RARE DISEASE
Fabry disease
Fabry disease
Fabry disease
Synonyms: Alpha-galactosidase A deficiency, Anderson-Fabry disease, Angiokeratoma corporis diffusum, Diffuse angiokeratoma, FD
Synonyms: Alpha-galactosidase A deficiency, Anderson-Fabry disease, Angiokeratoma corporis diffusum, Diffuse angiokeratoma, FD
Synonyms: Alpha-galactosidase A deficiency, Anderson-Fabry disease, Angiokeratoma corporis diffusum, Diffuse angiokeratoma, FD
Drug discovery
34
drugs
With orphan designations
Overview
Fabry disease is an X-linked lysosomal storage disorder caused by pathogenic GLA gene variants, leading to α-galactosidase A deficiency and globotriaosylceramide (GL-3) accumulation. This results in progressive multiorgan damage, primarily affecting kidneys, heart, and nervous system. Early symptoms (often childhood-onset) include neuropathic pain, gastrointestinal disturbances, hypohidrosis, and angiokeratomas. Untreated, it progresses to end-stage renal disease, cardiomyopathy, and stroke. Diagnosis involves enzyme activity assays and genetic testing. Current therapies include enzyme replacement therapy (ERT), chaperone therapy, and emerging strategies like gene therapy [1][3][11].
Burden
Clinical: Reduced lifespan (♂: ~16 years; ♀: 5–14 years), 100–1,000× higher ESRD risk in dialysis populations [1][6][9].
Psychosocial: Chronic pain, fatigue, depression, and reduced quality of life affect >50% of patients [9][16].
Economic: High costs from lifelong treatments, multidisciplinary care, and complications (e.g., stroke, cardiac interventions) [9][19].
Categories: rare cardiac diseases, rare circulatory system diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare renal diseases, rare skin diseases, rare transplant-related disorders
Research Papers
1,685 drug discovery papers about Fabry disease, with 5 first-in-class and 21 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,685 drug discovery papers about Fabry disease, with 5 first-in-class and 21 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
oligonucleotides
2026-08-13 | Nucleoside-Modified mRNA Encoding Alpha-Galactosidase A Ameliorates Fabry Disease Phenotypes in Human IPSC-Derived Cardiomyocytes.
The lysosomal storage disorder Fabry disease results from α-galactosidase A deficiency, leading to excessive glycosphingolipid substrate accumulation, primarily globotriaosylceramide (Gb3). While the underlying molecular mechanisms remain elusive, multi-systemic complications ultimately culminate in premature death, with heart failure being the leading cause of death. Current treatment options fail to treat Fabry disease adequately and only delay its progression. Preclinical studies on an alternative approach, systemic delivery of nucleoside-modified GLA mRNA (modGLA), suggest improved effectiveness over existing therapies in reducing glycosphingolipid levels in the heart. It remains unclear whether modGLA can rescue Fabry cardiomyopathy phenotypes at the cellular level, which are not faithfully recapitulated in current animal models. To address this, we investigated characteristic phenotypes in two new models of Fabry cardiomyopathy utilizing human iPSC-derived cardiomyocytes in transcriptomic and functional analyses. These human Fabry disease cardiomyocytes displayed broad transcriptional dysregulation, apoptosis, mitochondrial dysfunction, impaired reactive oxygen species handling, altered contractility, and enhanced calcium transient decay parameters. Mechanistically, phospholamban hyperphosphorylation may contribute to this calcium dysregulation. Consistently, modGLA therapy restored α-galactosidase A activity, reduced glycosphingolipid deposition, and normalized molecular alterations, including phospholamban hyperphosphorylation and calcium decay parameters, supporting modGLA as a promising therapeutic strategy for Fabry disease.
2026-05-22 | Nanomedicines for DNA and interference RNA co-delivery: Combined gene therapy for Fabry disease.
Fabry disease (FD) is a multisystemic rare disorder caused by mutations in the GLA gene encoding α-Galactosidase A (α-Gal A) enzyme. The deficiency of this enzyme leads to progressive lysosomal accumulation of glycosphingolipids, especially globotriaosylceramide (Gb3) and lyso-Gb3. Current therapies remain limited in efficacy and do not fully prevent disease progression. In this work, we designed solid lipid nanoparticles incorporating 5 nm gold nanoparticles ("golden SLNs") for the co-delivery of GLA plasmid DNA and siRNA against Gb3 synthase to simultaneously promote α-Gal A production and inhibit Gb3 synthesis, as a dual therapeutic strategy for FD. Nanomedicines were prepared by an optimized electrostatic assembly process, combining both the DNA and siRNA with golden SLNs, the peptide protamine and polysaccharides. They were characterized in terms of size, surface charge and nucleic-acid binding, and evaluated in an endothelial cell model of FD (IMFE-1 cells) to assess intracellular trafficking, α-Gal A expression, Gb3 synthase downregulation, Gb3 reduction, cell viability and hemocompatibility. The golden SLN-based nanomedicines, with a particle size from 200 to 300 nm and positive surface charge, increased α-Gal A activity and reduced Gb3 synthase expression and Gb3 levels for at least 15 days. Protamine and gold nanoparticles played key roles in nucleic-acid condensation and intracellular release, while lipid composition and polysaccharide coating determined efficacy and safety. This study presents the first co-delivery nanomedicine enabling simultaneous gene supplementation and genetic substrate reduction therapy, broadening the therapeutic scope for FD.
2025-10-01 | #972 Epigenetic clock and Fabry disease
Abstract Background and Aims Fabry's disease (FD) is a rare X-linked, lysosomal accumulation genetic disorder due to deficiency of the enzyme α-galactosidase-A due to pathogenic mutations in the GLA gene (Xq22.1). Due to these mutations, globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (lysoGb3), gradually accumulate within the lysosomes of various cells. The potential pathogenicity and clinical relevance of D313Y variation in patients with FD remains debated. D313Y patients do not show clear signs of alpha-galactosidase A deficiency and Gb3 accumulation at an early stage. For this reason, other molecular biomarkers are required for patient risk stratification. The development and application of epigenetic predictors, for healthcare research has grown dramatically over the last decade. These markers also known as epigenetic clocks, can aid FD risk stratification as they resulted to be very accurate for estimating biological age in different diseases. However, data on the epigenetic clock in Fabry disease are still lacking. Our working hypothesis is that the application of epigenetic clocks to quantify the biological age of Fabry patients could provide independent prognostic information for disease risk stratification in patients harboring the D313Y mutation. Therefore, we developed a mathematical model for biological age prediction in healthy individuals and applied it to blood samples from FD patients with the D313Y mutation to identify patterns of accelerated aging. Method The epigenetic clock was developed in a healthy cohort of 201 healthy subjects. FD sample was represented by a cohort including 25 untreated FD patients harboring the D313Y mutation. Genomic DNA from whole blood was extracted using a standard commercial kit. The clock includes five DNAm biomarkers strongly correlated with chronological age (ELOVL2, C1orf132, FHL2, KLF14 and TRIM59). Methylation levels were measured by using a SNaPshot assay and then through the Illumina Methylation EPICv2 Array technology. Results We found a strong correlation between the epigenetic clock and chronological age in DNA samples from healthy subjects (r = 0.97) (Fig. 1). Then, the formulated clock was applied to estimate biological age of patients harboring the D313Y mutation. These patients generally did not show clinical manifestations conformable with FD (enzymatic activity and lyso-Gb3 in plasma within normal limits). 7 patients did not present any sign of disease, 12 neurologic manifestations, 4 renal failure and 2 cerebrovascular events. Surprisingly, the epigenetic age of Fabry patients did not deviate significantly from that of healthy subjects of the same age (Fig. 2). These results were confirmed by epigenetics clocks estimated through EPICv2 methylation assay (Illumina). To further explore the role of the selected epigenetic markers in FD, we analyzed the DNA methylation levels of the 5 genes included in the clock. Only three of these (C1orf132, TRIM59, and KLF14) showed lower age-adjusted methylation levels in FD patients than in healthy subjects (P ≤ 0.001 SNaPshot assay) (Fig. 3). Conclusion To the best of our knowledge this is the first time that an epigenetic clock has been used to FD patient risk stratification. Although a clear direct relationship between epigenetic age and chronological age was not found, we identified epigenetic markers in TRIM59, C1orf132 and KLF14 that might contribute to improving the clinical characterization of FD patients with D313Y mutation. These three genes showed lower methylation levels in FD patients that might be cause an increased expression of the corresponding products. Further studies in additional cohorts are required to verify if monitoring epigenetic age over time might be a useful strategy to identify D313Y-positive patients with latent or early-FD pathology and to clarify the role of the investigated epigenetic biomarkers in
2025-06-16 | A4GALT-targeting siRNA lipid nanoparticles ameliorate Fabry disease phenotype: Greater efficacy in endothelial cells than in podocytes.
In this study, we explore the therapeutic feasibility of globotriaosylceramide (Gb3) synthase (A4GALT)-specific siRNA-loaded polyhistidine (pHis)-incorporated lipid nanoparticles (HLNPs) for Fabry disease (FD). HLNPs were developed to deliver siRNAs targeting A4GALT using a microfluidic device, with pHis aiding in endosome escape. The therapy was tested on GLA-knockout human-induced pluripotent-stem-cell-derived endothelial cells (GLA-KO-hiPSC-ECs) and podocytes (GLA-KO-hiPSC-PCs). GLA-KO-hiPSCs-ECs or -PCs, upon differentiation, were treated with A4GALT-siRNA-HLNP. Successful intracellular uptake of A4GALT-siRNA-HLNP was confirmed through fluorescence and electron microscopy in both cell types. A4GALT-siRNA-HLNP treatment confirmed both cell types' stability at 5 μg/mL. Increased Gb3 deposition and zebra body formation were detected in both cell types, but A4GALT-siRNA-HLNP treatment attenuated these FD phenotypes, demonstrating reduced expression of A4GALT through western blot analysis. RNA sequencing analysis revealed that the expression of transcripts associated with FD was restored by A4GALT-siRNA-HLNP treatment in GLA-KO-hiPSCs-ECs, whereas in GLA-KO-hiPSCs-PCs, this effect was relatively less pronounced. Suppression of A4GALT via siRNA/HLNP treatment significantly rescued FD phenotypes especially in EC, presenting a novel therapeutic approach for FD.
2025-04-16 | mRNA-based vaccines and therapies - a revolutionary approach for conquering fast-spreading infections and other clinical applications: a review.
