Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene 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 exp g the transgene. We have used liver-dircted approaches to gene therapy in mice to study mecanims 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 Ela and Elb). Our data are consistent with the following hypothesis. Cells harboring the recombinant viral genome express the transgene as desired; however, lowlevel 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 findigs suggest approaches for improving recombinant adenoviruses that are based on further crippling the virus to limit expression of nondeleted viral genes.Human adenoviruses have emerged as a promising technology for in vivo gene therapy. The 36-kb double-stranded

In vitro and in vivo asessment of adenovirus 41 as a vector for gene delivery to the intestine

“…1,41 The immune response against cells infected by viral gene therapy vectors may also be a major hindrance for gene delivery, resulting in destruction of infected cells, limitations in the length of transgene expression, and elimination of infected cells upon repeat administration of the vector. [42][43][44] The intestine is quite an inhospitable target for viral vectors from this aspect as it has been estimated that 1-2 m of human intestine contain more antibody-secreting cells than do all other tissues combined. 45 In addition, mucus secreted by gastric and intestinal cells may contain both specific (eg IgA) and nonspecific inhibitors of viral infection.…”

Calcium carbonate nanoparticle delivering vascular endothelial growth factor-C siRNA effectively inhibits lymphangiogenesis and growth of gastric cancer in vivo

“…Many vectors, including viral and nonviral vectors, have been used for gene therapy. All of them have some serious drawbacks, such as triggering an immune response, 20 severe hepatic inflammation, 21 random chromosomal integration 22 or cytotoxicity to the host cell. 23 Nanoparticles have emerged as very promising nonviral vectors because of their advantages over both viral and nonviral vectors: (1) they are safe; (2) cost-effective and (3) may also successfully overcome many limitations of the other vector types, such as risk of recombination, strong immunogenicity and carcinogenity.…”

Differential Chemokine and Chemokine Receptor Gene Induction by Ischemia, Alloantigen, and Gene Transfer in Cardiac Grafts

“…Adenovirus is attractive as a gene transfer vector because of its broad host range, capacity for large DNA inserts and high efficiency of transduction (7). Its major disadvantage is that gene expression from the vector is limited by the potent adenovirus-specific adaptive (8), as well as innate (9), immune responses directed to the infected cells. The molecular mechanisms underlying the immunologic interaction of vectors with the graft and characterization of these innate responses remain poorly defined.…”