Safety of retrovirus gene therapy, Temin, 
This analysis indicates that the public is likely to react to somatic gene therapy 
of human disease with retrovirus vectors in a worried and litigatious manner unless there 
is sufficient education about the therapy so as to allay most safety concerns. 
II. TYPES OF POTENTIAL BIOLOGICAL PROBLEMS WITH SOMATIC GENE 
THERAPY OF HUMAN DISEASE WITH RETROVIRUS VECTORS 
A. Problems That Can Not Be Removed By Further Genetic Engineering 
One of the key advantages of retrovirus vectors for somatic gene therapy of 
human disease is that retroviruses efficiently integrate into the cell chromosomes. Un- 
fortunately, this integration is essentially random with respect to the cellular DNA, al- 
though not with respect to the retrovirus DNA (Varmus and Swanstrom,1982). As such, 
the integration could take place in an essential cellular gene. If the integration is directly 
in the control or coding sequences of the gene, it would inactivate the gene. If the integra- 
tion is in untranslated sequences, untranscribed sequences, or intervening sequences, it 
could inactivate the gene as a result of the presence of the vector sequences. The integra- 
tion Into an essential gene could kill the infecte d cell. However , many cells are to be in- 
fected with the vector during the therapy, and these cells already have a deleterious muta- 
tion. Thus, killing a cell has the same effect on the disease as not infecting thar^elCthat 
is, the genetic mutation in the cell is not corrected for retranspl^mation back into the 
patient. Of more concern is the possibility that the presence of the control sequences for 
the inserted gene could result in activation of a potential proto-oncogene increasing the 
probability of subsequent cancer in the patient. ( ] 
The probability of such activation depends upon the number of cells infected, the 
number of potential proto-oncogenes that can be activated, and the efficiency of the con- 
trol sequences remaining in the retrovirus vector to activate the proto-oncogenes. The ef- 
fect of such activation on the probability of a malignancy depends upon the number of 
Recombinant DNA Research, Volume 12 l 381 ) 
