Lentivirus-mediated gene therapy for Fabry disease

Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments are expensive and require intrusive biweekly infusions; they are also not particularly efficacious. In this pilot, single-arm study (NCT02800070), five adult males with Type 1 (classical) phenotype Fabry disease were infused with autologous lentivirus-transduced, CD34(+)-selected, hematopoietic stem/progenitor cells engineered to express alpha-galactosidase A (alpha -gal A). Safety and toxicity are the primary endpoints. The non-myeloablative preparative regimen consisted of intravenous melphalan. No serious adverse events (AEs) are attributable to the investigational product. All patients produced alpha -gal A to near normal levels within one week. Vector is detected in peripheral blood and bone marrow cells, plasma and leukocytes demonstrate alpha -gal A activity within or above the reference range, and reductions in plasma and urine globotriaosylceramide (Gb(3)) and globotriaosylsphingosine (lyso-Gb(3)) are seen. While the study and evaluations are still ongoing, the first patient is nearly three years post-infusion. Three patients have elected to discontinue enzyme therapy. Treatments for Fabry disease, an inherited lysosomal disorder caused by the deficiency of the enzyme alpha-galactosidase A, are not fully efficacious. Here the authors report a single-arm phase I trial of gene therapy with autologous, lentivirus-transduced, hematopoietic cells that express alpha-galactosidase A to demonstrate that this approach is safe in five patients with Fabry disease.

Automated summary

Enzyme and chaperone therapies for Fabry disease are expensive, intrusive, and not fully efficacious. A pilot study was conducted using gene therapy with autologous, lentivirus-transduced hematopoietic cells expressing alpha-galactosidase A, showing safety and promising results in five patients.