Adipose Organ Transplant for Treatment of Maple Syrup Urine Disease

描述(申请人提供)：这项研究的长期目标是开发一种新的治疗枫糖浆尿病(MSUD)的方法，MSUD是一种先天的代谢错误，导致支链酮酸脱氢酶活性不足。在MSUD中，支链氨基酸和酮酸(BCAAs和BCKAs)在血浆和组织中积累，导致进行性神经损害、认知能力下降、呕吐、癫痫发作、昏迷和死亡。标准治疗包括强化营养支持，以减少支链氨基酸的摄入量。虽然这通常是有效的，但MSUD患者在疾病或压力下，由于蛋白质分解代谢，循环中BCAA和BCKA的水平可能会异常上升。尽管谨慎地坚持营养，但这种升高可能会引发严重的新陈代谢危机。器官移植可以用来提供一定的代谢能力，以预防或缓解这些代谢危机。事实上，已发表的研究以及正在进行的其他研究表明，随着许多受试者恢复正常饮食，选择性肝移植在MSUD中大有希望。然而，在不久的将来，选择性肝移植不太可能成为MSUD的标准护理。在目前的UNOS分配系统下，大多数MSUD患者在实验研究之外没有资格获得捐献肝脏，而且超过50万美元的肝脏移植第一年的成本挑战了这种方法的实用性。作为另一种选择，我们建议检验脂肪器官移植可能是治疗MSUD的有效方法的假设。我们实验室最近的研究表明，人类和啮齿动物的脂肪组织都具有比以前认识的更高的支链氨基酸氧化能力。脂肪组织是高度可移植的，因为它的低氧气需求，以及它的能力，既可以从细胞重组为组织，也可以重新形成血管。根据脂肪组织在整形手术中的使用情况，脂肪移植的第一年成本可能比肝脏低10-20倍，而且可以说，获得脂肪器官捐赠者会容易得多。另一种选择是修复脂肪前体细胞中的突变基因，以便进行自体重新植入。在初步研究中，将非常少量的正常脂肪组织移植到MSUD(BCATm KO)的小鼠模型中，可以显著减少循环中的BCAA。然而，需要在其他更接近于人类MSUD的模型中进行测试，以及在这一成功的基础上进行量化改进的方法。为了验证我们的假设，有两个特定的目标将确定脂肪组织移植在不同的MSUD小鼠模型中的效果，以及测试定量改善脂肪组织移植或脂肪前体细胞移植后血浆支链氨基酸降低的策略。这些研究的结果将为这一方法的可行性提供进一步的证据，并指导我们走向实现MSUD新疗法的最佳实践和方法。 公共卫生相关性：我们建议调查脂肪移植作为治疗枫糖浆尿病(MSUD)的一种方法。MSUD是一种遗传性疾病，会导致癫痫发作、昏迷、智力低下和死亡。它是由利用食物中某些蛋白质分解产物所需的一个或多个基因突变引起的。虽然这些产品在正常情况下是生命所必需的，但如果像MSUD那样累积，它们也可能导致大脑损伤。肝脏转移剂在治疗这种疾病的实验中取得了成功，但肝脏移植非常昂贵，而且供体肝脏不足以满足器官需求。然而，我们的团队发现，脂肪组织中有大量的酶活性在MSUD中缺失，令人惊讶。我们建议验证脂肪移植可能是治疗MSUD的一种有效的新疗法的假设。在MSUD模型上进行的第一次成功的脂肪移植试验很有希望。我们建议进一步评估这一想法和测试方法，以改进我们第一次成功测试的结果。这些研究的结果可能为MSUD的新治疗选择铺平道路。

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. PUBLIC HEALTH RELEVANCE: We propose to investigate the use of fat transplant as a treatment for Maple Syrup Urine Disease (MSUD). MSUD is an inherited disorder that leads to seizures, coma, mental retardation and death. It is caused by mutations in one or more genes required to utilize certain break down products of protein in food. While these products are essential for life under normal circumstances, they can also cause brain damage if allowed to accumulate as in MSUD. Liver translant has been tried experimentally for this disease with success, however liver transplants are extemely expensive and there are insufficient donor livers to meet organ demand. However, our group has discovered that fat tissue has a surprisingly great amount of the enzyme activity missing in MSUD. We propose to test the hypothesis that fat transplant might be an effective new treatment for MSUD. A first successful test of fat transplantation in a model of MSUD was promising. We propose to further evaluate this idea and test ways to improve upon the results of our first successful test. The outcome of these studies could lay a path to a new treatment option for MSUD.