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Tucson, AZ, United States

Savkovic B.,University of New South Wales | Nichols J.,University of New South Wales | Birkett D.,Flinders University | Applegate T.,University of New South Wales | And 4 more authors.
PLoS Computational Biology

Gene therapy represents an alternative and promising anti-HIV modality to highly active antiretroviral therapy. It involves the introduction of a protective gene into a cell, thereby conferring protection against HIV. While clinical trials to date have delivered gene therapy to CD4+T cells or to CD34+ hematopoietic stem cells (HSC), the relative benefits of each of these two cellular targets have not been conclusively determined. In the present analysis, we investigated the relative merits of delivering a dual construct (CCR5 entry inhibitor + C46 fusion inhibitor) to either CD4+T cells or to CD34+ HSC. Using mathematical modelling, we determined the impact of each scenario in terms of total CD4+T cell counts over a 10 year period, and also in terms of inhibition of CCR5 and CXCR4 tropic virus. Our modelling determined that therapy delivery to CD34+ HSC generally resulted in better outcomes than delivery to CD4+T cells. An early one-off therapy delivery to CD34+ HSC, assuming that 20% of CD34+ HSC in the bone marrow were gene-modified (G+), resulted in total CD4+T cell counts ≥180 cells/ μL in peripheral blood after 10 years. If the uninfected G+ CD4+T cells (in addition to exhibiting lower likelihood of becoming productively infected) also exhibited reduced levels of bystander apoptosis (92.5% reduction) over non gene-modified (G-) CD4+T cells, then total CD4+T cell counts of ≥350 cells/ μL were observed after 10 years, even if initially only 10% of CD34+ HSC in the bone marrow received the protective gene. Taken together our results indicate that: 1.) therapy delivery to CD34+ HSC will result in better outcomes than delivery to CD4+T cells, and 2.) a greater impact of gene therapy will be observed if G+ CD4+T cells exhibit reduced levels of bystander apoptosis over G- CD4+T cells. © 2014 Savkovic et al. Source

Savkovic B.,University of New South Wales | MacPherson J.L.,Royal Prince Alfred Hospital | Zaunders J.,St Vincents Center For Applied Medical Research | Kelleher A.D.,St Vincents Center For Applied Medical Research | And 7 more authors.
Clinical Immunology

Analysis and mathematical modeling of T-lymphocyte perturbation following administration of granulocyte colony stimulating factor (G-CSF) and two large-scale aphereses are reported. 74 HIV-1 positive antiretroviral-treated individuals were infused with gene- or sham-transduced CD34+ hematopoietic stem cells (HSC) in a Phase II clinical trial. T cell numbers were examined in four phases: 1) during steady state; 2) increases in peripheral blood (PB) following G-CSF administration; 3) depletion post-aphereses and 4) reconstitution post HSC infusion. The present analysis provides the first direct estimate of CD4+ T cell distribution and trafficking in HIV-infected individuals on stable HAART, indicating that CD4+ T lymphocytes in PB represent 5.5% of the pool of CD4+ T lymphocytes that traffic to PB. © 2012 Elsevier Inc. Source

Calimmune | Date: 2012-08-06

Pharmaceuticals, namely, anti-infectives; pharmaceuticals for treatment of infectious diseases.

Calimmune | Date: 2016-05-09

Gene therapy products, namely, treatments for diseases affecting the immune system or hematologic system; Pharmaceuticals for the treatment of diseases affecting the immune system or hematologic system. Promoting public interest and awareness of gene therapies and pharmaceuticals; Promoting the exchange of information and resources within the scientific research and medical communities to achieve advances in the field of gene therapy. Providing medical and scientific research information in the fields of pharmaceuticals and genetics.

Burke B.P.,Calimmune | Boyd M.P.,Calimmune | Impey H.,Calimmune | Breton L.R.,Calimmune | And 4 more authors.

Human immunodeficiency virus type 1 (HIV-1) infection of target cells requires CD4 and a co-receptor, predominantly the chemokine receptor CCR5. CCR5-delta32 homozygosity results in a truncated protein providing natural protection against HIV infection-this without detrimental effects to the host-and transplantation of CCR5-delta32 stem cells in a patient with HIV ("Berlin patient") achieved viral eradication. As a more feasible approach gene-modification strategies are being developed to engineer cellular resistance to HIV using autologous cells. We have developed a dual therapeutic anti-HIV lentiviral vector (LVsh5/C46) that down-regulates CCR5 and inhibits HIV-1 fusion via cell surface expression of the gp41-derived peptide, C46. This construct, effective against multiple strains of both R5- and X4-tropic HIV-1, is being tested in Phase I/II trials by engineering HIV-resistant hematopoietic cells. © 2013 by the authors; licensee MDPI, Basel, Switzerland. Source

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