Recombinant DNA Advisory Committee - 12/1-2/94 
Dr. Zallen asked the investigators to explain their decision to treat subjects with mild disease. Dr. Dorkin 
responded that data derived from mild to moderate disease states is very important since the likelihood of 
exacerbations, which could complicate interpretation, is less for this population. Dr. Moscicki added that the 
mild disease patients are the eventual target population for this therapy, therefore, the safety study should 
include this group of subjects. 
Dr. Straus asked the investigators to submit a specific written description of the proposed safety experiment 
for approval by the subcommittee prior to initiation of the experiment. Dr. Walters agreed that prior approval 
of the experimental design will avoid any misunderstanding between the RAC and the investigators. 
Committee Motion 2 
A substitute motion was made by Dr. Straus and seconded by Dr. Erickson to accept the protocol submitted 
by Drs. Dorkin and Lapey contingent on the review and approval of the following by a subcommittee of the 
RAC: Data derived from "mock" experiments demonstrating that health care workers (both inside and outside 
of the treatment room) will be protected from inadvertent exposure to the adenovirus vector during 
nebulization. These mock experiments will not be conducted by the investigators until the experimental design 
has been mutually agreed upon between the investigators and the members of the subcommittee via a 
telephone conference call (Drs. Ginsburg, Erickson, Straus, and Parkman). The substitute motion passed by a 
vote of 17 in favor, 0 opposed, and no abstentions. The RAC will be informed of the accepted experimental 
design. 
Summary 
Dr. Henry Dorkin of the New England Medical Center, Tuft University, Boston, Massachusetts, and Dr. Allen 
Lapey of Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, may conduct gene 
transfer experiments on 16 subjects (sl8 years of age) with CF. The replication-deficient adenovirus vector 
AD2/CFTR-2 will be used to deliver the human cystic fibrosis transmembrane conductance regulator (CFTR) 
gene to the lung of CF patients by aerosol administration. AD2/CFTR-2 is an El/partial E4 deleted type 2 
adenovirus. The adenovirus construct includes the phosphoglycerate kinase promotor which drives CFTR 
expression. AD2/CFTR-2 is identical to the vector used in Dr. Michael Welsh’s protocol #9312-067 and Drs. 
Dorkin and Lapey*s protocol #9409-091. This aerosol administration protocol will not be initiated until an 
initial safe dose has been determined in the lobar instillation arm of the study (Protocol #9409-091). Subjects 
will receive between 8 x 10 6 and 2.5 x 10 l ° IU of the adenovirus vector. The objective of the study is to 
evaluate the safety of a single aerosol dose of AD2/CFTR-2. Subjects will be monitored for evidence of virus 
shedding and transgene expression. 
VII. DISCUSSION OF ETHICAL CONSIDERATIONS RELATIVE TO IN UTERO SOMATIC CELL AND GENE 
THERAPIES/DRS. PATTERSON (FDA), ZALLEN, MOTULSKY, AND MR CAPRON 
In a letter dated November 3, Dr. Noguchi submitted a letter regarding the ethical considerations of in utero 
somatic cell and gene therapies. Dr. Noguchi’s letter states: 
"The extension of gene therapy to the treatment of fetal disease in utero is imminent. In view of the 
recent realignment between the RAC and the FDA in the consolidated review process for new gene 
therapy protocols, the many ethical considerations raised by in utero gene therapy would optimally be 
addressed in a public forum. The expertise and the resources of the RAC will be invaluable in laying 
the groundwork for the consideration of future protocols which will include in utero somatic cell and 
gene therapies." 
Dr. Walters called on Dr. Motulsky to initiate the discussion. Dr. Motulsky said the issue of in utero gene 
therapy is an outgrowth of fetal stem cell transplantation proposals. Fetal stem cell transplantation is currently 
under consideration because the fetus is immunologically tolerant. In utero gene therapy should be considered 
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Recombinant DNA Research, Volume 20 
