Geron Corporation Update

By John Hammell, Political Coordinator, Life Extension Foundation

As part of our PROJECT 2020 program to achieve total control over human aging by the year 2020, The Life Extension Foundation has contributed $136,000.00 to the Geron Corporation. Geron was the first company devoted substantially to age-related genetic research.

We've published several articles about Geron's research in Life Extension Magazine based upon our interpretation of the scientific literature and discussions with one of Geron's scientists. The following report, however, is based upon the company's own description of its research and proprietary technologies.

The Company

Geron is a biopharmaceutical company exclusively focused on discovering and developing therapeutic and diagnostic products based upon common biological mechanisms underlying cancer and other age-related diseases. As the pioneer in researching these mechanisms, the Company focuses on telomeres, which are structures at the ends of chromosomes that the Company has shown act as a molecular "clock" of cellular aging, and telomerase, an enzyme which appears to stop the "clock" and lead to cellular immortality.

Cellular Aging and Cellular Immortalization

Cells are the building blocks for all tissues in the human body. Cell division plays an important role in the normal growth, maintenance and repair of human tissue. However, cell division is a limited process in that cells generally divide only 60 to 100 times in the course of their normal lifespans. Once cells reach the end of their replicative capacity, they senesce. Cellular aging or senescence, although influenced by environmental factors, is a genetically determined process.

Geron and its collaborators have demonstrated that telomeres, the repeated sequence of DNA at the ends of each chromosome, are key genetic elements in this process. Telomeres are necessary to protect chromosomes from degradation and fusion. Each time a normal cell divides, however, telomeres shorten because cells are unable to replicate fully these repeated DNA sequences. Thus, Geron believes that telomeres serve as a molecular "clock" governing normal cell replication and lifespan. Geron has demonstrated that once telomeres reach a certain short length, cell division is halted, which is known as cell senescence. Although senescent cells have stopped dividing, these cells are still metabolically active and demonstrate an altered pattern of gene expression. Specifically, in senescent cells, some genes expressed by young and healthy cells are turned off and other genes are turned on, creating an imbalance of proteins and other cell products that has a direct and potentially destructive effect on the surrounding tissue. Geron believes that this cellular dysfunction, which occurs in numerous tissues throughout the body, causes or contributes to age-related diseases and conditions. The converse of cell senescence occurs in cancer cells. Normal cells have the potential to become cancerous if random mutations activate various oncogenes and deactivate tumor suppressor genes. With each mutation, pre-cancerous cells become increasingly aberrant and uncontrolled, and may begin to generate a tumor mass. The Company believes, however, that most cells which undergo such changes are eliminated when telomere shortening leads to either cell senescence or chromosomal instability and cell death. Geron and its collaborators' research indicates that for most cancerous tumors to attain life threatening size, or for cancer to metastasize throughout the body, cancer cells must become immortal, through activation of telomerase.

What Is Telomerase?

Figure 1

Telomerase is a complex germ line enzyme, composed of RNA and protein components, that maintains telomere length by replacing the DNA that is lost each time a cell divides. The result is that telomeres do not shorten and cell death is averted. (Fig. 1) Geron's research has shown that telomerase is abnormally reactivated in all of the major cancer types and that, conversely, it is not present in most normal cell types. Telomerase enables cancer cells to maintain telomere length, providing them with indefinite replicative capacity or cellular immortality.

Geron's Research Programs

Geron is applying its proprietary scientific platform to discover and develop novel therapeutics and diagnostics for cancer and other age-related diseases and conditions. In support of its programs, the Company employs advanced drug discovery technologies including proprietary assays, high-throughput screening, combinatorial chemistry, proprietary differential gene expression techniques, protein purification and gene sequencing.

Telomerase Inhibition and Detection

Geron seeks to develop a small molecule telomerase inhibitor, which, by blocking the activity of telomerase, will allow cancer cell telomeres to resume shortening, ultimately leading to cancer cell death. In addition, the Company seeks to develop telomerase as a marker for cancer diagnosis, prognosis, monitoring and screening.

