Grant: Project Grant

Tay-Sachs disease and Sandhoff Disease (also knows as the GM2 gangliosidoses) are inherited neurodegenerative diseases that result from genetic mutations that inactivate an enzyme known as HexA. HexA is a protein in our cells that degrades GM2-ganglioside (GM2), a molecule found primarily on neurons of the central and peripheral nervous system. HexA degrades GM2, and if it is not active, GM2 rapidly accumulates and causes severe neurological disease. The rate of GM2 accumulation depends on how severely the genetic mutations impact HexA activity. Totally inactive HexA leads to rapid GM2 accumulation and death by 1-4 years of age; whereas, mutations that allow for some residual HexA activity (1-10% of normal), GM2 accumulation is slowed and disease progression is delayed. While still neurologically debilitating, these late-onset forms of the disease may not significantly impact lifespan. Importantly, HexA activity as low as 10% can prevent, and possibly reverse, GM2 accumulation and the associated neurodegeneration. We hypothesize that a therapy for infantile and late-onset forms of GM2 gangliosidosis is achievable by supplementing patients with active Hex enzyme (i.e. enzyme replacement therapy), and in late-onset cases, combing enzyme replacement with drugs known to boost residual Hex activity to bring the total Hex activity above the critical 10% activity threshold. We have recently engineered HexA to markedly improve its stability and function for enzyme replacement therapy. We now propose to use the engineered enzyme, known as HexM, to develop an enzyme replacement therapy that will be evaluated in mouse models of GM2 gangliosidosis in combination with a drug known to rescue residual HexA activity in cells. Our approach holds promise to reduce GM2 accumulation and reverse the progression of this debilitating family of neurological diseases.