Recombinant DMA Advisory Committee - 6/9-10/94 
involves only post-menopausal women; however, such information will have greater 
significance if this treatment is successful and patients of reproductive age will be 
involved in future studies. (2) The HSV-TK suicide gene has been incorporated in the 
vector construct as a safeguard. What are the undesirable side effects that will trigger 
the use of Ganciclovir (GCV) to eliminate the transduced cells? (3) Have the 
investigators demonstrated their capability of preparing human synoviocytes in a timely 
fashion for use in this experiment so that patients will not endure any greater risks 
including pain and discomfort while waiting for such treatment? What is the maximum 
time allowed for preparation of the gene altered cells? How would a subject be handled 
as far as the protocol was concerned if this timetable was not met? (4) The 
investigators' response indicates that a neutral person will be involved in the informed 
consent process, but the presence of such a person is not clearly indicated in the 
Informed Consent document. She stated that the changes suggested for the Informed 
Consent document have been incorporated, and the investigators have clarified that the 
costs of the research and any research-related injury will be covered. 
Other Comments 
Dr. Walters summarized the written comments submitted by Dr. Brinckerhoff. Dr. 
Brinckerhoff states that the synovial fibroblasts of young rabbit knee joints are easier to 
grow in tissue culture than the diseased tissues from knuckle joints of older subjects. 
There is a finite number of fibroblast doubling from cells obtained from human joints. 
Growing 1 x 10^ synovial cells from tissue obtained from a single knuckle joint of an 
older patient with end-stage joint disease will be technically challenging and difficult to 
transduce. What is the transduction efficiency in the target cell population? Dr. 
Brinckerhoff commented that it is unreasonable to evaluate efficacy based on data 
obtained from a 7-day experiment with fibroblasts obtained from a patient with chronic 
disease. 
Dr. Walters summarized Ms. Meyers' written comments regarding the Informed Consent 
document. Several specific language changes were suggested to clearly describe the 
experimental nature of the treatment, recommendations regarding barrier contraception, 
and request for autopsy. 
Dr. Parkman asked whether biochemical data is available regarding the chronic phase of 
the joint disease in the rabbit model. Dr. Straus was concerned that the IRAP gene 
introduced into the joints to interrupt the IL-1 mediated inflammatory reaction might 
diminish the joint's inherent anti-bacterial capacity in the event of a septic joint infection. 
This risk is more of a concern if the IRAP gene persists in surrounding tissues following 
removal of the joint. Individuals undergoing this type of surgery with severe rheumatoid 
arthritis are at particular risk for developing serious infection as a complication. 
Dr. Miller raised several questions regarding the vector construct. The vector sequences 
provided by the investigators are those of the MFG backbone, not the insert. The 
proposed construct encodes genes for both IRAP and HSV-TK. Only the IRAP 
construct was used for the rabbit experiments. He suggested that the IRAP construct 
Recombinant DNA Research, Volume 19 
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