Telomerase is not present in most normal cells and as a result these cells age through telomere shortening. In contrast, telomerase is abnormally active in cancer cells causing telomere length to be maintained, which in turn appears to confer immortality to cancer cells in malignant tumors.

Research has shown that telomerase is present in all of the over 20 different cancer types that Geron and its collaborators have studied, including the ten most prevalent cancers of prostate, breast, lung, colon, bladder, uterus and ovary, along with lymphomas, melanomas and oral cancers. In all of these cancers, the majority of tumor samples contain telomerase. Because telomerase is present in all cancer types evaluated and is not biologically active in most normal cells, telomerase appears to be a universal and highly specific marker of cancer. These characteristics combine to make telomerase an attractive target for inhibition to treat cancer, and for detection to diagnose cancer.

                     

 

 

 

 

Geron Corporation Update

Therapeutics

Geron's research has demonstrated that a telomerase inhibitor blocks cancer cells from using telomerase to maintain telomere length. As a result, the telomeres in the cancer cells resume shortening as the cells continue to divide, reaching a certain short length, at which point the cancer cells die. Specifically, Geron scientists have blocked human telomerase in tumor cell lines in vitro using both a small molecule compound and an antisense compound to the human telomerase RNA component.

In both experiments, blocking telomerase led to telomere shortening and cancer cell death. Based on these results, Geron is aggressively pursing the identification of a number of telomerase inhibitors as potential lead compounds for preclinical and clinical development. While it has identified several strategies for inhibiting telomerase activity. Geron is primarily focused on developing a small molecule inhibitor. The Company believes the small molecule approach will produce a development candidate with a more favorable commercial profile-oral bioavailability, compound stability and low manufacturing cost. With one of its collaborators, the Company has initiated studies of these small molecule compounds in animal models of human tumor growth.

To advance this program, Geron has established proprietary screening technology, a structurally automated high throughput screening effort for the identification of telomerase inhibitors using proprietary assays based on human telomerase. Geron has used this proprietary screening capability to screen over 80,000 diverse small molecule candidates that Geron has either acquired or created through its internal combinatorial chemistry capabilities.

As a result of its screening efforts, Geron has identified several classes of compounds that demonstrate telomerase inhibition and is actively pursing structure/activity relationship studies to develop lead compounds. Geron believes that these screens provide a strong competitive advantage in view of the extreme difficulty and specialized skills required for their development and use. The United States Patent and Trademark Office has recently allowed a patent application on one of Geron's telomerase inhibitor screens.

Geron believes that blocking telomerase activity will cause the affected cancer cells to resume telomere shortening through cell division and thus lose their immortality. When telomeres reach a certain short length, the cells will die. Telomerase inhibition is therefore expected to have delayed efficacy as cancer cell telomeres resume normal shortening. Although Geron envisions that a telomerase inhibitor could be effective as a stand-alone treatment in certain cases, it is expected that in most cases a telomerase inhibitor will be used in conjunction with traditional anti-cancer therapies.

Geron has established a strategic alliance with Kyowa Hakko, a leading oncology company in Japan, for the development and commercialization in certain Asian countries of a telomerase inhibitor for the treatment of cancer. The Company has also established research collaborations for the study of telomerase inhibition with the National Cancer Institute and the Sloan-Kettering Institute for Cancer Research, and for the study of telomerase biology with Cold Spring Harbor Laboratory.

Diagnostics

The Company believes that telomerase is a universal and highly specific marker of cancer and, therefore, the detection and quantification of telomerase may have significant clinical utility for cancer diagnosis. While most cancer diagnostics apply to a single or limited number of cancer types, telomerase-based diagnostics could potentially address a broad range of cancer types. The Company also believes that the availability of telomerase-based diagnostics for cancer will enhance the commercial opportunity for a telomerase inhibitor by increasing the understanding of clinicians of the biological mechanisms underlying telomerase activity.

