OTCD, an inborn error of urea synthesis, often leads to life threatening episodes of hyperammonemia in early childhood. In an animal model of OTCD, the spf/Y mouse, this deficiency is associated with a 20 fold elevation of urinary orotate and a doubling of plasma glutamine. Recently, we have demonstrated that i.v. infusion of recombinant adenoviruses carrying mouse OTCcDNA effectively corrects these metabolic abnormalities in spf/Y mice for up to 60 days (JBC, 271:3639, 1996). One of the current limitations of this vector system, however, is a virus-induced humoral immune response that blocks effective readministration of the vector. We tested a strategy to transiently block CD4 mediated immune response at the time of virus administration using an anti-CD4 monoclonal antibody (GK1.5). Protein G purified GK1.5 was given four times i.p. at a dose of 100μg/mouse (D -3, 0, 3 and 6 relative to viral infusion of 1×10e11 particle/mouse). In studies using an adenovirus with a deletion in E1, the coadministration of GK1.5 allowed metabolic correction of urinary orotate and plasma glutamine after each of two consecutive viral infusions. In a subsequent experiment using an adenovirus with deletions in E1 and a tempertaure sensitive mutation in E2, the anti-CD4 antibody treatment resulted in a significantly diminished production of neutralizing antibody to the adenovirus. None of the 18 spf/Y mice receiving GK1.5 treatment showed detectable antibody titers, while all six untreated animals had antibody titers ranging from 80 to 320. A second infusion of virus(1×10e11 particles/mouse) in GK1.5 treated spf/Y mice also resulted in a complete normalization of liver OTC activity (202 vs. 63 μmol citrulline/mg protein/hr in wild type mice). In contrast, in spf/Y mice not treated with GK1.5, there was no evidence of enhanced OTC expression after the second infusion of virus (4.7 in virus-infused vs. 4.2 in control spf/Y mice). These results suggest that the host immune system can be modulated to permit repeated injections of adenoviral vectors, which is a prerequisite for effective in vivo gene therapy.(HD32649, HD26979)