Since the beginning of the COVID-19 pandemic, the development of messenger RNA (mRNA) vaccines has made significant progress in the pharmaceutical industry. The two COVID-19 mRNA vaccines from Moderna and Pfizer/BioNTech have been approved for marketing and have made significant contributions to preventing the spread of SARS-CoV-2. In addition, mRNA therapy has brought hope to some diseases that do not have specific treatment methods or are difficult to treat, such as the Zika virus and influenza virus infections, as well as the prevention and treatment of tumors. With the rapid development of in vitro transcription (IVT) technology, delivery systems, and adjuvants, mRNA therapy has also been applied to hereditary diseases such as Fabry's disease. This article reviews the recent development of mRNA vaccines for structural modification, treatment and prevention of different diseases; delivery carriers and adjuvants; and routes of administration to promote the clinical application of mRNA therapies.
small molecules
2026-09-09 | SGLT2 Inhibitors and Cardiovascular Outcomes in Patients With Fabry Disease: Observations From a Federated Research Network.
Fabry disease (FD) is frequently complicated by renal impairment and cardiovascular events; however, evidence on sodium-glucose cotransporter-2 inhibitors (SGLT2i) in this population is scarce. Accordingly, we assessed the association between SGLT2i exposure and cardiovascular outcomes in adults with FD. We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, including adults with Fabry disease and eGFR ≥ 20 mL/min/1.73 m2, excluding Type 1 diabetes. Patients were stratified by SGLT2 inhibitor exposure. The primary outcome was a composite of all-cause death, acute myocardial infarction and acute or acute-on-chronic heart failure at 2 and 5 years; secondary outcomes included individual components and progression to advanced kidney disease. Patients with prior non-fatal outcomes were excluded from the respective analyses. Propensity score matching (1:1) and Cox proportional hazards models were used. Sensitivity analyses included alternative follow-up periods, restriction to Fabry disease diagnosed from 2013 onwards and a stricter Fabry disease definition requiring ≥ 2 diagnoses; subgroup analyses were performed by sex and age. Among 14 940 FD patients, 1028 (6.9%) had recorded exposure to SGLT2 inhibitors (mean age: 65.5 ± 12.0 years; 53.0% male), who were older and had a higher comorbidity burden and worse baseline renal profile than non-exposed patients. After PSM, 732 patients per group (exposed and non-exposed patients) were available for analysis. At 2 years, SGLT2i exposure was associated with a lower risk of the composite outcome (HR 0.61; 95% CI 0.38-0.97) and all-cause death (HR 0.56; 95% CI 0.33-0.95). At 5 years, results were consistent for the composite outcome (HR 0.56; 95% CI 0.39-0.79) and all-cause death (HR 0.62; 95% CI 0.42-0.93), with reduced myocardial infarction risk (HR 0.53; 95% CI 0.30-0.90). In a large real-world FD cohort, SGLT2i exposure was associated with lower cardiovascular risk and mortality, supporting further prospective investigation.
2026-09-04 | Dysregulated phosphatidylglycerol metabolism in dorsal root ganglia contributes to pain hypersensitivity in a mouse model of Fabry disease.
Fabry disease (FD) is a genetic disorder caused by a deficiency of alpha-galactosidase A. Neuropathic pain is a hallmark of FD, beginning in early childhood and persisting throughout life. Current therapies for FD, such as enzyme replacement therapy and oral chaperone therapy, have limited impact on alleviating pain symptoms. Therefore, there is an urgent need to elucidate the precise molecular and metabolic mechanisms underlying FD-related pain to identify new therapeutic targets. In this study, we found that 8-week-old Fabry mice exhibited pronounced pain hypersensitivity, with no sex differences. Then, bilateral L4-L6 dorsal root ganglia (DRGs) were harvested from Fabry and wild-type (WT) mice of both sexes to dissect the molecular basis of pain. Transcriptomic profiling revealed distinct alterations in lipid metabolism-related genes within Fabry DRGs. Subsequent targeted lipidomic analysis identified robust accumulation of phosphatidylglycerol (PG), particularly elevated levels of PG (18:1/22:6) and PG (18:2/22:6) in Fabry DRGs. PG-associated synthase PGS1 was upregulated, while the PG hydrolytic activity of sPLA2s was inhibited. Following PGS1 knockdown or sPLA2s activity restoration, PG accumulation and pain hypersensitivity in Fabry mice were mitigated. Given the mitochondrial localization of PGS1, we observed profound mitochondrial disruption in Fabry DRGs, where aberrant PG metabolism contributes to this dysfunction. Thus, our study provides new insights into DRG pathogenesis in FD and uncovers dysregulated PG metabolism as a promising therapeutic target for alleviating Fabry pain.
2026-08-18 | Long-Term Cardiac Remodeling During Migalastat Therapy in a Heterozygote Woman With Fabry Disease (N224S): A 9 Year Case Report.
BACKGROUND Fabry disease (FD) is a rare X‑linked lysosomal disorder in which long‑term cardiac outcomes, particularly in heterozygous females, remain incompletely defined. The N224S alpha-galactosidase A gene (GLA) variant is recognized as pathogenic, yet its cardiac phenotype and response to prolonged migalastat therapy are not well characterized. Although clinical trials and observational studies have reported variable cardiac responses to migalastat, real‑world longitudinal data beyond 5 years remain limited. Understanding long‑term structural and functional changes is especially important in patients with pre‑existing cardiac involvement, where distinguishing favorable remodeling from fibrosis‑related progression can be challenging. CASE REPORT We describe a 9‑year follow‑up of a 71‑year‑old heterozygous woman with FD due to the N224S mutation treated with migalastat. Serial transthoracic echocardiography demonstrated a sustained reduction in left ventricular mass index (LVMI) over long‑term therapy. Left ventricular systolic function remained preserved throughout follow‑up, and there was no evidence of progressive structural deterioration. Available Doppler‑derived diastolic indices, including a gradual decline in early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e'), suggested improving left ventricular filling pressures over time. Although LVMI showed minor year‑to‑year variability, these changes were consistent with expected technical or physiological variation and did not alter the clear long‑term downward trend. CONCLUSIONS This case provides real‑world evidence of favorable long‑term cardiac remodeling during migalastat therapy in a heterozygous woman with the N224S variant. The sustained reduction in LVMI, preserved systolic function, and improving diastolic indices together indicate a durable cardiac response and extend the limited longitudinal data available for variant‑specific outcomes in FD.
2026-08-07 | Pain in Fabry disease: do experimental models reveal novel therapeutic targets?
Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and progressive accumulation of globotriaosylceramide (Gb3). Although FD is a multisystemic disorder affecting the heart, kidneys, skin, and nervous system, pain is one of its earliest, most prevalent, and disabling manifestations. While several review articles have already addressed the clinical features and management of FD-associated pain, this review specifically focuses on the mechanisms underlying pain as revealed by experimental and preclinical models of the disease. By integrating findings from cellular and animal studies, we provide an updated overview of the molecular and neurobiological pathways implicated in FD-related pain, including dorsal root ganglia dysfunction, ion channel dysregulation, neuroimmune interactions, vascular abnormalities, and central sensitization processes. We further discuss how preclinical studies have identified novel therapeutic targets for pain, such as acid-sensing ion channels (ASIC), transient receptor potential (TRP) receptors, the prokineticin system, glial activation, and glutamatergic signaling, which may complement current disease-modifying therapies. By highlighting the translational relevance of these mechanistic insights, this review aims to bridge the gap between experimental research and the development of more effective pain-focused interventions. A better understanding of the pathophysiology of FD-associated pain may ultimately contribute to improving management strategies with a significant impact on the quality of life for affected individuals.
2026-08-06 | Unraveling A4GALT Mechanism and Its Modulation With Adamantyl-Galactosylceramide Analogues: Advancing Fabry Disease Therapeutic Strategies.
Fabry disease (FD), one of the most prevalent lysosomal storage disorders in Europe, is caused by mutations in the GLA gene leading to deficient α-galactosidase A activity with lysosomal accumulation of globotriaosylceramide (Gb3). Enzyme replacement therapy (ERT) and pharmacological chaperone therapy (PCT) are used in the clinic to treat FD but are limited in efficacy, underscoring the need for alternative therapeutic strategies. Inhibiting α-1,4-galactosyltransferase (A4GALT), the glycosyltransferase responsible for Gb3 biosynthesis, represents an attractive strategy. Here, we reveal the molecular mechanism of human A4GALT at atomic detail using QM/MM simulations. We reveal a conformational rearrangement involving a 310-helix that stabilizes the donor substrate and promotes a front-face SNi-like catalytic mechanism, in which a short-lived oxocarbenium-ion intermediate forms. The simulations informed the synthesis of a panel of glycosylceramide substrate analogues. Among these, AdaGalCer (Ada = adamantyl) proved able to reduce Gb3 production in fibroblasts while simultaneously being converted by A4GALT into the galactosylated product AdaGb2. These results provide a clear path towards inhibiting A4GALT, paving the way for potential new and effective FD therapeutics.
gene therapies
2026-09-29 | Fabry disease beyond the classical model: clinical presentation and diagnostic challenges in women.
The prevailing concept of Fabry disease as a condition affecting only males, being females considered merely carriers has been superseded by a more nuanced understanding of the condition as a highly complex multisystemic disorder. Contemporary evidence contradicts the prevailing paradigm that heterozygous women are asymptomatic, thereby underscoring substantial phenotypic heterogeneity and a considerable risk of irreversible organ damage. A high index of clinical suspicion is required for diagnosis, which includes family screening, multisystemic evaluation, determination of enzyme activity, and genetic testing, especially in women, in whom residual α-galactosidase A activity may be normal. The treatment of this condition is based on three fundamental approaches: enzyme replacement therapy, pharmacological chaperones, and emerging therapeutic strategies. The latter includes substrate-depleting therapy, mRNA-based therapies, and gene therapy. It is imperative to initiate treatment at an early stage in order to delay disease progression. This review summarizes the current evidence on the epidemiology, pathophysiology, diagnosis and treatment of Fabry disease, with particular emphasis on clinical variability and the relevance of the disease in women - who have historically been considered asymptomatic carriers - as well as the need for sex-specific studies.
2026-07-28 | Autophagy-Lysosomal Dysfunction as a Converging Mechanism of Cardiomyopathy in Lysosomal Storage Disorders: From Pathobiology to Targeted Therapy.
