Investigations of Methylmalonic Acidemia and Related Disorders

甲基丙二酸血症及相关疾病的调查

基本信息

项目摘要

This research study encompasses the hereditary methylmalonic acidemias (MMA) and cobalamin deficiency disorders. These metabolic disorders are genetically heterogeneous and collectively represent an important subset of the organic acidemias. We study the hereditary methylmalonic acidemias and cobalmin deficiency disorders via a translational approach that includes a clinical and metabolic evaluation of affected patients and the use animal models to examine the disorder in the laboratory. We have developed mouse and worm models of methylmalonic acidemia in the past and have focused on mouse models and gene therapy in the past year. The general goal of the research is to define the complications seen in the patients, replicate the findings in mice or other organisms and use the combined information to guide the development and testing of new therapies, such as gene and stem cell therapy. We maintain a mouse colony, use cell culture facilities, perform experiments with radioactive and non-radioactive isotopes to study metabolism in cells, construct gene therapy vectors, administer gene therapy treatments to mice and use routine molecular biological and biochemical studies to analyze our experiments. The human subject research is focused on assessing the natural history of methylmalonic acidemia and cobalamin metabolic disorders in the United States to further understand the treatment, outcome and complications in this group of patients. We have developed a patient database for outcomes research and have enrolled more than 75 affected patients in our clinical research studies since beginning this project. We have studied the effects of solid organ transplantation on MMA, delineated a new neurologic syndrome in patients who have suffered from a disease-related stroke and described a range of eye findings seen in one subset of patients. The patients are usually admitted to the NIH Clinical Research Center as inpatients for 3 to 4 days and undergo extensive metabolic testing. Many patients need magnetic resonance imaging and magnetic resonance spectroscopy of the central nervous system. We use a high field strength magnet (3 Telsa) for these studies. Genotype-phenotype-enzymatic correlations are under investigation in the patients population. The combined approach of model organism and human investigations has allowed the development of a partial deficiency murine model of methylmalonic acidemia and provided new insights into the bioenergetic defect seen in this disorder. The details of these experimental advances that have used mouse and patient derived materials has resulted in a major publication that has expanded the understanding of the pathophysiology of methylmalonic acidemia. In the past year, we three major research papers have appeared describing our results and filed a US patent on a device and method used to track gene therapy using stable isotopes in mice. Efforts to develop and test viral gene delivery and cell therapy in the murine models of methylmalonic acidemia will also continue this year, with hope that extension to patients will follow. Novel mouse models of methylmalonic acidemia will also be generated and studied.
这项研究包括遗传性甲基丙二酸血症(MMA)和钴胺缺乏症。这些代谢紊乱在遗传上是不同的,共同代表了有机酸血症的一个重要子集。我们通过翻译方法研究遗传性甲基丙二酸血症和钴缺乏障碍,包括对受影响的患者进行临床和代谢评估,并使用动物模型在实验室检查该疾病。我们在过去建立了甲基丙二酸血症的小鼠和蠕虫模型,并在过去的一年里专注于小鼠模型和基因治疗。这项研究的总体目标是定义患者身上出现的并发症,在小鼠或其他生物身上复制发现,并使用组合信息来指导新疗法的开发和测试,如基因疗法和干细胞疗法。我们维持一个小鼠群体,使用细胞培养设施,对放射性和非放射性同位素进行实验,以研究细胞中的新陈代谢,构建基因治疗载体,对小鼠进行基因治疗,并使用常规的分子生物学和生化研究来分析我们的实验。 人体研究的重点是评估美国甲基丙二酸血症和钴胺代谢紊乱的自然病史,以进一步了解这类患者的治疗、结果和并发症。我们已经开发了一个用于结果研究的患者数据库,自开始这个项目以来,我们已经招募了超过75名受影响的患者参加我们的临床研究研究。我们研究了实体器官移植对MMA的影响,描述了患有疾病相关中风的患者中的一种新的神经综合征,并描述了在一组患者中看到的一系列眼部表现。患者通常作为住院患者在NIH临床研究中心住院3至4天,并接受广泛的代谢测试。许多患者需要对中枢神经系统进行磁共振成像和磁共振波谱检查。我们使用高场强磁铁(3Telsa)进行这些研究。在患者群体中,正在调查基因-表型-酶的相关性。 模式生物和人类研究的结合方法使甲基丙二酸血症的部分缺乏性小鼠模型得以发展,并为这种疾病中出现的生物能量缺陷提供了新的见解。这些使用小鼠和患者衍生材料的实验进展的细节导致了一本重要的出版物,扩大了对甲基丙二酸血症的病理生理学的理解。 在过去的一年里,我们发表了三篇主要的研究论文,描述了我们的结果,并申请了一项美国专利,该设备和方法用于跟踪小鼠使用稳定同位素进行的基因治疗。今年,在甲基丙二酸血症小鼠模型中开发和测试病毒基因传递和细胞疗法的努力也将继续下去,希望随后扩展到患者身上。还将建立和研究新的甲基丙二酸血症小鼠模型。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(3)

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Charles P Venditti其他文献

Charles P Venditti的其他文献

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{{ truncateString('Charles P Venditti', 18)}}的其他基金

Investigations of Methylmalonic Acidemia and Related Disorders
甲基丙二酸血症及相关疾病的调查
  • 批准号:
    10914590
  • 财政年份:
  • 资助金额:
    $ 162.74万
  • 项目类别:
Investigations of Methylmalonic Acidemia and Related Disorders
甲基丙二酸血症及相关疾病的调查
  • 批准号:
    8349996
  • 财政年份:
  • 资助金额:
    $ 162.74万
  • 项目类别:
Investigations of Methylmalonic Acidemia and Related Disorders
甲基丙二酸血症及相关疾病的调查
  • 批准号:
    8948366
  • 财政年份:
  • 资助金额:
    $ 162.74万
  • 项目类别:
Investigations of Methylmalonic Acidemia and Related Disorders
甲基丙二酸血症及相关疾病的调查
  • 批准号:
    10025112
  • 财政年份:
  • 资助金额:
    $ 162.74万
  • 项目类别:
Investigations of Methylmalonic Acidemia and Related Disorders
甲基丙二酸血症及相关疾病的调查
  • 批准号:
    8750680
  • 财政年份:
  • 资助金额:
    $ 162.74万
  • 项目类别:
Investigations of Methylmalonic Acidemia and Related Dis
甲基丙二酸血症及相关疾病的调查
  • 批准号:
    7316057
  • 财政年份:
  • 资助金额:
    $ 162.74万
  • 项目类别:
Investigations of Methylmalonic Acidemia and Related Dis
甲基丙二酸血症及相关疾病的调查
  • 批准号:
    7147996
  • 财政年份:
  • 资助金额:
    $ 162.74万
  • 项目类别:
Investigations of Methylmalonic Acidemia and Related Disorders
甲基丙二酸血症及相关疾病的调查
  • 批准号:
    10267093
  • 财政年份:
  • 资助金额:
    $ 162.74万
  • 项目类别:
Investigations of Methylmalonic Acidemia and Related Disorders
甲基丙二酸血症及相关疾病的调查
  • 批准号:
    9572262
  • 财政年份:
  • 资助金额:
    $ 162.74万
  • 项目类别:
Investigations of Methylmalonic Acidemia and Related Disorders
甲基丙二酸血症及相关疾病的调查
  • 批准号:
    8149433
  • 财政年份:
  • 资助金额:
    $ 162.74万
  • 项目类别:

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