Human Gene Therapy 
data provide hope that vectors can eventually be built with all the 
regulatory signals necessary to produce correctly controlled expres- 
sion of exogenous genes in target cells. 
Safety 
Finally, a human gene therapy protocol must be safe. Although 
retroviruses have many advantages for gene transfer, they also have 
disadvantages. One problem is that they can rearrange their own 
structure, as well as exchange sequences with other retroviruses. In 
the future it might be possible to modify non-infectious retroviral 
vectors in such a way that they remain stable. At present, however, 
there is the possibility that a retroviral vector might recombine with 
an endogenous viral sequence to produce an infectious recombinant 
virus. Properties that such a recombinant would have are unknown, 
but there is a potential homology between retroviral vectors and 
human T-ccll leukemia viruses so that the formation of a recombinant 
that could produce a malignancy is a possibility. There is, however, 
a built-in safety feature with the mouse retroviral vectors now in use. 
These mouse structures have a very different sequence from known 
primate retroviruses, and there appears to be little or no homology 
between the two. Therefore, it should be possible, with continuing 
research, to build a safe retroviral vector. 
With the present constructs, three types of experiments ought to 
be carried out before any retrovirus-treated bone marrow is injected 
into a patient. These protocols, designed to test the safety of the 
delivery-expression system, are necessary since once treated bone 
marrow is reinserted into a patient, it and all retroviruses that it con- 
tains are irretrievable. 
First, studies with human bone marrow in tissue culture are 
needed. Marrow cultures infected with the therapeutic vector should 
be tested for a period of time for the production of recombinant 
viruses. Any infectious virus isolated should be studied for possible 
pathogenicity. 
Second, studies in vivo with mice are needed. Treated animals 
should be followed to determine if genomic rearrangement or the site 
of chromosomal integration of the retroviral vector has resulted in 
any pathologic manifestations or the production of any infectious 
viruses. 
Third, studies in vivo with primates are needed. A protocol similar 
to the one planned for human application should be carried out in 
primates, not just mice, because the endogenous viral sequences in 
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