Adipose Organ Transplant for Treatment of Maple Syrup Urine Disease

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DESCRIPTION (provided by applicant): The long-term goal of this research is to develop a new treatment for Maple Syrup Urine Disease (MSUD), an inborn error of metabolism that results in deficient branched chain keto acid dehydrogenase activity. In MSUD, branched chain amino and keto acids (BCAAs & BCKAs) accumulate in plasma and tissues, leading to progressive neurological damage, cognitive decline, vomiting, seizures, coma, and death. Standard treatment involves intensive nutritional support to lower BCAA intake. While this is generally effective, MSUD patients can experience extraordinary rises in circulating BCAAs and BCKAs in response to protein catabolism in illness or stress. Such rises may precipitate acute metabolic crises despite careful nutritional adherence. Organ transplant could be used to provide some metabolizing capacity in order to prevent or alleviate these metabolic crises. Indeed, published studies as well as others underway indicate great promise for elective liver transplantation in MSUD, with many subjects resuming a normal diet. Nevertheless, it is unlikely that elective liver transplant will be adopted as standard care for MSUD in the near future. Under the current UNOS allocation system, most MSUD patients would not qualify for donor livers outside of experimental studies, and at over a half million dollars, the first year costs of liver transplants challenge the practicality of this approach. As an alternative, we propose to test the hypothesis that adipose organ transplant might be an effective treatment for MSUD. Recent studies from our laboratory have shown that both human and rodent adipose tissues possess far higher BCAA oxidative capacities than previously appreciated. Adipose tissue is highly amendable for transplantation because of its low oxygen requirements, along with its abilities to both reorganize into tissue from cells and re-vascularize. Based on adipose tissue's use in plastic surgery, first year costs of adipose transplant could be 10-20 times lower than that for liver and arguably, obtaining adipose organ donors would be much easier. Another option would be to repair mutated genes in adipose precursor cells for autogenic re-implantation. In preliminary studies, transplant of a very small amount of normal adipose tissue into a mouse model of MSUD (BCATm KO) led to considerable reductions in circulating BCAAs. However tests in other models that more closely mimic human MSUD are needed, as are approaches to quantitatively improve upon this success. To test our hypothesis, two specific aims will determine the effect of adipose tissue transplant in different mouse models of MSUD and test strategies to quantitatively improve upon the plasma BCAA lowering following adipose tissue transplant or transplant of adipose precursor cells. The results of these studies will provide further evidence of the feasibility of this approach and guide us toward best practices and approaches to achieve a new therapy for MSUD.