A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies.

摘要: Fabry disease results from deficient α-galactosidase A (α-Gal A) activity and the pathologic accumulation of globotriaosylceramide (GL-3) related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, affected patients generally die their 40s or 50s. Preclinical studies recombinant human α-Gal (r-hαGalA) infusions knockout mice demonstrated reduction GL-3 tissues plasma, providing rationale for a phase 1/2 clinical trial. Here, we report single-center, open-label, dose-ranging study r-hαGalA treatment 15 patients, each whom received five at one dose regimens. Intravenously administered was cleared circulation dose-dependent manner, via both saturable non-saturable pathways. Rapid marked reductions plasma tissue were observed biochemically, histologically, and/or ultrastructurally. Clearance dose-dependent. In with pre- posttreatment biopsies, mean content decreased 84% liver (n=13), markedly reduced kidney four after doses modestly lowered endomyocardium seven patients. deposits to near normal endothelium liver, skin, heart, kidney, on basis light- electron-microscopic evaluation. addition, reported less pain, increased ability sweat, improved quality-of-life measures. Infusions well tolerated; experienced mild-to-moderate reactions, suggestive hypersensitivity, that managed conservatively. Of 8 (53%) developed IgG antibodies r-hαGalA; however, not neutralizing, as indicated by unchanged pharmacokinetic values 1 5. This provides 3 trial enzyme-replacement therapy disease.