12/07/87 
future edits, it would become easier to read. The structure, according to Dr. Epstein, should 
highlight the most important issues, particularly in the Points to Consider section. 
Dr. Murray said he had little to add. He noted that the reviewers failed to agree that the protocol 
was ready for trial, citing concerns about the transformation of stem cells and PEG-ADA. How 
long would human trials be postponed? The in vitro fertilization issue was also important, though 
outside of NIH auspices. Finally, the structure of the protocol should include required 
information. 
Dr. Parkman had six issues to discuss. First, the helper virus was an important safety issue. 
Second, regarding technical efficacy, the researchers will have to show expression from totipotent 
stem cells for the specific gene being used, i.e. the specific gene and construct. 
Third, the PEG-ADA issue requires an update from Dr. Hirshfield: the data are both non- 
representative and incomplete. Five of six ADA-severe combined immune deficiency (ADA-SCID) 
patients thus were not representative of most ADA-deficient children. Moreover, while there is 
improvement in the T-cell function, data do not yet exist that prove T-cells can respond to the 
antigen. 
Fourth, Dr. Parkman continued, the Cook-Deegan questions on the relevance of antibodies also 
remained unanswered-one can find the antibodies, but their relation to, and long-term impact 
on, therapy are unknown. Fifth, regarding differentiation, the efficacy of histocompatible donors 
is approximately 70%, which gives a selective advantage for engraftment. It is possible to get 
engraftment of normal stem cells; drugs appear unneeded to make "space," though this remains 
unproven. If a non-histocompatible donor is available, about 70% will get grafts with drugs and 
the remaining 30% without drugs. With cytoxan and busulfan, engraftment will approach 100%. 
Twenty patients have received engraftment treatments, only one of whom was not discharged 
from the hospital. There have been no deaths due to toxicity. The ability to tolerate drugs may 
be limited by underlying problems, such as male sterility as a consequence of drug treatment. 
Sixth, efficacy must be balanced with safety. Bone marrow transplants are unsafe for some 
patients, with a mortality rate of 5-10%. Nonetheless, absolute safety or efficacy will remain 
impossible to achieve. 
Dr. Mahoney commented on several specific points: (1) if the defect is corrected in T-cells, other 
organs may still show pathology, which demonstrates the need for experimental animal models; 
(2) there must be a precise definition of when an attempt is labeled a "failure"; (3) neomycin 
resistance gene; and (4) initially, repeated attempts and close examination of drug effects will be 
required. 
Dr. Parkman added that bone marrow has been taken from a six-week old donor. Other organ 
systems have not failed in allogeneic transplants. Solely stem cell graftments would probably 
require drugs. A three-year old has received successful transplants. 
Dr. Childress questioned whether human gene therapy would offer a reasonable chance of 
success. He believed that safety and efficacy are not sufficient to justify a trial at this time. He 
noted that Dr. Anderson and others were talking about a "last hope" procedure rather than 
clinical trial. It appeared unclear what level of evidence was needed for a compassionate use 
[94] 
Recombinant DNA Research, Volume 13 
