Targeted approaches emerge in Fabry disease
By Agata Buczak
New clinical, cellular, and real‑world data (RWD) presented at WORLDSymposium 2026 (We’re Organizing Research on Lysosomal Diseases) reveal that measurable cardiac involvement in Fabry disease (FD) may occur far earlier than previously recognized, while evolving treatment and gene‑therapy data offer insights into how different therapeutic strategies perform across the disease spectrum.
Ashwin Roy (University of Birmingham Institute of Cardiovascular Sciences, UK) presented serial clinical, cellular, and computational analyses indicating that atrial electrical abnormalities emerge at the earliest detectable stage of FD. Electrocardiographic (ECG) data from 115 adults with FD showed that stage 1 disease was associated with P‑wave duration and PQ interval shortening, preceding structural changes. FD cohorts also demonstrated a higher burden of premature atrial complexes and atrial fibrillation compared with controls.
The team used genome‑edited induced pluripotent stem cell (iPSC)‑derived atrial cardiomyocytes carrying a GLA p.N215S variant alongside biatrial computer models. These systems showed intrinsic electrical and calcium-handling abnormalities, which the presenters noted reproduced early ECG findings and created a proarrhythmic substrate.
Roy concluded: “Stage 1 phenotype‑negative disease is not truly phenotype‑negative, as even patients with normal routine cardiac investigations show early changes… all of which may be proarrhythmic when incorporated into our computer model.” He added that these findings may prompt reconsideration of treatment timing in FD.
Another study addressed treatment outcomes in patients newly initiating therapy for FD. Using RWD from the followME Fabry Pathfinders registry, Peter Nordbeck (University of Würzburg, Germany) presented a propensity‑matched analysis comparing migalastat with enzyme replacement therapy (ERT). Fabry‑associated clinical events (FACEs) occurred at 55.3 events per 1,000 patient–years with migalastat versus 100.7 events per 1,000 patient–years with ERT. This corresponded to an event rate ratio of 0.55. Cardiac, renal, and cerebrovascular FACEs were also assessed, and renal outcomes were evaluated in a matched subgroup using the eGFR CKD‑EPI slope.
Nordbeck noted that the analysis reflects ongoing real‑world follow‑up and concluded that “these data provide evidence supporting beneficial treatment effects of long‑term migalastat in patients with FD.”
Michael West (Dalhousie University, Halifax, Nova Scotia, Canada) presented long‑term findings from an investigational lentiviral gene‑therapy approach in the phase 1 FACTS trial. West reported that all five treated male patients with classical FD engrafted by day 12 with no safety issues, demonstrating feasibility and sustained α‑galactosidase A increases over 5 years. Renal function remained stable, and substrate levels decreased or remained stable over 5 years. No FACEs occurred in the gene‑therapy cohort, compared with 51 events in 22 of 55 matched controls in the Canadian Fabry Disease Initiative registry receiving ERT.
West stated that “the absence of clinical events and stable organ measures supports the favorable long‑term profile observed in this early‑phase study.”
Collectively, these studies highlight advances spanning early disease detection, personalized therapy selection, and emerging gene‑therapy strategies, each contributing new evidence toward more targeted management of FD.
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