Lentivirus-mediated gene therapy for Fabry disease.

Khan, Aneal; Barber, Dwayne L; Huang, Ju; Rupar, C Anthony; Rip, Jack W; Auray-Blais, Christiane; Boutin, Michel; O'Hoski, Pamela; Gargulak, Kristy; McKillop, William M; Fraser, Graeme; Wasim, Syed; LeMoine, Kaye; Jelinski, Shelly; Chaudhry, Ahsan; Prokopishyn, Nicole; Morel, Chantal F; Couban, Stephen; Duggan, Peter R; Fowler, Daniel H; Keating, Armand; West, Michael L; Foley, Ronan; Medin, Jeffrey A

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 (α-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 α-gal A to near normal levels within one week. Vector is detected in peripheral blood and bone marrow cells, plasma and leukocytes demonstrate α-gal A activity within or above the reference range, and reductions in plasma and urine globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) 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.