Grant: Project Grant

Infants who have ABGM2 accumulate a type of brain fat known as GM2 ganglioside in their brain cells. This leads to rapid degeneration of their brain and death by 4-5 years of age. Early childhood mortality, coupled with a lack of treatment, underscores an urgent need to develop a gene therapy for this highly debilitating and lethal disorder. In recent years, there have been significant developments on the gene therapy front, including trials that have shown curative promise. ABGM2 arises from mutations in a single gene which makes it ideal for gene therapy. Gene therapy works by using viruses to deliver a normally functioning gene to replace a mutant version. ABGM2 arises because of inheritance of a gene called GM2A, which carries ABGM2-causing mutations. Because of these mutations, GM2A produces a poorly working version of the protein which it normally codes. This protein is known as the GM2A-protein, or GM2AP for short. GM2AP works to breakdown GM2 gangliosides. However, the poorly working version of GM2AP is unable to do this. This results in accumulation of GM2 gangliosides in brain cells, which ultimately kills them, and leads to brain degeneration. Our lab specializes in developing gene therapies. We developed a gene therapy (called hB-A) that treats two other diseases like ABGM2 called Tay-Sachs and Sandhoff disease. hB-A is being tested in first gene therapy trial for TSD/SD. Working along similar lines, we have established proof that a gene therapy, which we call hGM2A-3, can treat mild forms of ABGM2 in animals. In this study, we will test the safety and effectiveness of hGM2A-3 in a mouse model representative of a more prevalent and severe form of ABGM2. Our goal is to identify a treatment-dose with acceptable safety for testing in a future clinical trial for individuals born with ABGM2. We will also collect data on cases of ABGM2 worldwide to build a database that will serve as a control-arm for detecting positive therapeutic responses in a trial.