Risk of bias was assessed independently by two reviewers using RoB 2.0 for randomized trials; certainty of evidence was graded as high, moderate, low or very low (GRADE). Synthesis. Given the high heterogeneity across studies and populations, no meta-analysis was performed; a structured qualitative synthesis was conducted, comparing clinical and economic results (including costs and ICER), and assessing consistency, heterogeneity, transferability and limitations. The synthesis of economic evaluations followed the CHEERS guidance. Funding. The study received funding from KURA S.A.C. through an unrestricted grant administered by Universidad de San Martín de Porres for methodological support. Registration note. This review was not prospectively registered due to an administrative oversight; it is registered here retrospectively, upon completion, in the interest of transparency. The methods were defined a priori and were not modified post hoc.
2026-01-01 | Conflicting Clues in Severe LV Hypertrophy: An Unusual Presentation of ATTR Amyloidosis
Introduction In recent decades, major advances have reshaped the clinical and epidemiological understanding of transthyretin (TTR) cardiac amyloidosis (ATTR). Progress in cardiovascular imaging has enabled earlier and more accurate identification of the disease. In particular, bone scintigraphy with 99mTc-labeled tracers has markedly simplified the non-invasive diagnosis of ATTR cardiomyopathy, substantially reducing the need for endomyocardial biopsy in most cases., Nevertheless, diagnostic challenges may arise when clinical, genetic, and imaging findings are discordant. We report a case of biopsy-proven hereditary ATTR [...]
2025-12-31 | Prevalence and incidence of amyloid transthyretin amyloidosis in the USA: insights from claims databases and electronic health records.
Amyloid transthyretin (ATTR) amyloidosis is a rare, life-threatening disease frequently manifesting with cardiomyopathy (ATTR-CM), polyneuropathy (ATTR-PN) or both (ATTR-mixed). We retrospectively analysed US electronic health records and claims data to provide up-to-date estimates of ATTR amyloidosis epidemiology (overall and by phenotype). Data were extracted from the Clarivate Real-World Data repository (2016-2023). Given the lack of established coding for ATTR amyloidosis, we used different combinations of diagnostic codes to obtain narrow and broad estimates of incident and prevalent cases in the USA in 2022. Temporal trends (2019-2022) were also assessed. Using narrow definitions, the 2022 estimated incidence of ATTR amyloidosis overall, ATTR-CM, ATTR-PN and ATTR-mixed was 16.6, 12.7, 3.5 and 1.9 cases per million people, respectively; the corresponding prevalence estimates were 59.8, 41.1, 15.1 and 9.8 cases per million people. Estimates were consistently lower with the narrow (vs broad) definitions. Over time, the incidence and prevalence of ATTR amyloidosis overall increased, driven by ATTR-CM cases. No major changes were reported for the other phenotypes. This study provides comprehensive and up-to-date epidemiological data for ATTR amyloidosis in the USA. Our findings corroborate the need for appropriate differential diagnostic coding and standardised criteria.
cell therapies
2025-12-26 | Predictors of poor prognosis in a large cohort of patients with hereditary cardiac transthyretin amyloidosis.
Hereditary transthyretin amyloidosis (hATTR) is a rare, multisystemic, autosomal dominant disease. Cardiac involvement worsens prognosis. We aimed to characterize Spanish patients with hATTR cardiac amyloidosis (hATTR-CA) and to identify predictors of poor prognosis. We conducted a retrospective, multicenter study in 39 Spanish hospitals, including adults with genetically confirmed hATTR and cardiac involvement (January 2000-September 2022). Independent predictors of poor prognosis (death, heart transplantation, heart failure, or cardiovascular hospitalization) were identified using multivariate logistic regression. Data were also collected on clinical and genetic characteristics, management patterns, and event-free survival. A total of 442 patients were included (67.6% male; median age at diagnosis, 65 years). Fifteen TTR variants were identified, with p.Val30Met being the most frequent (64.9%). The most common extracardiac manifestation was neuropathy (64.6%). At baseline, most patients were in New York Heart Association class I-II, with progressive worsening during follow-up. Overall, 48.9% of patients were hospitalized, and 21.9% died; 25.3% of deaths were heart failure-related. Five-year event-free survival was 80.2% from symptom onset and 66.9% from diagnosis. Disease-specific treatments (tafamidis, patisiran, inotersen, or liver transplant) were associated with improved survival (P <.001). In an exploratory analysis stratified by diagnosis before vs after 2018, event-free survival did not differ significantly (HR, 1.04; 95%CI, 0.63-1.72; P=.88). Independent predictors of poor prognosis included New York Heart Association class II-IV, lower left ventricular ejection fraction, elevated N-terminal pro-B-type natriuretic peptide, and the presence of neurological involvement. This national cohort-the largest reported to date-highlights the clinical and genetic heterogeneity of hATTR -CA in Spain. Early diagnosis and disease-specific therapies are essential to improving prognosis.
