Recombinant DNA Advisory Committee- 9/12-13/94 
will have to be coordinated with FDA. The ad hoc review is a long-term process; and it 
can proceed in a series of phases, dealing with the immediate streamlining problem first 
and then other more difficult issues. Dr. Doi said different ad hoc groups can be formed 
to deal with different problems. Dr. Varmus emphasized that he is not coming to the 
RAC with a concrete proposal but rather to initiate a process to respond to the changing 
field of gene therapy. Dr. Zallen said that no matter what the final outcome of these 
changes, the tradition of public openness and public involvement of the RAC should be 
continued. Dr. Varmus indicated that he is committed to this tradition. Dr. Walters 
thanked Dr. Varmus for his comments to the RAC. 
VII. ADDITION TO APPENDIX D OF THE NIH GUIDELINES REGARDING A HUMAN 
GENE TRANSFER PROTOCOL ENTITLED: A PHASE I STUDY OF AN ADENO- 
ASSOCIATED VIRUS-CFTR GENE VECTOR IN ADULT CF PATIENTS WITH MILD 
LUNG DISEASE /DR, FLOTTE 
Review~Dr. Samulski 
Dr. Walters called on Dr. Samulski to present his primary review of the protocol 
submitted by Dr. Terence R. Flotte of the Johns Hopkins Children’s Center, Baltimore, 
Maryland. Cystic fibrosis (CF) is caused by defects in the cystic fibrosis transmembrane 
conductance regulator (CFTR) gene. The CFTR gene product is required for regulation 
of epithelial chloride transport in multiple organs including the lung airways. CF lung 
disease develops gradually over many years as abnormally viscous secretions lead to airway 
obstruction, infection, inflammation, and fibrosis. It ultimately may lead to respiratory 
failure, which is the cause of death in more than 90% of CF patients. Several protocols 
have been approved to employ adenovirus vectors or liposome-based vectors to transduce 
the CFTR gene to replace the missing gene function in CF patients. These investigators 
have developed an alternative vector system based on adeno-associated virus (AAV). 
AAV vectors can have long-term persistence in the host cells, and AAV-CFTR vectors 
have been shown to confer stable correction of the physiological defects when 
administered to CF bronchial epithelial cells in vitro. Long-term vector expression up to 6 
months has been observed in a New Zealand white rabbit model. An additional 
advantage of the AAV vector is the absence of wild-type viral coding sequence in the 
vector construct that eliminates the possibility of vector-induced inflammatory reactions. 
The current protocol is a Phase I study of AAV-CFTR vector administered to the nose 
and bronchial epithelium of adult CF patients with mild lung disease. This protocol will 
be a dose escalation study to evaluate vector expression and safety. Vector doses ranging 
up to 10 10 particles will be administered to the nasal epithelium and through a fiberoptic 
bronchoscope to a single lung lobe. 
Dr. Samulski asked 6 specific questions. (1) Study cohorts. What is the rationale for the 
dose escalation schedule for the nose and lung since the number of target cells are 
different? Will patients treated with AAV be excluded from treatment with other vectors, 
specifically adenovirus vectors? The investigators answered that the plan is to escalate the 
nasal dose in advance of the pulmonary dose escalation. The issue of exclusion has been 
discussed at the CF Foundation/FDA Williamsburg Conference, and the consensus was 
Recombinant DNA Research, Volume 20 
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