© The American Society of Gene Therapy
Why Bother?: Is In Utero Gene Therapy Worth the Effort?
n utero gene therapy in humans remains controversial, despite the increasing use of fetal gene delivery in animals. Advantages of in utero gene therapy include the beneficial vector-to-cell ratio, the presence of expanding and developing stem cell populations during fetal life, the possibility of achieving tolerance against vector and transgenic proteins, and the prospect of preventing irreparable tissue damage associated with early-onset inherited disease. Therapeutic proof of principle by this approach has been demonstrated in several rodent models of human genetic conditions. Recent advances in fetal medicine—particularly in imaging and minimally invasive intervention—have opened the way, in large animal models, for clinically relevant delivery of gene therapy vectors to virtually any fetal organ. However, although postnatal gene therapy has seen its first successful clinical applications, no trials are planned for human gene therapy in utero, now or in the near future. Indeed, many view the concept as having only academic value, with no potential for translation into the clinic. At present, the options for a couple at risk of having a child with a serious mendelian disease are preimplantation genetic diagnosis and embryo selection, abortion, or caring for an affected child. Safe, effective, and curative gene therapy in utero would be by far a better option. Research toward this goal may also facilitate postnatal gene therapy by providing insights into the problems associated with stem cells and immunologic rejection later in life. The most frequent objection to in utero therapy is that, if a fetus is shown to be affected by a serious inherited disease, abortion is a logical and clinically safe procedure that should not be rejected in favor of the initially unproven outcome that would result from a gene therapy approach in utero. However, it is not rare for a family to decide against abortion, even though this may mean assuming the burden of caring for an affected child. Prenatal gene therapy may offer an answer to this dilemma, although the first families to choose this option would certainly face a difficult decision because of the perceived and real dangers, and the unproven reliability of the procedure. Molecular Therapy vol. 16 no. 2 february 2008
It is often argued that in vitro fertilization followed by preimplantation genetic diagnosis should be the preferred way forward for couples known to be at risk of having a child with a mendelian disease. Preimplantation selection is a proven option, whereas in utero gene therapy still awaits such proof in humans. However, in vitro fertilization is neither simple nor risk-free, and the complex procedures involved will need to be compared with what should be a relatively simple, “one-shot” injection of a gene therapy vector under ultrasound guidance. Moreover, preimplantation selection requires family analysis and molecular diagnosis before conception and thus cannot be used if a case is detected by prenatal screening during pregnancy. Further objections to in utero gene therapy arise from perceived risks. Because these risks—in particular, long-term adverse effects—are unknown or unproven, reliable risk–benefit analysis is difficult at this time. This is not unusual in emerging experimental therapies. However, whereas a highrisk therapy may be accepted as the only option to secure health or ameliorate suffering for a severe disease after birth, for a condition diagnosed in utero, abortion may be preferred by most—but not all—families as a traumatic but still more acceptable option. The only way to resolve this dilemma is through research to define and exclude such risks to as great an extent as possible, although, as with any other therapy, a final answer will come only after clinical trials. Possible specific dangers of prenatal gene therapy include acute adverse effects directly related to the procedures, short-term effects during intrauterine development, and long-term postnatal effects. Risks due to the procedures of vector application can be well defined, because these techniques are applied routinely in fetal medicine, and the risks of acute adverse effects from the vector would not be different from those in postnatal gene therapy. Hypothetically, untimely or ectopic expression or overexpression of a transgene in the treated fetus could result in unknown effects on fetal 219
© The American Society of Gene Therapy
and postnatal development. They are difficult to predict, will be specific for individual proteins, and will most likely depend on the gestation age at vector application. Stringent control of expression may help to avoid such effects, but animal experiments may not be sufficient to predict outcome in the human fetus and careful prenatal monitoring will be required to exclude them. Lifelong postnatal observation of any individual treated in utero should be conducted as in any other gene therapy trial. Vector-related oncogenesis is now an established, although not fully understood, risk of gene therapy with integrating vectors. Hepatocellular tumors have been observed in fetal and neonatal mice after applying early third-generation equine infectious anemia virus vectors with self-inactivating configuration and after neonatal application of adeno-associated virus vectors. This observation suggests that the developing mouse fetus and neonate may be particularly sensitive to the effects of integrating vectors, perhaps as a result of the expression of a high proportion of genes involved in development and cell growth during early life. In this context it may not be a coincidence that myeloproliferative disease following murine leukemia virus vector treatment occurred in the youngest patients in the French X-linked severe combined immune deficiency trial. Again, research on in utero gene delivery may help us to understand problems of vector-associated oncogenesis, serve as a tool to identify new cancer genes, and help as a sensitive in vivo test system in the development of safer gene therapy vectors. Finally, does in utero application pose an increased risk of germline transduction? Low-level retroviral transduction of germ cell progenitors has been observed in the male and female gonads after intraperitoneal vector application into fetal sheep and monkeys, respectively. However, no indication of germline transmission after fetal vector administration has been found
in rodents or sheep in experiments designed to address this question. As for postnatal gene therapy, this problem requires monitoring in the context of any clinical trial. At this point, fetal gene therapy can be envisaged only for severe genetic diseases for which no other therapeutic option, including postnatal gene therapy, is available. It remains to be seen how big a window of opportunity neonatal gene transfer can offer in providing these advantages. Effectiveness, reliability, and safety will be the main criteria by which any family contemplating prenatal gene therapy over abortion will make its decision. It will be important to demonstrate effectiveness in a model in which both target disease and vector system are similar to those to be used in a clinical trial. Optimally, monitoring fetal morphology and therapeutic gene expression levels in utero would allow confidence in reliability of outcome or an informed decision to terminate a pregnancy if fetal aberrations are observed or if only insufficient gene expression is achieved. Given the complexity of the above-discussed issues, it will be necessary to give particular attention to informed maternal consent based on a detailed understanding of the perceived risks and envisaged benefits of the proposed procedure. We are only at the beginning of the development of effective therapeutic approaches for severe human genetic diseases. These conditions are so varied and complex that each will require a specific approach by drug, cell, or gene therapy. None of these approaches will provide a “magic bullet,” and, until we have clinically proven results, no one can predict which approach will be successful for which disease. In utero gene therapy should thus have a place in our potential arsenal.
Charles Coutelle Associate Editor (2005−2007)
www.moleculartherapy.org vol. 16 no. 2 february 2008