2025-10-01 | S6462 Gastric Transthyretin Amyloidosis: A Unique Case of Gastric Outlet Obstruction and Gastroparesis
Introduction: Gastric transthyretin amyloidosis (ATTR) affects the interstitial cells of Cajal, which are pivotal for gastric motility. The rare complications include gastroparesis secondary to autonomic neuropathy and gastric outlet obstruction (GOO) due to pyloric stenosis from fibril deposits. The exact incidence and prevalence of the disease with these complications are currently unknown. We present a unique case of hereditary ATTR complicated with recurrent GOO and gastroparesis requiring a gastric simulator. Case Description/Methods: An 80-year-old woman with a past medical history of hereditary transthyretin cardiac amyloidosis presented with persistent nausea and vomiting. The admission vital signs were stable, with a benign physical examination, and labs were pertinent for hypokalemia and hyperchloremic metabolic alkalosis. She received antiemetics without any relief. Subsequently, the computed tomography (CT) abdomen revealed thickened gastric folds. This prompted an esophagogastroduodenoscopy (EGD), which revealed retained food in the stomach, raising concerns for gastroparesis. The pyloric junction was stenosed and required balloon catheter dilation. The EGD biopsy showed amyloid deposits in the gastric wall, positive for Congo red stain. Immunohistochemistry detected ATTR. After the EGD, her symptoms initially improved, and on discharge, she continued Tafamidis and Eplontersen. Three months later, she was hospitalized again with persistent vomiting, not responding to any antiemetics. She required a repeat EGD with pyloric dilation. Following a multidisciplinary team approach, a joint decision was made to place a gastric simulator for refractory vomiting. After this intervention, her symptoms improved significantly, and she closely followed up with the gastroenterologist. Discussion: Gastrointestinal symptoms in ATTR are often nonspecific, making diagnosis challenging; therefore, a high clinical suspicion is warranted to establish a definitive diagnosis promptly. The mainstay treatments for gastric ATTR are disease-modifying therapies (TTR stabilizers and gene silencing). Moreover, a gastric simulator is used as a last resort for patients with gastric ATTR complicated with gastroparesis who haven't responded to other treatments. Due to the rare co-occurring complications and underreported incidence, we aim to raise awareness and strongly advocate for the need for large, multi-center, prospective studies to capture the impact of gastric ATTR and its burden on the US healthcare system.
2025-07-07 | Uncovering cell type-specific phenotypes using a novel human in vitro model of transthyretin amyloid cardiomyopathy.
Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the misfolding of transthyretin (TTR), fibrillogenesis, and progressive amyloid fibril deposition in the myocardium, leading to cardiac dysfunction with dismal prognosis. In ATTR-CM, either destabilizing mutations (variant TTR, ATTRv) or ageing-associated processes (wild-type TTR, ATTRwt) lead to the formation of TTR amyloid fibrils. Due to a lack of representative disease models, ATTR-CM disease mechanisms are largely unknown, thereby limiting disease understanding and therapeutic discovery. Here, we report a novel in vitro ATTR-CM model which uncovers cell type-specific disease phenotypes by exposing the three major human cardiac cell types to TTR fibrils, thereby providing novel insights into the cellular mechanisms of ATTR-CM disease. Human recombinant TTR proteins (WT, V122I, V30M) and respective fibrils were generated and characterized using Thioflavin T, Amytracker, Congo red and dot blot analyses. Seeding human induced pluripotent stem cell-derived-cardiomyocytes (hiPSC-CMs) and endothelial cells (ECs) on TTR fibrils resulted in reduced cell viability. Confocal microscopy revealed extracellular localization of TTR fibrils to hiPSC-CMs, leading to sarcomere disruption, altered calcium handling and disrupted electromechanical coupling, while ECs showed a reduced migration capacity with aberrant cell morphology. hiPSC-fibroblasts (hiPSC-FBs) were largely unaffected by TTR fibrils, presenting normal viability, but showing enhanced localization with TTR fibrils. Our model shows that WT and variant TTR fibrils lead to cell type-specific phenotypes, providing novel insights into the underlying cellular disease mechanisms of ATTR-CM, thereby facilitating the identification of novel therapeutic targets and biomarkers.
2025-06-21 | 40 years of CEPARM: transforming amyloidosis related to transthyretin from neglect to recognition.
Variant transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTRv-CM), formerly known as familial amyloidotic polyneuropathy (FAP), is a severe, progressive disorder caused by mutations in the transthyretin (TTR) gene. Historically, FAP was considered a neglected disease due to its rarity and the limited understanding of its pathophysiology, which led to minimal research funding and few therapeutic options. The present article explores the transformative role of Centro de Paramiloidose Antônio Rodrigues de Mello (CEPARM), established in 1984, in elevating the status of FAP through significant advancements in research and treatment. Although CEPARM was not the sole catalyst for this shift, its contributions in liver transplantation, the development of pharmacological therapies, and holistic patient care have substantially improved the recognition and management of FAP. The article also examines CEPARM's impact on patient care, the ongoing challenges, and ethical considerations within the field.
2023-05-30 | A rare pathogenic variant identified in a heart transplant recipient with hereditary transthyretin amyloidosis: a case report.
Hereditary transthyretin (ATTRv) amyloidosis is a rare and complex genetic disorder that can lead to life-threatening cardiac amyloidosis and rapid disease progression. Early diagnosis and treatment with disease-modifying drugs can improve patient outcomes; however, heart transplantation may be necessary in some patients. We present the unique case of a 65-year-old Korean woman diagnosed with ATTRv amyloidosis after experiencing progressive neurological symptoms, followed by heart failure. Despite the absence of significant symptoms of heart failure, subsequent screening revealed cardiac amyloid infiltration, which caused left ventricular hypertrophy and rapid disease progression. The patient underwent successful heart transplantation, and subsequent genetic testing revealed a pathogenic variant, NM_000371.3:c.425T>C (p.Val142Ala), which affects both the nerves and heart and has not been previously reported in Korea. Our report underscores the potential benefits of heart transplantation in managing advanced ATTRv amyloidosis and emphasizes the need for continued research on the genetic heterogeneity of the disease. Clinicians should consider ATTRv amyloidosis in the differential diagnosis of patients presenting with neurological symptoms and heart failure, particularly in those with a family history of the disease.
small molecules
2026-09-30 | Clinical Benefit of the Transthyretin Stabiliser Tafamidis in Hereditary Transthyretin Amyloid Cardiomyopathy: A Case Report.
