Lentivirus-mediated gene therapy for Fabry disease

• Published in: Nature communications Vol. 12; no. 1; pp. 1178 - 9
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 25.02.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: a-Galactosidase; Adult; Adverse events; alpha-Galactosidase - genetics; alpha-Galactosidase - therapeutic use; Antigens, CD34; Autografts; Bone marrow; Bone Marrow Cells; CD34 antigen; Enzymes; Fabry Disease - enzymology; Fabry Disease - genetics; Fabry Disease - therapy; Fabry's disease; Galactosidase; Gene therapy; Genetic Therapy - methods; Genetic Vectors; Globotriaosylceramide; Hematopoietic Stem Cells; Humans; Intravenous administration; Lentivirus - genetics; Leukocytes; Male; Medical treatment; Melphalan; Middle Aged; Peripheral blood; Phenotypes; Progenitor cells; Toxicity; Trihexosylceramides - blood; Trihexosylceramides - urine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21371-5

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 (Gb ) and globotriaosylsphingosine (lyso-Gb ) 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.