Proof-of-principle prenatal gene therapy studies have shown long-term expression of proteins at therapeutic levels and induction of immune tolerance in both small and large animals and cured congenital disease in some animal models. This chapter describes current progress with fetal gene therapy and discusses how this therapy may be eventually translated into the clinic. The genodermatoses may be good candidates for prenatal gene therapy, where gene transfer to the skin via the amniotic fluid may provide an obvious advantage to cumbersome postnatal therapy. Most of this work is performed in animals, mostly in mice that can provide transgenic models of human disease necessary to demonstrate proof-of-principle. The most commonly tested vectors in prenatal gene therapy pre-clinical studies have been adenovirus and adeno-associated virus, lentivirus and retrovirus vectors. Targeting of vectors to organs or specific tissues is the ultimate goal, and will most likely require the use of several combined approaches.

Prenatal gene therapy has the ability to target rapidly dividing cells, thus providing a large population of transduced cells that should provide a better therapeutic effect. The list of candidate diseases for prenatal gene therapy includes not only many single-gene disorders but also some pregnancy-specific conditions and structural abnormalities of the fetus. The ideal vector for fetal somatic gene therapy is the one that can produce long-term regulated and therapeutic expression of the transferred gene through the use of a single and efficient gene delivery method. Over the past few years, proof-of-principle studies in small-animal models have shown that prenatal gene therapy can result in permanent phenotypic correction of early single-gene disorders. Prenatal gene therapy in humans will depend critically on the ability to demonstrate its safety and efficiency in treating severe genetic disease. Improvements in vector design and safety and in delivery techniques to the fetus are the key.