This case report aims to illustrate the critical importance of a standardized diagnostic approach and genotype-specific therapy in hereditary transthyretin amyloid cardiomyopathy (ATTR-CM). It highlights the clinical challenge of diagnosing ATTR-CM amidst complex comorbidities and addresses the evidence gap regarding the long-term efficacy of tafamidis for the rare and aggressive p.Val40Ile (protein-level substitution of valine to isoleucine at codon 40) mutation. A 72-year-old East Asian man with multiple comorbidities presented with refractory heart failure. Key clinical clues included the classic "red flag" of electrocardiogram (ECG)-echocardiogram discordance (low voltage with ventricular hypertrophy). Genetic testing identified the pathogenic p.Val40Ile transthyretin (TTR) mutation. The diagnosis was confirmed non-invasively via cardiac magnetic resonance (CMR) and technetium-99m pyrophosphate scintigraphy. Following the initiation of tafamidis, the patient's symptoms significantly improved. Over a two-year follow-up period, he sustained clinical stability with a marked reduction in heart failure-related hospitalizations. This report provides detailed case-based evidence supporting the long-term efficacy of tafamidis in stabilizing disease and improving prognosis for patients with ATTR-CM harboring the p.Val40Ile mutation. It underscores the value of timely diagnosis, genetic subtyping, and access to targeted therapy in altering the clinical course of this aggressive genotype.
2026-08-30 | Gastric amyloid pathology and mucosal denervation in ATTRv amyloidosis: insights from patients, mice, and gut microenvironment profiles.
Hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN) frequently presents with gastrointestinal autonomic dysfunction, but its underlying pathology remains unclear. We examined gastric mucosal amyloid deposition and innervation using conventional endoscopic biopsies in ATTRv-PN patients and a human TTR (hTTR A117S) knock-in mouse model. Clinical assessments, gut microbiota, metabolomics, and neurite growth assays were integrated. Among 33 patients, 84.8% showed TTR(+) amyloid deposition in gastric mucosa. Gastric mucosal innervation density (GMID) was significantly reduced in all gastric regions compared with controls and was similarly decreased in hTTR(A117S) mice. Lower GMID correlated with gastroparesis and reflux symptom severity. Integrated analyses revealed positive associations between GMID, four microbial genera, and histidine levels. Both microbiota-derived principal components and histidine independently correlated with GMID. Histidine also promoted neurite growth in vitro. Endoscopic biopsy enables assessment of both gastric amyloid pathology and mucosal innervation in ATTRv-PN. Reduced GMID is closely associated with gastrointestinal symptoms, microbiota alterations, and metabolomic changes, providing insights into disease mechanisms and potential biomarkers of autonomic gastrointestinal dysfunction.
2026-08-26 | Hereditary ATTR amyloidosis with prominent central nervous system involvement associated with the p.Arg54Gly (Arg34Gly) substitution
Hereditary ATTR amyloidosis (ATTRv amyloidosis) is a multisystem disorder caused by pathogenic variants in the TTR gene, which encodes transthyretin, a tetrameric protein that transports thyroxine ...
2026-08-12 | Differential Effects of Tafamidis on Cardiac Remodelling in Transthyretin Amyloid Cardiomyopathy: Evidence From Contemporary Imaging Data.
Tafamidis is the only approved disease-modifying therapy for transthyretin amyloid cardiomyopathy (ATTR-CM) in Australia. Although its clinical efficacy is established, its effects on cardiac remodelling assessed by contemporary multimodality imaging remain incompletely defined. MEDLINE, Embase and Cochrane databases were systematically searched from 2000 to 2025. Observational studies evaluating tafamidis-treated versus untreated/control patients that reported serial TTE, CMR or bone-tracer scintigraphy measurements were eligible. Change-from-baseline values were used to derive measures. Outcomes were pooled as standardised mean differences (SMDs) with 95% confidence intervals using random-effects modelling. A two-sided p < 0.05 was considered statistically significant. Over a mean follow-up of 16 months, tafamidis was associated with significant improvements in left atrial reservoir strain (LASr) (SMD +0.58, 95% CI +0.27 to +0.89; p < 0.001; I2 = 0) on TTE and right ventricular ejection fraction (RVEF) (SMD +0.51, 95% CI +0.16 to +0.86; p = 0.004; I2 = 0) on CMR. A reduction in left atrial volume index (LAVi) was observed (SMD -0.24, 95% CI -0.46 to -0.02; p = 0.034; I2 = 0) on TTE. No consistent effects were seen for LV parameters including LVEF, LV-GLS, LV mass index, wall thickness, diastolic indices, pulmonary pressures, tissue characterisation markers (native T1, ECV), or H/CL ratio, despite trends toward benefit in some. Tafamidis demonstrates selective remodelling effects in ATTR-CM, with the most benefits noted in left atrial function and RV systolic performance, rather than LV structural or functional parameters. Imaging parameters such as LASr, LAVi, and RVEF may serve as sensitive endpoints of therapeutic response in future clinical trials, offering mechanistic insights beyond conventional LV metrics. PROSPERO CRD420251145891.