The Company has developed several proprietary assays for the detection of telomerase based on its activity or components. The first generation assay is the Telomeric Repeat Amplification Protocol ("TRAP") assay which detects telomerase activity in malignant tumor tissue. The second generation assay detects the RNA component of human telomerase, which was first cloned by Geron scientists. This RNA technology enables the Company to use proprietary in situ hybridization and other detection methods to detect the presence of telomerase. The Company is the exclusive licensee of an issued United States patent which it believes covers cancer diagnostic applications of its TRAP technology, and the U.S. Patent and Trademark Office has allowed one of Geron's patent applications relating to the RNA component of telomerase.

Geron is conducting clinical evaluations to assess the full potential of its telomerase detection technology. Preliminary data from a number of studies indicate telomerase levels correlate with clinical outcome in cancer patients. In the event evaluations of a larger number of patients continue to present favorable results, the Company intends to proceed to full scale development of its telomerase detection technology as a novel and important diagnostic for numerous cancers.

Oncor and Boehringer Mannheim have licensed the Company's TRAP assay and Dako has licensed the Company's RNA detection technology on a non-exclusive basis for sale to the research use only market. Oncor commenced commercial sale of the TRAP-ezeTM kit in May 1996. The Company has also concluded collaborative agreements with Dianon and Ventana for additional technology development and clinical assessment. In each of its clinical diagnostic agreements, Geron has retained significant development and commercialization rights. The Company has also established research collaborations for the study of telomerase detection with The Cleveland Clinic, the University of Texas, San Antonio and the University of Texas Southwestern Medical Center at Dallas.

Cell Senescence Modulation-Regulation of Cellular Aging

Geron seeks to develop therapeutics to modulate the biological processes leading to and regulating cell aging or senescence. Telomere shortening occurs as cells divide, which, Geron believes, eventually triggers the destructive genetic changes found in senescent cells. The Company is pursuing two distinct approaches to modulate cell senescence (1) extending cell lifespan by slowing telomere loss, thereby extending the period of normal cell replication and delaying the destructive onset of cell senescence and (2) applying proprietary genomics and screening techniques to target and modulate the destructive genetic changes that occur in senescent cells. Geron has entered into research collaborations with several research institutions to support its cell senescence modulation program, including Lawrence Berkeley Laboratory, Stanford University, Baylor College of Medicine, Aarhus University (Denmark), the University of Groningen (The Netherlands) and the University of Washington.

Cell Lifespan Extension

Geron believes that maintaining telomere length will extend cell lifespan by delaying the onset of cell senescence. The Company and its collaborators have demonstrated in vitro that telomere length and replicative senescence can be modulated with synthetic compounds. The Company's initial focus is on the transient activation of telomerase to maintain telomere length and postpone cell senescence without immortalizing an otherwise mortal cell.

As the first and fundamental step in this program, the Company is working to complete the cloning of telomerase and its regulators. Geron has already cloned, and has received an allowance for a United States patent application relating to, the RNA component of human telomerase. Geron believes that the cloning of the telomerase enzyme and its regulators may also provide the Company with next generation telomerase inhibitor screens, new reagents for telomerase detection and other markers useful in cancer diagnosis.

The initial therapeutic target of the cell lifespan extension effort is ex vivo applications such as T cell therapy and bone marrow transplantation to treat cancer or immune dysfunctions in the elderly. Ex vivo cell therapies typically involve the extraction of certain cells from a patient, expansion of the number of cells ex vivo and the reintroduction of the cells into the patient to strengthen the patient's immune system. Current cell therapies have several limitations, including, Geron believes, senescence of transplanted cells before they can benefit the patient.

Geron believes this is attributable in part to the premature senescence of cells during the expansion process or during growth in vivo. Geron's approach to extending cell lifespan could improve ex vivo therapy by allowing enhanced expansion of extracted cells and the reintroduction to the patient of cells with greater replicative capacity.

