We have concluded that ornithine transcarbamylase deficiency (OTCD) is a well suited disease for the development of both acute and long-term gene therapy. Current treatment of OTCD has failed to avert a high mortality or morbidity rate; Given the relative frequency of OTCD, an adequate population is available for study; The OTC gene has been sequenced and preliminary studies of gene therapy in animal models have been promising; The OTC gene is not rate-limiting for ureagenesis, so excessive activity should not have adverse consequences; The disorder is X-linked and hemizygous males have virtually absent enzyme activity; and Restoration of enzyme activity in the liver, should suffice to normalize metabolism without the need to introduce the gene into the central nervous system. We propose to study in vivo gene therapy for OTCD with a recombinant adenovirus in order to control acute, life-threatening hyperammonemic crises. We also propose to use ex vivo transfer of the OTC gene with a recombinant retrovirus to provide long-term management of patients who are clinically stable at the time of gene therapy, but who remain at high risk of sustaining brain damage or of dying because of a future hyperammonemic episode. Stable transduction will also be tested in children using a second generation recombinant adenovirus. Studies will focus on duration of metabolic, neurochemical, toxicologic, and immunologic consequences, and neurodevelopmental outcome. There are three specific aims to this project: (I) We hypothesize that a recombinant adenovirus containing the OTC gene will be effective and safe for the short-term treatment of neonates and older children with OTCD who are in hyperammonemic crisis. To establish the effective and safe dose we will initially test various doses of the construct in adult asymptomatic OTCD heterozygotes. We will subsequently treat neonates in hyperammonemic coma and infants, children and adults with symptomatic OTCD using the recombinant adenovirus. Efficacy will be measured by normalization of plasma ammonium, urea cycle intermediates, and urinary orotate excretion, rate of flux through the urea cycle, and OTC correction in liver. (II) We hypothesize that long-term correction of OTCD can be achieved either by ex vivo or in vivo gene therapy using a recombinant retrovirus or a second generation temperature sensitive recombinant adenovirus. (III) Finally, we hypothesize that immune activation following gene therapy may affect safety, efficacy and duration of gene therapy.
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