2026-08-04 | Efficacy and tolerability of sodium-glucose cotransporter-2 inhibitors in transthyretin amyloid cardiomyopathy: A systematic review and stratified meta-analysis.
Although disease-modifying therapies have changed the management of transthyretin amyloid cardiomyopathy (ATTR-CM), supportive heart failure care remains crucial. Patients with ATTR-CM were excluded or underrepresented in randomized trials of sodium-glucose cotransporter-2 inhibitors (SGLT2i), leaving their role in this population uncertain. We performed a systematic review and stratified meta-analysis evaluating their efficacy, safety, and tolerability. PubMed/MEDLINE, Scopus, and the Cochrane Library/CENTRAL were searched up to 1 May 2026. The primary endpoint was ATTR-specific HR-based all-cause mortality. For studies enrolling both ATTR and AL amyloidosis, only separable ATTR subcohort estimates were extracted for the primary synthesis; AL estimates were excluded. Risk of bias was assessed using ROBINS-I and certainty of evidence using GRADE. Eighteen studies were included, comprising 12,039 SGLT2i-treated patients and 12,016 comparator patients across all analytic domains, although possible database overlap should be considered. The primary ATTR-specific HR-based synthesis showed an association between SGLT2i therapy and lower all-cause mortality (HR 0.65, 95% CI 0.56-0.76; I²=37.5%; 8 studies). HF-related events were directionally favourable but non-definitive (HR 0.73, 95% CI 0.50-1.06; I²=73.2%; 5 studies). Composite mortality/HF-related outcomes were associated with a lower risk (HR 0.69, 95% CI 0.55-0.85; I²=3.1%; 3 studies). Arrhythmic outcomes were only exploratory. SGLT2i therapy appeared well tolerated, with low pooled rates of definite discontinuation (6.9%), genitourinary events (4.7%), and AKI/renal adverse events (2.3%). Current non-randomized ATTR-specific evidence suggests that SGLT2i therapy in ATTR-CM/ATTR-HF is associated with lower all-cause mortality and acceptable safety and tolerability. Certainty remains low because of observational design, endpoint heterogeneity, heterogeneous background disease-modifying therapy, potential database overlap, and lack of patient-level amyloidosis subtype/stage stratification. Dedicated randomized trials are needed.
proteins
2025-08-06 | Cardiovascular and brain effects of liraglutide in transthyretin amyloidosis (ATTR) mice models.
Aim: The effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in hereditary transthyretin amyloidosis (ATTRv) remain uncertain. This study aims to investigate whether liraglutide interacts with transthyretin protein (TTR) and thereby exerts therapeutic effects for ATTRv. Methods: High throughput screening was conducted to characterize the drug targets of liraglutide, and microscale thermophoresis was used to observe direct binding of liraglutide to TTR. Humanized RBP4/TTR (normal)and RBP4/TTRVal50Met (ATTRv) mice were constructed, and treated with liraglutide (0.3mg/kg/d) or placebo for 28 days. Fasting plasma glucose, intraperitoneal glucose tolerance test (IPGTT), and plasma brain natriuretic peptide (BNP) were measured. Brain and cardiac tissues were processed with western blot, enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (PCR), and pathological staining to evaluate the lesion status in corresponding organs. Results: Liraglutide exhibited high affinity and direct combination ability to TTR. In ATTRv mice, liraglutide significantly decreased the contents of TTR protein in brain compared with placebo. However, the cardiovascular prognosis measurements including heart failure (plasma BNP concentrations), cardiac fibrosis (the relative expression levels of Cola1 and TGFβ1 in cardiac tissues), and pathological changes (right ventricular collagen percentage, ventricular septum thickness, left ventricular wall thickness, and left ventricular internal diameter) were statistically comparable between mice receiving liraglutide and placebo treatment. Conclusion: Liraglutide could decrease the deposition of TTR in brain tissues, while it did not improve cardiovascular outcomes in ATTRv mice compared to placebo. More researches regarding the mechanisms and therapeutic effects of GLP-1RAs to ATTRv are still required.
2024-07-28 | Identification of the interfacial regions in misfolded transthyretin oligomers.
Misfolding and aggregation of transthyretin (TTR) is associated with numerous ATTR amyloidosis. TTR aggregates extracted from ATTR patients consist of not only full-length TTR, but also N-terminally truncated TTR fragments that can be produced by proteolytic cleavage, suggesting the presence of multiple misfolding pathways. Here, we report mechanistic studies of an early stage of TTR aggregation to probe the oligomerization process for the full-length as well as N-terminally truncated TTR. Our kinetic analyses using size exclusion chromatography revealed that amyloidogenic monomers dissociated from wild-type (WT) as well as pathogenic variants (V30M and L55P) form misfolded dimers, which self-assemble into oligomers, precursors of fibril formation. Dimeric interfaces in the full-length misfolded oligomers were investigated by examining the effect of single-point mutations on the two β-strands (F and H). The single-point mutations on the two β-strands (E92P on strand F and T119W on strand H) inhibited the dimerization of misfolded monomers, while the TTR variants can still form native dimers through the same F and H strands. These results suggest that the two strands are involved in intermolecular associations for both native and misfolded dimers, but detailed intermolecular interactions are different in the two forms of dimers. In the presence of a proteolytic enzyme, TTR aggregation is greatly accelerated. The two mutations on the two β-strands, however, inhibited TTR aggregation even in the presence of a proteolytic enzyme, trypsin. These results suggest that the two β-strands (F and H) play a critical role in aggregation of the N-terminally truncated TTR as well.
