. TELOMERASE INHIBITOR
Geron Corporation Update
http://www.lef.org/magazine/mag97/jan-proj97_2.html
Texte de synthèse en français : ICI

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.



For further information about Geron contact: David L. Greenwood, V.P., C.F.O.
Geron Corporation - 200 Constitution Drive - Menlo Park, CA 94025 - Tel: 415-473-7705 / Fax: 415-473-7701
Email: dgreenwood@geron.com