Replication defective vectors derived from simple retroviruses or the more complex genomes of lentiviruses continue to offer the advantages of long-term expression, cell and tissue specific tropism, and large packaging capacity for the delivery of therapeutic genes. The occurrence of adverse events caused by insertional mutagenesis in three patients in a gene therapy trial for X-linked SCID emphasizes the potential for problems in translating this approach to the clinic. Several genome-wide studies of retroviral integration are now providing novel insights into the integration site preferences of different vector classes. We review recent developments in vector design, integration, biosafety, and production.

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Lentiviral vectors transduce dividing and postmitotic cells and thus are being developed toward therapies for many diseases affecting diverse tissues. One essential requirement for efficacy will be that vector particles are resistant to inactivation by human serum complement. Most animal studies with lentiviral vectors have utilized VSV-G pseudotyped envelopes. Here we demonstrate that VSV-G pseudotyped HIV and FIV vectors produced in human cells are inactivated by human serum complement, suggesting that alternative envelopes may be required for therapeutic efficacy for many clinical applications of lentiviral vectors.

Gene transfer vectors based on lentiviruses can transduce terminally differentiated cells in the brain; however, their ability to reverse established behavioral deficits in animal models of neurodegeneration has not previously been tested. When recombinant feline immunodeficiency virus (FIV)-based vectors expressing ␤-glucuronidase were unilaterally injected into the striatum of adult ␤-glucuronidase deficient [mucopolysaccharidosis type VII (MPS VII)] mice, an animal model of lysosomal storage disease, there was bihemispheric correction of the characteristic cellular pathology. Moreover, after the injection of FIV-based vectors expressing ␤-glucuronidase into brains of ␤-glucuronidase-deficient mice with established impairments in spatial learning and memory, there was dramatic recovery of behavioral function. Cognitive improvement resulting from expression of ␤-glucuronidase was associated with alteration in expression of genes associated with neuronal plasticity. These data suggest that enzyme replacement to the MPS VII central nervous system goes beyond restoration of ␤-glucuronidase activity in the lysosome, and imparts improvements in plasticity and spatial learning.