2022-05-25 | The effect of mutation on an aggregation-prone protein: An in vivo, in vitro, and in silico analysis
Aggregation of initially stably structured proteins is involved in more than 20 human amyloid diseases. Despite intense research, however, how this class of proteins assembles into amyloid fibrils remains poorly understood, principally because of the complex effects of amino acid substitutions on protein stability, solubility, and aggregation propensity. We address this question using β 2 -microglobulin (β 2 m) as a model system, focusing on D76N-β 2 m that is involved in hereditary amyloidosis. This amino acid substitution causes the aggregation-resilient wild-type protein to become highly aggregation prone in vitro, although the mechanism by which this occurs remained elusive. Here, we identify the residues key to protecting β 2 m from aggregation by coupling aggregation with antibiotic resistance in E. coli using a tripartite β-lactamase assay (TPBLA). By performing saturation mutagenesis at three different sites (D53X-, D76X-, and D98X-β 2 m) we show that residue 76 has a unique ability to drive β 2 m aggregation in vivo and in vitro. Using a randomly mutated D76N-β 2 m variant library, we show that all of the mutations found to improve protein behavior involve residues in a single aggregation-prone region (APR) (residues 60 to 66). Surprisingly, no correlation was found between protein stability and protein aggregation rate or yield, with several mutations in the APR decreasing aggregation without affecting stability. Together, the results demonstrate the power of the TPBLA to develop proteins that are resilient to aggregation and suggest a model for D76N-β 2 m aggregation involving the formation of long-range couplings between the APR and Asn76 in a nonnative state.
2022-04-06 | Amyloid seeding as a disease mechanism and treatment target in transthyretin cardiac amyloidosis
Transthyretin (TTR) is a tetrameric transport protein mainly synthesized by the liver and choroid plexus. ATTR amyloidosis is characterized by the misfolding of TTR monomers and their accumulation within tissues as amyloid fibres. Current therapeutic options rely on the blockade of TTR production, TTR stabilization to maintain the native structure of TTR, amyloid degradation, or induction of amyloid removal from tissues. "Amyloid seeds" are defined as small fibril fragments that induce amyloid precursors to assume a structure rich in β-sheets, thus promoting fibrillogenesis. Amyloid seeds are important to promote the amplification and spread of amyloid deposits. Further studies are needed to better understand the molecular structure of ATTR seeds (i.e. the characteristics of the most amyloidogenic species), and the conditions that promote the formation and multiplication of seeds in vivo. The pathological cascade may begin months to years before symptom onset, suggesting that seeds in tissues might potentially be used as biomarkers for the early disease stages. Inhibition of amyloid aggregation by anti-seeding peptides may represent a disease mechanism and treatment target in ATTR amyloidosis, with an additional benefit over current therapies.
2021-08-31 | In Vitro and In Vivo Effects of SerpinA1 on the Modulation of Transthyretin Proteolysis
Transthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo.
gene therapies
2026-09-25 | Transthyretin Amyloidosis: From Mechanisms to Treatment
Transthyretin amyloidosis (ATTR) is a progressive systemic disorder driven by the misfolding of transthyretin (TTR) proteins and their deposition as amyloid fibrils. It manifests as hereditary ATTR (ATTRv), caused by pathogenic variants, and wild-type ATTR (ATTRwt), linked primarily to aging. These deposits preferentially affect the myocardium and peripheral nerves, producing severe cardiomyopathy and polyneuropathy. The amyloidogenic cascade is initiated by the dissociation of TTR tetramers into misfolded monomers that aggregate into insoluble fibrils. Historically, treatment was limited to supportive care or organ transplantation; however, it has been transformed by TTR stabilizers, RNA interference (RNAi) agents, and antisense oligonucleotides (ASOs). More recently, CRISPR-Cas9 genome editing has emerged as a potential single-dose strategy for durable TTR suppression. In parallel, anti-fibril therapies, including amyloid-depleting monoclonal antibodies designed to clear existing tissue deposits, are being developed as a complementary disease-modifying strategy. This review delineates the molecular mechanisms of amyloidogenesis and evaluates current clinical management strategies. Recent advances in noninvasive diagnostics and targeted molecular therapies, enabled by precision medicine, have markedly improved disease management and clinical outcomes.
2026-08-31 | Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN): integrating epidemiological insights with diagnostic and therapeutic progress
Abstract Background Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a progressive, fatal multisystem disorder characterized by significant genotypic and geographic heterogeneity. Despite recent therapeutic breakthroughs, overlapping clinical features frequently lead to misdiagnosis and delayed intervention. Methods A comprehensive narrative review of the literature was conducted to synthesize recent advancements in the epidemiology, diagnostic workflows, and therapeutic landscape of ATTRv-PN, with an emphasis on clinical translation and multidisciplinary management. Results The epidemiological profile of ATTRv-PN highlights region-specific variant distributions (e.g., p.Val50Met, p.Ala117Ser). The diagnostic paradigm has shifted towards prioritizing early genetic testing and minimally invasive biopsies, complemented by emerging serum biomarkers like neurofilament light chain (NfL) and advanced neuroimaging. Therapeutically, the landscape has been transformed by disease-modifying therapies (DMTs). Gene-silencing agents (siRNAs and ASOs) and TTR stabilizers have demonstrated robust efficacy in halting neuropathy progression. Furthermore, novel modalities, including amyloid-depleting monoclonal antibodies and in vivo CRISPR/Cas9 gene-editing therapies, show unprecedented promise in ongoing clinical trials. Conclusions ATTRv-PN has entered an era of precision medicine. Overcoming diagnostic delays through “red-flag” recognition and routine genetic screening is imperative. Early, stage-adapted initiation of DMTs within a multidisciplinary care framework is crucial for optimizing long-term patient outcomes.
