3.4.9 Clinical Research that Involves in utero Stem Cell and Genome Editing Interventions
In utero administration of a stem cell-based or gene-based intervention (whether based on gene replacement or genome editing) may offer several advantages, including 1) early intervention before tissue damage is established and when the tissue/cells have the highest growth and regeneration potential; 2) more effective bio-distribution of the intervention within the intended tissue while interstitial diffusion is facilitated, tissue barriers are still immature, and more comprehensive modification of the target cell population is possible because of its smaller size; and 3) low risk of eliciting immune response to the stem cell-based or gene product, because of the incomplete development of the adaptive immune system.
Considerations for in utero Genome Editing Interventions
While there may be therapeutic advantages, in utero genome editing interventions may also exacerbate some safety concerns, particularly those associated with genetic interventions. Early and more comprehensive exposure to gene transfer/editing techniques may increase the risk of genotoxicity, because of the high rate of cell proliferation and tissue growth and increased proportion of self-renewing progenitors. The broad biodistribution of the therapeutic product may also reach unintended tissues or cell populations that are otherwise shielded at older ages, such as germline cells. Finally, any acute or delayed toxicity triggered by the administered cell/gene product at the target and off-target tissues may have far more damaging consequences than observed when genome editing is performed at later stages of life, including teratogenicity. Ad hoc comprehensive studies should thus be designed in surrogate small and large animal models to assess these risks and investigate any long-term consequences of the intervention.
Recommendation 220.127.116.11 Clinical research involving in utero stem cell-based interventions or genome editing involves risks to both the pregnant woman and the future child, and should be undertaken only when it offers the prospect of a benefit greater than that of post-natal interventions, does not pose excessive risk to the pregnant woman, and where there is institutional capacity for autopsy (in the case of miscarriage or stillbirth) or follow-up (in the case of live birth).
Clinical research involving in utero genome editing or stem cell-based interventions should only be performed in centers with personnel trained for in utero surgery and with existing guidelines or practices regarding the treatment of extreme preterm births or births of children with devastating/life-threatening conditions. Research protocols for experimental in utero interventions must be reviewed and approved by a research oversight committee prior to recruiting patients. The interventions should be conducted as early in pregnancy as medically appropriate in case termination is unexpectedly needed due to risks to maternal health or the prospect of miscarriage, stillbirth or neonatal condition inconsistent with survival. While there is a risk of pregnancy complications after fetal intervention, the anticipated prospect of benefit from the intervention should be greater than the risk of complications in experienced hands.
Furthermore, the pregnant woman should be competent and able to voluntarily choose or refuse the intervention. The consent process should include a full discussion of alternative post-natal therapeutic interventions, as well as the possibility that even if this prenatal intervention is successful, there might nonetheless be a miscarriage, a stillbirth, or a child born with serious health problems. If permitted by the pregnant woman or required by law, the intended rearing partner should be consulted.