Recombinant DNA Advisory Committee - 09/9-10/93 
immunized against challenge with HIV. The ribozyme acts at two steps in the viral life 
cycle by cleaving: (1) afferent genomic viral RNA, and (2) efferent viral mRNA 
expressed from integrated provirus. The investigators propose to evaluate the safety and 
efficacy of gene transfer in 6 patients with HIV-1 infection by reinfusing autologous 
CD4( + ) T cells that have been transduced ex vivo with a retrovirus vector that expresses 
the hairpin ribozyme. The in vivo kinetics and survival of ribozyme-transduced cells will 
be compared by limiting dilution polymerase chain reaction (PCR) with cells transduced 
with a control vector. Dr. Straus stated that the PI is a renowned and accomplished 
retrovirologist, who has enlisted qualified clinical collaborators to facilitate the project. 
The protocol relies on a vector and a packaging cell line that are well defined. Dr. 
Straus raised the following concerns about the protocol: (1) What assays will be 
performed for the detection of RCR and who will perform these assays? (2) Is rabbit 
pyrogen testing of clinical materials necessary? (3) Is azidothymidine (AZT) antiviral 
therapy required for subjects entering this study? and (4) Will 4 or 6 patients be accrued 
onto the study? Dr. Straus said that this study is creative and with clarification of these 
issues, he recommends approval of the protocol. 
Review-Dr. Hirano 
Dr. Hirano stated that the results of the preclinical studies and the objective of this 
protocol are very exciting, but there are five concerns that should be addressed: (1) 
Although the vector and packaging cell lines have previously been approved, production 
of vector supernatant is currently being performed in a different laboratory. Results of 
RCR testing in the new laboratory should be provided. (2) There is a lack of PCR data 
comparing the survival of transduced T cells in the background of a large excess of 
untransduced cells as a function of time in tissue culture. (3) Transduction efficiency 
and the ability to expand these transduced cells to numbers that correlate to a patient 
dose has not been demonstrated. (4) The transduction procedure described in the 
preclinical studies is different from that proposed in this protocol. (5) Data are not 
provided regarding testing of ribozyme toxicity in vivo in the severe combined 
immunodeficiency (SCID)-Hu mouse model. (6) The effectiveness of the ribozyme in 
cleaving HIV RNA in lymphocytes obtained from HIV patients with uncloned virus 
strains has not been demonstrated. 
Review-Dr. Chase 
Dr. Chase raised four major issues: (1) The investigators are proposing to use FDA 
criteria for RCR testings, which have not been totally agreed upon by the RAC. (2) The 
necessity for AZT administration, which was mandated by IRB, is questionable. Dr. 
Chase recommended that AZT administration should be at the discretion of the treating 
physicians. (3) The financial risks to patients for treatment procedures are not clearly 
stated in the Informed Consent document. (4) The kinetics of cell survival, which 
compares ribozyme-transduced with control cells, have not been adequately described. 
Pending clarification on these issues, Dr. Chase recommended approval of the protocol. 
Other Comments 
Recombinant DNA Research, Volume 18 
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