Telomerase Prevents Onset of Liver Cirrhosis in Mice.

Medical &Health Writers

MENLO PARK, Calif.--(BW HealthWire)--Feb. 17, 2000

Geron Corporation (Nasdaq: GERN) reported the publication of independent scientific research that supports the potential role of telomerase as a therapeutic agent in liver cirrhosis. The research, performed by scientists at the Dana-Farber Cancer Institute of Harvard Medical School and Albert Einstein College of Medicine and published in the February 18 issue of Science, provides evidence of the efficacy of telomerase therapy in a mouse model of cirrhosis, a chronic liver disease.

Geron provided funding for development of the original telomerase knock-out mouse which led to this study, and has exclusive intellectual property rights to key human telomerase assays, proteins and genes, as well as therapeutic applications of these molecules.

Telomerase is an enzyme that synthesizes telomeric DNA at the ends of chromosomes and thereby confers extended replicative capacity to cells. In the absence of telomerase, telomeres gradually shorten until a critical limit is reached and cells stop dividing and either die or senesce. Numerous in vitro and in vivo studies have established a strong correlation between telomere erosion and cellular aging and disease, but this report is the first published evidence that introduction of telomerase by gene therapy in an animal model prevents the onset of a serious chronic disease. Liver cirrhosis in humans is typically caused by hepatitis or chronic exposure to alcohol, and is the seventh leading cause of death by disease. There is currently no adequate treatment.

In previous work led by the senior author of this study, Dr. Ron DePinho, it was shown that although mice normally have very long telomeres, short telomeres could be achieved by eliminating the gene for one of the components of mouse telomerase. Eventually, critically short telomeres are reached and the mice display several age-related disorders similar to those seen in elderly humans, including: an increase in hair graying and loss, ulcerative skin lesions, chromosomal fusions and cancer; and a decrease in body weight and lifespan. The mice also showed a decreased ability to recover from stress which resulted in a decreased regenerative capacity of hematopoietic (blood) and gastrointestinal systems, including the liver, as well as a decreased wound healing capability.

In previous experiments, in three separate disease models of chronic stress to the liver, mice with short telomeres were shown to have impaired capacity to recover from such stress compared to mice with long telomeres. DePinho's team has now demonstrated that when DNA for the telomerase gene is delivered by gene therapy to the telomerase knock-out mice, the mice become equally capable of recovery following liver stress as are normal young mice with long telomeres.

&uot;This study is important for two fundamental reasons,&uot; noted Calvin B. Harley, Ph.D., Geron's chief scientific officer and a pioneer in telomere and telomerase biology. &uot;First, it shows telomere loss can be the key factor in chronic age-related diseases. In this in vivo model, the only difference between the experimental mice and the control mice is the lack of telomerase which results in significant telomere loss. This difference generates disease conditions similar to that seen in humans. Second, by showing that telomerase gene therapy can prevent cirrhosis in these mice, it provides a model system to test the safety and efficacy of telomerase therapy in humans, not just for liver disease, but for multiple other disorders in which telomere loss is implicated.&uot;

In DePinho's studies, the gene for the RNA component of mouse telomerase (mTR) was first genetically deleted, and then, later, delivered by gene therapy just before telomeres became critically short. In humans, the natural repression of telomerase activity in cells is largely controlled by turning off the gene for the catalytic protein component of telomerase (hTERT). Geron scientists cloned the hTERT gene in 1997 in collaboration with researchers at the University of Colorado, Boulder. Subsequently, in collaboration with investigators at the University of Texas Southwestern Medical School at Dallas, Geron scientists showed that hTERT alone was sufficient to extend the healthy lifespan of numerous cell types, without inducing cancerous changes in the cells (Bodnar, et al 1998, Science 279:349-352; Jiang, et al 1999, Nature Genetics 21:111-114). These discoveries have opened the door for the development of therapeutics to treat numerous degenerative diseases of aging by cell, gene, protein, or small molecule (drug-like) therapies that result in telomerase activation.

Geron has an extensive intellectual property portfolio of more than 40 issued patents and numerous pending patent applications covering telomerase, including the mouse model used in these recent studies. Geron's patent portfolio includes patents and applications covering both the RNA and protein components of human telomerase, the genes encoding these human molecules, and methods of modulating cell function by administering these molecules to cells.

Geron Corporation is a biopharmaceutical company focusing on discovering, developing and commercializing therapeutic and diagnostic products to treat cancer and other age-related chronic degenerative diseases. Geron's technology platform includes the discovery of small molecule inhibitors of telomerase for cancer therapy; telomere and telomerase-based research and diagnostic tools; telomerase activation to extend the replicative lifespan of normal cells; and complementary stem cell, gene therapy and nuclear transfer approaches to restore the function of degenerating organs.

Statements in this press release regarding product development and future applications of Geron's technology constitute forward-looking statements that are subject to certain risks and uncertainties. Actual results may differ materially from the results anticipated in these forward-looking statements. Additional information on potential factors that could affect the company's results is included in the company's quarterly report on Form 10-Q for the quarter ended September 30, 1999.

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