2026-07-15 | Disease-Modifying Therapies for Hereditary Transthyretin Amyloidosis with Polyneuropathy: Current Status and Future Perspectives
Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is an autosomal dominant disorder caused by pathogenic variants in the transthyretin (TTR) gene resulting in progressive sensorimotor neuropathy, autonomic dysfunction, and effects on other organs, particularly the heart. Historically, treatment options have been limited to liver transplantation and symptomatic management, and the disease was associated with poor prognosis and progressive disability. However, over the past decade, the therapeutic landscape has been transformed by the development of disease-modifying therapies that target the underlying pathophysiology of TTR amyloid formation. These therapies include TTR stabilizers, such as tafamidis, diflunisal, and acoramidis, as well as RNA-silencing agents, such as patisiran, vutrisiran, inotersen, and eplontersen, which reduce hepatic production of TTR and slow disease progression. Clinical trials of RNA interference therapies have demonstrated significant improvements in neuropathy impairment scores, quality of life, and functional outcomes, with acceptable safety profiles and sustained long-term benefits. Emerging gene-editing approaches, including CRISPR-based therapies like NTLA-2001, may provide a one-time treatment and long-term disease control, representing a promising future direction for managing ATTRv-PN. Despite these advances, important challenges remain. These include high treatment costs, limited global accessibility, uncertainty regarding optimal treatment selection and sequencing, and the need for long-term real-world, patient-centered outcome data. This review summarizes current disease-modifying therapies for ATTRv-PN, compares their mechanisms and clinical evidence, and discusses unmet needs and future research directions, with the aim of providing a practical and comprehensive overview for clinicians treating patients with ATTRv-PN.
2026-01-02 | Targeting transthyretin by one Cas9 variant with superfidelity and broad compatibility.
Amyloid transthyretin (ATTR) amyloidosis is a fatal disease caused by the accumulation of misfolded transthyretin proteins. Although knocking down the TTR gene by CRISPR-Cas9 represents a promising strategy for treating ATTR amyloidosis, its efficiency and safety remain to be further investigated. Here, we report a systematic investigation of SpCas9-based TTR editing. Besides the target site, wild-type SpCas9 and the reported variants induced extensive off-target edits. To improve the fidelity, we performed structural analysis and designed a series of SpCas9 variants. Studies demonstrated that SpCas9-Mut5 is an ultrahigh-fidelity variant, which induces extremely low levels of off-target edits and translocations without substantial impairment of on-target editing activity. SpCas9-Mut5 is compatible with the adenine base editor (ABE) system, markedly reducing off-target edits and narrowing the editing window. In conclusion, our study suggests that SpCas9-Mut5 is an excellent candidate for TTR gene editing. Besides ATTR amyloidosis, SpCas9-Mut5 and its derivative ABE could be widely used in the treatment of other diseases.
2025-09-26 | Nexiguran Ziclumeran Gene Editing in Hereditary ATTR with Polyneuropathy.
Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare, multisystem, progressive, debilitating, and fatal disease characterized by tissue deposition of misfolded transthyretin (TTR) in peripheral nerves. Nexiguran ziclumeran (nex-z) is an investigational in vivo therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) that is designed to reduce serum TTR levels through selective inactivation of TTR in the liver. In this phase 1, open-label study, we administered one infusion of nex-z to patients with ATTRv-PN. Primary objectives included assessment of the safety and pharmacodynamics of nex-z. Secondary end points included changes in the familial amyloid polyneuropathy stage, polyneuropathy disability score, serum neurofilament light chain (NfL) level, modified body-mass index (modified BMI, defined as the conventional BMI [weight in kilograms divided by square of height in meters] multiplied by the albumin level in grams per liter), and modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment). A total of 36 patients received nex-z; the mean follow-up was 27 months. The mean percent change from baseline in the serum TTR level was -90% at day 28, which was sustained through month 24 (-92%). Treatment-related adverse events included transient infusion-related reactions (in 21 patients), decreased thyroxine level without hypothyroidism or elevated thyrotropin level (in 8), and headache (in 4). One participant died from cardiac amyloidosis, and one withdrew owing to progressive decline in motor function. Serious adverse events were reported in 11 patients. At month 24, the familial amyloid polyneuropathy stage and polyneuropathy disability score remained stable in 29 and 27 patients, respectively; improved in 2 and 5, respectively; and worsened in 2 and 2, respectively. The mean change in the serum NfL level was -9.0 pg per milliliter, and the change in the modified BMI was 24.7. The mean change from baseline in the mNIS+7 was -8.5. A single administration of nex-z in patients with ATTRv-PN was associated with rapid, deep, and durable reductions in serum TTR levels. The results support further investigation of nex-z to treat ATTRv-PN. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).
other
2026-07-09 | Guidelines for the management of hereditary ATTR amyloidosis 2026.
