Recombinant DNA Advisory Committee - 12/1-2/94 
rare diseases. Dr. Patterson said most of the ground work for in utero therapy including the vector and stem 
cell technology has been developed for the treatment of other genetic diseases such as Gaucher disease. 
Dr. Parkman noted that many diseases such as SCID do not have in utero abnormality, and there is no 
justification to perform in utero gene therapy when the same result can be achieved with newborns. There are 
a limited number of diseases in which there is significant morbidity and mortality prior to birth that will 
benefit from the in utero gene therapy. Dr. Motulsky noted several examples, i.e., /3-thalassemia, and some 
fetal lung and CNS diseases. Dr. Parkman mentioned the fetal lamb studies by Dr. Esmail Zanjani of the 
University of Nevada School of Medicine that are relevant to in utero gene therapy. 
Dr. Straus stated that in utero therapy is a challenging issue. However, the RAC is not a proper forum to 
discuss fetal therapies that do not involve gene therapy. Since gene therapy still needs proof of efficacy in 
post-natal individuals, the issue of prenatal treatment is premature. 
Dr. Samulski noted that the promising research of stem cell technology will have the best chance of succeeding 
in prenatal therapy. Dr. Glorioso stated that the present discussion is related to the future of fetal research. 
The stem cell technology has potential applications to diseases of lung, liver, colon, and others. For example, a 
preventive gene therapy can be performed by transducing the p53 tumor suppressor gene to stem cells in utero 
in multiple copies since many more mutations of this gene would have to occur in order for a tumor to 
develop. 
Dr. Zallen stated the prospect of current investigation using stem cells in utero could lead directly to attempts 
to genetically modifying stem cells and to conduct gene therapy in utero. The subject is of considerable 
interest to the RAC and to FDA as well. Dr. Zallen supported Dr. Patterson’s suggestion to form a 
subcommittee to examine these issues in details. The subcommittee could evaluate the issues with the public 
involvement and subsequently recommend appropriate amendments to the Points to Consider. 
Dr. Zallen said there is no ethical impediment using medical technology to treat a fetus in utero under 2 
conditions: (1) if the intervention directly benefits the fetus, and (2) if the medical outcome requires 
intervention in utero because of additional complexities of the disease if it is treated after birth. The proposal 
would have to be judged by both the overall scientific merit and a favorable risk/benefit ratio. The informed 
consent process will guide the potential subjects to make their decision to participate in the study. Responding 
to the question of whether willingness of the mother to undergo abortion should be a factor of the enrollment 
criteria. Dr. Zallen said that women who have decided to proceed with the pregnancy are the most deserving 
candidates since the decision to have the baby would allow medical evaluation of the treatment after birth. On 
the other hand, it could be argued that women who are willing to have an abortion will allow termination of 
pregnancy if serious problems of the intervention are detected before birth. In this case, the women should 
agree to an autopsy so that scientifically useful information could be obtained. Dr. Zallen stated that 
someone’s willingness to consider abortion should not be the determining factor in eligibility for a protocol; all 
potential subjects should be presented with the protocol. Responding to the question of fetal enrollment 
criteria, Dr. Zallen said scientists and clinicians are most able to choose the appropriate diseases to be treated 
by in utero gene therapy. While fetal intervention should be first given to extremely serious life threatening 
diseases, the degree of seriousness has to be factored into the degree of knowledge possessed and the 
likelihood that the intervention could produce a beneficial result. Responding to the question of the informed 
consent process, Dr. Zallen said that timing of informing the potential subjects is the most critical factor since 
there is very little time lapse between genetic testing and the optimal time to perform the fetal intervention. 
The informed consent process should be planned with a long lead time. Both the pregnant woman and her 
husband should be invited to make their joint decision. In addition, there is a need to involve a neutral 
resource person such as the woman’s obstetrician or an expert in fetal medicine to provide the information 
about the complicated aspects of the research protocol. Dr. Zallen emphasized that this person should have 
no conflict of interest. Dr. Zallen said the need for long-term follow-up is absolutely necessary in doing the in 
utero gene therapy. Since the treated subjects are expected to outlive the investigators, a mechanism has to be 
in place to keep track of the patients. In conclusion. Dr. Zallen stated that the RAC should form a 
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