Recombinant DNA Advisory Committee- 9/12-13/94 
event that they choose to withdraw from the study after the vector construct has been 
administered, they will be strongly discouraged from leaving the hospital until the lack of 
virus shedding has been demonstrated. The revised Informed Consent document must be 
reviewed and approved by the RAC primary reviewers. 
(Dr. Miller abstained from voting due to his association with Targeted Genetics, Inc., a 
sponsoring company of the protocol.) 
Summary 
Dr. Terence R. Flotte of the Johns Hopkins Children’s Center, Baltimore, Maryland, may 
conduct gene transfer experiments on 16 subjects (>18 years of age) with mild CF. A 
vector derived from AAV will be used to transduce a human CFTR gene. The vector 
construct is termed tgAAVCF. The vector will be administered by direct application to 
the nasal epithelium and by bronchoscopic delivery to the right lower lobe of the lung. 
This is a dose escalation study in 8 cohorts of patients. Each individual will receive a 
single nasal dose of 1 x 10 6 to 1 x 10 9 and a single lung dose of 1 x 10 7 to 1 x 10 10 vector 
particles. The primary goal of the study is to assess safety of vector administration. As a 
secondary objective, brushed respiratory and nasal epithelial cells will be evaluated for 
gene transfer, gene expression, and physiologic correction of the CF defect. Pulmonary 
function testing and lung imaging studies will be used to assess clinical impact. 
VIII. ADDITION TO APPENDIX D OF THE NIH GUIDELINES REGARDING A HUMAN 
GENE TRANSFER PROTOCOL ENTITLED: GENE THERAPY FOR THE 
TREATMENT OF METASTATIC BREAST CANCER BY IN VIVO INFECTION WITH 
BREAST-TARGETED RETROVIRAL VECTORS EXPRESSING ANTISENSE C-FOS OR 
ANTISENSE C-MYC RNA/DRS . HOLT AND ARTEAGA 
Review-Dr. Miller 
Dr. Walters solicited help from RAC members to review the information collected for 
data management to be presented at the coming December RAC meeting. He then called 
on Dr. Miller to present his primary review of the protocol submitted by Drs. Jeffrey Holt 
and Carlos B. Arteaga of the Vanderbilt University, Nashville, Tennessee. Dr. Miller 
stated that the investigators propose to use retroviral vectors that express antisense fos or 
myc oncogene sequences to treat malignant breast cancer cells in the meninges, 
peritoneum, or pleura. The vectors would be directly injected into these areas. The 
antisense sequences are expressed by using a tissue-specific mouse mammary tumor virus 
(MMTV) promoter to direct expression to malignant breast cancer cells. The 
investigators have shown that cultured MCF-7 human breast cancer cells have reduced 
tumorigenicity in animals after vector transduction, and that not all cells need to be 
modified in order to see this antitumor effect. The investigators stated that experiments 
in animals to demonstrate efficacy of this technique on established tumors are in progress. 
Dr. Miller stated that these data will be important for evaluating this protocol. Dr. Miller 
said that the oncogene sequences used to construct the antisense vectors are relatively 
short and have no potential for oncogenicity if the oncogene sequences are inadvertently 
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