Recombinant DNA Advisory Committee - 12/1-2/94 
Dr. Glorioso noted that the extensive precautions proposed by the investigators is impressive, and provides a 
greater level of containment than the Biosafety Level (BL)-2 that is required for vector production. 
Committee Motion 1 
A motion was made by Dr. Straus and seconded by Dr. Erickson to defer approval of the protocol until the 
investigators return to the full RAC with additional safety data regarding virus transmission following aerosol 
administration. 
Dr. Judith St. George (Genzyme) requested permission to present additional safety data derived from a 
"sentinel" mouse experiment. The original experiment was flawed because the animals were allowed to come 
in contact with each other. The experiment was redesigned such that animals shared the same air but were 
physically separated by a porous barrier. Two mice received 1 x 10'° IU of the adenovirus vector in the nose 
and were placed opposite (separated by the porous barrier) 3 "sentinel" mice. On Day 3, the animals were 
sacrificed and assayed for vector sequences by PCR. Vector sequences were detected in the lung and nose of 
the treated animals, whereas there was no evidence of virus sequences in the "sentinel" animals at any site. 
There is no evidence of virus spread through the air. Dr. Samulski asked about the sensitivity of the PCR 
assay. Dr. St. George responded that lung tissue spiking experiments demonstrated a level of sensitivity 
between 1 in 1 x 10 3 and 1 x 10 4 particles. Dr. Parkman noted that the level of sensitivity is very low and does 
not adequately address virus spread through aerosol administration. 
Dr. Haselkorn noted that the proposed adenovirus vector is replication-defective and that the proposed safety 
precautions exceed the requirements for previous adenovirus vector/CF studies. Dr. Dorkin requested that the 
requirement for additional safety studies be included as a contingency for approval. 
Dr. Walters reminded the committee that the current motion involves deferral of the protocol until the 
investigators return to the full RAC with additional safety data. Dr. Miller suggested approval of the protocol 
contingent on review and approval of the additional data. Dr. Straus accepted Dr. Miller’s recommendation to 
approve the protocol with stipulations. 
In formulating the stipulations, Dr. Straus noted the necessity for data demonstrating safety to health care 
workers both inside and outside of the nebulization chamber. Dr. Meeker emphasized that the multiple levels 
of containment represent "state of the art" technology to prevent virus spreading. Dr. Straus noted that this 
protocol is a precedent setting study for aerosol adenovirus vector administration, and he would prefer to 
review the data before approval Dr. Parkman stated that aerosol administration is obviously crucial to the 
long-term potential applicability of gene therapy for CF, and the burden of proof is on this precedent-setting 
case. 
Mr. Capron asked for clarification of the proposed experiments that would be required. Dr. Straus stated that 
a mock experiment would be required involving either fluorescein marking or a sensitive PCR assay to detect 
vector DNA and to monitor virus spread inside and outside of the treatment room over a specified time 
course. Dr. Miller expressed concern that coughing during the nebulization procedure could introduce 
potential hazard. 
Dr. Motulsky proposed an amendment to Dr. Straus’s motion to defer the protocol. A motion was made by 
Dr. Motulsky and seconded by Mr. Capron to approve the protocol contingent on submission of safety data 
and subsequent review by a subcommittee via a telephone conference call. The amendment passed by a vote 
of 18 in favor, 0 opposed, and no abstentions. Ms. Meyers remarked that the entire RAC should review this 
data before recommending approval. The RAC should not rush approval of this study. 
Dr. Parkman remarked that the subcommittee should have the option to approve/disapprove the study based 
on subsequent data or request that the data be presented to the entire RAC if deemed necessary. Drs. 
Erickson and Parkman requested inclusion on the subcommittee and expressed their reservations regarding the 
sensitivity of the PCR assay. 
Recombinant DNA Research, Volume 20 
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