HESC-DERIVED HEMATOPOIETIC CELLS PREVENT IMMUNE REJECTION.

Geron Corporation (Nasdaq:GERN), Menlo Park, Calif., has announced new research data that advance the promise of cell therapies based upon human embryonic stem cells (hESCs). The new data show that hESCs can be used to produce hematopoietic (blood-forming) cells at efficiencies comparable to human cord blood and mobilized peripheral blood.

These hESC-derived hematopoietic cells not only have potential application in hematopoietic transplantation therapies, but also could be used to prevent immune rejection of transplanted cells derived from hESCs, thereby potentially eliminating the need for immunosuppressive drugs or nuclear transfer technologies.

In addition to the new research data, Geron announced that it has licensed intellectual property rights from two research institutions for these hematopoietic cells and the approach of using them to achieve immune tolerance to hESC-derived transplants.

Background

When cells, tissues or organs are transplanted into the human body, the immune system generally recognizes the tissue as foreign, and mounts an immune response which can lead to the rejection of the transplant. Currently, this rejection response is controlled by the long-term administration of immunosuppressive drugs that suppress the patient's entire immune system. These drugs often have severe side effects and are costly. Similar, but possibly less severe rejection responses may be encountered in certain instances following transplantation of cells made from hESCs.

In conjunction with its collaborators, Geron has been studying various ways by which the immune response against transplanted hESC-derived cells could be reduced or eliminated. In earlier clinical organ transplantation studies, patients who first received a bone marrow transplant (BMT) and then later received an organ transplant from a donor with identical tissue type to that of the prior BMT donor were less likely to reject the organ than patients who had not received such prior BMT. The patients were said to have been "tolerized" to the tissue of the organ donor by virtue of receiving the prior BMT.

Specifically, hematopoietic cells from the donated bone marrow combined permanently with the immune system of the BMT recipients such that their immune system no longer recognized tissues from the organ donor as foreign. In this way, the patient's immune system was taught to tolerate the transplanted organ.

This "tolerizing" approach has subsequently been validated with solid organ transplants. It represents an attractive alternative to immunosuppressive drugs because the patient's immune system remains available to fight off infection and disease. The method could be applied to hESC transplantation by using hematopoietic cells derived from a particular hESC line to "tolerize" a patient to any other transplanted tissue derived from the same hESC line.

The New Research

Geron and its collaborators have been working to produce hematopoietic cells from hES cells. Work in Dr. James Thomson's laboratory at the University of Wisconsin, Madison, (PNAS, 2001;98:10716-10721) used co-cultivation of the hESCs with stromal cells to produce hematopoietic cells. On January 11, 2003, Dr. Mick Bhatia of Robarts Research Institute (London, Ontario) presented new data at the "Mechanisms Regulating Developmental Plasticity" conference held in New Zealand. Dr. Bhatia's data show that direct differentiation of hESCs using cytokines can generate hematopoietic progenitor cells which produce all three blood cell lineages (red cells, white cells and platelets). This work was funded by and performed in collaboration with Geron Corporation. The efficiency of hematopoietic progenitor production from hESCs was comparable to that produced from human cord blood and mobilized peripheral blood -- two commonly used sources of cells for hematopoietic reconstitution procedures.

"We are very excited by these new findings," said Thomas B. Okarma Ph.D., M.D., Geron's president and chief executive officer. "The ability to produce scalable quantities of hematopoietic progenitors from hESCs adds to our growing list of differentiated cell types useful for human cell therapy applications. And, while these cells may be useful in BMT-like therapies, an additional significant aspect of this work is the prospect of using these cells to prevent immune rejection when other hESC-derived cells are transplanted."

Dr. Okarma continued, "Geron is developing hESCs for large therapeutic opportunities -- scalable products that will benefit large numbers of patients (in contrast to service-type treatments for individual patients). If hESC-derived hematopoietic cells prove to be a scalable way to prevent immune rejection, this will certainly benefit our approach, and could obviate the scientific rationale for patient-specific therapies that are based on adult stem cells or nuclear transfer."

New Licenses to Intellectual Property

Geron also has secured key license rights to intellectual property relating to hESC-derived hematopoietic cells and their use in transplantation therapies. Specifically, through its funding of Dr. Bhatia, Geron holds a license from Robarts Research Institute to patent applications covering Dr. Bhatia's work on the production of hematopoietic stem cells from hESCs. In addition, Geron has received a license from the Wisconsin Alumni Research Foundation (WARF) to patent rights covering Dr. Thomson's work on hematopoietic cells. The Wisconsin patents include issued U.S. Patent No. 6,280,718, the claims of which cover methods of transplanting hESC- derived cells into human patients in which the patients are tolerized to the transplanted cells by receiving hESC-derived hematopoietic cells.

"These patent licenses provide Geron with the freedom to operate in the production and use of hematopoietic cells in hESC-based therapies," noted David J. Earp, J.D., Ph.D., Geron's vice president of intellectual property. "They add a new dimension to Geron's intellectual property portfolio in regenerative medicine, which already includes an exclusive commercial license from WARF for the use of hESCs to produce neural cells, cardiomyocytes and pancreatic islets cells for therapeutic uses, and non-exclusive commercial rights to produce hepatocytes, chondrocytes, osteoblasts and hematopoietic cells, as well as over 70 Geron-owned pending patent applications filed worldwide for stem cell technologies developed by Geron-funded scientists."

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.

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