ANIMAL MODELS OF ORNITHINE TRANSCARBAMYLASE DEFICIENCY

点击翻译按钮获取中文摘要

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.