Abstract
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.
Highlights
Enzyme and chaperone therapies are used to treat Fabry disease
Male patients with known Fabry disease from the Canadian Fabry Disease Initiative study of enzyme therapy (ET) were approached for possible enrollment
Seven male Fabry disease patients previously treated with ET, ages 29–48 years, were enrolled (Table 1, Supplementary Table 1); two patients failed screening tests associated with inclusion and exclusion trial criteria
Summary
Enzyme and chaperone therapies are used to treat Fabry disease Such treatments are expensive and require intrusive biweekly infusions; they are not efficacious. In Fabry disease, mutations of the X-linked GLA gene lead to accumulation of glycosphingolipids including globotriaosylceramide (Gb3)[1,2] and globotriaosylsphingosine (lyso-Gb3)[3,4] This results in end-organ damage to the kidneys, heart, and brain leading to a decreased life expectancy[5,6]. The short plasma half-life[12] requires biweekly infusions at considerable cost Despite these issues, ET is recommended for treatment of Fabry patients to prevent progression in conjunction with nonspecific adjunctive therapies[13,14,15]. Transgenic mice, with tissue α-gal A activity >10,000 times endogenous levels, were healthy and did not have altered cyto-architecture;[18,19] high levels of α-gal A may not be deleterious
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