Date of Degree

9-2017

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor

David H. Calhoun

Committee Members

Haiping Cheng

M. Lane Gilchrist

Frederick R. Maxfield

Kevin Ryan

Subject Categories

Biochemistry | Chemicals and Drugs

Keywords

alpha Galactosidase, Enzyme Replacement Therapy, Fabry Disease, Mannose Receptor, Scavenger Receptor

Abstract

Mutations in the GLA gene that encodes the lysosomal enzyme α-galactosidase A (αGal) result in the sphingolipidoses named Fabry disease. This enzymatic defect is inherited as an X-linked recessive disorder and is associated with a progressive deposition of glycosphingolipids, including globotriaosylceramide (GB3), galabioasylceramide, and blood group B substance in the cell. In affected males, and in some females, this leads to early death due to occlusive disease of the heart, kidney, and brain. This disease is currently treated by infusions of αGal, prolonging patients’ lives but producing antibodies against the enzyme reducing the treatment efficacy. Treatment also causes numerous and sometimes life threatening infusion related adverse reactions, including anaphylactic shock, and even death in rare occasions. Here we propose two potential improvements to the current therapeutic practices which would allow for more effective enzyme therapies. The first is constructing and analyzing potentially more active carboxyl-terminal deletions of αGal and the second focuses on targeting of αGal to the very high uptake scavenger receptor (SR) for improved transport to the lysosome.

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