Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy.

TLDR

Adenovirus gene therapy is limited by loss of transgene expression coinciding with organ pathology. The study used liver‑directed gene therapy in mice to investigate mechanisms behind transient expression and pathology of first‑generation E1‑deleted adenoviruses. Liver‑directed gene therapy in mice was employed to probe the mechanisms causing transient expression and pathology in these viruses. Transgene‑expressing hepatocytes were destroyed by a virus‑specific immune response, leading to massive hepatitis and repopulation by non‑transgene cells, suggesting that further crippling of the virus to limit non‑deleted gene expression could improve therapy.

Abstract

An important limitation that has emerged in the use of adenoviruses for gene therapy has been loss of recombinant gene expression that occurs concurrent with the development of pathology in the organ expressing the transgene. We have used liver-directed approaches to gene therapy in mice to study mechanisms that underlie the problems with transient expression and pathology that have characterized in vivo applications of first-generation recombinant adenoviruses (i.e., those deleted of E1a and E1b). Our data are consistent with the following hypothesis. Cells harboring the recombinant viral genome express the transgene as desired; however, low-level expression of viral genes also occurs. A virus-specific cellular immune response is stimulated that leads to destruction of the genetically modified hepatocytes, massive hepatitis, and repopulation of the liver with nontransgene-containing hepatocytes. These findings suggest approaches for improving recombinant adenoviruses that are based on further crippling the virus to limit expression of nondeleted viral genes.