Cardiac disease is a leading cause of morbidity and early death across several lysosomal storage disorders (LSDs); however, the cardiomyopathies of Fabry, Pompe, and Danon disease are still largely treated as separate, substrate-specific disorders. We argue that they are better understood as variations on a single theme: the breakdown of the autophagy-lysosome system within cardiomyocytes. In the healthy heart, this system clears damaged proteins and organelles and is regulated by mTORC1 and the master regulator TFEB. Once lysosomal degradation or autophagosome-lysosome fusion fails, undegraded substrates and defective mitochondria accumulate, driving hypertrophy, interstitial fibrosis, and conduction disease. Danon disease, resulting from the loss of LAMP2, is the clearest example of a primary defect in autophagic flux, whereas the glycogen storage of Pompe disease and the globotriaosylceramide accumulation of Fabry disease impair flux through different upstream mechanisms that converge on the same downstream injury. The same framework extends to other storage disorders with cardiac involvement, such as mucopolysaccharidosis (MPS). We trace this shared pathobiology from molecule to bedside, examine biomarkers that reflect lysosomal and autophagic dysfunction rather than storage alone, and re-examine treatment in that light: why enzyme replacement therapy corrects substrate accumulation but leaves much of the autophagic and mitochondrial damage unresolved, and why gene therapy-particularly AAV9-LAMP2B for Danon disease-together with autophagy- and TFEB-directed strategies may help close that gap. Viewing these disorders through a single mechanistic lens reshapes how we monitor them and where future therapies should be directed.
2026-05-29 | Capsid Engineering of Adeno-Associated Viruses for Targeted Gene Therapy in Kidney Diseases.
The global burden of chronic and genetic kidney diseases poses a significant challenge to healthcare systems. Current therapies, including dialysis, transplantation, and supportive pharmacotherapies, cannot halt disease progression or address root causes, especially in monogenic disorders like Alport syndrome and Fabry disease. Adeno-associated virus (AAV)-based gene therapy is promising, enabling targeted correction of underlying genetic defects. However, renal delivery faces challenges, including cellular heterogeneity, anatomical barriers, and pre-existing immunity. This review evaluates advances in AAV capsid engineering to overcome these obstacles, focusing on strategies to enhance kidney-specific tropism, transduction efficiency, and immune evasion. We outline the evolution from conventional serotype selection to precision engineering via rational design, directed evolution, and in silico approaches. Artificial intelligence (AI) has emerged as a pivotal accelerator, with machine learning models and generative frameworks enabling data-efficient capsid optimization despite limited datasets. Multimodal AI, reinforcement learning, and agentic systems can refine renal targeting by balancing glomerular penetration, cell specificity, and safety. Future progress relies on scaling high-quality datasets through collaborative consortia, lab-in-the-loop validation, and explainable AI. By combining capsid engineering with renal pathophysiology insights, this roadmap paves the way for curative AAV therapies that move beyond current suboptimal treatments to correct underlying pathogenic mechanisms.
2026-04-27 | Liver Gene Therapy in Fabry Disease Mice With Low Doses of rAAV2/8 Expressing a Codon-Optimized hGLA cDNA Results in Long-Term Disease Correction.
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene, which encodes for Alpha Galactosidase-A (α-Gal A). α-Gal A deficiency leads to glycosphingolipid accumulation, like globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (lyso-Gb3), resulting in systemic symptoms and reduced lifespan. Current treatments such as enzyme replacement therapy (ERT) and chaperone therapy are noncurative and have limitations. Gene therapy is an interesting alternative approach that may overcome most of these limitations, and different approaches are currently being tested. Here, we developed a gene therapy approach using rAAV2/8 vectors, delivered intravenously, that target the liver to produce and secrete functional α-Gal A into circulation. This enzyme is then captured by organs expressing mannose-6-phosphate receptors, reducing glycosphingolipid accumulation in affected tissues. We generated a codon-optimized GLA cDNA with enhanced translatability that was expressed under a strong liver-specific promoter. In a dose escalation study in juvenile Gla knock-out (ko) mice, the lowest dose (3.0E11vg/kg) resulted in 85%-95% clearance of lyso-Gb3 in plasma and tissues, while doses of 3.0E12 vg/kg and higher showed 98%-100% clearance of the glycosphingolipid. All AAV doses were more effective than systemic α-Gal A administration (ERT). Long-term treatment showed normal levels of lyso-Gb3 in plasma and tissues, and corrected neuropathic involvement, as shown in the hot plate test. This study provides a proof-of-concept showing that the tested liver-specific gene therapy vector is capable of preventing disease progression in juvenile Fabry mice at relatively low doses and shows potential in treating both early- and late-onset FD in patients.
2026-04-19 | Beneficial bystander-enhanced cryptic splice rescue of cardiac-type Fabry GLA IVS4+919G>A by adenine base editing in patient fibroblasts.
The IVS4+919G>A mutation in the GLA gene, prevalent in East Asian populations, causes cardiac-type Fabry disease by creating an abnormal splice site. This results in the insertion of a 57-nucleotide segment between exon 4 and exon 5, introducing a premature stop codon and leading to a truncated, non-functional α-Gal A protein. We evaluated whether adenine base editing (ABEmax) can modulate this allele-induced cryptic splice event in patient-derived fibroblasts in vitro as a proof-of-concept. Two ABEmax/sgRNA constructs targeting intron 4 (ABEmax-sgRNA1 and ABEmax-sgRNA2) were tested; both induced on-target +919 A → G conversion with frequent bystander edits at +918/+920. Edited bulk populations and single-cell-derived clones showed restoration of correctly spliced GLA mRNA with reduced aberrant transcripts, increased GLA protein, higher α-Gal A activity (approaching wild-type levels in some clones), and reduced intracellular Gb3 signal. A focused next-generation sequencing panel identified a low-frequency intronic change at one predicted off-target locus without predicted coding consequences. These findings demonstrate in vitro splice rescue of a deep intronic, cardiac-type Fabry disease variant by adenine base editing and suggest that bystander edits in non-coding sequence can further enhance correction by suppressing cryptic splicing, with concordant improvements in α-Gal A activity and Gb3 signals.
proteins
2026-09-18 | Cardiomegaly of Unknown Origin: Why Morphology Still Matters in the Genetic Era - A Case of Cardiac Fabry Disease.
We report a 72-year-old man with long-standing hypertension, type 2 diabetes, and ischemic heart disease, in whom autopsy, following a fatal acute coronary syndrome, revealed marked cardiomegaly (heart weight, 911 g) and concentric myocardial hypertrophy (left ventricular wall thickness up to 2.4 cm) that appeared disproportionate to the expected degree of hypertensive and ischemic remodeling. Histological examination showed diffuse vacuolization of cardiomyocytes with a negative periodic acid-Schiff reaction; amyloidosis and glycogen storage diseases were excluded. Electron microscopy, α-galactosidase A activity, lyso-globotriaosylceramide measurement, and genetic testing were not available. Sudan III staining of frozen myocardial sections demonstrated intracellular lipid inclusions, providing supportive but non-specific evidence of a suspected non-classical (cardiac) variant of Fabry's disease. This case highlights the importance of careful morphological evaluation in the differential diagnosis of unexplained severe left ventricular hypertrophy and illustrates both the diagnostic utility and the limitations of conventional histopathological methods in autopsy practice.
2026-08-20 | Clinical and Biochemical Improvement After Switching From Agalsidase Alfa to Beta in a Boy With Classic Fabry Disease: A Case Report.
We described a 12-year-old boy with classic Fabry disease who was diagnosed through newborn screening. At age 6.2, he started agalsidase alfa based on evidence of subclinical organ involvement. At age 7.2, acroparesthesia subsequently developed. At age 10.9, after switching to agalsidase beta due to an insufficient clinical and biochemical response, his acroparesthesia resolved and plasma Lyso-Gb3 decreased. This report broadens the clinical understanding of children with Fabry disease.
2026-06-23 | Fabry Disease: Current Perspectives on Diagnosis and Management Strategies.
Fabry disease is a rare, X-linked lysosomal storage disorder caused by deficient α-galactosidase A activity, leading to progressive accumulation of globotriaosylceramide in multiple tissues. Its estimated incidence ranges from 1 in 40,000 to 1 in 117,000 live births. Fabry disease manifests primarily as 2 phenotypes: classic (type 1), presenting in childhood with neuropathic pain, fatigue, thermal intolerance, and early multiorgan involvement; and late onset (type 2), typically manifesting in adulthood with predominant cardiac or renal complications. Timely diagnosis requires clinical suspicion combined with enzymatic assays and genetic testing; however, atypical presentations and variability in female patients often delay recognition, underscoring the necessity for heightened clinical vigilance. Current therapeutic approaches primarily focus on enzyme replacement therapy and pharmacologic chaperones, aimed at enhancing quality of life and delaying organ dysfunction. Optimal management necessitates an individualized, multidisciplinary strategy encompassing nephrology, cardiology, genetics, clinical pharmacy, and pain management. Emerging treatments, including next-generation enzyme replacement therapies, substrate reduction therapy, gene therapy, and mRNA-based therapeutics, offer promising avenues for more effective and durable outcomes. Ongoing clinical trials and comprehensive long-term outcome studies are crucial for refining these innovative therapeutic strategies and further advancing patient care.
2026-05-29 | Modeling Fabry nephropathy: insights from experimental systems towards precision nephrology.
Fabry nephropathy is a major cause of kidney failure in Fabry disease, caused by pathogenic GLA variants that reduce α-galactosidase A activity and lead to globotriaosylceramide (Gb3) accumulation. In recent years, rapid advances in experimental modeling and emerging therapeutic strategies have dramatically reshaped understanding and treatment prospects for Fabry nephropathy. Experimental models - including cellular systems, patient-derived kidney organoids, and animal models such as zebrafish, Drosophila, mice and rats - have been pivotal in elucidating classic Gb3-dependent and novel Gb3-independent pathogenic mechanisms. These insights challenge the traditional Gb3-centric paradigm by highlighting other contributors, such as its metabolite lyso-Gb3, as well as α-synuclein accumulation and endothelial dysfunction. Despite established therapies for Fabry nephropathy, such as enzyme replacement and pharmacological chaperones, disease progression remains a clinical challenge, underscoring the urgent need for deeper mechanistic understanding and precision medicine approaches. This timely Review summarizes diverse model systems' unique strengths, limitations and translational potential to guide future research and therapeutic development for this complex disease.
2026-04-27 | Sex-based antibody subclass maturation drives direct enzymatic inhibition in fabry disease patients receiving enzyme replacement therapy.
