Recombinant DNA Advisory Committee - 12/1-2/94 
cell development is extremely important. Many marking protocols appear on the surface to be "repetitive" 
studies; however, the unexpected results about stem cells from these "repetitive" studies have contributed 
important aggregate data. 
Dr. Par km an identified two problematic areas involving gene marking studies that need improvement in the 
future: (1) Several protocols have not been initiated or are not progressing at the expected rate due to 
problems with vector availability. (2) Future Data Reporting Forms should be modified to request more 
detailed information about gene marking, i.e., polymerase chain reaction (PCR) data should be requested in a 
schematic (time-course) format. 
Dr. Erickson commented that different categories of gene transfer experiments require different types of 
information to be obtained. He suggested that separate questionnaires should be used for each category. Dr. 
Ross noted that the data obtained through this semiannual reporting mechanism is useful to the RAC, the 
public, and investigators. Dr. Parkman stated that the data generated from these studies should eventually be 
published in peer-reviewed journals, and in the interim, the RAC data reporting process would serve as a 
mechanism to inform the public about the current state of the art. Dr. Smith stated that Dr. Parkman has 
identified problems that need to be addressed in the future review of gene marking protocols and their 
modifications. He noted the problem previously identified by Dr. Haselkorn regarding failure to accrue 
patients on an approved study for more than 1 year. 
Report on Gene Therapy/Cancer/Non-Vaccines-Dr. Samulski 
Dr. Samulski stated that 21 gene therapy/cancer/non-vacdne protocols have been approved by the RAC to 
date. The majority of these studies employ retrovirus vectors. Adenovirus vectors are used for 3 protocols in 
this category and 5 involve direct injection of “naked" DNA into target cells in vivo. Four strategies have been 
used to date: (1) incorporation of cytokine genes to stimulate an antitumor response, (2) antisense strategies 
designed to turn off oncogenes, e.g., myc , (3) tumor suppressor gene strategies, i.e., p53 to protect cells from 
converting to a tumorigenic state, and (4) drug enhancement therapy, Le., introduction of the multi-drug 
resistance gene and Herpes simplex virus (HSV) thymidine kinase (TK)/ganciclovir (GCV) strategy. The 
primary endpoints of these Phase I studies are to address questions of safety and gene expression at the target 
sites. Sensitive techniques such as PCR are used to evaluate gene expression. Efficacy is not a primary 
endpoint for these Phase I studies. Dr. Samulski noted that significant toxidties have been reported for the 
HSV-TK studies. These toxidties will be addressed later in the meeting. 
Report on Gene Therapy/Cancer/Vacclnes-Dr. Erickson 
Dr. Erickson stated that 17 of the 21 RAC-approved protocols on gene therapy/cancer/vaccine (lethally 
irradiated tumor cells) have been approved by the N1H Director. Only 11 of these studies are currently active. 
A total of 70 subjects have been entered onto these 17 NIH-approved studies, with 38 deaths (due to 
progressive disease). Dr. Erickson recommended that future Data Report forms should request information 
about humoral and cellular immunity. He stated that with one possible exception (Dr. Brenner’s Protocol 
#9206-018), there has been no evidence of biological efficacy in any of the studies. No significant toxidties 
have been observed. 
Report on Gene Therapy/Inherited Genetic Disorders-Dr. Motulsky 
Dr. Motulsky noted that approximately 20% of the RAC-approved studies involve inherited genetic disorders. 
The data derived from these studies are limited due to the fact that monogenic diseases are extremely rare. 
The information derived from Dr. Blaese’s SCID-ADA protocol (#9007-002) is encouraging; however, gene 
transfer into stem cells has not been demonstrated, and all subjects are concurrently receiving PEG-ADA 
enzyme replacement therapy. Dr. Motulsky stated that 5 subjects were entered on Dr. Wilson’s familial 
hypercholesterolemia study (#9105-005). Although the data from Dr. Wilson’s study were published in the 
peer-reviewed journal. Nature Genetics , these data have been challenged by experts in the field who contend 
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