Geron Demonstrates Differentiation of Cardiomyocytes From Human Embryonic Stem Cells.

Business Editors & Health/Medical Writers

MENLO PARK, Calif.--(BUSINESS WIRE)--Sept. 3, 2002

Geron Corporation (Nasdaq:GERN) announced today the publication of research results that describe the differentiation of cardiomyocytes from human embryonic stem cells (hESCs). The studies demonstrate that functional, contractile cardiomyocytes can be efficiently differentiated from hESCs, and have potential for clinical use in treating diseases such as acute myocardial infarction and heart failure.

As published in the September issue of Circulation Research, Geron scientists developed unique methods capable of generating cardiomyocytes from three different hESC lines that were maintained in culture for one year. The differentiated cardiomyocytes contracted for over 70 days in vitro and expressed molecular markers characteristic of human cardiomyocytes as well as proteins such as cardiac troponin I and N-cadherin. Further, pharmacological agents modulated the contractile rate of the hESC-derived cardiomyocytes in the same manner as observed with cardiomyocytes isolated from primary heart tissue. The publication is available online, at http://circres.ahajournals.org/.

"The hESC culture and differentiation methods produced enriched cardiomyocyte populations of 70% purity," stated Jane S. Lebkowski, Ph.D., Geron's vice president of research and development, regenerative medicine. "The presence of characteristic proteins critical for cardiomyocyte function and metabolic activity in these hESC-derived populations will be important for their integration and coordination with adjacent host cardiomyocytes after transplantation."

Previous animal studies by other investigators have shown that isolated fetal cardiomyocytes can improve cardiac function upon transplantation into the myocardium of infarcted animals. In addition, derivatives of mouse embryonic stem cells have been found to engraft the rodent myocardium, integrating with the host cardiomyocytes.

Human embryonic stem cells are unique stem cells because they are pluripotent. They can develop into all cells and tissues in the body. Also, because they express telomerase, they continuously self-renew in the undifferentiated state without losing pluripotency. The extended replicative capacity of hESC lines will facilitate the scalable and reproducible production of multi-dose lots of cardiomyocytes, allowing rigorous efficacy and safety testing and, ultimately, widespread availability for therapy.

"The purities, yields, and functionality of the hESC-derived cardiomyocyte populations allow us to advance this program to animal testing," remarked Thomas B. Okarma, Ph.D., M.D., Geron's president and chief executive officer. "The next milestone for this program is to demonstrate safety and efficacy of these cells in animal models of human myocardial disease."

Geron holds licenses under U.S. Patent Nos. 5,843,780 and 6,200,806, including exclusive rights to develop and commercialize neural, cardiomyocyte and islet cells derived from hESCs for therapeutic applications. Further, Geron has built its own international portfolio of patent applications covering technologies it has developed to enable the scalable growth and differentiation of hESCs, as well as various differentiated cell types that can be produced from hESCs.

Geron is a biopharmaceutical company focused on developing and commercializing therapeutic and diagnostic products for applications in oncology and regenerative medicine, and research tools for drug discovery. Geron's product development programs are based upon three patented core technologies: telomerase, human embryonic stem cells and nuclear transfer.

This news release may contain forward-looking statements made pursuant to the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Investors are cautioned that such forward-looking statements in this press release regarding product development and future applications of Geron's technology constitute forward-looking statements that involve risks and uncertainties, including, without limitation, risks inherent in the development and commercialization of potential products and the maintenance of our intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements. Additional information on potential factors that could affect our results and other risks and uncertainties are detailed from time to time in Geron's periodic reports, including the quarterly report on Form 10-Q for the quarter ended June 30, 2002.

Additional information about Geron Corporation can be obtained at http://www.geron.com.

             GENERATION OF FUNCTIONAL CARDIOMYOCYTES FROM
                      HUMAN EMBRYONIC STEM CELLS

          "Characterization and Enrichment of Cardiomyocytes
               Derived From Human Embryonic Stem Cells"
                Circulation Research 91, 501-508 (2002)

                             BACKGROUNDER
                            SEPTEMBER 2002

Introduction

Human embryonic stem cells (hESCs) have been derived from donated, IVF-produced blastocysts which develop into immortal cell lines that propagate indefinitely. When exposed to appropriate culture conditions, hESCs can differentiate into all major lineages of cells that form the body, and therefore are termed "pluripotent." These unique properties of hESCs make them a potential self-renewing source for the production of specific differentiated cell types for the treatment of degenerative diseases. Geron has developed culture systems for hESCs enabling their long-term expansion. These systems avoid the use of direct contact with mouse cell feeders previously used with human embryonic stem cell propagation (Xu, et al., 2002). This "feeder free" system facilitates efficient and scalable manufacturing methods to produce cells for transplantation and drug discovery applications. Geron is focusing on the production of functional differentiated cell types for the treatment of neurological disease, heart failure and diabetes.

