Enzyme replacement therapy (ERT) controls Fabry disease but does not cure it, and its limitations fall into five categories: incomplete tissue reach, pharmacokinetic instability, immunogenicity, treatment burden, and cost.

Fabry disease is an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A (alpha-Gal A). Without adequate enzyme activity, the substrate globotriaosylceramide (Gb3) and its deacylated form (lyso-Gb3) accumulate in cells throughout the body, driving progressive kidney failure, cardiac disease, stroke, and neuropathic pain. ERT, delivered as a biweekly intravenous infusion of recombinant enzyme, is the long-standing standard of care. Its limitations are well documented:

Incomplete tissue penetration. Infused enzyme does not distribute equally to all affected compartments. Uptake into cardiomyocytes and the nervous system is limited, so cardiac and renal disease can continue to progress even in adherent patients. Long-term registry and natural-history data show ongoing organ decline despite consistent ERT.

Short half-life and peak-to-trough variability. Circulating enzyme clears within hours, so substrate can begin re-accumulating well before the next infusion. Patients often describe feeling relatively well after a dose and symptomatic again in the days before the next one, rather than experiencing the steady-state enzyme exposure that continuous endogenous production would provide.

Immunogenicity. A substantial share of patients, particularly those with classic (near-zero enzyme) genotypes, develop anti-drug antibodies against the infused enzyme. These antibodies can neutralize activity and reduce clinical benefit over time, and this population has limited alternatives.

Lifelong treatment burden. ERT requires roughly 26 infusions per year, indefinitely, each typically taking several hours. This carries meaningful quality-of-life, adherence, and discontinuation consequences, and the burden compounds across decades of treatment.

Cost and access. Annual ERT costs commonly run $300,000 to $500,000 dollars per patient and do not fully prevent long-term organ damage, which raises persistent questions about long-term value and access.

These limitations are not abstract; they track closely with what patients say matters most. In a Glafabra patient-community survey (n = 51) asking which single symptom a new therapy should improve, the top three responses were peripheral neuropathic pain of the feet and hands (31%), fatigue (22%), and gastrointestinal symptoms (20%), together roughly 73% of respondents. A further ~12% named a cardiac symptom as a write-in even though no cardiac option was listed, suggesting cardiac concern is under-counted. Those leading priorities, peripheral nerve, systemic energy, GI, and cardiac, are precisely the domains ERT addresses least completely, which helps explain why symptom burden often persists despite adherence. This is a self-selected community sample and a symptom-prioritization exercise, not a powered clinical outcome measure, but it is a useful window into lived patient priorities.

Two points of balance are worth stating. ERT remains a genuine advance over no disease-specific treatment and has improved outcomes for many patients, especially when started early. And the alternatives each carry their own constraints: the oral chaperone migalastat only works for the roughly 35 to 50 percent of patients with an amenable GLA variant and does not create new enzyme, while investigational one-time gene therapies raise separate questions around durability, re-dosing, and eligibility. The limitations of ERT are best understood not as reasons to abandon it, but as the unmet needs a next generation of therapies is trying to close: durable, steady-state enzyme production, broader tissue reach, and freedom from the infusion cycle.

Glafabra is developing Live-cel, an autologous cell-based gene therapy (GT-GLA-S03) aimed at these specific gaps. It is at the pre-IND stage.