Our lab focuses on Lafora Disease (LD), which is the severest of the epilepsies. It strikes previously healthy young teenagers with seizures, which after they start never stop until the young patients dies after about 10 years of constant seizures. Our lab discovered the genes causing this disease and have made major progress understanding its pathogenesis. The two genes involved encode the laforin, a glycogen phosphatase, and malin, a ubiquitin E3 ligase. In the absence of either, neuronal glycogen is hyperphosphorylated, poorly branched, and insoluble. It precipitates and accumulates into massive neurotoxic Lafora bodies. The precise role of phosphate in glycogen is not known and exactly how the absence of these two proteins leads to the glycogen disturbance remains unclear. Meanwhile, we have shown that a mere reduction of glycogen synthesis by 50 percent completely rescues the mouse models of this disease, affording great hope for therapy for LD patients.
We have embarked in a multipronged approach to identify inhibitors of glycogen synthase, including antisense oligonucleotides, CRISPR/Cas9 delivered by AAV9 adenovirus, and small molecule inhibitors of glycogen synthase.
Our Lafora lab, therefore, is divided into two sections; one continuing the work on understanding the precise biochemistry of the glycogen disturbance, and the other in identifying the above molecules for therapy. In addition, we have experiments underway for straight gene replacement (laforin or malin) delivery to animal models of the disease.