Rare / Orphan, Metabolic, Neuroscience
Glycogen Synthase-Targeting Divalent siRNAs as a Therapy for the Fatal Teenage-Onset Epilepsy, Lafora Disease
2023 Harrington Scholar-Innovator
The most severe form of human epilepsy, Lafora Disease (LD), cruelly strikes patients in adolescence, progressing to continuous seizures during every waking moment of their shortened lives. Today’s treatment is primarily palliative and aimed at reducing seizures. Dr. Minassian, a pediatric neurologist who began investigating LD genetics in the mid-1990s, is testing a unique, divalent siRNA-based approach in mouse models with potential for transforming and saving human lives.
“Lafora Disease results from mutations of two genes, EPM2A and EPM2B, which encode for the Lafora and Malin proteins,” explains Dr. Minassian. “The proteins are integral to storing and releasing cellular glycogen molecules to make glucose for fueling body and brain functions. Normally, glycogen chains are shaped for solubility in the surrounding cellular fluid, enabling access by enzymes for glucose production. In LD, the chains lengthen and twist together, becoming insoluble. They precipitate occlusions of glycogen-derived particles called Lafora bodies. Glucose production is disrupted, ultimately leading to seizures.”
Collaborating with a University of Massachusetts genetics team, Dr. Minassian is testing divalent small interfering RNAs (siRNAs) to replace Laforin and Malin functions. Targeting and downregulating the glycogen synthase enzyme with siRNAs prevents glycogen chain deformity and particle accumulation. Normal glucose production and whole brain functioning is restored.
“If we can prevent abnormal glycogen accumulation in the mouse models for months at a time, we potentially can develop an annual therapy for commercialization,” he says. “My Harrington team has expertise in that area, which is invaluable for this project.”
Halting this horrific disease with a drug is tantamount to a cure, Dr. Minassian believes. “I want to help make a fundamental difference in families’ lives by eliminating Lafora Disease in as many cases as we can,” he says.