Enzyme replacement therapy (ERT) for Fabry disease can elicit anti-drug antibodies (ADAs) that may diminish efficacy and limit clinical benefit. To develop and apply a multiplexed proteomic assay for quantitative, subclass-specific ADA and complement profiling in Fabry disease to inform personalized ERT selection. We created a targeted LC-MS/MS platform to quantify ADA binding across IgG1-4, IgM, and IgA1, and complement proteins C1Qc-C9, in serum from Fabry patients (n = 39) and healthy controls. Neutralizing capacity was measured via enzymatic inhibition assay. Subclass-specific cross-reactivity was assessed for agalsidase alfa, agalsidase beta, and pegunigalsidase alfa. IgG4 binding was significantly higher in Fabry males (p = 0.007), with no sex-based differences for other Ig classes. Complement binding (C1Qc, C3) was elevated in ∼25% of patients, with IgG1, IgG2, IgM, and IgA1 correlating with C1Qc (r > 0.6). Seven patients (three female) exhibited >50% ERT inhibition; IgG4 binding correlated with enzymatic inhibition (p < 0.0025) and elevated lyso-Gb3 in males (p < 0.02). We assessed cross-reactivity of IgG4 in a patient who had received only agalsidase alfa, finding a 49% reduction in IgG4 binding to Pegunigalsidase alfa compared to Agalsidase alfa (p = 0.003) and 45% to Peguingalsidase alfa compared to agalsidase beta (p = 0.035). IgG4 comprised >50% of immune complexes for agalsidase alfa/beta but only 25% for pegunigalsidase alfa, indicating a potentially distinct immunogenic profile. Quantitative subclass-specific ADA and complement profiling reveals sex-specific IgG4 patterns, neutralizing capacity, and ERT-specific immunogenic differences, supporting its utility for personalized therapy in Fabry disease. A novel multiplex LC-MS/MS assay quantifies ADA subclasses and complement in Fabry disease, uncovering distinct IgG4 patterns and ERT-specific profiles that enhance understanding of treatment immunogenicity.
other
2026-09-04 | Generation of the functionally enhanced proximal tubular cells from human iPSC-derived kidney organoids.
Human renal proximal tubular epithelial cells (RPPTCs) are crucial for exploring the molecular and cellular mechanisms underlying the pathophysiology of kidney injuries. In this study, we generated the functionally enhanced kidney organoid-derived proximal tubule cells (FEKOPTCs) from human induced pluripotent stem cells. Heparan sulfate proteoglycans and transforming growth factor-β receptor inhibitor enhanced the functionality of PTCs isolated from the kidney organoids of which the vascularization and maturation were improved by heparan sulfate proteoglycans and vascular endothelial growth factor. FEKOPTCs showed significantly enhanced epithelial barrier function, polarization state, and transporter function, compared with primary human RPTECs, which led to improve the function of drug uptake. Transcriptomic characterization of FEKOPTCs revealed high similarity to PTCs of native human adult kidney. FEKOPTCs-on-chip are more sensitive predictors than RPTECs-on-chip for nephrotoxicity testing. By using CRISPR-Cas9 genetic mutation of alpha-galactosidase A, the causative gene of Fabry disease, alpha-galactosidase A-mutant FEKOPTCs, recapitulated the functional phenotype of Fabry disease. When FEKOPTCs were transplanted into the kidney parenchyma of NOD-SCID mice, they reassembled and regenerated proximal tubular structures with intact lumens and functional transporters. Taken together, our results suggest that FEKOPTCs are functionally enhanced PTCs and can be applied for nephrotoxicity testing, disease modeling, and regenerative medicine.
2026-06-25 | Inflammation in Cardiomyopathies: Cellular Mechanisms Across Cardiac Phenotype.
Cardiomyopathies are traditionally classified by structural and genetic phenotypes, but emerging evidence highlights chronic myocardial inflammation as a pivotal driver of disease progression across different etiologies. This review synthesizes the current literature on the cellular and molecular inflammatory mechanisms underlying hypertrophic cardiomyopathy, Anderson-Fabry disease, cardiac amyloidosis, arrhythmogenic cardiomyopathy, and dilated cardiomyopathy. Across these distinct conditions, endogenous triggers such as metabolic substrates, misfolded amyloid fibrils, mechanical stress, or viral genomes act as damage-associated molecular patterns. These stimuli activate innate and adaptive immune cascades, notably the Toll-like receptors, the NF-κB pathway, and the NLRP3 inflammasome. This immune activation establishes a pro-inflammatory microenvironment that promotes fibroblast reprogramming, myocardial edema, and progressive fibrotic or fibro-fatty remodeling. Inflammation is an active, core pathophysiological mechanism rather than a passive secondary bystander in cardiomyopathies. Recognizing these shared immune pathways provides a framework for improved risk stratification and highlights the potential for targeted immunomodulatory therapies to alter disease trajectories.
2026-03-14 | Advancing Gene Therapies and Novel Treatment Strategies for Infiltrative Cardiomyopathies: A Comprehensive Review of Targeted Interventions.
Recent progress in unraveling the molecular mechanisms of infiltrative Cardiomyopathies (CMPs) has created exciting opportunities for targeted therapies. These conditions, which include cardiac amyloidosis, sarcoidosis, Danon disease, Fabry disease, Mucopolysaccharidoses (MPS), and cardiac oxalosis, significantly impair cardiac function through complex pathogenic mechanisms. In cardiac amyloidosis, the accumulation of misfolded proteins into fibrillary amyloids disrupts myocardial structure, leading to inflammation, oxidative stress, and apoptosis. New treatments such as Antisense Oligonucleotides [ASOs], small interfering RNA [siRNA], and monoclonal antibodies have shown promising results in preclinical and clinical settings for managing amyloid deposition. Gene editing technologies, particularly CRISPR-Cas9, also have significant potential to deliver lasting therapeutic benefits by precisely correcting pathogenic mutations. Furthermore, managing Fabry disease with Enzyme Replacement Therapies [ERT] and chaperone molecules has improved cardiac outcomes; however, challenges remain in advanced stages due to ongoing myocardial involvement. Immunomodulatory strategies and innovative antibody-based therapies targeting pathological protein aggregates represent groundbreaking approaches that have shown efficacy in preclinical and earlyphase clinical trials. Despite these advancements, challenges remain, including the efficiency of drug delivery, possible off-target effects, and inconsistent clinical responses among different patient groups. Future research should focus on improving these therapies to increase their specificity and safety, ultimately enhancing patient outcomes and quality of life in infiltrative cardiomyopathies.
2026-01-01 | P055: Successful utilization of immune tolerance induction in a pediatric patient with classic Fabry disease: A case report
Fabry disease is a rare X-linked lysosomal disorder caused by a deficiency or absence of alpha-galactosidase A (α-Gal-A) enzyme. Fabry disease can largely be classified into two types: classic and atypical. Classic disease is defined by onset in childhood or adolescence with little to no α-Gal-A activity, while atypical disease is characterized by later disease onset with higher residual α-Gal-A enzyme activity. To date, the only FDA-approved enzyme replacement therapy for pediatric patients is agalsidase beta (Fabrazyme).
2025-11-01 | Complement and cardiac MRI biomarkers in Fabry disease cardiomyopathy
Abstract Introduction Fabry disease (FD) is a lysosomal storage disorder caused by α-galactosidase A deficiency, leading to globotriaosylceramide (Gb3) accumulation. Cardiomyopathy is the leading cause of FD-related mortality, yet its pathophysiology remains unclear. Current treatments have limited efficacy once left ventricular hypertrophy (LVH) develops, suggesting additional mechanisms such as inflammation. Complement-mediated inflammation, implicated in other lysosomal storage disorders (e.g., Gaucher disease),(1) may also contribute to FD cardiomyopathy. Purpose This study investigated inflammatory biomarkers associated with FD cardiomyopathy and their relationship with cardiac magnetic resonance (CMR) markers of disease severity to improve early diagnosis and intervention. Methods A total of 147 Fabry patients (58% female, 45 ±14 years, 43% LVH-positive; 42% ERT), 41 apical hypertrophic cardiomyopathy (aHCM) patients (75% male, 55 ±13 years), and 82 healthy controls (46% female, 51 ±18 years) with paired plasma and CMR were included. Prior targeted proteomic studies guided mass spectrometry-based biomarker profiling.(2) A validated AI tool assessed Left ventricular volumetrics and wall thickness.(3) A subset of Fabry patients (n=72) underwent comprehensive CMR analysis (GLS, T1/T2, LGE). Biomarkers were compared across cohorts using ANOVA with Dunnett’s post hoc testing. Correlations with myocardial parameters were assessed using Pearson’s coefficient and regression modelling. Sex differences in statistically significant complement biomarkers were analysed within the FD group using t-tests. Results Of 146 biomarkers, 53 were statistically significant. Fabry LVH showed complement activation via classical (C3, C4b, C4d) and alternative: complement factor D (CFD) pathways, amplified by immune complexes (IGHA1, IGHG2, IGHG3), distinct from aHCM, which exhibited predominantly extracellular matrix remodelling (Talin, NGAL, Versican, ECM1), fig 1. Complement activation was also present in Fabry patients without LVH, suggesting a pre-hypertrophy inflammatory phase. C3 and C4d were the only biomarkers differing between sexes in the LVH group (p<0.05), with higher complement levels in females, fig 2. GLS correlated with CFD (r= 0.40, p<0.05) and IGHG3 (-0.31, p<0.05), indicating a role for innate immunity in early myocardial dysfunction. While T1 mapping showed no significant correlations, T2 correlated with inflammatory markers (A2M, AGT). C3 was the only biomarker differing between LGE-positive and negative groups (p<0.05). Conclusions CMR detects early myocardial dysfunction in FD before hypertrophy, correlating with complement activation. These findings suggest revising the current staging model (4) to include a subclinical inflammatory phase. Complement-targeted therapies may enable early intervention, while CMR and biomarker analysis could facilitate early detection, risk stratification, and LVH prevention.
oligonucleotides
2026-08-13 | Nucleoside-Modified mRNA Encoding Alpha-Galactosidase A Ameliorates Fabry Disease Phenotypes in Human IPSC-Derived Cardiomyocytes.
The lysosomal storage disorder Fabry disease results from α-galactosidase A deficiency, leading to excessive glycosphingolipid substrate accumulation, primarily globotriaosylceramide (Gb3). While the underlying molecular mechanisms remain elusive, multi-systemic complications ultimately culminate in premature death, with heart failure being the leading cause of death. Current treatment options fail to treat Fabry disease adequately and only delay its progression. Preclinical studies on an alternative approach, systemic delivery of nucleoside-modified GLA mRNA (modGLA), suggest improved effectiveness over existing therapies in reducing glycosphingolipid levels in the heart. It remains unclear whether modGLA can rescue Fabry cardiomyopathy phenotypes at the cellular level, which are not faithfully recapitulated in current animal models. To address this, we investigated characteristic phenotypes in two new models of Fabry cardiomyopathy utilizing human iPSC-derived cardiomyocytes in transcriptomic and functional analyses. These human Fabry disease cardiomyocytes displayed broad transcriptional dysregulation, apoptosis, mitochondrial dysfunction, impaired reactive oxygen species handling, altered contractility, and enhanced calcium transient decay parameters. Mechanistically, phospholamban hyperphosphorylation may contribute to this calcium dysregulation. Consistently, modGLA therapy restored α-galactosidase A activity, reduced glycosphingolipid deposition, and normalized molecular alterations, including phospholamban hyperphosphorylation and calcium decay parameters, supporting modGLA as a promising therapeutic strategy for Fabry disease.
