First demonstration of telomerase activator enhancing antiviral function of immune cells in HIV patients

November 2008

Geron Corporation (Nasdaq:GERN) has announced the publication of preclinical data on TAT2, a small molecule telomerase activator. The studies show that human CD8+ T-cells from HIV-infected donors exposed to TAT2 exhibited increased telomerase activity, resulting in retardation of telomere shortening, an increase in T-cell proliferation, and enhancement of critical antiviral functions against HIV-1.

The studies, published online in advance of print in the November 15 issue of The Journal of Immunology, were conducted by Dr Rita B Effros and colleagues at UCLA in collaboration with Geron scientists.

“Current treatments of HIV/AIDS are primarily directed at the HIV virus itself, but our understanding of telomerase has led to a pharmacologic approach aimed at enhancing the anti-HIV function of a patient’s T-cells by activating telomerase,” said Calvin Harley, PhD, Geron’s chief scientific officer. “This is consistent with clinical studies showing that HIV-positive individuals with significantly higher lymphocyte telomerase activity are able to control their infection for a longer period of time compared to other patients, with lower lymphocyte telomerase activity, who progress quickly to AIDS.”

CD8+ T-cells play a crucial role in controlling HIV-1 infection by killing infected cells and secreting antiviral cytokines in response to viral stimulation. Most non-dividing cells show little or no telomerase activity, but telomerase is up-regulated by cells that must repeatedly divide, such as T-cells responding to viral antigen. However, during chronic HIV-1 infection, CD8+ T-cells exhaust their ability to up-regulate telomerase, leading to critically short telomeres and other changes associated with replicative senescence (cellular aging), reducing their antiviral activity.

The in vitro studies show that short term exposure to TAT2 increased telomerase activity in CD8+ T-cells from healthy and HIV-infected individuals. The increase was most dramatic in cells of chronically HIV-infected individuals or those who had progressed to AIDS, where endogenous telomerase activity was the lowest. Chronic exposure to TAT2 during long-term culture of CD8+ T-cells from healthy and HIV-infected individuals showed an increase in proliferative capacity and retardation in telomere shortening of the T-cells, indicating a slowing of replicative senescence.

The data also demonstrate that telomerase activation by TAT2 boosts the antiviral function of CD8+ T-cells against HIV-1. TAT2-treated cells showed increased production of cytokines and chemokines (IFN-γ, RANTES, MIP-1α, and MIP-1β) that are critical inhibitors of HIV-1. Furthermore, the replication of HIV-1 in CD4+ T-cells from infected donors was markedly suppressed when the CD4+ T-cells were cultured together with TAT2-treated CD8+ T-cells compared to untreated CD8+ T-cells. To confirm that the boost in antiviral activity is dependent on telomerase activation, a potent and specific telomerase inhibitor was added to CD8+ T-cells at the same time as TAT2 and no enhancement of anti-HIV activity was observed.

“In previous studies we have achieved a similar antiviral enhancement by transducing CD8+ T-cells with the telomerase gene, hTERT, but pharmacologic telomerase activation has far more potential therapeutically because it is more practical to administer than gene therapy, allows for greater regulation of dosing, and importantly, we have now shown that TAT2 does not promote a loss of growth control or cell immortalization,” said Thomas B. Okarma, Ph.D. M.D., Geron’s president and chief executive officer. “In addition to HIV/AIDS and other immune-associated diseases, telomerase activators have potential as therapeutics for multiple other degenerative and age-related conditions involving loss of cellular function due to chronic physiological stress.”

TAT2 is a potential development candidate for HIV/AIDS by TA Therapeutics Ltd. The company is exploring multiple applications for telomerase activators in chronic degenerative and infectious diseases. TA Therapeutics is a majority owned subsidiary of Geron that was established in collaboration with the Biotechnology Research Corporation, a company formed by the Hong Kong University of Science and Technology (HKUST).

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