Immunology of Neonatal Gene Transfer

Abstract

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.

Direct gene transfer to the CNS prevents emergence of neurologic disease in a murine model of mucopolysaccharidosis type I

“…Human IDUA is known to be highly immunogenic, and has been shown to elicit both humoral and cytotoxic T lymphocyte responses in adult MPS I mice, newborn cats, and dogs (Di Domenico et al, 2006; Di Domenico et al, 2005; Lutzko et al, 1999; Ma et al, 2007; Ponder et al, 2006; Shull et al, 1996). Newborn mice are immunologically naïve (Adkins et al, 2004; Landers et al, 2005; Ponder, 2007; Schelonka and Infante, 1998; West, 2002), so it is possible that our AAV-treated animals were immunotolerized by the expression of IDUA soon after birth, before development of the immune system as we have previously observed (Hartung et al, 2004). Also, a significant challenge will be the application of ICV infusion of AAV to achieve gene transfer in the human brain, which is several thousand-fold larger than the neonatal mouse brain and in which the effectiveness of the procedure will be further limited by diffusion of the vector into deep brain tissues.…”

Hepatic Gene Transfer in Neonatal Mice by Adeno-Associated Virus Serotype 8 Vector

“…Gene therapy has achieved correction or amelioration of the clinical manifestations of many genetic diseases in animal models and in some human patients. Neonatal gene transfer has the advantages of achieving therapeutic effects before disease manifestation, a low vector requirement and high vector-to-cell ratio, and a relatively immature immune system (Waddington et al, 2004;Ponder, 2007;McKay et al, 2011). However, vigorous cell proliferation in the newborn stage is a significant challenge for nonintegrating vectors.…”

Neonatal helper-dependent adenoviral vector gene therapy mediates correction of hemophilia A and tolerance to human factor VIII

“…A number of reports suggest that there are advantages to initiating gene therapy in the neonatal period (3)(4)(5)(6)(7)(8). These advantages include the following: (i) early gene expression to avoid the development of irreversible pathology; (ii) administering vector earlier results in greater vector to cell ratio, allowing for less vector administration; (iii) stem and progenitor cells, likely less accessible later in life, may be more easily transduced; and (iv) immune responses may be reduced or absent (7).…”