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 disclose 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. We will administr a single dose of a recombinant adenovirus by selective intra-arterial infustion 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). We will perform a single percutaneous liver biopsy at Day +8 to determine direct evidence of gene transfer. In addition, blood samples for immunology will be collected every six months for three years after the date of gene instillation. Termination of the study will occur in the presence of either significant toxicity or efficacy. The exact numbver 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 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.
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