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: 3735739
• 负责人: MICHAEL B ROBINSON
• 金额: --
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3735739
• 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 两种鸟氨酸动物模型中的重组腺病毒治疗 经氨基甲基酶缺乏症（OTCD），稀疏皮草（SPF）小鼠和 皮肤和头发异常（SPF/灰）鼠标。有用动物的存在 模型允许我们尝试在新生儿和成年动物中进行基因治疗 使用各种重组腺病毒并检测代谢和 神经化学变化将在人类研究中被证明有用 在项目III中进行了描述。我们的研究将围绕这些回答 对体内基因疗法将对 人类研究：（1）代谢反应，特别是 氨转化为尿素； （2）腺病毒的安全 行政; （3）对神经化学/神经病理学的反应 基因疗法，因为最糟糕的后果（死亡） 高症血症是脑损伤和智力低下。有四个 具体目的：我开发代谢和神经化学措施 将允许评估基因疗法的功效； II研究 基因表达的水平，分布和时间顺序并研究 校正代谢异常，包括牙酸酯排泄， 体内尿素产生稳定的同位素，稳态水平 氨基酸； III测试基因​​治疗在新生儿SPF和 SPF/灰小鼠以确定持续时间和耐受性的存在；和IV 检测神经化学和行为改变以及 高氨血症诱导的神经病理学是可预防的，在新生儿和 在老年动物中可逆。