8 
Mr. Capron suggested the points to consider document should describe the types 
of concerns vhich have been raised, a description of the process by which 
these concerns have been discussed, and an explanation of the working group’s 
position vis-a-vis these concerns. 
Dr. Mahoney agreed the working group document could explicitly describe the 
difference between somatic cell gene therapy and germ line gene therapy. The 
document could also discuss vector characteristics and the probability of the 
crippled retroviral vector being transmitted to other individuals. 
Dr. Temin said the points to consider document insists the vector be an inac- 
tivated virus. The use of retroviruses as vectors in hunan gene therapy is 
thus a genetic engineering problem; a great deal is Vnown about modifying the 
retrovirus to inactivate it and the points to consider document reflects this 
level of knowledge. He explained that when a retrovirus enters a cell, a ENA 
copy is made from the RNA tenplate. The DNA copy then goes into the chromosomal 
DNA. This form of the virus is called a provirus. The provirus gets out of 
the chromosome by copying itself into RNA. Technically, this last step can be 
prevented by constructing the virus vector in a certain way. Dr. Temin added 
that 10% of the human genome consists of proviruses; these proviruses are in 
the germ line cells as well as in other cells in the body. 
Dr. Temin said in addition to requiring the investigator to use a crippled 
vector, the working group could also specify the initial studies should involve 
trans fb oration of narrow cells by the vector. Since these cells would be trans- 
formed outside of the patient's body, they could be examined to determine the 
point of vector insertion in the genome . The cells the patient receives would 
then be much better characterized . This procedure would also ensure that the 
vector has no opportunity to insert in germ line cells. 
Dr. Mot ul sky said he might accept the risk involved with introducing an intact 
virus vector into a very ill child who could not be helped by other therapies. 
Dr. Temin said the working group would have to evaluate different considerations 
if an intact virus vector wore used. Dor example, the possibility a new virus 
could be created by recombination would have to be considered. 
Mr. Capron agreed systemic introduction of vectors would clearly raise different 
considerations than the _in vitro modification of bone marrow cells. He suggested 
the points to consider document might specifically state this distinction and 
request investigators to address these issues. Dr. Temin said the points are 
currently constructed to elicit this type of information from investigators. 
The working group returned to the discussion of Dr. Grobstein's proposed alternate 
language (Attachment V) . Dr. Motulsky said the primary aim of all therapies 
including human gene therapy is to help the patient. He suggested the words 
"principally" or "fundamentally" be substituted for the words "in clinical 
terms . " 
Mr. Capron and Dr. Grobstein did not agree with this proposal; they felt the 
words "principally" and "fundamentally" suggest the therapy can differ to seme 
degree from traditional therapies. 
[ 93 ] 
