MOUSE MODELS OF METHYLMALONIC ACIDEMIA

描述(由申请人提供)： 先天性新陈代谢障碍包括一组不同类型的遗传疾病，在美国人口中的总发病率约为1：1500。其中许多与儿童时期的严重发病率和死亡率以及频繁住院有关。现代筛查方法正在允许对症状前受影响的患者进行诊断，但在开发新的治疗方法和疗法方面所做的工作很少，部分原因是对疾病状态的自然历史没有完全了解，许多疾病也不存在动物模型。甲基丙二酸血症(MMA)是一种比较常见的先天性代谢错误，通常由甲基丙二酸辅酶A变位酶缺乏引起。这是一种毁灭性的代谢性疾病，也是最常见的有机酸血症之一。目前还没有明确的治疗方法，尽管一些患者已经从肝和肾-肝移植中受益。 为了研究MMA，我们将建立一系列小鼠模型来复制人类的疾病状态，并检验以下假设：(1)缺乏甲基丙二醛-辅酶A变位酶活性的小鼠将出现严重的代谢表型，其特征是致死性酮症酸中毒和甲基丙二酸的大量积累。(2)肝脏特异性表达甲基丙二醛-辅酶A变位酶可恢复缺陷小鼠的代谢稳态，但不能完全纠正其代谢异常。甲基丙二酸血症的小动物模型将有助于研究MMA的自然病史和病理生理学，并评估肝脏导向基因表达作为MMA治疗的可能性。

DESCRIPTION (provided by applicant): Inborn errors of metabolism comprise a heterogeneous group of genetic disorders that occur with an overall incidence of about 1: 1500 in the US population. Many are associated with significant childhood morbidity and mortality as well as frequent hospitalizations. Modern screening methodologies are allowing for the diagnosis of presymptomatic, affected patients but little is being done to develop new treatments and therapies, in part because the natural histories of the disease states are not fully understood and animal models do not exist for many of the disorders. One relatively common inborn error of metabolism is methylmalonic acidemia (MMA), which usually is caused by a deficiency of methylmalonyI-CoA mutase. It is a devastating metabolic disease and one of the most common organic acidemias. No definitive treatment exists, although some patients have benefited from liver and kidney-liver transplantation. To study MMA, we will produce a series of murine models to replicate the human disease state and test the following hypotheses: (1) Mice lacking methylmalonyI-CoA mutase activity will have a severe metabolic phenotype characterized by fatal ketoacidosis and massive accumulation of methymalonic acid. (2) Liver specific expression of methylmalonyI-CoA mutase will restore metabolic homeostasis in deficient mice but will not fully correct their metabolic abnormalities. A small animal model of methylmalonic acidemia will be of great use to examine the natural history and pathophysiology of MMA and to assess the possibility of liver-directed gene expression as a treatment for MMA.