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- W2008553681 abstract "Lentiviruses are well known for their species specificity, and consequently lentivirus-derived vectors exhibit the highest gene transfer efficiency in cells of the same species from which the vectors were derived. Therefore, to accurately model a gene therapy approach for HIV in a monkey model, a parallel simian immunodeficiency virus (SIV) vector should be developed to accurately model the vector-cell-virus interactions. Our first therapeutic HIV-derived vector VRX496 contains an antisense targeting HIV env region. We established the safety of this novel vector in a Phase I open label clinical trial, which was allowed to proceed without preliminary studies in monkeys due to 1) the engineered safety features of the vector and 2) the observation that a monkey study would not be informative regarding the dynamics of an HIV-based vector. After demonstrating safety of this vector with early indications of efficacy in humans, we hypothesized that subsequent generations of this vector that have an improved ability to mobilize may increase the therapeutic efficacy of our anti-HIV gene therapy. However, such mobilizing vectors are considered too risky to test directly in patients, due to concerns regarding insertional oncogenesis. Therefore, we chose to test this hypothesis in monkeys in order to safely model the dynamics of these new vectors in vivo. Accordingly, we developed three SIVmac239 based lentiviral vectors, one that parallels our clinical vector VRX496 that contains no viral proteins (pN1), a second generation (pN2) containing the gag-pol protein that may have an improved ability to mobilize as a result of reduced dependency on wtSIV-proteins, and a third (empty pN2) containing gag-pol and no antisense payload to serve as a control. We demonstrated that the SIV based vectors were able to transduce the primary simian CD4 cells significantly better than the counterpart of HIV based vector by an approximately 6-fold improvement in gene transfer. We also showed that the vector potently inhibited the SIVmac239 replication in both transduced CEMx174 cells and primary simian CD4 cells to below the limit of detection, as previously observed with VRX496 and HIV in primary human CD4 cells. Detailed analysis of these results and modelling of these vectors in a monkey SIV model will be discussed." @default.
- W2008553681 created "2016-06-24" @default.
- W2008553681 date "2005-05-01" @default.
- W2008553681 modified "2023-09-25" @default.
- W2008553681 title "477. Development of SIV Based Vectors with Efficient Delivery for Vector Dynamic Studies in the Simian System" @default.
- W2008553681 doi "https://doi.org/10.1016/j.ymthe.2005.07.017" @default.
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