Adeno-associated virus production of soluble tumor necrosis factor receptor neutralizes tumor necrosis factor α and reduces arthritis

Academic Article

Abstract

  • The major limitation of adenovirus is its association with induction of an inflammatory response and relatively short-term production of the gene therapy transgene product. Adeno-associated virus (AAV) is a 4.68kb single-strand DNA virus that contains ITRs for viral replication and a packaging signal, and also has been engineered to contain therapeutic genes up to 5 kb in length. Transduction of recombinant AAV (rAAV) resuits in low inflammatory response and long-term expression. We have cloned a low-immunogenic form of human sTNFRI (sTNFRI2.6D) into AAV (rAAVsTNFRI). This vector was analyzed for its ability to transfect and neutralize the effect of TNF-α on primary rheumatoid arthritis synovial fibroblast (RASFs). The rAAVsTNFRI was transduced into the cells at 1.8 x 101, 1.8 x 102, and 1.8 x 103 viral particles per cell. There was greater than 90% neutralization of TNF-α at 1.8 x 103 viral particles/cell. There was a significant decrease in the synovial cell hyperplasia and cartilage and bone destruction in human TNF-α transgenic mice treated intraarticularly with rAAVsTNFRI. These results indicate that the low-immunogenic and long-term expressing vector, rAAVsTNFRI, can be used to deliver the soluble TNF-α in vitro and in vivo and effectively reduce the severity of arthritis.
  • Published In

  • Human Gene Therapy  Journal
  • Digital Object Identifier (doi)

    Pubmed Id

  • 22695737
  • Author List

  • Zhang HG; Xie J; Yang P; Wang Y; Xu L; Liu D; Hsu HC; Zhou T; Edwards CK; Mountz JD
  • Start Page

  • 2431
  • End Page

  • 2442
  • Volume

  • 11
  • Issue

  • 17