ANIMAL MODELS OF ORNITHINE TRANSCARBAMYLASE DEFICIENCY

鸟氨酸转氨甲酰酶缺乏症的动物模型

• 批准号: 6217849
• 负责人: Michael Byrne Robinson
• 金额: $ 14.69万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-16 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6217849
• 关键词: Adenoviridae; athymic mouse; avoidance behavior; defective virus; disease /disorder model; enzyme therapy; gene expression; gene therapy; genetic transduction; glutamine; histopathology; immune tolerance /unresponsiveness; laboratory mouse; mature animal; neurochemistry; newborn animals; nonhuman therapy evaluation; ornithine carbamoyl phosphate deficiency; ornithine carbamoyltransferase; orotate; quinolinate; serotonin; transfection /expression vector; urea cycle; urinalysis

The overall goal of this project is to study the efficacy of in vivo gene therapy with recombinant adenoviruses in two animal models of ornithine transcarbamylase deficiency (OTCD), the sparse fur (Spf) mouse and the abnormal skin and hair (Spf/ash) mouse. The presence of a useful animal model permits us to attempt gene therapy in neonatal and adult animals using various recombinant adenoviruses and detect metabolic and neurochemical changes that will prove useful in the human studies described in Project III. Our studies will revolve around those responses to in vivo gene therapy that will be of greatest significance to the human studies: (1) The metabolic response, particularly with regard to the conversion of ammonia to urea; (2) The safety of adenoviral administration; and (3) The neurochemical/neuropathologic response to gene therapy, since the worst consequence (other than death) of hyperammonemia is brain damage and mental retardation. There are four specific aims: I to develop the metabolic and neurochemical measures that will permit assessment of efficacy of gene therapy; II to study the level, distribution, and time-course of gene expression and to study correction of metabolic abnormalities, including orotate excretion, in vivo urea production with stable isotopes, and steady state levels of amino acids; III to test the efficacy of gene therapy in neonatal Spf and Spf/ash mice to determine duration and the presence of tolerance; and IV to detect if the neurochemical and behavioral alterations and neuropathology induced by hyperammonemia are preventable in neonates and reversible in older animals.

该项目的总体目标是研究体内基因的功效。 重组腺病毒对两种鸟氨酸动物模型的治疗 转氨甲基酶缺乏症(OTCD)、稀毛(SPF)小鼠和 皮肤和毛发异常(SPF/ASH)小鼠。一种有用的动物的出现 模型允许我们尝试在新生和成年动物身上进行基因治疗 使用各种重组腺病毒并检测代谢和 将被证明对人体研究有用的神经化学变化 我们的研究将围绕这些反应展开 对体内基因治疗将具有最大意义的 人体研究：(1)新陈代谢反应，特别是关于 氨转化为尿素；(2)腺病毒的安全性 给药；以及(3)神经化学/神经病理反应 基因治疗，因为最坏的后果(死亡除外) 高氨血症是脑损伤和智力低下。一共有四个 具体目标：i开发代谢和神经化学措施，以 将允许评估基因疗法的疗效；ii研究 基因表达的水平、分布和时程及其研究 纠正代谢异常，包括旋转排泄，在 体内尿素生产具有稳定的同位素和稳定的水平 氨基酸；III测试基因治疗对新生儿SPF和 SPF/ASH小鼠以确定持续时间和耐受性的存在；以及IV 以检测神经化学和行为改变是否 高氨血症引起的神经病理是可以预防的 在年长的动物身上是可逆的。