Recombinant adenovirus gene transfer in adults with partial ornithine transcarbamylase deficiency (OTCD)

1.1 Background. Ornithine transcarbamylase (OTC), a mitochondrial matrix enzyme, is the second enzyme in the urea cycle. Deficient liver OTC activity results in accumulation of ammonia in blood and brain with resultant encephalopathy (Batshaw, 1994). Other biochemical abnormalities include accumulations of glutamine in blood and of orotic acid in urine behind the enzyme block. Glutamine and orotic acid prove to be useful indicators of OTC deficiency (OTCD) and will be used as a measure of efficacy of gene therapy. Stable isotope studies have also proven helpful in assessing residual urea synthetic capacity. The rate of flux through the urea cycle is measured by administering orally 15NH4Cl and measuring appearance of 15N urea in blood and urine. We have performed these stable isotope studies in 20 controls and OTCD patients and found it to be a sensitive in vivo indicator of residual OTC activity. OTCD is ideally suited for treatment using in vivo gene therapy to restore partial OTC activity to the patient. 1.2 Objective. 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 disclose a dose of the virus that we will subsequently utilize in controlled studies of efficacy. 1.3 Study Population. 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 ratio of 1:2 males to females. The mutation responsible for OTCD has been seen in most races. 1.4 Study Interventions. Three patients will be treated at each dose starting with the lowest dose 2 x 109 particles/kg, with subsequent 1/2 log increases in the absence of toxicity. Termination of the study will occur in the presence of either significant toxicity or efficacy. 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. 1.5 Outcomes. The primary outcome is the development of Grade III or higher significant toxicity or the evidence of significant metabolic correction in the absence of significant toxicity. Secondary outcomes will focus on immune responses to the vector and evidence of gene transfer.