Adipose Organ Transplant for Treatment of Maple Syrup Urine Disease

脂肪器官移植治疗枫糖浆尿病

基本信息

批准号：
8281453
负责人：
CHRISTOPHER JOHN LYNCH
金额：
$ 22.95万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8281453
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

项目摘要

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.

描述（由申请人提供）：这项研究的长期目标是为枫糖浆尿液疾病（MSUD）开发新的治疗方法，这是一种代谢的天生误差，导致分支链酮酮酸酸性脱氢酶活性不足。在MSUD中，分支链氨基和酮酸（BCAAS和BCKAS）积聚在血浆和组织中，导致逐渐造成神经系统损害，认知能力下降，呕吐，癫痫发作，昏迷，昏迷和死亡。标准治疗涉及降低BCAA摄入量的密集营养支持。尽管这通常是有效的，但MSUD患者可以在疾病或压力中响应蛋白质分解代谢而在循环的BCAA和BCKA中出现巨大的上升。尽管营养遵守谨慎，这种升高可能会导致急性代谢危机。器官移植可用于提供一些代谢能力，以防止或减轻这些代谢危机。实际上，发表的研究以及正在进行的其他研究表明，在MSUD中选择性肝移植的巨大希望，许多受试者恢复了正常饮食。然而，在不久的将来，选举肝移植不太可能被用作MSUD的标准护理。在当前的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供体肝脏，并且在超过500万美元的情况下，肝脏移植的第一年成本挑战了这种方法的实用性。作为替代方案，我们建议检验以下假设：脂肪器官移植可能是MSUD的有效治疗方法。我们实验室的最新研究表明，人类和啮齿动物脂肪组织的BCAA氧化能力都比以前所欣赏的要高得多。脂肪组织对于移植的高度修正是由于其低氧的需求低，并且能力既可以从细胞中重新组织为组织又可以重新血管化。根据脂肪组织在整形手术中的使用，脂肪移植的第一年成本可能比肝脏低10-20倍，可以说，获得脂肪器官供体的供体会容易得多。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BCAA大大降低。然而，在其他模型中，需要更紧密地模拟人类MSUD的测试，以及对这一成功的定量改进的方法。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小鼠MSUD和测试策略中的影响，以对脂肪组织移植或脂肪前体细胞移植后的血浆BCAA降低进行定量改进。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，并指导我们采取最佳实践和方法，以实现MSUD的新疗法。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adipose transplant for inborn errors of branched chain amino acid metabolism in mice.

DOI：
10.1016/j.ymgme.2013.05.010
发表时间：
2013-08
期刊：
MOLECULAR GENETICS AND METABOLISM
影响因子：
3.8
作者：
Zimmerman, Heather A.;Olson, Kristine C.;Chen, Gang;Lynch, Christopher J.
通讯作者：
Lynch, Christopher J.

Alloisoleucine differentiates the branched-chain aminoacidemia of Zucker and dietary obese rats.

DOI：
10.1002/oby.20691
发表时间：
2014-05
期刊：
OBESITY
影响因子：
6.9
作者：
Olson, Kristine C.;Chen, Gang;Xu, Yuping;Hajnal, Andras;Lynch, Christopher J.
通讯作者：
Lynch, Christopher J.