Fabry's Disease

Fabry’s Disease an X-linked lysosomal storage disease that is caused by a mutation in the gene that controls production of the enzyme trihexosidase, also called alpha-galactosidase-A (α-Gal A). The mutation results in the lack of or faulty production of this enzyme which is required to catabolise certain lipids. As a result there is progressive lysosomal deposition of the glycolipid, globotriaosylceramide (Gb3), to harmful levels in the eyes, kidneys, autonomic nervous system, and cardiovascular system. Glycolipid storage may lead to impaired arterial circulation and increased risk of heart attack or stroke.

The only known gene to be associated with this disease is GLA, with nearly 100% of affected males having an identifiable mutation. Heterozygous females typically have milder symptoms at a later age of onset than males. A carrier female has a 50% chance of transmitting the GLA mutation in each pregnancy. An affected male transmits his mutation to all of his daughters.

Treatment
Enzyme Replacement Therapy (ERT) is the only treatment currently available. Recombinant or gene-activated human α-Gal A enzymes Fabrazyme® (algalsidase beta) and ReplagalTM (algalsidase alpha) are both in use in Australia. ERT is an on-going treatment, approximately every 14 days, which replaces the missing enzyme thus reducing the plasma glycolipid levels.

Research
Gene replacement therapy has been investigated in the mouse model of Fabry’s disease but no human trials have been undertaken to date.

Recent gene transfer experiments have revealed the expression of human α-gal A in Fabry’s induced mice treated with a recombinant adeno-associated virus (rAAV) encoding the human α-gal A gene driven by a modified chicken β-actin.

Figure 1. Western blot analysis of α-gal A expression in the liver of wild-type and α-gal A knockout mice.
Lane 1, liver lysates from wild-type mice;
Lane 2, noninjected α-gal A knockout mice;

Lanes 3–5, liver lysates from three separate α-gal A knockout mice i.v.-injected with rAAV-CAG-hAGA vector;
Lane 6, human α-gal A.

These findings may lead to the development of an effective curative treatment for patients with Fabry’s Disease as well as for other lysosomal storage disorders.

by Mark Meyers
4208068

References:

Articles:

Atul Mehta, Derralynn A Hughes: Fabry’s Disease http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=fabry#fabry

The Lancet, Volume 357, Issue 9250, Pages 138 - 140, 13 January 2001

Jinhee Park, Gary J. Murray, Advait Limaye, Jane M. Quirk, Monique P. Gelderman, Roscoe O. Brady, and Pankaj Qasba:
Long-term correction of globotriaosylceramide storage in Fabry mice by recombinant adeno-associated virus-mediated gene transfer
http://www.pnas.org/content/100/6/3450.full

Image: http://www.pnas.org/content/100/6/3450/F1.small.gif