Recombinant DNA Advisory Committee - 12/1-2/94 
as handling HIV in clinical specimens or in a production scale. She said that her group of Mid-Atlantic 
Biological Safety Association has experience on quantitative risk assessment. Dr. Straus suggested that the 
BMBL book should be included in the next mailing to the RAC members in order to facilitate the review of 
the proposal. Dr. Par km an suggested to have the proposal announced in the E-mail for wide public comment. 
XV. PRESENTATION OF ETHICAL CONSIDERATIONS RELATIVE TO IN UTER O SOMATIC CELL AND 
GENE THERAPIES/DR. PATTERSON 
Dr. Amy Patterson of FDA presented an overview of some of the ethical issues involving in utero cell and gene 
therapies with an overhead slide illustration. Her presentation covered 4 major areas: (1) In utero bone 
marrow transplantation, its rationale and the proof of concept; (2) Human experience; (3) Experiments 
involving potential protocols; and (4) Ethical considerations inherent in prenatal cell and gene therapies, 
including informed consent process and patient enrollment and eligibility criteria. The meeting materials 
included an article by Drs. Morton J. Cowan and Mitchell Golbus entitled: In Utero Hematopoietic Stem Cell 
Transplants for Inherited Diseases , published in the Journal of Pediatric Hematology /Oncology, Volume 16, 
pages 35-42, 1994. 
Overview-Dr. Patterson 
The proof of the concept for in utero bone marrow transplantation relies on immuno-incompetence of the fetal 
immune system early in gestation. Evidence for immuno-incompetence of the fetal immune system is as 
follows: (1) Aborted fetuses have decreased T-cell immunity in vitro ; (2) Donor lymphoid cells reportedly 
engraft in fetuses transfused with unirradiated blood transfusions; (3) Fetal liver or thymus transplants given to 
SCID children have shown significantly lower risks of graft versus host disease (GVHD) when fetal tissue is 
less than 10 to 12 weeks gestational age. Human immunocompetence emerges at roughly 16 weeks of 
gestation. The rationale for doing in utero transplantation rests on the following provisions: (1) the genetic 
disease is diagnosed early enough in gestation; (2) the fetus would be relatively immuno- in competent; and (3) 
engraftment could be achieved without the usual toxic preconditioning or the ablative regimen. In addition, 
there could be relatively low risk of damage to target organs. 
At present, 14 attempts have been made at in utero transplantation in humans worldwide involving genetically 
unmodified human stem cells. The sources of stem cells include parental, sibling, fetal liver and fetal thymus. 
5 of those 14 attempts have shown evidence of engraftment. It is notable that 2 of those 5 engraftments were 
conducted at a gestational age of less than 16 weeks when the fetus was still immuno- incompetent. There are 
evidence of mixed chimerism in all instances. 
Mr. Capron asked at what gestational age the transplantation was performed in the 9 cases that failed to show 
engraftment. Dr. Patterson said they were conducted between 14 and 32 weeks; not all transplantations 
conducted before 16 weeks were successful. Dr. Par km an explained that most of these patients are SCID 
children, and there are many other variables contributing to the failure of engraftment. 
Of the 5 patients with evidence of engraftment, 1 infant had bare lymphocyte syndrome. This transplant was 
performed in France using fetal liver and thymus administered through the umbilical vein. The infant is now 
16 months postnatal, and there is no evidence of GVHD, and 26% of its lymphocytes are of donor origin. An 
infant with p -thalassemia was transplanted in France at 14 weeks gestational age using fetal liver and thymus. 
Another infant with SCID was transplanted in France with fetal liver and thymus at the gestational age of 28 
weeks. This child is now 22 months old and remains out of the isolation chamber. Two families elected 
abortion at 20 to 24 weeks when testing failed to show engraftment. However, on examination of the aborted 
fetuses, it was found that donor cells had indeed engrafted into fetal marrow. These 2 cases raise difficult 
medical and ethical issues when counseling parents for abortion. 
The potential obstetrical complications of in utero bone marrow transplantation include both fetal and 
maternal infection, fetal death, premature rupture of membranes, fetal trauma, and persistent fetal 
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