Clinical And Clinical Safety Issues

As this is written, these vectors appear to be on the point of being used in the clinic (see The first indication is likely to be for HIV therapy, but it is likely that protocols for neurodegen-erative diseases such as Parkinson's disease will follow. In the clinic, the major vector-related safety issues [apart from contamination of vector preparations with adventitious agents (149) such as RCL, and see above) that have been raised relate to recombination or rescue by preexisting (and perhaps unrecognized) infection with HIV (150-152), interaction with endogenous sequences (65) in the trial subject, and more recently insertional mutagenesis (4,153,154) and resultant predilection to development of cancers. The HIV ''rescue'' issue can probably be dealt with by using SIN vectors (75) that are not able to be rescued, although the final answer will come from clinical data. It should also be noted that large numbers of HIV-infected individuals have been treated with MLV vectors without obvious vector-related side effects [see the web site of the National Institutes of Health Office of Biotechnology Activities (OBA) at SAE_rpts/Mod0902s/Sep02_M0Ds.htm]. The insertional mutagenesis issue has been prompted by the appearance of treatment-related leukemias in 2 of 11 children treated by bone marrow transduction and reimplantation (153,154) from X-linked severe combined immunodeficiency disease (X-SCID). The data in the first child suggests some kind of transcriptional activation event of the LMO-2 gene was involved. Interestingly, it has been reported that lentiviral vectors should be less likely to have this kind of effect as they have less read through of the 3'LTR polyadenylation site than vectors based on MLV-type C retrovirus (155). However, lentiviral SIN vectors are as leaky as MLV vectors. The X-SCID trial was performed using MLV-type vectors, and the results were unexpected given the large numbers of other retroviral vector-treated trial patients in unrelated protocols. Nevertheless, the observation will undoubtedly lead to further examination of the probability of such events in other trials using integrating vectors (155). There is no indication, however, from the hundreds or thousands of animals treated with lentiviral vectors so far that this issue will be a significant one in general.

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