Category — telomerase activation

MENLO PARK, Calif. — Geron Corporation (Nasdaq:GERN) and TA Therapeutics, Ltd., a joint venture between Geron Corporation and the Biotechnology Research Corporation of Hong Kong (BRC), announced today the presentation of studies demonstrating that their small molecule telomerase activator, TAT0002, enhances the anti-viral activity of CD8 T-cells from HIV/AIDS donors against infected CD4 cells from the same donors. TA Therapeutics is exploring multiple applications for telomerase activators in chronic degenerative and infectious diseases. The company’s most advanced program is HIV/AIDS, and it has selected TAT0002 as the lead development candidate for this indication.

The new research was presented at the annual meeting of the American Association of Immunologists in Boston by Steve Fauce, from the laboratory of Rita Effros, Ph.D., professor of pathology and laboratory medicine and a member of the AIDS Institute at the David Geffen School of Medicine at UCLA. The studies are the product of a collaboration between Geron scientists, Dr. Effros and colleagues at UCLA.

As HIV disease progresses, certain immune cells called CD8 cytotoxic T-cells undergo accelerated replicative senescence (cellular aging) and lose their ability to proliferate and kill HIV-infected CD4 T-cells. Previously, Dr. Effros and colleagues demonstrated that introducing the telomerase gene into CD8 cells from HIV/AIDS donors increased: 1) their proliferative capacity, 2) their ability to produce IFN-gamma, and 3) their ability to inhibit virus production and kill HIV-infected T-cells. Dr. Effros’ team also showed that Geron’s small molecule telomerase activators had similar activity enhancing the ability of certain HIV-specific CD8 T-cells to inhibit virus production when co-cultured with an HLA-matched HIV-infected CD4 T-cell line.

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Researcher who Discovered Telomerase’s Role in Aging and Cell Mutation among Five Women Scientists Awarded in Paris

NEW YORK, NY – December 6, 2007 – For her pioneering work with telomeres, the protective caps at the ends of chromosomes, and their relation to cell aging and disease, Dr. Elizabeth Blackburn was presented the prestigious L’ORÉAL -UNESCO For Women in Science Award. An expert in the area of telomere and telomerase research, Dr. Blackburn, Morris Herzstein Professor of Biology and Physiology in the Department of Biochemistry and Biophysics at the University of California, San Francisco, has worked to create a better understanding of stress as a cause leading to cell aging and the diseases of old age, including cancer.

Selected as the North American Laureate for her discovery of the ribonucleoprotein enzyme telomerase, Dr. Blackburn’s research examines the function of the enzyme as it relates to cell aging and mutations that can cause cancer. During DNA synthesis, telomerase restores the ends of eukaryotic chromosomes, called telomeres, and Dr. Blackburn’s research has found that mutant variations of telomerase impair cell division, which can contribute to aging and cancer.

“I would like to see our research be useful in furthering human well-being,” said Dr. Blackburn. “Perhaps it will be useful in understanding what happens to our cells’ telomere maintenance that can cause common diseases to progress. Perhaps this understanding will prompt and guide interventions to try to improve health.”

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Joseph M. Raffaele MD gave a very well-received presentation November 11 2007 to the Age Management Medical Group (AMMG) Annual Meeting titled: “Report on Clinical Trials Involving Telomerase Activation, and the Impact on Aging.”. Topics covered include: h-tert, senescence, telomere length as biomarker for aging and survival, telomerase is not an oncogene.

Click below to view the presentation

Siegl-Cachedenier I, Flores I, Klatt P, Blasco MA. J Cell Biol. ;179(2):277-90.

Organ homeostasis and organismal survival are related to the ability of stem cells to sustain tissue regeneration. As a consequence of accelerated telomere shortening, telomerase-deficient mice show defective tissue regeneration and premature death. This suggests a direct impact of telomere length and telomerase activity on stem cell biology. We recently found that short telomeres impair the ability of epidermal stem cells to mobilize out of the hair follicle (HF) niche, resulting in impaired skin and hair growth and in the suppression of epidermal stem cell proliferative capacity in vitro. Here, we demonstrate that telomerase reintroduction in mice with critically short telomeres is sufficient to correct epidermal HF stem cell defects. Additionally, telomerase reintroduction into these mice results in a normal life span by preventing degenerative pathologies in the absence of increased tumorigenesis.