2026-05-22 | Nanomedicines for DNA and interference RNA co-delivery: Combined gene therapy for Fabry disease.
Fabry disease (FD) is a multisystemic rare disorder caused by mutations in the GLA gene encoding α-Galactosidase A (α-Gal A) enzyme. The deficiency of this enzyme leads to progressive lysosomal accumulation of glycosphingolipids, especially globotriaosylceramide (Gb3) and lyso-Gb3. Current therapies remain limited in efficacy and do not fully prevent disease progression. In this work, we designed solid lipid nanoparticles incorporating 5 nm gold nanoparticles ("golden SLNs") for the co-delivery of GLA plasmid DNA and siRNA against Gb3 synthase to simultaneously promote α-Gal A production and inhibit Gb3 synthesis, as a dual therapeutic strategy for FD. Nanomedicines were prepared by an optimized electrostatic assembly process, combining both the DNA and siRNA with golden SLNs, the peptide protamine and polysaccharides. They were characterized in terms of size, surface charge and nucleic-acid binding, and evaluated in an endothelial cell model of FD (IMFE-1 cells) to assess intracellular trafficking, α-Gal A expression, Gb3 synthase downregulation, Gb3 reduction, cell viability and hemocompatibility. The golden SLN-based nanomedicines, with a particle size from 200 to 300 nm and positive surface charge, increased α-Gal A activity and reduced Gb3 synthase expression and Gb3 levels for at least 15 days. Protamine and gold nanoparticles played key roles in nucleic-acid condensation and intracellular release, while lipid composition and polysaccharide coating determined efficacy and safety. This study presents the first co-delivery nanomedicine enabling simultaneous gene supplementation and genetic substrate reduction therapy, broadening the therapeutic scope for FD.
2025-10-01 | #972 Epigenetic clock and Fabry disease
Abstract Background and Aims Fabry's disease (FD) is a rare X-linked, lysosomal accumulation genetic disorder due to deficiency of the enzyme α-galactosidase-A due to pathogenic mutations in the GLA gene (Xq22.1). Due to these mutations, globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (lysoGb3), gradually accumulate within the lysosomes of various cells. The potential pathogenicity and clinical relevance of D313Y variation in patients with FD remains debated. D313Y patients do not show clear signs of alpha-galactosidase A deficiency and Gb3 accumulation at an early stage. For this reason, other molecular biomarkers are required for patient risk stratification. The development and application of epigenetic predictors, for healthcare research has grown dramatically over the last decade. These markers also known as epigenetic clocks, can aid FD risk stratification as they resulted to be very accurate for estimating biological age in different diseases. However, data on the epigenetic clock in Fabry disease are still lacking. Our working hypothesis is that the application of epigenetic clocks to quantify the biological age of Fabry patients could provide independent prognostic information for disease risk stratification in patients harboring the D313Y mutation. Therefore, we developed a mathematical model for biological age prediction in healthy individuals and applied it to blood samples from FD patients with the D313Y mutation to identify patterns of accelerated aging. Method The epigenetic clock was developed in a healthy cohort of 201 healthy subjects. FD sample was represented by a cohort including 25 untreated FD patients harboring the D313Y mutation. Genomic DNA from whole blood was extracted using a standard commercial kit. The clock includes five DNAm biomarkers strongly correlated with chronological age (ELOVL2, C1orf132, FHL2, KLF14 and TRIM59). Methylation levels were measured by using a SNaPshot assay and then through the Illumina Methylation EPICv2 Array technology. Results We found a strong correlation between the epigenetic clock and chronological age in DNA samples from healthy subjects (r = 0.97) (Fig. 1). Then, the formulated clock was applied to estimate biological age of patients harboring the D313Y mutation. These patients generally did not show clinical manifestations conformable with FD (enzymatic activity and lyso-Gb3 in plasma within normal limits). 7 patients did not present any sign of disease, 12 neurologic manifestations, 4 renal failure and 2 cerebrovascular events. Surprisingly, the epigenetic age of Fabry patients did not deviate significantly from that of healthy subjects of the same age (Fig. 2). These results were confirmed by epigenetics clocks estimated through EPICv2 methylation assay (Illumina). To further explore the role of the selected epigenetic markers in FD, we analyzed the DNA methylation levels of the 5 genes included in the clock. Only three of these (C1orf132, TRIM59, and KLF14) showed lower age-adjusted methylation levels in FD patients than in healthy subjects (P ≤ 0.001 SNaPshot assay) (Fig. 3). Conclusion To the best of our knowledge this is the first time that an epigenetic clock has been used to FD patient risk stratification. Although a clear direct relationship between epigenetic age and chronological age was not found, we identified epigenetic markers in TRIM59, C1orf132 and KLF14 that might contribute to improving the clinical characterization of FD patients with D313Y mutation. These three genes showed lower methylation levels in FD patients that might be cause an increased expression of the corresponding products. Further studies in additional cohorts are required to verify if monitoring epigenetic age over time might be a useful strategy to identify D313Y-positive patients with latent or early-FD pathology and to clarify the role of the investigated epigenetic biomarkers in
2025-06-16 | A4GALT-targeting siRNA lipid nanoparticles ameliorate Fabry disease phenotype: Greater efficacy in endothelial cells than in podocytes.
In this study, we explore the therapeutic feasibility of globotriaosylceramide (Gb3) synthase (A4GALT)-specific siRNA-loaded polyhistidine (pHis)-incorporated lipid nanoparticles (HLNPs) for Fabry disease (FD). HLNPs were developed to deliver siRNAs targeting A4GALT using a microfluidic device, with pHis aiding in endosome escape. The therapy was tested on GLA-knockout human-induced pluripotent-stem-cell-derived endothelial cells (GLA-KO-hiPSC-ECs) and podocytes (GLA-KO-hiPSC-PCs). GLA-KO-hiPSCs-ECs or -PCs, upon differentiation, were treated with A4GALT-siRNA-HLNP. Successful intracellular uptake of A4GALT-siRNA-HLNP was confirmed through fluorescence and electron microscopy in both cell types. A4GALT-siRNA-HLNP treatment confirmed both cell types' stability at 5 μg/mL. Increased Gb3 deposition and zebra body formation were detected in both cell types, but A4GALT-siRNA-HLNP treatment attenuated these FD phenotypes, demonstrating reduced expression of A4GALT through western blot analysis. RNA sequencing analysis revealed that the expression of transcripts associated with FD was restored by A4GALT-siRNA-HLNP treatment in GLA-KO-hiPSCs-ECs, whereas in GLA-KO-hiPSCs-PCs, this effect was relatively less pronounced. Suppression of A4GALT via siRNA/HLNP treatment significantly rescued FD phenotypes especially in EC, presenting a novel therapeutic approach for FD.
2025-04-16 | mRNA-based vaccines and therapies - a revolutionary approach for conquering fast-spreading infections and other clinical applications: a review.
Since the beginning of the COVID-19 pandemic, the development of messenger RNA (mRNA) vaccines has made significant progress in the pharmaceutical industry. The two COVID-19 mRNA vaccines from Moderna and Pfizer/BioNTech have been approved for marketing and have made significant contributions to preventing the spread of SARS-CoV-2. In addition, mRNA therapy has brought hope to some diseases that do not have specific treatment methods or are difficult to treat, such as the Zika virus and influenza virus infections, as well as the prevention and treatment of tumors. With the rapid development of in vitro transcription (IVT) technology, delivery systems, and adjuvants, mRNA therapy has also been applied to hereditary diseases such as Fabry's disease. This article reviews the recent development of mRNA vaccines for structural modification, treatment and prevention of different diseases; delivery carriers and adjuvants; and routes of administration to promote the clinical application of mRNA therapies.
small molecules
2026-09-09 | SGLT2 Inhibitors and Cardiovascular Outcomes in Patients With Fabry Disease: Observations From a Federated Research Network.
Fabry disease (FD) is frequently complicated by renal impairment and cardiovascular events; however, evidence on sodium-glucose cotransporter-2 inhibitors (SGLT2i) in this population is scarce. Accordingly, we assessed the association between SGLT2i exposure and cardiovascular outcomes in adults with FD. We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, including adults with Fabry disease and eGFR ≥ 20 mL/min/1.73 m2, excluding Type 1 diabetes. Patients were stratified by SGLT2 inhibitor exposure. The primary outcome was a composite of all-cause death, acute myocardial infarction and acute or acute-on-chronic heart failure at 2 and 5 years; secondary outcomes included individual components and progression to advanced kidney disease. Patients with prior non-fatal outcomes were excluded from the respective analyses. Propensity score matching (1:1) and Cox proportional hazards models were used. Sensitivity analyses included alternative follow-up periods, restriction to Fabry disease diagnosed from 2013 onwards and a stricter Fabry disease definition requiring ≥ 2 diagnoses; subgroup analyses were performed by sex and age. Among 14 940 FD patients, 1028 (6.9%) had recorded exposure to SGLT2 inhibitors (mean age: 65.5 ± 12.0 years; 53.0% male), who were older and had a higher comorbidity burden and worse baseline renal profile than non-exposed patients. After PSM, 732 patients per group (exposed and non-exposed patients) were available for analysis. At 2 years, SGLT2i exposure was associated with a lower risk of the composite outcome (HR 0.61; 95% CI 0.38-0.97) and all-cause death (HR 0.56; 95% CI 0.33-0.95). At 5 years, results were consistent for the composite outcome (HR 0.56; 95% CI 0.39-0.79) and all-cause death (HR 0.62; 95% CI 0.42-0.93), with reduced myocardial infarction risk (HR 0.53; 95% CI 0.30-0.90). In a large real-world FD cohort, SGLT2i exposure was associated with lower cardiovascular risk and mortality, supporting further prospective investigation.
2026-09-04 | Dysregulated phosphatidylglycerol metabolism in dorsal root ganglia contributes to pain hypersensitivity in a mouse model of Fabry disease.
Fabry disease (FD) is a genetic disorder caused by a deficiency of alpha-galactosidase A. Neuropathic pain is a hallmark of FD, beginning in early childhood and persisting throughout life. Current therapies for FD, such as enzyme replacement therapy and oral chaperone therapy, have limited impact on alleviating pain symptoms. Therefore, there is an urgent need to elucidate the precise molecular and metabolic mechanisms underlying FD-related pain to identify new therapeutic targets. In this study, we found that 8-week-old Fabry mice exhibited pronounced pain hypersensitivity, with no sex differences. Then, bilateral L4-L6 dorsal root ganglia (DRGs) were harvested from Fabry and wild-type (WT) mice of both sexes to dissect the molecular basis of pain. Transcriptomic profiling revealed distinct alterations in lipid metabolism-related genes within Fabry DRGs. Subsequent targeted lipidomic analysis identified robust accumulation of phosphatidylglycerol (PG), particularly elevated levels of PG (18:1/22:6) and PG (18:2/22:6) in Fabry DRGs. PG-associated synthase PGS1 was upregulated, while the PG hydrolytic activity of sPLA2s was inhibited. Following PGS1 knockdown or sPLA2s activity restoration, PG accumulation and pain hypersensitivity in Fabry mice were mitigated. Given the mitochondrial localization of PGS1, we observed profound mitochondrial disruption in Fabry DRGs, where aberrant PG metabolism contributes to this dysfunction. Thus, our study provides new insights into DRG pathogenesis in FD and uncovers dysregulated PG metabolism as a promising therapeutic target for alleviating Fabry pain.
