Factor VIII DNA Transfer Stimulates Anti-Transgene Antibodies in Mice

Strategic Insights -

A study conducted by P.Q. Ye and colleagues from the University of Washington's Department of Pediatrics has found that the transfer of factor VIII DNA in mice stimulates the production of anti-transgene antibodies, potentially limiting the success of human gene therapy approaches. The researchers inserted factor VIII cDNA from human, canine, or murine origin into a liver-specific vector and injected it into hemophilia A mice, resulting in initial high levels of functional factor VIII that gradually decreased to undetectable levels within 2-3 weeks, accompanied by the generation of high-titer, inhibitory anti-FVIII antibodies.

Key Takeaways:

  • Factor VIII DNA transfer in mice stimulates the production of anti-transgene antibodies, which can limit the success of human gene therapy approaches.
  • The immune response occurred independently of the species of origin of the exogenous factor VIII, with antibody titers to factor VIII being detected beginning at 2 weeks and remaining at high levels for over 6 months.
  • The majority of anti-hFVIII immunoglobulin (Ig)G was IgG1 isotype specific, indicating a humoral response mediated by Th2-induced signals.
  • Transient immunosuppression by cyclophosphamide significantly delayed or abolished inhibitory antibody formation against the transgene in a separate group of mice.
  • The study highlights the need for caution when using gene therapy approaches that involve the transfer of recombinant proteins, as it may lead to an immune response against the transgene.

Statistics:

  • Factor VIII levels ranged from 3 to 12 IU/ml in mice 3 days after treatment (normal is 1 IU/ml in human plasma).
  • Antibody titers to factor VIII were detected beginning at 2 weeks and remained at high levels for over 6 months.
  • 5 out of 6 mice treated with pBS-HCRHPI-FVIIIA and administered cyclophosphamide showed delayed or abolished inhibitory antibody formation against the transgene.
  • The study was published in Molecular Therapy (Naked DNA transfer of factor VIII induced transgene-specific, species-independent immune response in hemophilia A mice. Mol Ther, 2004;10(1):117-126).

Sources:

  • Ye, P.Q., et al. (2004). Naked DNA transfer of factor VIII induced transgene-specific, species-independent immune response in hemophilia A mice. Mol Ther, 10(1), 117-126.
  • Miao, C.H. (Contact person)
  • Health & Medicine Week editors (2004)
  • Academic Press Inc. Elsevier Science (Publisher of Molecular Therapy)
  • University of Washington, Department of Pediatrics (Author institution)