Recombinant DNA Advisory Committee - 6/9-10/94 
synovial fluid and joint material 1 week later to determine the presence and location of 
the transduced synovial fibroblasts and the level of ERAP in the joint fluid. This 
proposal is based upon the demonstrated efficacy of IRAP administration in either 
human clinical trials or preclinical animal studies. 
The investigators indicated in their written response that they are not unswervingly 
committed to IRAP as the only antiarthritic agent in the human trial. Once the gene 
transfer techniques have been established, these methods can be employed to transfer 
genes other than IRAP. The proposed study is similar to a gene marking protocol in 
that a therapeutic outcome is not expected. He asked the investigators to clarify whether 
it is intended to be a marking protocol or a study with therapeutic intent since the 
criteria for approval will be different. 
Dr. Parkman said that three outstanding issues remain: (1) Are the high titer vector 
producer cells described in the protocol currently available for the proposed study? (2) 
What is the transduction efficiency and the level of IRAP production in the proposed 
target cells? (3) If the present study is intended as a therapeutic protocol rather than a 
marking study, histopathologic data should be provided demonstrating the therapeutic 
effect, i.e., prevention of joint destruction in a rabbit model. 
Review~Dr. Motulsl^ 
Dr. Motulsky said that the proposed study is an innovative approach attempting to treat 
autoimmune disease in the affected joints of chronic arthritis patients. Current 
treatment is symptomatic and unsatisfactory. Although the IRAP gene is proposed for 
the current study, the investigators have reserved the option to use other cytokine genes 
if this procedure is successful. He asked the investigators to respond to the following 
questions: (1) What is the frequency of severe reactions? (2) 'TOat systemic or local 
reactions to IRAP have been observed that might cause patients to withdraw from the 
study? (3) What is the status of the experimental animal models described by Dr. 
Parkman? Preclinical data has been submitted in an antigen-induced arthritis rabbit 
model. The animals are presensitized to ovalbumin by intradermal injection and then 
given an intraarticular injection of ovalbumin in the knee joints to induce arthritis. What 
additional procedures will be required for this study that are not normally performed on 
patients with advanced knuckle joint arthritis? Dr. Motulsky recommended that a 
research clinical rheumatologist should be involved in this study to assist in patient 
evaluation and follow-up. The investigators agreed to include such an expert in this 
study. Dr. Motulsky recommended approval of this protocol if the requested information 
is provided. 
RevieW“Dr. Zallen 
Dr. Zallen explained that the investigators had already responded to several aspects of 
the protocol addressed in her written comments. She then raised the following 
additional questions: (1) Is the viral genetic material spread beyond the joint, 
specifically to gonadal tissue? This issue is of less concern in the proposed study since it 
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Recombinant DNA Research, Volume 19 