Genomics Of Aging

The goal of Geron's Genomics of Aging program is to treat age-related diseases and conditions by modulating the destructive pattern of gene expression that occurs in cells as they reach the end of their replicative capacity, or become senescent. Geron's approach to genomics is unique in that it focuses on the differences in gene expression between replicatively young and senescent cells.

Geron believes there is a significant advantage in defining differences in gene expression between young and senescent cells and then utilizing senescent cells in drug discovery screens. Most genomics companies use diseased tissue, which is complex in structure and varies from patient to patient, for research and drug discovery. By comparison, Geron believes that senescent cells are more representative of the disease process and provide a homogeneous and reproducible population of cells for both gene and drug discovery.

Genetic Analysis Techniques

Geron has developed proprietary genetic analysis techniques called "Enhanced Differential Display" and "Subtractive Differential Display". These technologies have enabled the Company to identify genes, including those which express products at low levels, that are differentially expressed by replicatively young versus senescent cells and mortal versus immortal cells. The Company is using these gene targets and their products to design automated screens to discover small molecule drugs that counteract the destructive effects caused by these genes and their gene products.

The Company's Genomics of Aging program is targeted at a wide range of age-related diseases and conditions, including skin aging, atherosclerosis, osteoporosis and Alzheimer's disease. Geron's initial focus is on skin aging and atherosclerosis.

Skin Aging

Geron and its collaborators have established that when dermal fibroblasts age, or senesce, they undergo numerous changes in gene expression. Geron and its collaborators have discovered over 100 gene markers of genes that are differentially expressed in replicatively young versus senescent dermal fibroblasts. Some of these gene products appear to be destructive to the extracellular matrix.

The Company believes that these and other changes contribute to the characteristic age-related atrophy of skin. Reversing or offsetting the effects of such altered gene expression in senescent fibroblasts by targeted and cell-based drug discovery could provide an effective treatment for dermal atrophy in aging adults. The Company is establishing automated screens to discover small molecule modulators of gene expression in senescent cells.

Atherosclerosis

Atherosclerotic plaques frequently form in blood vessels at areas of turbulent blood flow. Geron and its collaborators have shown that endothelial cells lining arteries with turbulence and cell turnover and thus cell division is high, have shorter telomeres than cells in regions with less blood turbulence and cell turnover. Further, some gene products differentially expressed in senescent endothelial cells have been shown to play a role in atherosclerosis. The Company believes that altering expression of the senescence-associated genes and their products in the vascular endothelium could provide a unique and effective therapy for atherosclerosis.

Primordial StemCell Therapies

Geron seeks to generate a broad array of cell types from PS cells for cellular transplantation. PS cells are germ line cells that are unique in that they are both immortal, consistent with their normal telomerase expression, and capable of differentiation into any and all types of cells and tissues in the body.

The Company believes that PS cells offer significant advantages over other stem cells, which can differentiate only into a limited array of cell types, an example being the hematopoietic stem cell, which is capable of becoming only blood cells. In addition, PS cells, unlike other stem cells, are immortal and can potentially be expanded and grown indefinitely. Finally, these cells may be used repeatedly for transplantation and they can be thoroughly characterized and shown to be free of viruses or other pathogens.

Initially, Geron plans to pursue transplantation applications using PS cells derived from non-human primates. These cells were recently derived for the first time at the University of Wisconsin-Madison and are currently licensed exclusively to Geron. These cells have been shown to differentiate into numerous cell types that could be useful clinically. There are many strong similarities between these primate tissues and human tissues that may prevent the rejection seen with transplantation from other species.

The Company is in the early stages of research directed towards differentiating PS cells for transplantation in circumstances in which the risk of histoincompatibility will be minimized. Specifically, the Company is focused on cardiomyocytes for the treatment of congestive heart failure and neurons for the treatment of Parkinson's disease.