Ornithine transcarbamylase deficiency (OTCD) is the most common inborn error of urea synthesis with an incidence of approximately 1 in 40,000. OTCD is an X-linked disorder for which no effective treatment is yet available. The purpose of this study is to establish a safe dose of recombinant adenovirus to serve as a treatment for adults with partial OTCD. The principal objective of this study is to determine a dose of the virus that we will subsequently utilize in controlled studies of efficacy. We intend to study both males and females with partial OTCD in a dose escalation toxicity study. Due to the paucity of male survivors, we predict an enrollment ration of 1:2 males to females. Three patients will be treated at each dose starting with the lowest dose of 2x109 particles/kg. with subsequent 1/2 log increases in the absence of toxicity. A single dose of a recombinant adenovirus expressing the OTC gene is administered by selective intra-arterial infusion into the right lobe of the liver of clinically stable adults with paratial OTCD. Over the subsequent 5 months we will obtain blood and urine for studies of evidence of toxicity, immune response, and efficacy (metabolic correction). A single percutaneous liver biopsy is performed at Day +8 to determine direct evidence of gene transfer. In addition, blood samples for immunology are collected every three months for three years after the date of gene instillation. Termination of the study will occur in the presence of significant toxicity. The exact number of participants will depend on the number of doses that will be required to show toxicity and/or efficacy. We anticipate this to require a total of 6 cohorts in 1/2 log increments. The primary outcome is the development of Grade III or higher significant toxicity. Secondary outcomes will focus on immune responses to the vector and evidence of gene transfer and evidence of significant metabolic correction. To date four cohorts of study participants have been enrolled. No serious adverse effects have occurred as a result of this study. There have been no significant treatment-related toxicities or procedure-related toxicities, and all participants have remained well. Fever, back pain, and general malaise have been observed within 48 hours of the gene transfer. In addition, platelet counts have dropped by an average of 55% within 4 days of the vector infusion. Though the cause of this decrease has not been determined, the investigators have not found evidence of platelet consumption nor disseminated intravascular coagulation. Many participants have also developed anemia, most likely secondary to the study-related phlebotomy.
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