Differentiation of Cardiomyocytes from hESCs

In the studies reported in the September 2002 issue of Circulation Research, Geron scientists demonstrated that cardiomyocytes can be efficiently differentiated from hESCs. Cardiomyocytes were differentiated from three different hESC lines, that had been maintained in culture for 50 passages (one year). The hESC-derived cardiomyocytes contracted (i.e. beat) for at least 70 days in culture, and expressed a series of molecular markers characteristic of cardiomyocytes. Specifically, the hESC-derived cardiomyocytes expressed cardiac troponin I and N-cadherin, predicting that these cells could integrate and coordinate with adjacent host cardiomyocytes. To further characterize the hESC-derived cardiomyocytes, they were exposed to pharmacological agents known to modulate the contraction frequency of adult tissue-derived cardiomyocytes. In these studies, the contractile rate of the hESC-derived cardiomyocytes responded consistently to that of the primary heart tissue-derived cardiomyocytes. Finally, the report describes methods to purify the hESC-derived cardiomyocytes to approximately 70% purity with no evidence of contaminating undifferentiated hESCs.

Next Steps for the Development of hESC-Based Therapies for Heart Disease

The high purity, yield and functionality of hESC-derived cardiomyocytes enable the testing of these cells in animal models of human myocardial disease. Successful completion of these studies demonstrating proof-of-concept for the utility and safety of hESC-derived cardiomyocytes for the treatment of heart disease is the next project milestone. To date, other cell types such as skeletal muscle cells, fetal cardiomyocytes, adult cardiomyocytes, and bone marrow-derived stem cells have been tested in either animal models or other human clinical studies to improve cardiac function (Scorsin, et al, 2000; Roell, et al., 2002; Li, et al., 2000; Sakai, et al, 1999; Tomita, et al., 1999; Orlic, et al., 2001; Taylor, et al., 1998). Importantly, only cardiomyocytes have the molecular capacity to electrically couple with endogenous cardiomyocytes to produce coordinated cardiac contractions (Murry, et al., 1996). It has been demonstrated in rodent and pig studies that cardiomyocytes derived from fetal heart tissue can integrate into the damaged tissue of infarcted rats and improve cardiac function (Roell, et al., 2002; Scorsin, et al., 2000; Li, et al., 2000; Sakai, et al., 1999). Moreover, cardiomyocytes derived from mouse embryonic stem cells have been shown to survive, integrate, and rescue cardiac contractibility in infarcted rodents (Min, et al., 2002). These results suggest that the development of hESC-derived cardiomyocytes for cellular transplantation therapy of congestive heart failure and myocardial infarction in humans is technically feasible.

The derivation of cardiomyocytes on a large scale from hESCs allows for testing the utility of cells in animal models and eventually in humans. This cardiomyocyte differentiation process, coupled with Geron's proprietary methods to expand hESCs should lead to the scalable production of cardiomyocytes for preclinical and clinical safety and efficacy testing and eventual commercialization. Development of hESC-derived cardiomyocytes calls for hESCs to be expanded into large banks which would be quality-tested for use as a starting material for the production of cells for therapeutic uses. Cells from this bank would be further expanded, differentiated into cardiomyocytes, vialed and stored. Geron's approach to the production of cells for transplantation would lead to large batch manufacturing lots available at low cost for on-demand use by patients. There is an annual incidence of 450,000 people in the U.S. and 300,000 people in Europe who are affected by heart disease which may be treatable by hESC-derived cardiomyocyte-based therapies.

In addition to cell therapies, hESC-derived cardiomyocytes could be utilized in cell-based screens to identify drugs that improve cardiomyocyte function or test drugs for cardiotoxicity. There is a paucity of human cardiac or cardiomyocyte disease models to screen for candidate therapeutic drugs or to thoroughly test the efficacy and safety of drugs selected for advanced development. In addition, there are no good and reliable human systems to test the potential cardiotoxicity of a new drug under development prior to clinical testing. The reliable availability and uniform quality of hESC-derived cardiomyocytes could enable the development of more representative models of human heart disease and of screening procedures to more thoroughly assess the safety and efficacy of a new drug compound prior to clinical studies.

Geron is a biopharmaceutical company focused on developing and commercializing therapeutic and diagnostic products for applications in oncology and regenerative medicine, and research tools for drug discovery. Geron's product development programs are based upon three patented core technologies: telomerase, human embryonic stem cells and nuclear transfer.

This news release may contain forward-looking statements made pursuant to the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Investors are cautioned that such forward-looking statements in this press release regarding product development and future applications of Geron's technology constitute forward-looking statements that involve risks and uncertainties, including, without limitation, risks inherent in the development and commercialization of potential products and the maintenance of our intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements. Additional information on potential factors that could affect our results and other risks and uncertainties are detailed from time to time in Geron's periodic reports, including the quarterly report on Form 10-Q for the quarter ended June 30, 2002.

References

Xu, Chunhui, et al., Nat Biotechnol 2001; 19:971

Roell, Wilhelm, et al., Circulation 2002; 105:2435

Scorsin, Marcio, et al., J Thorac Cardiovasc Surg 2000; 119:1169

Li, Ren-Ke, et al., J Thorac Cardiovasc Surg 2000; 119:62

Sakai, Tetsuro, et al., J Thorac Cardiovasc Surg 1999; 118:715

Murry, Charles, et al., J Clin Invest 1996; 98:251

Tomita, Shinji, et al., Circulation 1999; 100(suppl II): II-247

Orlic, Donald, et al., PNAS 2001; 98(18):10344

Taylor, Doris, et al., Nat Medicine 1998; 4(8):929

Min, Jiang-Yong, et al., J Appl Physiol 2002; 92:288

For Additional Information:

Geron Corporation

David L. Greenwood

Chief Financial Officer

650/473-7765