Gene therapy could result in the permanent correction or amelioration of the clinical manifestations of many genetic diseases. However, immune responses to the therapeutic protein pose a significant hurdle for successful gene therapy. Problematic immune responses can include the development of a cytotoxic T lymphocyte (CTL) response that results in the destruction of genetically-modified cells and/or the formation of antibodies directed against the therapeutic protein. One approach to avoid an immune response is to perform gene therapy in newborns, which takes advantage of the fact that the immune system is relatively immature at birth. This approach has been highly effective in mice, and has resulted in stable expression without antibody formation for proteins that are highly immunogenic after transfer to adults. High levels of expression after neonatal gene therapy were more effective at inducing tolerance than low levels of expression in mice, which suggests that high antigen levels are more efficient at inducing tolerance. A criticism of this approach is that the murine immune system is less mature at birth than the immune systems of larger animals. Indeed, neonatal gene therapy to cats with mucopolysaccharidosis I resulted in a CTL response that destroyed expressing cells. Nevertheless, the immune system was still relatively immature, as transient administration of a single immunosuppressive agent at the time of neonatal gene therapy resulted in stable expression. Neonatal administration can reduce, but not eliminate, immune responses after gene therapy.
Keywords: Tolerance, hemophilia, mucopolysaccharidosis, lysosomal storage disease, T regulatory cells
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