Human Gene Therapy Subcommittee - 11/21-22/91 
Dr. Epstein stated that the issue of homologous recombination versus transgenesis is a 
recurrent issue. When creating a transgenic animal, the goal is to insert a gene into the 
germ line, not cure disease; homologous recombination replaces a specific gene. The 
distinction between homologous recombination and transgenesis is central to discussing 
ethical and legal implications of germ line intervention. 
Dr. Parkman said that he was not aware of any whole animal model designed to address 
the issue of gene integration into gametes of the animal which has received genetic 
therapy. Dr. Neiman suggested that the reverse situation should be discussed. The 
HGTS should extrapolate from available quantitative data derived from specific gene 
delivery systems for germ line intervention. Dr. Miller said that the rate of mutagenesis 
in the germ line, e.g., from retrotransposons and radiation, is another pertinent issue to 
consider. Dr. Neiman noted that there are several investigators analyzing genetic 
instability who are studying specific gene loci under various settings and through 
generational changes. Dr. Miller suggested that the first topic for discussion regarding 
germ line therapy should be a report on baseline levels of genetic change and the 
frequency of mutational events. Dr. Epstein suggested that Dr. James Neel, an expert on 
human mutation rates, would be a good choice as a speaker for the next meeting. The 
HGTS members agreed that a speaker should be invited to the next meeting to provide 
background information on human mutation rates. 
Ms. Meyers inquired as to how long it would take to change the Points to Consider 
document to accommodate the consideration of germ line therapy protocols. Dr. Wivel 
stated that any proposed amendment to the Points to Consider would have to be 
published in the Federal Register 30 days prior to the RAC meeting. If the RAC votes 
for approval of the amendment, the action is referred to the Director of NIH who has 
the option to approve or disapprove the recommended action. If approved, the 
amendment would be published in the Federal Register as a major action under the NIH 
Guidelines for Research Involving Recombinant DNA Molecules. Dr. Leventhal stated that 
such an action would require the equivalent of two meetings, the one in which the action 
is proposed, and a second at which the action is voted on. 
Dr. R. Murray inquired as to whether such an action would have to be approved at a 
level higher than the Director of NIH. Dr. Wivel responded that the decision is at the 
NIH level; however, this does not preclude the Director of NIH from seeking the advice 
of the Assistant Secretary for Health and Human Services (HHS) or the Secretary of 
HHS. 
Ms. Meyers inquired about gene therapy protocols that have already been initiated, e.g., 
the adenosine deaminase deficiency (ADA) study. Have genes been inserted 
therapeutically into children that may have an effect on their offspring? Dr. Miller 
explained that germ line transfer is not an issue in protocols such as ADA, because the 
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