The pathogenesis of hereditary ATTR (ATTRv) amyloidosis has been elucidated, and disease-modifying drugs with multiple mechanisms of action are used clinically. The International Society of Amyloidosis (ISA) guidelines strongly recommend treating ATTRv amyloidosis patients with transthyretin (TTR) tetramer stabilizers or TTR gene silencers (e.g. small-interfering RNA, antisense oligonucleotide). Tafamidis and vutrisiran are indicated for both polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTR-CM), patisiran, eplontersen and diflunisal are for ATTRv-PN only, and acoramidis is for ATTR-CM only. Eligibility for treatment varies by country and is heterogeneous. These disease-modifying drugs are most effective before significant end-organ dysfunction has ensued, making early diagnosis of ATTRv amyloidosis essential. With multiple treatment options existing, it is important to accumulate evidence regarding treatment selection, switching and combination therapy. The currently available disease-modifying therapeutics have a limited effect on central nervous system (CNS) and ocular manifestations since they target either blood circulating TTR from the liver or ATTR amyloid fibrils misfolding in the blood and depositing in systemic (non-CNS, non-ocular) tissues. Development of disease-modifying therapies for CNS and ocular ATTR amyloidosis is an urgent unmet medical need.
2026-04-06 | Transthyretin stabilizer therapy increases naturally-occurring antibodies in ATTR cardiomyopathy.
Amyloid transthyretin cardiomyopathy (ATTR-CM) results from extracellular deposition of misfolded transthyretin (TTR), causing progressive heart failure. Naturally-occurring antibodies (nAbs) targeting misfolded proteins exist in neurodegenerative disease, but their presence in ATTR-CM is unknown. The objective of this study is to determine whether nAbs against TTR (nAbsTTR) exist in humans and whether they are influenced by disease or its treatment. Serum from healthy donors, umbilical cord blood (UCB), and patients with ATTR-CM - both untreated and receiving TTR-stabilizing therapy - was analyzed for nAbsTTR using immunoassays, blotting, and binding studies. Functional activity was evaluated in a fibril formation assay. nAbsTTR binding both native and amyloid TTR (ATTR) with high affinity (KD 30 nM/7 nM) were detected in healthy serum and UCB. NAbsTTR levels were significantly altered in ATTR-CM compared to controls: nAbsTTR (IgG) were higher while nAbsTTR (IgM) were lower. nAbsTTR of both subtypes significantly increased by 22% (p ≤ 0.05) in patients receiving TTR-stabilizing therapy. In vitro, nAbsTTR suppressed TTR fibril aggregation. Naturally-occurring TTR-targeting antibodies are present from birth, modulated by disease and therapy, and inhibit fibril formation. These findings reveal an unrecognized immune mechanism with potential relevance for ATTR-CM pathogenesis and treatment.
2026-01-01 | Clinical and economic impact of inotersen for the treatment of hereditary transthyretin amyloidosis (ATTRv) in adults: a systematic review.
This registration corresponds to a completed systematic review, registered retrospectively for transparency. Background. Hereditary transthyretin amyloidosis (ATTRv) is a rare disease caused by the deposition of transthyretin-derived amyloid fibrils in tissues such as the heart, peripheral nerves and liver, leading to organ dysfunction. Inotersen is an antisense oligonucleotide developed for its treatment. Objective. To systematically review the existing literature on the efficacy, safety and economic impact of inotersen in the treatment of adults diagnosed with ATTR. Methods. The review was conducted in accordance with the methodological guidelines of the Cochrane Collaboration and reported following the PRISMA recommendations. Two research questions were defined (clinical and economic). Clinical question — Population: adults with familial transthyretin amyloidosis and stage 1 or 2 polyneuropathy (Coutinho classification); Intervention: inotersen (Tegsedi, ISIS 420915) 300 mg subcutaneously once weekly; Comparator: best available supportive therapy or placebo; Outcomes: quality of life, mortality, reduction of disease-associated symptoms, incidence of adverse and serious adverse events, and thrombocytopenia; Study design: randomized controlled trials. Economic question — Population: adults with familial transthyretin amyloidosis and stage 1 or 2 polyneuropathy (Coutinho); Outcomes: cost-effectiveness (ICER; QALY/DALY), direct and indirect costs, budget impact and cost of illness, from a health-system/payer perspective. Information sources. MEDLINE, EMBASE, SciELO and CENTRAL (Cochrane) were searched. Risk of bias and certainty. Risk of bias was assessed independently by two reviewers using RoB 2.0 for randomized trials; certainty of evidence was graded as high, moderate, low or very low (GRADE). Synthesis. Given the high heterogeneity across studies and populations, no meta-analysis was performed; a structured qualitative synthesis was conducted, comparing clinical and economic results (including costs and ICER), and assessing consistency, heterogeneity, transferability and limitations. The synthesis of economic evaluations followed the CHEERS guidance. Funding. The study received funding from KURA S.A.C. through an unrestricted grant administered by Universidad de San Martín de Porres for methodological support. Registration note. This review was not prospectively registered due to an administrative oversight; it is registered here retrospectively, upon completion, in the interest of transparency. The methods were defined a priori and were not modified post hoc.
2026-01-01 | Conflicting Clues in Severe LV Hypertrophy: An Unusual Presentation of ATTR Amyloidosis
Introduction In recent decades, major advances have reshaped the clinical and epidemiological understanding of transthyretin (TTR) cardiac amyloidosis (ATTR). Progress in cardiovascular imaging has enabled earlier and more accurate identification of the disease. In particular, bone scintigraphy with 99mTc-labeled tracers has markedly simplified the non-invasive diagnosis of ATTR cardiomyopathy, substantially reducing the need for endomyocardial biopsy in most cases., Nevertheless, diagnostic challenges may arise when clinical, genetic, and imaging findings are discordant. We report a case of biopsy-proven hereditary ATTR [...]
2025-12-31 | Prevalence and incidence of amyloid transthyretin amyloidosis in the USA: insights from claims databases and electronic health records.
