Prenatal gene therapy for the early treatment of genetic disorders

Abstract

renatal gene therapy aims to deliver genes to cells and tissues early in prenatal life, allowing the correction of a genetic defect before long-term tissue damage has occurred. In contrast to postnatal gene therapy, prenatal application has a number of advantages, including targeting genes in a large population of dividing stem cells, and the smaller fetal size, which allows a higher vector-to-target cell ratio to be achieved. Early gestational delivery may result in the fetus developing immune tolerance to the transgenic protein, which would allow postnatal repeat of vector administration if needed. Recent advances in vector design and stem cell research have benefited this potential treatment. Although still in the preclinical stage, proof-of-principle studies in animal models of congenital disease, such as the hemophilic mouse, have shown the potential of prenatal gene therapy. Investigators have devised delivery strategies in large animals that could be used clinically to apply gene therapy to a human fetus, and prenatal gene therapy may be available for the treatment of certain life-threatening congenital disorders in the near future. With this treatment, pregnant women and their partners would have a third choice when faced with an affected fetus, where currently the only options are terminating the pregnancy or continuing with an affected fetus with a poor prognosis. A number of problems need to be resolved, including the long-term safety and efficacy of the therapy, the potential for germ-line gene transfer, how best to achieve informed consent for the therapy, as well as regulatory and ethical issues. In this article, we evaluate the current state and future implications of prenatal therapy in severe genetic diseases and outline the factors that will influence its movement into clinical practice.