A new study uses a creative structure-based remodeling strategy to design a therapeutic protein that exhibits significant advantages over currently available treatments for a rare disease that often leads to cardiac and renal failure. The research, published by Cell Press on October 22nd in the American Journal of Human Genetics, describes a new and highly promising candidate for enzyme replacement therapy (ERT) for Fabry disease.
Fabry disease is a rare genetic disorder caused by a deficiency in alpha-galactosidase-A (GLA), an enzyme that breaks down fatty substances called glycolipids. Without the proper level of enzyme activity, a glycolipid called globotriaosylceramide (Gb3) accumulates to harmful levels inside cellular structures called lysosomes and damages the skin, nerves, eyes, kidneys and cardiovascular system. Although scientists have generated GLA for ERT, thus far this approach has proved challenging.
"Many patients have been successfully treated with these manufactured GLA proteins, but there are still problems to be resolved," explains senior study author Dr. Hitoshi Sakuraba from Meiji Pharmaceutical University in Tokyo. "For example, these enzymes are unstable in the blood, do not effectively reach the kidneys and heart and frequently cause an allergic reaction in Fabry patients."
Dr. Sakuraba and colleagues took a different approach and, instead of making recombinant GLA, attempted to alter a different enzyme, called ?-N-acetylgalactosaminidase (NAGA), so that it could function like GLA. Normally, NAGA catalyses the hydrolysis of a different type of substrate and does not recognize the same substrates as GLA. Importantly, although NAGA is structurally similar to GLA, it does not react with the immune system in the same way.