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Rita Effros Presentation Summary for SENS (Aubrey de Grey) Conference 6 Sept 2007

R.B. Effros David Geffen School of Medicine at UCLA, Department of Pathology and Laboratory Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, USA

The immune system plays a role not only in controlling infections, but also in certain age-related pathologies, such as atherosclerosis, osteoporosis, cancer and Alzheimer’s disease. In humans, ageing is associated with the accumulation of high proportions of CD8 (cytotoxic) T lymphocytes with markers of replicative senescence, including inability to proliferate, altered cytokine profiles, absence of the critical co-stimulatory receptor, CD28, reduced anti-viral function, shortened telomeres and loss of telomerase inducibility. Most of these senescent CD8 T lymphocytes are specific for latent viruses acquired early in life, and thus, reflect the constant “work” required over many decades to keep these infections from re-emerging. Since high proportions of senescent CD8 T lymphocytes are correlated with such deleterious outcomes as early mortality in the very old, reduced responses to vaccines, immune suppression, and, in persons infected with HIV, accelerated progression to AIDS, our research has focused on strategies to prevent or retard the process of replicative senescence. In earlier work, we documented that gene transduction with the human telomerase catalytic component (hTERT) leads to enhanced proliferation, telomere length stabilization, and increased anti-viral immunity. Current experiments are testing small molecule telomerase activators, which would be more suitable for clinical use, for their effects on CD8 T lymphocyte biology. Our data demonstrate that exposure to TAT2, one of these activators, significantly enhances telomerase activity, increases the ability of T lymphocytes to control viral production, enhances proliferation, increases production of anti-viral cytokines/chemokines, and retards telomere loss. The enhanced telomerase activity is associated with increased hTERT gene transcription. These studies support the notion that therapeutic manipulation of telomerase in human T lymphocytes may provide novel clinical avenues to enhancing viral immunity and retarding the immune exhaustion associated with ageing. (These studies were supported by the National Institutes of Health, TA Therapeutics, Ltd, and Geron Corporation).

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Geron Corporation (Nasdaq: GERN) and the Biotechnology Research Corporation (BRC) of Hong Kong today announced that Geron has increased its stake in their joint venture entity, TA Therapeutics Limited (TAT), from 50% ownership to 75% ownership.

TAT is a Hong Kong company that conducts research and develops therapeutics based on telomerase activator drugs to restore the functional and regenerative capacity of cells. BRC, a company established by The Hong Kong University of Science and Technology (HKUST), continues to hold the remaining 25% of the shares of TAT.

“TAT has made great progress in its development of telomerase activator compounds for therapeutic applications,” said David J. Earp, J.D., Ph.D., Geron’s senior vice president of business development and a director of TAT. “The company is now expanding its efforts in pre-clinical development and working toward the filing of an Investigational New Drug (IND) Application with the U.S. Food and Drug Administration for a small molecule compound for the treatment of HIV/AIDS. This is an opportune time for Geron, the development and commercial partner in the joint venture, to negotiate for a larger interest in the company.”

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Rita B. Effros, Experimental Gerontology, Volume 42, Issue 5, 416-420.

Clinical studies have shown that high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8(+)CD28(-) T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging and HIV disease. Gene therapy of HIV-specific CD8 T cells with the telomerase catalytic component (hTERT) results in enhanced proliferative capacity, increased anti-viral functions, and a delay in the loss of CD28 expression, with no changes in karyotype or growth kinetics. These proof-of-principle studies have led to screening for pharmacological approaches that might mimic the gene therapy effects, in a more clinically suitable formulation.”

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E Hiyama and K Hiyama, British Journal of Cancer 96, 1020-1024.

