Cell-based interventions in utero: time to reconsider

Introduction In 1999, the NIH Recombinant DNA Advisory Committee held a Gene Therapy Policy Conference on in utero gene transfer (NIH 1999) and determined that it would be premature to undertake in utero gene transfer research in humans (RAC 1999). Much has happened since then. Gene transfer research enrolling infants and very young children as patient-subjects has had results both beneficial and harmful in several conditions (Hacein Bey-Abina et al., 2003; Aiuti et al., 2012; Corrigan-Curay et al., 2012). Some fetal surgical interventions have become accepted (Adzick et al., 2011). And much has been learned about the immune system and how pregnancy influences immune response. We now know a lot more about how much more there is to learn. Researchers in cell- and gene-based interventions are eager to move to human trials in order to continue the learning process. Yet funders and oversight bodies are reluctant to support cell-based intervention research in human fetuses. In this commentary we address probable reasons for this hesitancy, reasons to move forward with caution, and issues to address in planning first-in-human (FIH) trials of cell-based interventions in utero. Reasons for reluctance First, there is concern that existing alternatives obviate the need for in utero interventions -- that is, if in utero treatments are unnecessary, then in utero research is too. For couples known to be at risk of giving birth to offspring with serious genetic or metabolic anomalies, in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD) are available (Dresser, 2004). For couples without known risk factors, prenatal diagnosis and abortion are available. However, IVF and PGD are costly, burdensome, and thus unavailable for many couples, and abortion is morally unacceptable to many and increasingly difficult to obtain for many others. Thus, these alternatives by no means eliminate the need for or the value of in utero interventions, and cannot justify failure to support in utero research (Strong, 2011). Second, the growing tendency to categorize unprecedented and untested stem cell interventions as innovation rather than research may be thought to offer investigators an alternate route to the clinic. However, the extensive cautionary literature on the problem of innovation makes clear that FIH in utero cell-based interventions should be regarded and treated as research (Sugarman, 2012; Hyun et al. 2008; Chescheir and Socol, 2005; Daley, 2012). Finally, and most important, federal regulations restrict research involving pregnant women and fetuses. 45