At the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Phase 1 trial data evaluating SB-728-T (Sangamo BioSciences) as a novel therapeutic approach as a “functional cure” for HIV/AIDS was presented. SB-728-T, is generated by ZFN-mediated modification of the gene encoding the CCR5 receptor in a patient’s own T-cells. ZFN modification disrupts the expression of this key co-receptor for HIV entry and renders cells resistant to HIV infection.
The approach is based on the observation that a naturally occurring mutation in the CCR5 gene, CCR5 delta-32, provides protection from HIV infection. Individuals in whom both copies of the CCR5 gene carry the delta-32 mutation are generally not susceptible to the most common strain of HIV.
The data demonstrate that SB-728-T infusion in HIV-infected subjects is well-tolerated, and results in significant and sustained increases in CD4+ T-cells above baseline throughout the year-long period reported in the study. Statistically significant improvement in CD4 counts were observed even at 12 months post infusion (P<0.038). In particular, CD4 counts improved to greater than 500cells/mm3 in five of nine subjects in the study at one year post-treatment.
Analysis of the specific types of CD4 T-cells that comprise the initial increase in CD4+ T-cells post-infusion revealed that they were primarily transitional memory T-cells (TTM). The frequency of TTM expressing CD25 (a marker that identifies activated T-cells) within the SB-728-T product correlated with the peak CD4 count post-infusion (r=0.733, P=0.0172). This suggests that replication of activated TTM SB-728-T cells post-infusion accounts for the initial peak improvement in CD4+ T-cells.
As the infused cells consist of only 1–10% of total memory cells at six months post-treatment, the prolonged increase in absolute numbers of CD4+ T-cells may be accounted for by the enhanced survival and differentiation of host central memory T-cells (TCM). Specifically, while the magnitude of the increase in TTM positively correlated with the peak of CD4+ T-cells in the first weeks post-infusion (r= 0.9, P=0.083), the increase in TCM correlated with the maintenance of high CD4+ T cell counts at later time points (r= 0.9, P=0.083).
Proliferation of the SB-728-T product post-infusion was sustained over the year-long period reported in the study with median modified circulating cell numbers measured to be 2.04-fold relative to input at seven days, 0.96-fold at six months and 1.15-fold at one year post-infusion.
These preliminary data confirm the prolonged engraftment of SB-728-T, and suggest that SB-728-T has the attributes to provide sustained improvement in the CD4 memory compartment and the potential to reconstitute the immune system in immune non-responders.
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