2026-08-18 | Long-Term Cardiac Remodeling During Migalastat Therapy in a Heterozygote Woman With Fabry Disease (N224S): A 9 Year Case Report.
BACKGROUND Fabry disease (FD) is a rare X‑linked lysosomal disorder in which long‑term cardiac outcomes, particularly in heterozygous females, remain incompletely defined. The N224S alpha-galactosidase A gene (GLA) variant is recognized as pathogenic, yet its cardiac phenotype and response to prolonged migalastat therapy are not well characterized. Although clinical trials and observational studies have reported variable cardiac responses to migalastat, real‑world longitudinal data beyond 5 years remain limited. Understanding long‑term structural and functional changes is especially important in patients with pre‑existing cardiac involvement, where distinguishing favorable remodeling from fibrosis‑related progression can be challenging. CASE REPORT We describe a 9‑year follow‑up of a 71‑year‑old heterozygous woman with FD due to the N224S mutation treated with migalastat. Serial transthoracic echocardiography demonstrated a sustained reduction in left ventricular mass index (LVMI) over long‑term therapy. Left ventricular systolic function remained preserved throughout follow‑up, and there was no evidence of progressive structural deterioration. Available Doppler‑derived diastolic indices, including a gradual decline in early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e'), suggested improving left ventricular filling pressures over time. Although LVMI showed minor year‑to‑year variability, these changes were consistent with expected technical or physiological variation and did not alter the clear long‑term downward trend. CONCLUSIONS This case provides real‑world evidence of favorable long‑term cardiac remodeling during migalastat therapy in a heterozygous woman with the N224S variant. The sustained reduction in LVMI, preserved systolic function, and improving diastolic indices together indicate a durable cardiac response and extend the limited longitudinal data available for variant‑specific outcomes in FD.
2026-08-07 | Pain in Fabry disease: do experimental models reveal novel therapeutic targets?
Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and progressive accumulation of globotriaosylceramide (Gb3). Although FD is a multisystemic disorder affecting the heart, kidneys, skin, and nervous system, pain is one of its earliest, most prevalent, and disabling manifestations. While several review articles have already addressed the clinical features and management of FD-associated pain, this review specifically focuses on the mechanisms underlying pain as revealed by experimental and preclinical models of the disease. By integrating findings from cellular and animal studies, we provide an updated overview of the molecular and neurobiological pathways implicated in FD-related pain, including dorsal root ganglia dysfunction, ion channel dysregulation, neuroimmune interactions, vascular abnormalities, and central sensitization processes. We further discuss how preclinical studies have identified novel therapeutic targets for pain, such as acid-sensing ion channels (ASIC), transient receptor potential (TRP) receptors, the prokineticin system, glial activation, and glutamatergic signaling, which may complement current disease-modifying therapies. By highlighting the translational relevance of these mechanistic insights, this review aims to bridge the gap between experimental research and the development of more effective pain-focused interventions. A better understanding of the pathophysiology of FD-associated pain may ultimately contribute to improving management strategies with a significant impact on the quality of life for affected individuals.
2026-08-06 | Unraveling A4GALT Mechanism and Its Modulation With Adamantyl-Galactosylceramide Analogues: Advancing Fabry Disease Therapeutic Strategies.
Fabry disease (FD), one of the most prevalent lysosomal storage disorders in Europe, is caused by mutations in the GLA gene leading to deficient α-galactosidase A activity with lysosomal accumulation of globotriaosylceramide (Gb3). Enzyme replacement therapy (ERT) and pharmacological chaperone therapy (PCT) are used in the clinic to treat FD but are limited in efficacy, underscoring the need for alternative therapeutic strategies. Inhibiting α-1,4-galactosyltransferase (A4GALT), the glycosyltransferase responsible for Gb3 biosynthesis, represents an attractive strategy. Here, we reveal the molecular mechanism of human A4GALT at atomic detail using QM/MM simulations. We reveal a conformational rearrangement involving a 310-helix that stabilizes the donor substrate and promotes a front-face SNi-like catalytic mechanism, in which a short-lived oxocarbenium-ion intermediate forms. The simulations informed the synthesis of a panel of glycosylceramide substrate analogues. Among these, AdaGalCer (Ada = adamantyl) proved able to reduce Gb3 production in fibroblasts while simultaneously being converted by A4GALT into the galactosylated product AdaGb2. These results provide a clear path towards inhibiting A4GALT, paving the way for potential new and effective FD therapeutics.
gene therapies
2026-09-29 | Fabry disease beyond the classical model: clinical presentation and diagnostic challenges in women.
The prevailing concept of Fabry disease as a condition affecting only males, being females considered merely carriers has been superseded by a more nuanced understanding of the condition as a highly complex multisystemic disorder. Contemporary evidence contradicts the prevailing paradigm that heterozygous women are asymptomatic, thereby underscoring substantial phenotypic heterogeneity and a considerable risk of irreversible organ damage. A high index of clinical suspicion is required for diagnosis, which includes family screening, multisystemic evaluation, determination of enzyme activity, and genetic testing, especially in women, in whom residual α-galactosidase A activity may be normal. The treatment of this condition is based on three fundamental approaches: enzyme replacement therapy, pharmacological chaperones, and emerging therapeutic strategies. The latter includes substrate-depleting therapy, mRNA-based therapies, and gene therapy. It is imperative to initiate treatment at an early stage in order to delay disease progression. This review summarizes the current evidence on the epidemiology, pathophysiology, diagnosis and treatment of Fabry disease, with particular emphasis on clinical variability and the relevance of the disease in women - who have historically been considered asymptomatic carriers - as well as the need for sex-specific studies.
2026-07-28 | Autophagy-Lysosomal Dysfunction as a Converging Mechanism of Cardiomyopathy in Lysosomal Storage Disorders: From Pathobiology to Targeted Therapy.
Cardiac disease is a leading cause of morbidity and early death across several lysosomal storage disorders (LSDs); however, the cardiomyopathies of Fabry, Pompe, and Danon disease are still largely treated as separate, substrate-specific disorders. We argue that they are better understood as variations on a single theme: the breakdown of the autophagy-lysosome system within cardiomyocytes. In the healthy heart, this system clears damaged proteins and organelles and is regulated by mTORC1 and the master regulator TFEB. Once lysosomal degradation or autophagosome-lysosome fusion fails, undegraded substrates and defective mitochondria accumulate, driving hypertrophy, interstitial fibrosis, and conduction disease. Danon disease, resulting from the loss of LAMP2, is the clearest example of a primary defect in autophagic flux, whereas the glycogen storage of Pompe disease and the globotriaosylceramide accumulation of Fabry disease impair flux through different upstream mechanisms that converge on the same downstream injury. The same framework extends to other storage disorders with cardiac involvement, such as mucopolysaccharidosis (MPS). We trace this shared pathobiology from molecule to bedside, examine biomarkers that reflect lysosomal and autophagic dysfunction rather than storage alone, and re-examine treatment in that light: why enzyme replacement therapy corrects substrate accumulation but leaves much of the autophagic and mitochondrial damage unresolved, and why gene therapy-particularly AAV9-LAMP2B for Danon disease-together with autophagy- and TFEB-directed strategies may help close that gap. Viewing these disorders through a single mechanistic lens reshapes how we monitor them and where future therapies should be directed.
2026-05-29 | Capsid Engineering of Adeno-Associated Viruses for Targeted Gene Therapy in Kidney Diseases.
The global burden of chronic and genetic kidney diseases poses a significant challenge to healthcare systems. Current therapies, including dialysis, transplantation, and supportive pharmacotherapies, cannot halt disease progression or address root causes, especially in monogenic disorders like Alport syndrome and Fabry disease. Adeno-associated virus (AAV)-based gene therapy is promising, enabling targeted correction of underlying genetic defects. However, renal delivery faces challenges, including cellular heterogeneity, anatomical barriers, and pre-existing immunity. This review evaluates advances in AAV capsid engineering to overcome these obstacles, focusing on strategies to enhance kidney-specific tropism, transduction efficiency, and immune evasion. We outline the evolution from conventional serotype selection to precision engineering via rational design, directed evolution, and in silico approaches. Artificial intelligence (AI) has emerged as a pivotal accelerator, with machine learning models and generative frameworks enabling data-efficient capsid optimization despite limited datasets. Multimodal AI, reinforcement learning, and agentic systems can refine renal targeting by balancing glomerular penetration, cell specificity, and safety. Future progress relies on scaling high-quality datasets through collaborative consortia, lab-in-the-loop validation, and explainable AI. By combining capsid engineering with renal pathophysiology insights, this roadmap paves the way for curative AAV therapies that move beyond current suboptimal treatments to correct underlying pathogenic mechanisms.
2026-04-27 | Liver Gene Therapy in Fabry Disease Mice With Low Doses of rAAV2/8 Expressing a Codon-Optimized hGLA cDNA Results in Long-Term Disease Correction.
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene, which encodes for Alpha Galactosidase-A (α-Gal A). α-Gal A deficiency leads to glycosphingolipid accumulation, like globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (lyso-Gb3), resulting in systemic symptoms and reduced lifespan. Current treatments such as enzyme replacement therapy (ERT) and chaperone therapy are noncurative and have limitations. Gene therapy is an interesting alternative approach that may overcome most of these limitations, and different approaches are currently being tested. Here, we developed a gene therapy approach using rAAV2/8 vectors, delivered intravenously, that target the liver to produce and secrete functional α-Gal A into circulation. This enzyme is then captured by organs expressing mannose-6-phosphate receptors, reducing glycosphingolipid accumulation in affected tissues. We generated a codon-optimized GLA cDNA with enhanced translatability that was expressed under a strong liver-specific promoter. In a dose escalation study in juvenile Gla knock-out (ko) mice, the lowest dose (3.0E11vg/kg) resulted in 85%-95% clearance of lyso-Gb3 in plasma and tissues, while doses of 3.0E12 vg/kg and higher showed 98%-100% clearance of the glycosphingolipid. All AAV doses were more effective than systemic α-Gal A administration (ERT). Long-term treatment showed normal levels of lyso-Gb3 in plasma and tissues, and corrected neuropathic involvement, as shown in the hot plate test. This study provides a proof-of-concept showing that the tested liver-specific gene therapy vector is capable of preventing disease progression in juvenile Fabry mice at relatively low doses and shows potential in treating both early- and late-onset FD in patients.
