Review Procedure 
The initial clinical protocols designed 
to carry out gene therapy in patients will 
probably be evaluated in the following 
way. Under current Department of 
Health and Human Services regulations 
for the protection of human research 
subjects, a human gene therapy protocol 
must be reviewed by the Institutional 
Review Board at the investigator's home 
institution. In addition, because of the 
widespread public interest and concern 
in this area, the National Institutes of 
Health has announced (5#) that any fed- 
erally funded gene therapy experiment 
involving recombinant DNA must first 
be approved by the NIH after review by 
the Recombinant DNA Advisory Com- 
mittee (RAC). Prior to review by RAC. 
proposals will be examined by a special 
RAC working group on human gene ther- 
apy (59). In addition, the Food and Drug 
Administration could regulate the DNA 
used in a human trial as a biological drug, 
analogous to polynucleotide interferon 
inducers, interferons, and vaccines (60). 
The Food and Drug Administration is 
currently exploring its regulatory re- 
sponsibilities in this area ( 61 ). 
Representative Albert Gore's proposal 
for a President's Commission on the 
Human Applications of Genetic Engi- 
neering (62) has just passed both houses 
of Congress in a modified form. This 
commission, if signed into law. would 
probably concern itself primarily with 
matters of policy and procedure rather 
than the review of individual recombi- 
nant DNA research proposals ( 63 ): the 
initial protocols, however, might be of 
particular interest to the commission in 
helping it to define the scope of its ef- 
forts. 
Conclusion 
It now appears that effective delivery- 
expression systems are becoming avail- 
able that will allow reasonable attempts 
at human gene therapy. These systems 
are based on treatment of bone marrow 
cells with retroviral-vectors carrying a 
normal gene. The safety of the proce- 
dures is the remaining major issue. Pa- 
tients severely debilitated by being ho- 
mozygous for a defect in the gene for one 
of the enzymes HPRT. PNP. or ADA are 
the most likely first candidates for gene 
therapy. 
It is unrealistic to expect a complete 
cure from the initial attempts at gene 
therapy. Many patients who suffer from 
severe genetic diseases, as well as their 
families, are eager to participate in early 
40K 
clinical trials even if the likelihood is low 
that the original experiments will allevi- 
ate symptoms. However, for the protec- 
tion of the patients, particularly since 
those with the most severe diseases and. 
therefore, the most ethically justifiable 
first candidates, are children, gene thera- 
py trials should not be attempted until 
there arc good animal data to suggest 
that some amelioration of the biochemi- 
cal defect is likely. Then it would be 
necessary to weigh the potential risks to 
the patient, including the possibility of 
producing a pathologic virus or a malig- 
nancy. against the anticipated benefits to 
be gained from the functional gene. This 
risk to benefit determination, a standard 
procedure for all clinical research proto- 
cols. would need to be carried out for 
each patient. 
In summary, institutional review 
boards should carefully evaluate thera- 
peutic protocols to ensure that the deliv- 
ery system is effective, that sufficient 
expression can be obtained in bone mar- 
row cultures and in laboratory animals to 
predict probable benefit, even if small, 
for the patient, and that safety protocols 
have demonstrated that the probability is 
low for the production of either a malig- 
nant cell or a harmful infectious retrovi- 
rus. Once these criteria are met, I be- 
lieve that it would be unethical to delay 
human trials. Patients with serious ge- 
netic diseases have little other hope at 
present for alleviation of their medical 
problems. The issues of germ line thera- 
py and enhancement engineering need to 
be debated widely in society, but argu- 
ments that genetic engineering might 
someday be misused do not justify the 
needless perpetuation of human suffering 
that would result from an unnecessary 
delay in the clinical application of this 
potentially powerful therapeutic proce- 
dure ( 64 ). 
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