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.

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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.

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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.

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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.

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2026-07-20 | Population Pharmacokinetic Modeling for the Iminosugar Lucerastat Supports Dose Adaptation in Patients With Fabry Disease and Moderate to Severe Renal Function Impairment.

Lucerastat is an iminosugar with the potential to provide substrate reduction therapy for the treatment of Fabry disease (FD), an inherited X-linked lysosomal storage disorder. The aims of this study were to develop a population pharmacokinetic (PK) model describing lucerastat plasma concentration over time, to investigate the relationships between subject-specific characteristics and model parameters, and to assess the influence of these differences between subjects on lucerastat exposure via model-based simulations. Longitudinal nonlinear mixed effects modeling was applied to develop a model based on data from 250 participants in six Phase 1 and two Phase 3 studies. Lucerastat pharmacokinetics were described by a two-compartment model with linear first-order absorption and elimination, including allometric scaling of body weight on clearance and volume parameters. Lucerastat clearance was reduced in subjects with lower estimated glomerular filtration rate (eGFR). Disease status (with/without FD) was found to impact clearance and volumes of distribution to a limited extent. The model described the data well across the dose range from 100 to 4000 mg. Body weight, disease status, and renal function were shown to influence exposure, with dose adaptation only required in patients with renal function impairment, as body weight and disease status had limited impact. Dose adaptation as applied in Phase 3 (i.e., eGFR [mL/min/1.73 m2] ≥60: 1000 mg; ≥45 and <60: 750 mg; ≥30 and <45: 500 mg; ≥15 and <30: 250 mg b.i.d.) resulted in achieving similar exposure in study participants with FD with different levels of renal function impairment.

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