Mutagenesis Screens for Prostate Cancer Using Replication-Incompetent Lentiviral Vectors.

Prostate cancer (PC) is the second leading cause of cancer-related deaths in US men, and progression to androgen-independent PC (AIPC) typically results in metastasis and is lethal. However, the mechanisms whereby PC progresses from androgen dependence to androgen independence are not completely understood. Mutagenesis screens to identify novel genes involved in the progression to AIPC have been performed using replication-incompetent lentiviral vectors (LVs).

Efficacy and safety of a clinically relevant foamy vector design in human hematopoietic repopulating cells.

Background: Previous studies have shown that foamy viral (FV) vectors are a promising alternative to gammaretroviral and lentiviral vectors and also that insulators can improve FV vector safety. However, in a previous analysis of insulator effects on FV vector safety, strong viral promoters were used to elicit genotoxic events. In the present study, we developed and analyzed the efficacy and safety of a high-titer, clinically relevant FV vector driven by the housekeeping promoter elongation factor-1α and insulated with an enhancer blocking A1 insulator (FV-EGW-A1).

Rapid immune reconstitution of SCID-X1 canines after G-CSF/AMD3100 mobilization and in vivo gene therapy.

Hematopoietic stem-cell gene therapy is a promising treatment of X-linked severe combined immunodeficiency disease (SCID-X1), but currently, it requires recipient conditioning, extensive cell manipulation, and sophisticated facilities. With these limitations in mind, we explored a simpler therapeutic approach to SCID-X1 treatment by direct IV administration of foamy virus (FV) vectors in the canine model. FV vectors were used because they have a favorable integration site profile and are resistant to serum inactivation.

Replication-incompetent gammaretroviral and lentiviral vector-based insertional mutagenesis screens identify prostate cancer progression genes.

Replication-incompetent gammaretroviral (γRV) and lentiviral (LV) vectors have both been used in insertional mutagenesis screens to identify cancer drivers. In this approach the vectors stably integrate in the host cell genome and induce cancers by dysregulating nearby genes. The cells that contain a retroviral vector provirus in or near a proto-oncogene or tumor suppressor are preferentially enriched in a tumor.

Insulators to Improve the Safety of Retroviral Vectors for HIV Gene Therapy.

Retroviral vector gene therapy is a promising approach to treating HIV-1. However, integrated vectors are mutagens with the potential to dysregulate nearby genes and cause severe adverse side effects. Leukemia has already been a documented severe adverse event in gene therapy clinical trials for the treatment of primary immunodeficiencies.