Adipose Organ Transplant for Treatment of Maple Syrup Urine Disease

脂肪器官移植治疗枫糖浆尿病

• 批准号: 8091967
• 负责人: CHRISTOPHER JOHN LYNCH
• 金额: $ 19.14万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091967
• 关键词: 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); Acids; Acute; Adherence; Adipose tissue; Adopted; Affect; Amish; Blood Vessels; Brain Injuries; Branched-Chain Amino Acids; Catabolism; Cells; Cessation of life; Clinic; Coma; Complex; Coupled; Data; Diet; Dietary Intervention; Disease; Disease model; Effectiveness; Enzymes; Exploratory/Developmental Grant; Fatty acid glycerol esters; Food; Future; Genes; Goals; Human; Impaired cognition; In Vitro; Inborn Errors of Metabolism; Inborn Genetic Diseases; Infection; Intake; Keto Acids; Laboratories; Laparotomy; Lead; Life; Liver; Maple Syrup Urine Disease; Mental Retardation; Metabolic; Metabolism; Modeling; Mus; Mutate; Mutation; Nervous System Trauma; Nutritional; Nutritional Support; Odors; Operative Surgical Procedures; Organ; Organ Donor; Organ Transplantation; Outcome; Outcome Study; Oxygen; Patients; Peripheral; Plasma; Plastic Surgical Procedures; Procedures; Production; Proteins; Publishing; Qualifying; Reconstructive Surgical Procedures; Recruitment Activity; Research; Risk; Rodent; SCID Mice; Sampling; Seizures; Stress; System; Technology; Telomerase; Testing; Time; Tissues; Transgenic Organisms; Transplantation; United Network for Organ Sharing; United States National Institutes of Health; Urine; Vomiting; Wild Type Mouse; Work; Xenograft procedure; base; cost; effective therapy; enzyme activity; experience; gene cloning; implantation; improved; in vivo; innovation; liver transplantation; meetings; mouse model; offspring; precursor cell; prevent; repaired; research study; response; standard care; standard of care; success

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.

描述（由申请人提供）：本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，这是一种先天性代谢缺陷，导致支链酮酸脱氢酶活性不足。在MSUD中，支链氨基酸和酮酸（BCAA & BCKAs）在血浆和组织中积累，导致进行性神经损伤、认知下降、呕吐、癫痫发作、昏迷和死亡。标准治疗包括强化营养支持以降低BCAA摄入量。虽然这通常是有效的，但MSUD患者可以在疾病或压力中对蛋白质catenin做出反应，从而经历循环BCAA和BCKAs的异常升高。这种升高可能会导致急性代谢危机，尽管谨慎的营养坚持。器官移植可以提供一定的代谢能力，以预防或缓解这些代谢危机。事实上，已发表的研究以及其他正在进行的研究表明，MSUD的选择性肝移植前景广阔，许多受试者恢复正常饮食。然而，在不久的将来，选择性肝移植不太可能被采纳为MSUD的标准治疗。根据目前的UNOS分配系统，大多数MSUD患者在实验研究之外没有资格获得供体肝脏，并且超过50万美元，肝脏移植的第一年费用挑战了这种方法的实用性。作为替代方案，我们建议测试的假设，脂肪器官移植可能是一种有效的治疗MSUD。我们实验室最近的研究表明，人类和啮齿动物的脂肪组织具有比以前认识到的更高的BCAA氧化能力。脂肪组织是高度可移植的，因为它的低氧气需求，沿着其能力，既重组成组织的细胞和再血管化。基于脂肪组织在整形外科中的使用，脂肪移植的第一年成本可能比肝脏低10-20倍，并且可以说，获得脂肪器官供体要容易得多。另一种选择是修复脂肪前体细胞中的突变基因，以进行自体再植入。在初步研究中，将非常少量的正常脂肪组织移植到MSUD小鼠模型（BCATm KO）中，导致循环中的支链氨基酸显著减少。然而，需要在更接近模拟人类MSUD的其他模型中进行测试，以及在此成功基础上定量改进的方法。为了检验我们的假设，两个具体的目标将确定脂肪组织移植在不同的MSUD小鼠模型中的作用，并测试策略，以定量改善脂肪组织移植或脂肪前体细胞移植后血浆BCAA的降低。这些研究的结果将为这种方法的可行性提供进一步的证据，并指导我们走向最佳实践和方法，以实现MSUD的新疗法。 公共卫生相关性：我们建议调查使用脂肪移植作为治疗枫糖浆尿病（MSUD）。MSUD是一种遗传性疾病，可导致癫痫发作、昏迷、智力迟钝和死亡。它是由利用食物中蛋白质的某些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对生命至关重要，但如果允许它们像MSUD那样积累，它们也会导致脑损伤。肝脏移植已经成功地用于这种疾病的实验，但是肝脏移植非常昂贵，并且没有足够的供体肝脏来满足器官需求。然而，我们的研究小组发现，脂肪组织具有令人惊讶的大量MSUD中缺失的酶活性。我们建议验证脂肪移植可能是MSUD有效的新治疗方法的假设。在MSUD模型中首次成功进行脂肪移植试验是有希望的。我们建议进一步评估这一想法，并测试方法，以改善我们第一次成功测试的结果。这些研究的结果可能为MSUD的新治疗选择奠定了基础。