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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