Telomeres, guanine-rich tandem DNA repeats of the chromosomal end, provide chromosomal stability, and cellular replication causes their loss. In somatic cells, the activity of telomerase, a reverse transcriptase that can elongate telomeric repeats, is usually diminished after birth so that the telomere length is gradually shortened with cell divisions, and triggers cellular senescence. In embryonic stem cells, telomerase is activated and maintains telomere length and cellular immortality; however, the level of telomerase activity is low or absent in the majority of stem cells regardless of their proliferative capacity. Thus, even in stem cells, except for embryonal stem cells and cancer stem cells, telomere shortening occurs during replicative ageing, possibly at a slower rate than that in normal somatic cells. Recently, the importance of telomere maintenance in human stem cells has been highlighted by studies on dyskeratosis congenital, which is a genetic disorder in the human telomerase component. The regulation of telomere length and telomerase activity is a complex and dynamic process that is tightly linked to cell cycle regulation in human stem cells. Here we review the role of telomeres and telomerase in the function and capacity of the human stem cells.

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Calvin B. Harley, PhD., Geron Corporation, 230 Constitution Drive, Menlo Park, CA, USA, 94025. Current Molecular Medicine, 2005.

Telomerase is active in early embryonic and fetal development but is down-regulated in all human somatic tissues before birth. Since telomerase is virtually absent or only transiently active in normal somatic cells throughout postnatal life, telomere length gradually decreases as a function of age in most human tissues. Although telomerase repression likely evolved as a tumor suppressor mechanism, a growing body of evidence from epidemiology and genetic studies point to a role of telomerase repression and short telomeres in a broad spectrum of diseases: (a) Humans with shorter than average telomere length are at increased risk of dying from heart disease, stroke, or infection; (b) Patients with Dyskeratosis congenita are born with shortened telomeres due to mutations in telomerase components, suffer from a variety of proliferative tissue disorders, and typically die early of bone marrow failure; and (c) Individuals with long-term chronic stress or infections have accelerated telomere shortening compared to age-matched counterparts. Telomerase activation may prove useful in the treatment of diseases associated with telomere loss. While human cells dividing in culture lose telomeric DNA and undergo changes that mirror certain age- or disease-associated changes in vivo, telomerase transduced cells have extended replicative capacities, increased resistance to stress, improved functional activities in vitro and in vivo, and no loss of differentiation capacity or growth control. In addition, telomerase transduction in vivo can prevent telomere dysfunction and cirrhotic changes in liver of telomerase knockout mice. Thus, pharmacological activation of telomerase has significant potential for the treatment of a broad spectrum of chronic or degenerative diseases.

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Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn EH. Psychoneuroendocrinology. 2006 Apr;31(3):277-87.

We previously reported that psychological stress is linked to and possibly accelerates cellular aging, as reflected by lower PBMC telomerase and shortened telomeres. Psychological stress is a major risk factor for cardiovascular disease (CVD), with multiple behavioral and physiological mediators. Telomere shortness has been associated with CVD, but the relationship between low telomerase activity, a potential precursor to telomere shortening, and CVD risk factors has not been examined in humans. Here we examine whether telomere length and telomerase in leukocytes are associated with physiological signs of stress arousal and CVD risk factors in 62 healthy women. Low telomerase activity in leukocytes was associated with exaggerated autonomic reactivity to acute mental stress and elevated nocturnal epinephrine. Further, low telomerase activity was associated with the major risk factors for CVD -smoking, poor lipid profile, high systolic blood pressure, high fasting glucose, greater abdominal adiposity-as well as to a composite Metabolic Syndrome variable. Telomere length was related only to elevated stress hormones (catecholamines and cortisol). Thus, we propose that low leukocyte telomerase constitutes an early marker of CVD risk, possibly preceding shortened telomeres, that results in part from chronic stress arousal. Possible cellular mechanisms by which low telomerase may link stress and traditional risk factors to CVD are discussed. These findings may implicate telomerase as a novel and important mediator of the effects of psychological stress on physical health and disease.

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