Evaluating the efficiency of in vivo gene transfer to correct the molecular neuropathology causing psychiatric disease in MSUD - Project summary Maple Syrup Urine Disease (MSUD) is an autosomal recessive amino acid metabolism disorder that is regarded as the most severe amino acidopathy and is invariably fatal if left untreated. MSUD is caused by buildup of the branched chain amino acids (BCAAs) leucine, isoleucine and valine. The current standard of care for MSUD is either BCAA-free formula diet or liver transplantation. MSUD liver transplantation does do not reverse prior damage to the CNS, does not prevent the low IQ, ADHD or the profound psychiatric disease, which is unresponsive to antidepressants. MSUD also naturally occurs in calves, and the disease is strikingly similar to humans both in disease course, biochemistry and post-mortem analyses. In proof-of-concept data we treated an MSUD calf by intravenous adeno associated viral (AAV) gene therapy and our therapeutic response was equivalent to that of the standard of care (liver transplant or formula diet) in MSUD patients. However, the calf exhibited white matter abnormalities on MRI like that of MSUD patients, low glutamate on MR spectroscopy and in cerebrospinal fluid, also consistent with human MSUD. Therefore, this proposal focuses on addressing the neurological aspects of MSUD while maintaining the biochemical correction in the periphery. Our team consists of Dr. Dan Wang, an AAV gene therapy expert that tested this therapy in MSUD mice and showed profound efficacy, Dr. Guangping Gao the director of the Horae Gene Therapy Center who has subsidized the cost to make sufficient amounts of AAV to treat MSUD calves and Dr. Kevin Strauss, the physician who cares for all the MSUD patients and has pioneered all the therapeutic approaches for MSUD including liver transplant and developed the MSUD formula. Dr. Gray-Edwards (PI) is an expert in large animal AAV gene therapy and has taken several AAV gene therapies to the clinic through testing in large animal models of human genetic diseases. The experimental aims of the proposal is as follows: Aim 1: Determine if high dose intravenous or combined intravenous and CSF delivery of AAV9-A-BiP-B can address the neurological components of MSUD. Aim 2: Long term assessment of the best AAV gene therapy approach Aim 3: Underpinning transcriptomic and metabolomic changes in the MSUD brain receiving the standard of care and determining the effect of gene therapy.
