16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

DRUG CANDIDATE TAT0002, A TELOMERASE ACTIVATOR, ENHANCES ANTIVIRAL FUNCTIONS OF HIV-1-SPECIFIC CD8 T CELLS

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. ThLB0305

C.B. Harley¹, S.R. Fauce², A.C. Chin¹, B.D. Jamieson², O.O. Yang², R.B. Effros^2
1Geron Corporation, Menlo Park, United States, ²Geffen School of Medicine at UCLA, Los Angeles, United States

BACKGROUND: New targets and therapeutic approaches for HIV-1 infection are needed. Telomerase activation has been shown to mitigate loss of replicative capacity and functional decline caused by chronic stress and cellular aging. CD8+ T-cells play a key immunoprotective role and we previously showed that telomere-dependent senescence of these cells contributes to their dysfunction. We discovered a small molecule telomerase activator, TAT0002, and are developing it for HIV/AIDS therapy. TAT0002 significantly enhances proliferation, IFN-γ production and HIV-1-specific cytolytic activity of CD8 cells from infected donors. Here we report recent progress on development of TAT0002 as a therapeutic agent, including mechanistic studies and pilot pharmacokinetic measurements.

METHODS: The effects of 1 µM TAT0002 during a 14d expansion of CD8+ T-cells from HIV-1-infected persons on 48h CD3-stimulated production of MIP-1α/β and RANTES was assessed by ELISA. Dependence of TAT0002 effects on telomerase activation was verified by co-incubation with a telomerase inhibitor. Pharmacokinetics of orally administered TAT0002 in mice was assessed with a newly developed LC/MS assay.

RESULTS: The mean TAT0002-mediated enhancements of MIP-1α, MIP-1β, and RANTES production by CD8+ T-cells from 3 HIV-1-infected donors were 24% (p<0.01), 33% (p<0.05), and 36% (p<0.01) respectively. This TAT0002-effect was essentially eliminated by co-incubation with a telomerase inhibitor, suggesting telomerase-dependence and agreeing with prior results on TAT0002-mediated enhancement of CD8+ T-cell antiviral activity. TAT0002 activated telomerase in multiple cell systems at 10-1000 nM. Pilot oral PK measurements of TAT0002 in mice showed reasonably sustained levels in this range at the lowest dose tested (10 mg/kg; C_max=3 µM; apparent T(½)α~40min), suggesting that active doses should be obtainable with oral formulation.

CONCLUSIONS: Mechanistic, safety, and PK data obtained to date suggest that TAT0002 and telomerase represent a promising drug candidate and target for treatment of HIV-1-infected persons.

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2006-08-13
ThLB0305

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