2026-04-19 | Beneficial bystander-enhanced cryptic splice rescue of cardiac-type Fabry GLA IVS4+919G>A by adenine base editing in patient fibroblasts.
The IVS4+919G>A mutation in the GLA gene, prevalent in East Asian populations, causes cardiac-type Fabry disease by creating an abnormal splice site. This results in the insertion of a 57-nucleotide segment between exon 4 and exon 5, introducing a premature stop codon and leading to a truncated, non-functional α-Gal A protein. We evaluated whether adenine base editing (ABEmax) can modulate this allele-induced cryptic splice event in patient-derived fibroblasts in vitro as a proof-of-concept. Two ABEmax/sgRNA constructs targeting intron 4 (ABEmax-sgRNA1 and ABEmax-sgRNA2) were tested; both induced on-target +919 A → G conversion with frequent bystander edits at +918/+920. Edited bulk populations and single-cell-derived clones showed restoration of correctly spliced GLA mRNA with reduced aberrant transcripts, increased GLA protein, higher α-Gal A activity (approaching wild-type levels in some clones), and reduced intracellular Gb3 signal. A focused next-generation sequencing panel identified a low-frequency intronic change at one predicted off-target locus without predicted coding consequences. These findings demonstrate in vitro splice rescue of a deep intronic, cardiac-type Fabry disease variant by adenine base editing and suggest that bystander edits in non-coding sequence can further enhance correction by suppressing cryptic splicing, with concordant improvements in α-Gal A activity and Gb3 signals.
proteins
2026-09-18 | Cardiomegaly of Unknown Origin: Why Morphology Still Matters in the Genetic Era - A Case of Cardiac Fabry Disease.
We report a 72-year-old man with long-standing hypertension, type 2 diabetes, and ischemic heart disease, in whom autopsy, following a fatal acute coronary syndrome, revealed marked cardiomegaly (heart weight, 911 g) and concentric myocardial hypertrophy (left ventricular wall thickness up to 2.4 cm) that appeared disproportionate to the expected degree of hypertensive and ischemic remodeling. Histological examination showed diffuse vacuolization of cardiomyocytes with a negative periodic acid-Schiff reaction; amyloidosis and glycogen storage diseases were excluded. Electron microscopy, α-galactosidase A activity, lyso-globotriaosylceramide measurement, and genetic testing were not available. Sudan III staining of frozen myocardial sections demonstrated intracellular lipid inclusions, providing supportive but non-specific evidence of a suspected non-classical (cardiac) variant of Fabry's disease. This case highlights the importance of careful morphological evaluation in the differential diagnosis of unexplained severe left ventricular hypertrophy and illustrates both the diagnostic utility and the limitations of conventional histopathological methods in autopsy practice.
2026-08-20 | Clinical and Biochemical Improvement After Switching From Agalsidase Alfa to Beta in a Boy With Classic Fabry Disease: A Case Report.
We described a 12-year-old boy with classic Fabry disease who was diagnosed through newborn screening. At age 6.2, he started agalsidase alfa based on evidence of subclinical organ involvement. At age 7.2, acroparesthesia subsequently developed. At age 10.9, after switching to agalsidase beta due to an insufficient clinical and biochemical response, his acroparesthesia resolved and plasma Lyso-Gb3 decreased. This report broadens the clinical understanding of children with Fabry disease.
2026-06-23 | Fabry Disease: Current Perspectives on Diagnosis and Management Strategies.
Fabry disease is a rare, X-linked lysosomal storage disorder caused by deficient α-galactosidase A activity, leading to progressive accumulation of globotriaosylceramide in multiple tissues. Its estimated incidence ranges from 1 in 40,000 to 1 in 117,000 live births. Fabry disease manifests primarily as 2 phenotypes: classic (type 1), presenting in childhood with neuropathic pain, fatigue, thermal intolerance, and early multiorgan involvement; and late onset (type 2), typically manifesting in adulthood with predominant cardiac or renal complications. Timely diagnosis requires clinical suspicion combined with enzymatic assays and genetic testing; however, atypical presentations and variability in female patients often delay recognition, underscoring the necessity for heightened clinical vigilance. Current therapeutic approaches primarily focus on enzyme replacement therapy and pharmacologic chaperones, aimed at enhancing quality of life and delaying organ dysfunction. Optimal management necessitates an individualized, multidisciplinary strategy encompassing nephrology, cardiology, genetics, clinical pharmacy, and pain management. Emerging treatments, including next-generation enzyme replacement therapies, substrate reduction therapy, gene therapy, and mRNA-based therapeutics, offer promising avenues for more effective and durable outcomes. Ongoing clinical trials and comprehensive long-term outcome studies are crucial for refining these innovative therapeutic strategies and further advancing patient care.
2026-05-29 | Modeling Fabry nephropathy: insights from experimental systems towards precision nephrology.
Fabry nephropathy is a major cause of kidney failure in Fabry disease, caused by pathogenic GLA variants that reduce α-galactosidase A activity and lead to globotriaosylceramide (Gb3) accumulation. In recent years, rapid advances in experimental modeling and emerging therapeutic strategies have dramatically reshaped understanding and treatment prospects for Fabry nephropathy. Experimental models - including cellular systems, patient-derived kidney organoids, and animal models such as zebrafish, Drosophila, mice and rats - have been pivotal in elucidating classic Gb3-dependent and novel Gb3-independent pathogenic mechanisms. These insights challenge the traditional Gb3-centric paradigm by highlighting other contributors, such as its metabolite lyso-Gb3, as well as α-synuclein accumulation and endothelial dysfunction. Despite established therapies for Fabry nephropathy, such as enzyme replacement and pharmacological chaperones, disease progression remains a clinical challenge, underscoring the urgent need for deeper mechanistic understanding and precision medicine approaches. This timely Review summarizes diverse model systems' unique strengths, limitations and translational potential to guide future research and therapeutic development for this complex disease.
2026-04-27 | Sex-based antibody subclass maturation drives direct enzymatic inhibition in fabry disease patients receiving enzyme replacement therapy.
Enzyme replacement therapy (ERT) for Fabry disease can elicit anti-drug antibodies (ADAs) that may diminish efficacy and limit clinical benefit. To develop and apply a multiplexed proteomic assay for quantitative, subclass-specific ADA and complement profiling in Fabry disease to inform personalized ERT selection. We created a targeted LC-MS/MS platform to quantify ADA binding across IgG1-4, IgM, and IgA1, and complement proteins C1Qc-C9, in serum from Fabry patients (n = 39) and healthy controls. Neutralizing capacity was measured via enzymatic inhibition assay. Subclass-specific cross-reactivity was assessed for agalsidase alfa, agalsidase beta, and pegunigalsidase alfa. IgG4 binding was significantly higher in Fabry males (p = 0.007), with no sex-based differences for other Ig classes. Complement binding (C1Qc, C3) was elevated in ∼25% of patients, with IgG1, IgG2, IgM, and IgA1 correlating with C1Qc (r > 0.6). Seven patients (three female) exhibited >50% ERT inhibition; IgG4 binding correlated with enzymatic inhibition (p < 0.0025) and elevated lyso-Gb3 in males (p < 0.02). We assessed cross-reactivity of IgG4 in a patient who had received only agalsidase alfa, finding a 49% reduction in IgG4 binding to Pegunigalsidase alfa compared to Agalsidase alfa (p = 0.003) and 45% to Peguingalsidase alfa compared to agalsidase beta (p = 0.035). IgG4 comprised >50% of immune complexes for agalsidase alfa/beta but only 25% for pegunigalsidase alfa, indicating a potentially distinct immunogenic profile. Quantitative subclass-specific ADA and complement profiling reveals sex-specific IgG4 patterns, neutralizing capacity, and ERT-specific immunogenic differences, supporting its utility for personalized therapy in Fabry disease. A novel multiplex LC-MS/MS assay quantifies ADA subclasses and complement in Fabry disease, uncovering distinct IgG4 patterns and ERT-specific profiles that enhance understanding of treatment immunogenicity.
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2026-09-04 | Generation of the functionally enhanced proximal tubular cells from human iPSC-derived kidney organoids.
Human renal proximal tubular epithelial cells (RPPTCs) are crucial for exploring the molecular and cellular mechanisms underlying the pathophysiology of kidney injuries. In this study, we generated the functionally enhanced kidney organoid-derived proximal tubule cells (FEKOPTCs) from human induced pluripotent stem cells. Heparan sulfate proteoglycans and transforming growth factor-β receptor inhibitor enhanced the functionality of PTCs isolated from the kidney organoids of which the vascularization and maturation were improved by heparan sulfate proteoglycans and vascular endothelial growth factor. FEKOPTCs showed significantly enhanced epithelial barrier function, polarization state, and transporter function, compared with primary human RPTECs, which led to improve the function of drug uptake. Transcriptomic characterization of FEKOPTCs revealed high similarity to PTCs of native human adult kidney. FEKOPTCs-on-chip are more sensitive predictors than RPTECs-on-chip for nephrotoxicity testing. By using CRISPR-Cas9 genetic mutation of alpha-galactosidase A, the causative gene of Fabry disease, alpha-galactosidase A-mutant FEKOPTCs, recapitulated the functional phenotype of Fabry disease. When FEKOPTCs were transplanted into the kidney parenchyma of NOD-SCID mice, they reassembled and regenerated proximal tubular structures with intact lumens and functional transporters. Taken together, our results suggest that FEKOPTCs are functionally enhanced PTCs and can be applied for nephrotoxicity testing, disease modeling, and regenerative medicine.
2026-06-25 | Inflammation in Cardiomyopathies: Cellular Mechanisms Across Cardiac Phenotype.
Cardiomyopathies are traditionally classified by structural and genetic phenotypes, but emerging evidence highlights chronic myocardial inflammation as a pivotal driver of disease progression across different etiologies. This review synthesizes the current literature on the cellular and molecular inflammatory mechanisms underlying hypertrophic cardiomyopathy, Anderson-Fabry disease, cardiac amyloidosis, arrhythmogenic cardiomyopathy, and dilated cardiomyopathy. Across these distinct conditions, endogenous triggers such as metabolic substrates, misfolded amyloid fibrils, mechanical stress, or viral genomes act as damage-associated molecular patterns. These stimuli activate innate and adaptive immune cascades, notably the Toll-like receptors, the NF-κB pathway, and the NLRP3 inflammasome. This immune activation establishes a pro-inflammatory microenvironment that promotes fibroblast reprogramming, myocardial edema, and progressive fibrotic or fibro-fatty remodeling. Inflammation is an active, core pathophysiological mechanism rather than a passive secondary bystander in cardiomyopathies. Recognizing these shared immune pathways provides a framework for improved risk stratification and highlights the potential for targeted immunomodulatory therapies to alter disease trajectories.
