Transient depletion of CD4 lymphocyte improves efficacy of repeated administration of recombinant adenovirus in the ornithine transcarbamylase deficient sparse fur mouse

One of the current limitations of adenoviral gene therapy is a vector-induc ed humoral immune response that blocks effective re-administration of the v ector. In an animal model of the inborn error of urea synthesis ornithine t ranscarbamylase (OTC) deficiency, the sparse fur (spf/y) mouse, we tested a strategy to transiently block the CD4 mediated immune response at the time of virus administration using an anti-CD4 monoclonal antibody (GK1.5). The co-administration of GK1.5 resulted in a significantly diminished producti on of neutralizing antibody to the adenovirus vector, but minimally prolong ed metabolic correction. A second infusion of the same virus in GK1.5 treat ed spf/y mice led to a complete normalization of liver OTC activity at day 3 after infection and a significant metabolic correction of urinary orotate and plasma glutamine. In contrast, there was no evidence of enhanced OTC e xpression or metabolic correction (measured by normalization of plasma glut amine and urinary orotate) after the second infusion of virus in spf/y mice not treated with GK1.5. Furthermore, when co-administered with two consecu tive doses of adenovirus, the anti-CD4 treatment allowed improved transgene expression upon a third administration of virus and a partial normalizatio n of the metabolic abnormalities compared with mice that did not receive an ti-CD4 treatment. The level of OTC expression from the third viral infusion , however, was lower than that from the second viral infusion. Passive tran sfer experiments suggest that low levels of neutralizing antibodies develop ing over repeated Viral administration was the likely cause of the reduced transgene expression. Together, these findings demonstrated that the host i mmune system can be modulated to permit effective transgene expression at t herapeutic levels by re-administered adenoviral vectors.