Safety Considerations

Currently, the 2 most significant concerns for the use of ret-roviral vectors in humans stem from the possibility of an RCR arising, or insertional mutagenesis leading to tumor formation. RCR formation can occur during the manufacturing process (which can be screened for) (92), or in the patient following vector administration. Such a virus could result from recombination between the vector and packaging components in the producer cells, even with split packaging cell lines (93), or be due to the acquisition of sequences from endogenous re-troviruses. Essentially all mammalian cells have their own endogenous retroviruses that could potentially recombine with the vector to produce a new and possibly pathogenic RCR, and many of these endogenous viruses are still unknown. Although any cell line is suspect, the use of primate or human cells as packaging cells raises the greatest safety concerns in this regard. There is no way to predict the pathogenicity of such potential recombinants, and it would be naive to assume that nonnatural combinations of viral components will not be infectious. For example, it has been demonstrated that if the use of an simian immunodeficiency virus (SIV)-based vector pseudotyped with the amphotropic MuLV Env protein gave rise to an RCR, such a chimeric virus could indeed replicate in vivo in monkeys (94).

The subjects of RCR production, safety, and potential tumor induction were extensively analyzed in a report to the National Institutes of Health recombinant DNA advisory committee (NIH RAC) and the Food and Drug Administration (FDA) (95). The report concluded that the QA/QC procedures required by the FDA make it unlikely that any patient could receive sufficient RCR to be pathogenic. However, the manufacturing and testing processes required to ensure this degree of safety are complex and expensive.

As already discussed, a major concern for the use of ret-roviral vectors is the possibility of insertional mutagenesis. In response to the serious adverse events in the SCID-XI trial in France, clinical trials with retroviral vectors in the US have been put on clinical hold. Until more is known, it is unclear how significant this risk will be, and whether the use of these vectors for life-threatening diseases with no therapeutic alternatives will still be warranted.

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