Towards in vivo gene therapy for methylmalonic-acidemia with homocystinuria

Combined methylmalonic acidemia and homocystinuria, cblC type, is a severe inherited metabolic disease due to a defect in a gene involved in the intracellular transport of cobalamin, a derivative of vitamin B12, obtained from the diet. This defect leads to several dysfunctions in multiple organs. The current treatment involves daily administrations of high-dose cobalamin-based drugs, which appear to control disease progression. However, the lack of a mouse model of the disease currently limits the development of potentially curative genetic therapies and a better understanding of the disease mechanisms and biology. In this project, we propose to generate such a model by genetic modification, starting from previously available genetically modified mice. Moreover, we will construct genetic engineering tools that represent the first step to developing genetic correction strategies for this disease in the future. Overall, the new mouse model of the disease will improve our understanding of the disease itself, and it will be crucial to develop new therapeutic approaches, including gene therapies.