Amyloid transthyretin (ATTR) amyloidosis is a rare, life-threatening disease frequently manifesting with cardiomyopathy (ATTR-CM), polyneuropathy (ATTR-PN) or both (ATTR-mixed). We retrospectively analysed US electronic health records and claims data to provide up-to-date estimates of ATTR amyloidosis epidemiology (overall and by phenotype). Data were extracted from the Clarivate Real-World Data repository (2016-2023). Given the lack of established coding for ATTR amyloidosis, we used different combinations of diagnostic codes to obtain narrow and broad estimates of incident and prevalent cases in the USA in 2022. Temporal trends (2019-2022) were also assessed. Using narrow definitions, the 2022 estimated incidence of ATTR amyloidosis overall, ATTR-CM, ATTR-PN and ATTR-mixed was 16.6, 12.7, 3.5 and 1.9 cases per million people, respectively; the corresponding prevalence estimates were 59.8, 41.1, 15.1 and 9.8 cases per million people. Estimates were consistently lower with the narrow (vs broad) definitions. Over time, the incidence and prevalence of ATTR amyloidosis overall increased, driven by ATTR-CM cases. No major changes were reported for the other phenotypes. This study provides comprehensive and up-to-date epidemiological data for ATTR amyloidosis in the USA. Our findings corroborate the need for appropriate differential diagnostic coding and standardised criteria.
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Drug Discovery Landscape
29 orphan drug designations for Hereditary ATTR amyloidosis, including 8 approved therapies.
29 orphan drug designations for Hereditary ATTR amyloidosis, including 8 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
diflunisal | small molecules | FDA | Purpose Pharma International AB | |
small interfering ribonucleic acid -GalNAc conjugate targeting the transthyretin messenger RNA | RNAs | FDA | — | Chengdu Brilliant Pharmaceutical Co., Ltd. |
Florbetaben (18F) | small molecules | EMA | Lantheus Germany GmbH | |
CRISPR-associated protein 9-based TTR gene editing therapy | gene editing enzymes | FDA | — | Accuredit Therapeutics US Ltd. |
Coramitug | antibodies | EMA | Novo Nordisk A/S | |
a fusion protein of humanized immunoglobulin G1 (IgG1) with a pan amyloid-reactive peptide (p5R) genetically incorporated into the C-terminus of the light chain | proteins | FDA | Attralus, Inc. | |
coramitug | antibodies | FDA | Novo Nordisk Inc. | |
Humanised IgG1 monoclonal antibody against misfolded immunoglobulin G, fused with pan-amyloid-reactive peptide p5R | antibodies | EMA | Raremoon Consulting Esp S.L. | |
Human IgG1 monoclonal antibody targeting amyloid transthyretin | antibodies | EMA | Alexion Europe | |
Eplontersen [Wainzua] | oligonucleotides | EMA | AstraZeneca AB | |
recombinant human anti-ATTR-immunoglobulin G1 monoclonal antibody | antibodies | FDA | Alexion Pharmaceuticals, Inc. | |
Iodine (124I) evuzamitide | small molecules | EMA | Raremoon Consulting Esp S.L. | |
Iodine (I-124) evuzamitide | small molecules | FDA | Attralus, Inc. | |
Diflunisal [Attrogy] | small molecules | EMA | Purpose Pharma International AB | |
eplontersen [Wainua] | RNAs | FDA | Approved | Ionis Pharmaceuticals, Inc. |
clustered regularly interspaced short palindromic repeats CRISPR/ Cas9-based gene therapy consisting of a single guide RNA targeting the human TTR gene and a messenger RNA encoding Cas9 | gene editing enzymes | FDA | Intellia Therapeutics, Inc. | |
Messenger RNA encoding Cas9, single guide RNA targeting the human TTR gene | combination | EMA | Pharma Gateway AB | |
Acoramidis [Beyonttra] | small molecules | EMA | BridgeBio Europe B.V. | |
acoramidis [Attruby] | small molecules | FDA | Approved | BridgeBio Pharma, Inc. |
vutrisiran [Amvuttra] | RNAs | FDA | Approved | Alnylam Pharmaceuticals, Inc. |
Synthetic double-stranded siRNA oligonucleotide targeted against transthyretin mRNA, with six phosphorothioate linkages in the backbone, and nine 2'-fluoro and thirty-five 2'-O-methyl nucleoside residues in the sequence, which is covalently linked via a phosphodiester group to a ligand containing three N-acetylgalactosamine residues [Amvuttra] | RNAs | EMA | Approved | Alnylam Netherlands B.V. |
revusiran | RNAs | FDA | Alnylam Pharmaceuticals, Inc. | |
Phosphorothioate oligonucleotide targeted to transthyretin [Tegsedi] | oligonucleotides | EMA | Approved | Akcea Therapeutics Ireland Limited |
Tolcapone | small molecules | FDA | Corino Therapeutics, Inc. | |
Inotersen [TEGSEDI™] | oligonucleotides | FDA | Approved | Akcea Therapeutics, Inc. |
patisiran [ONPATTRO] | RNAs | FDA | Approved | Alnylam Pharmaceuticals, Inc. |
Doxycycline hyclate | small molecules | EMA | Giampaolo Merlini | |
Synthetic double-stranded siRNA oligonucleotide directed against transthyretin mRNA [Onpattro] | RNAs | EMA | Approved | Alnylam Netherlands B.V. |
tafamidis | small molecules | FDA | Pfizer, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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