2026-03-14 | Advancing Gene Therapies and Novel Treatment Strategies for Infiltrative Cardiomyopathies: A Comprehensive Review of Targeted Interventions.
Recent progress in unraveling the molecular mechanisms of infiltrative Cardiomyopathies (CMPs) has created exciting opportunities for targeted therapies. These conditions, which include cardiac amyloidosis, sarcoidosis, Danon disease, Fabry disease, Mucopolysaccharidoses (MPS), and cardiac oxalosis, significantly impair cardiac function through complex pathogenic mechanisms. In cardiac amyloidosis, the accumulation of misfolded proteins into fibrillary amyloids disrupts myocardial structure, leading to inflammation, oxidative stress, and apoptosis. New treatments such as Antisense Oligonucleotides [ASOs], small interfering RNA [siRNA], and monoclonal antibodies have shown promising results in preclinical and clinical settings for managing amyloid deposition. Gene editing technologies, particularly CRISPR-Cas9, also have significant potential to deliver lasting therapeutic benefits by precisely correcting pathogenic mutations. Furthermore, managing Fabry disease with Enzyme Replacement Therapies [ERT] and chaperone molecules has improved cardiac outcomes; however, challenges remain in advanced stages due to ongoing myocardial involvement. Immunomodulatory strategies and innovative antibody-based therapies targeting pathological protein aggregates represent groundbreaking approaches that have shown efficacy in preclinical and earlyphase clinical trials. Despite these advancements, challenges remain, including the efficiency of drug delivery, possible off-target effects, and inconsistent clinical responses among different patient groups. Future research should focus on improving these therapies to increase their specificity and safety, ultimately enhancing patient outcomes and quality of life in infiltrative cardiomyopathies.
2026-01-01 | P055: Successful utilization of immune tolerance induction in a pediatric patient with classic Fabry disease: A case report
Fabry disease is a rare X-linked lysosomal disorder caused by a deficiency or absence of alpha-galactosidase A (α-Gal-A) enzyme. Fabry disease can largely be classified into two types: classic and atypical. Classic disease is defined by onset in childhood or adolescence with little to no α-Gal-A activity, while atypical disease is characterized by later disease onset with higher residual α-Gal-A enzyme activity. To date, the only FDA-approved enzyme replacement therapy for pediatric patients is agalsidase beta (Fabrazyme).
2025-11-01 | Complement and cardiac MRI biomarkers in Fabry disease cardiomyopathy
Abstract Introduction Fabry disease (FD) is a lysosomal storage disorder caused by α-galactosidase A deficiency, leading to globotriaosylceramide (Gb3) accumulation. Cardiomyopathy is the leading cause of FD-related mortality, yet its pathophysiology remains unclear. Current treatments have limited efficacy once left ventricular hypertrophy (LVH) develops, suggesting additional mechanisms such as inflammation. Complement-mediated inflammation, implicated in other lysosomal storage disorders (e.g., Gaucher disease),(1) may also contribute to FD cardiomyopathy. Purpose This study investigated inflammatory biomarkers associated with FD cardiomyopathy and their relationship with cardiac magnetic resonance (CMR) markers of disease severity to improve early diagnosis and intervention. Methods A total of 147 Fabry patients (58% female, 45 ±14 years, 43% LVH-positive; 42% ERT), 41 apical hypertrophic cardiomyopathy (aHCM) patients (75% male, 55 ±13 years), and 82 healthy controls (46% female, 51 ±18 years) with paired plasma and CMR were included. Prior targeted proteomic studies guided mass spectrometry-based biomarker profiling.(2) A validated AI tool assessed Left ventricular volumetrics and wall thickness.(3) A subset of Fabry patients (n=72) underwent comprehensive CMR analysis (GLS, T1/T2, LGE). Biomarkers were compared across cohorts using ANOVA with Dunnett’s post hoc testing. Correlations with myocardial parameters were assessed using Pearson’s coefficient and regression modelling. Sex differences in statistically significant complement biomarkers were analysed within the FD group using t-tests. Results Of 146 biomarkers, 53 were statistically significant. Fabry LVH showed complement activation via classical (C3, C4b, C4d) and alternative: complement factor D (CFD) pathways, amplified by immune complexes (IGHA1, IGHG2, IGHG3), distinct from aHCM, which exhibited predominantly extracellular matrix remodelling (Talin, NGAL, Versican, ECM1), fig 1. Complement activation was also present in Fabry patients without LVH, suggesting a pre-hypertrophy inflammatory phase. C3 and C4d were the only biomarkers differing between sexes in the LVH group (p<0.05), with higher complement levels in females, fig 2. GLS correlated with CFD (r= 0.40, p<0.05) and IGHG3 (-0.31, p<0.05), indicating a role for innate immunity in early myocardial dysfunction. While T1 mapping showed no significant correlations, T2 correlated with inflammatory markers (A2M, AGT). C3 was the only biomarker differing between LGE-positive and negative groups (p<0.05). Conclusions CMR detects early myocardial dysfunction in FD before hypertrophy, correlating with complement activation. These findings suggest revising the current staging model (4) to include a subclinical inflammatory phase. Complement-targeted therapies may enable early intervention, while CMR and biomarker analysis could facilitate early detection, risk stratification, and LVH prevention.
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Drug Discovery Landscape
34 orphan drug designations for Fabry disease, including 3 approved therapies.
34 orphan drug designations for Fabry disease, including 3 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
CD34+ hematopoietic stem/progenitor cells transduced with a lentiviral vector containing human codon-optimized alpha-gal A cDNA | gene therapies | FDA | Glafabra Therapeutics, Inc. | |
non-replicating, rep/cap-deleted, recombinant adeno-associated virus vector expressing human alpha-galactosidase A (hGLA) | gene therapies | FDA | — | Exegenesis Bio Co. |
adeno-associated viral vector serotype 5 encoding human alpha-galactosidase A | gene therapies | FDA | uniQure biopharma B.V. | |
recombinant human alpha-galactosidase A fused in-frame to the aglycosylated human IgG4 Fc mutein | proteins | FDA | — | GC Biopharma Corp. |
Recombinant adeno-associated virus vector serotype 5 (AAV5) harboring a codon-optimized human GLA transgene | gene therapies | FDA | — | Sichuan Real&Best Biotech Co., Ltd. |
autologous B cells engineered to secrete intact alpha-galactosidase A enzyme | cell therapies | FDA | — | Walking Fish Therapeutics |
a recombinant adeno-associated virus (AAV) vector that contains a bioengineered capsid (AAV-Spark100) and a codonoptimized expression cassette to drive expression of a secretable form of alpha-galactosidase A (alpha-Gal A) | gene therapies | FDA | — | Spark Therapeutics, Inc. |
N-[(1R,2R)-2-(3-chloro-4-cyclopropoxyphenyl)-2-hydroxy-1-(pyrrolidinylmethyl)ethyl]-2-(6-chloro(2-naphthyl))-2-(hydroxyimino)acetamide. | small molecules | FDA | AceLink Therapeutics, Inc. | |
Duvalgagene otiparvovec | gene therapies | EMA | Pharma Gateway AB | |
Cultured human retinal pigment epithelial cells (ARPE-19) genetically modified with a non-viral vector to express Human alpha-galactosidase A (h alpha-Gal A), encapsulated within two-layer modified alginate spheres | cell therapies | FDA | — | Sigilon Therapeutics, Inc. |
Alpha galactosidase A | proteins | EMA | Consejo Superior de Investigaciones Cientificas (CSIC) | |
Voxeralgagene autotemcel | gene therapies | EMA | PPD Bulgaria EOOD | |
Recombinant adeno-associated viral vector serotype S3 containing DNA encoding for human alpha-galactosidase A | gene therapies | FDA | Freeline Therapeutics Limited | |
Adeno-Associated Virus Serotype 2 capsid variant (4D-C102) carrying a transgene encoding a codon-optimized human alpha-galactosidase A gene | gene therapies | FDA | 4D Molecular Therapeutics, Inc. | |
Adeno-associated viral vector serotype S3 encoding human alpha-galactosidase A cDNA | gene therapies | EMA | Spur Therapeutics (Ireland) Limited | |
Adeno-associated virus serotype 2/6 encoding human alpha-galactosidase A cDNA | gene therapies | EMA | Yes Pharmaceutical Development Services GmbH | |
adeno-associated virus serotype 2/6 encoding a human alpha-galactosidase A cDNA | gene therapies | FDA | PTC Therapeutics, Inc. | |
autologous CD34+ cell- enriched population transduced with lentiviral vector encoding the codon-optimized human alpha-galactosidase A complementary deoxyribonucleic acid sequence. | gene therapies | FDA | AVROBIO, Inc. | |
Pegunigalsidase alfa [Elfabrio] | proteins | EMA | Chiesi Farmaceutici S.p.A. | |
Adeno-associated viral vector serotype 8 containing the human alpha-galactosidase A gene | gene therapies | EMA | Spur Therapeutics (Ireland) Limited | |
lucerastat | small molecules | FDA | Idorsia Pharmaceuticals US Inc. | |
Venglustat | small molecules | FDA | Genzyme Corporation | |
(3S)-1-azabicyclo[2.2.2]oct-3-yl{2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]propan-2-yl}carbamate | small molecules | EMA | Sanofi B.V. | |
N-Butyldeoxygalactonojirimycin | small molecules | EMA | Idorsia Pharmaceuticals Deutschland GmbH | |
Migalastat hydrochloride [Galafold] | small molecules | EMA | Approved | [INACTIVE] Amicus Therapeutics UK Limited |
migalastat hydrochloride [GALAFOLD] | small molecules | FDA | Approved | Amicus Therapeutics, Inc. |
a-Galactosidase A | proteins | FDA | iBio, Inc. | |
Agalsidase beta [Fabrazyme] | proteins | EMA | [INACTIVE] Sanofi B.V. | |
Agalsidase alfa [Replagal] | proteins | EMA | [INACTIVE] Shire Human Genetic Therapies AB | |
Alpha-galactosidase A | proteins | FDA | Takeda Pharmaceuticals U.S.A., Inc. | |
1,5-(Butylimino)-1,5 dideoxy,D-glucitol | small molecules | FDA | — | Oxford GlycoSciences |
Alpha-galactosidase A | proteins | FDA | David Calhoun, Ph.D. | |
Alpha-galactosidase A | proteins | FDA | Desnick, Robert J. M.D. | |
agalsidase beta [Fabrazyme] | proteins | FDA | Approved | Genzyme Corporation |
“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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