Recombinant DNA Advisory Committee - 12/1-2/94 
bradycardia. Reported outcome of 14 attempts includes 5 engraftments, 2 fetal deaths due to miscarriage 1 
week after treatment, and septic abortion within 24 hours of treatment. 
With the precedent of in utero bone marrow transplantation, one could envision the application of gene 
therapy in this setting. A potential Phase I protocol might propose to harvest whole marrow from the 
biological mother or father of a fetus with a documented inherited disease. The stem cells would be enriched 
from the marrow and transduced with a vector. The transduced stem cells could be subsequently infused 
intravenously or by direct intraperitoneal injection into the fetus at an age while it is still immuno-incompetent. 
The size of fetus at this stage would easily fit into the palm of a hand. 
With this background information. Dr. Patterson raised the major issues and questions that would be inherent 
in any prenatal gene therapy protocol: 
Issue A: What is the optimal informed consent process for fetal somatic cell and gene therapy? In any 
clinical context, informed consent consists of a process and not simply Informed Consent document. The 
ethical problems of obtaining valid informed consent in fetal therapy have been developed in other contexts, 
such as surgical correction of fetal heart defects, hydrocephalus, and hydronephrosis. Due to the possibility 
that a mother may be likely to disregard her own well-being for the sake of the fetus and the possibility that 
clinical investigators will communicate enthusiasm about new and unproven approaches to fetal therapy, special 
precautions for the informed consent process have been recommended. These recommendations include: (1) 
an impartial physician from the fetal medicine team to "speak for" the fetus; (2) the mother’s own physician, 
available at least by phone to assist in the assessment and comprehension of maternal risks; (3) requisite 
involvement of a genetics counselor in the decision making process; and (4) documentation of the full 
informed consent process. 
Issue B: This issue regards patient enrollment criteria. There are 4 questions in regard to this issue: (1) 
Should prenatal somatic cell and gene therapies (Phase I clinical trials) be restricted at this time to diseases in 
which it is a current standard practice to offer "therapeutic abortion?" (2) Should enrollment in prenatal 
somatic cell and gene therapies (Phase I clinical trials) be restricted to mothers who have been offered the 
option of "therapeutic abortion" and for religious purpose and/or personal motives decline this option? (3) 
Should enrollment be extended to include mothers who have already chosen "therapeutic abortion," and would 
this option potentially enhance the risk/benefit ratio of in utero therapy? (4) At what point are mothers 
informed about this protocol (e.g., after already having made a decision about abortion)? 
Issue C: This issue regards fetal enrollment criteria. There are 3 major questions related to this issue: (1) 
Should inclusion criteria be restricted to diseases with known early fatality? Of particular note is the instance 
of diseases with a known genetic defect diagnosed in utero but with wide phenotypic variability. As in the case 
with many of the inherited metabolic diseases, it is often difficult to made a diagnosis of fetuses with 
devastating diseases. (2) Will the studies be restricted to singleton pregnancies? In order to potentially 
safeguard the well-being of unaffected fetuses if multiple gestations are present, should the studies be 
restricted to cases where both fetuses are affected? (3) Should fetuses with other concomitant abnormalities 
detected by sonography, karyotype, amniocentesis, or biochemical analyses be excluded? 
In terms of future directions, Dr. Paterson asked the RAC to consider the formation of a subcommittee to 
address the following issues: (1) expedited analysis of the ethical considerations inherent in prenatal cell and 
gene therapy clinical trials; (2) definition of an informed consent process in this clinical setting, and (3) 
definition of parameters for patient enrollment and eligibility criteria for both mother and fetus that would 
optimize the risk/benefit ratio. 
Other Comments 
Ms. Meyers and Mr. Capron commented on the thought-provoking presentation made by Dr. Patterson. Ms. 
Meyers was concerned that there will not be much financial incentive to develop the in utero gene therapy for 
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Recombinant DNA Research, Volume 20 
