Geron Demonstrates Derivation of Neurons and Neural Progenitors From hESC

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Geron Demonstrates Derivation of Neurons and Neural Progenitors From Human Embryonic Stem Cells


Updated: Thu, Nov 29 7:32 AM EST


MENLO PARK, Calif. (BW HealthWire) - Geron Corporation (NASDAQ:GERN) announced today the publication of research results that describe the derivation of neurons and neural precursors from human embryonic stem cells (hESCs). The studies demonstrate
that Geron can differentiate hESCs into populations of neural precursors and mature, functional neurons, including dopaminergic neurons that have the potential for use in treating Parkinson's Disease.

Published in the December 2001 issue of Experimental Neurology, the studies were undertaken by Geron scientists and academic collaborators. Using specific culture conditions, hESCs were maintained in feeder-free conditions for over 100 population doublings and
were subsequently differentiated into populations of cells highly enriched (70% - 90%) of proliferating neural precursor cells. These progenitor populations were further differentiated into mature neurons that showed similar functional characteristics to human
fetal-derived neurons. The hESC-derived neurons expressed the relevant biochemical markers and showed appropriate functional activity measured by electrophysiological techniques. In addition, 3% of the hESC-derived neurons expressed tyrosine hydroxylase, the
rate-limiting enzyme for dopamine synthesis.

"These studies confirm that cells derived from hESCs have the same characteristics as adult differentiated cells," stated Jane S. Lebkowski, Ph.D., Geron's vice president of Research and Development, Regenerative Medicine. "Also, the presence of neural progenitor
cells enables the generation of different types of mature neurons for transplantation into animal models of neurological disease as well as for in vitro use in drug discovery and predictive toxicology."

Geron is developing hESC-based cell therapies for the treatment of a variety of degenerative diseases. Dopaminergic neurons derived from hESCs, for example, could be used to treat Parkinson's Disease. Currently, experimental cell therapies for the treatment of
neurodegenerative diseases are limited to neurons extracted from fetal brain tissue. This approach requires multiple fetal donors for each treated patient, which is logistically problematic and cannot be scaled. Because of the unlimited growth potential of hESCs and
Geron's technology for extending the replicative capacity of differentiated cells with telomerase, the production of cells for transplantation can occur in large manufacturing lots allowing rigorous safety and quality control testing. This could translate into scaleable,
low cost manufacturing and distribution which has been unachievable with traditional individualized cell therapies.

"Our work with hESCs continues to advance," remarked Thomas B. Okarma, Ph.D., M.D., Geron's president and chief executive officer. "The next steps in developing our hESC-derived neurons will be transplantation studies in animal models of neurodegenerative
disease to demonstrate their utility for treating neurological diseases in humans."

Human embryonic stem cells are unique stem cells because they are pluripotent. They can develop into all cells and tissues in the body. And, because they express telomerase, they continuously self-renew in the undifferentiated state without losing pluripotency.

Geron holds an exclusive license under U.S. Patent Nos. 5,943,780 and 6,200,806 for the development and commercialization of certain cell types derived from hESCs, including neural cells, 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 cell types that can be produced from hESCs. These technologies may facilitate the commercialization of products
derived from hESCs, including therapeutic, diagnostic and research products.

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, dependence on
collaborative partners, 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 September 30, 2001.

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

Generation of Functional Neurons From Human Embryonic Stem Cells
"Enrichment of Neurons and Neural Precursors from
Human Embryonic Stem Cells"
Experimental Neurology 172, 383-397 (2001)
Backgrounder
November 2001

Introduction

Human embryonic stem (hES) cells isolated from blastocysts are immortal and have the capacity to differentiate into mesoderm, ectoderm and endoderm in vitro and in vivo. Geron has previously demonstrated that hES cells can undergo as many as 250 population
doublings and still retain all their fundamental characteristics including telomerase activity, pluripotency and stable karyotype (Amit et al, 2000). These remarkable properties make hES cells a potential source for the production of cells useful for the treatment of
numerous degenerative diseases. Geron has also developed a culture system which allows the long term culture of hES cells in the absence of mouse feeder layers (Xu et al., 2001) which should facilitate efficient and scalable manufacturing methods to produce cells
qualified for transplantation studies and for use in drug discovery research. Geron is focusing on the production of multiple types of functional differentiated cells and their progenitors for the treatment of degenerative diseases, such as heart failure, liver failure, and
diabetes. This paper focuses on the derivation and functional testing of neuronal cells.

Isolation of hES Cells

hES cells were isolated by removing the inner cell mass (ICM) from embryos produced from in vitro fertilization procedures that were no longer needed for reproductive purposes and donated under informed consent (Thomson et al, 1998). Cells of the ICM were
placed onto a layer of irradiated mouse fibroblasts. These mouse cells serve as "feeders" and provide a substrate for the long-term maintenance and proliferation of undifferentiated hES cells. Undifferentiated hES cells express the immortalizing enzyme, telomerase,
conveying to hES cells an unlimited capacity to divide. The hES cells, when subsequently placed in appropriate culture conditions and treated with specific growth and differentiation factors, differentiate into functional cells representing each of the three
developmental lineages of the body: endoderm (liver), mesoderm (cardiac muscle), and ectoderm (neurons).

Generation of Neurons from hES Cells

In the studies reported in the December 2001 issue of Experimental Neurology, Geron scientists and their collaborators have demonstrated that hES cells can differentiate into enriched populations of neural precursors and neurons. Using specific culture conditions, the
hES cells, maintained in feeder-free conditions (Xu et al., 2001) for over 100 population doublings, were differentiated into populations of cells containing up to 30% neurons with characteristics similar to those of human neurons derived directly from human fetal
tissue. These neurons showed mature morphology and expressed normal neural markers such as (beta)-tubulin III and microtubule associated protein-2 (MAP-2) and markers associated with synapse formation, such as synaptophysin. These neurons also synthesized
neurotransmitters, responded appropriately to the application of neurotransmitters and were able to generate normal action potentials. Notably, 3% of the hES-derived neurons expressed tyrosine hydroxylase, the rate limiting enzyme for dopamine synthesis. These
findings demonstrate that the hES-derived neurons have marker expression, electrical activity and physiological function characteristic of normal adult human neurons.

It is likely that the most appropriate population for cell transplantation in neurodegenerative diseases will be a population of neural progenitor cells. It has been demonstrated in animal studies that, upon transplantation, neural progenitors can integrate into the host
brain and form neurons. However, such neural progenitor cells are rare, difficult to isolate and have limited replicative potential. In contrast, the production of neural progenitors from immortal hES cells may provide an abundant source of these cells for therapeutic
applications.

Using culture conditions and cell separation techniques, populations of cells were generated from hES cells which contained 70-90% proliferative neural precursor cells. These populations contained cells that expressed nestin, PS-NCAM and A2B5, markers indicative
of neural progenitor cells. These progenitor populations were subsequently differentiated into populations containing about 30% mature neurons. The neurons generated from the hES-derived precursors also synthesized neurotransmitters and a subpopulation expressed
tyrosine hydroxylase.

Implications

Geron is developing hES cell-based therapies for the treatment of a variety of degenerative diseases. For example, dopaminergic neurons derived from hES cells could be used to treat Parkinson's Disease. Parkinson's Disease is the second most common degenerative
central nervous system disease. Currently, 500,000 people in the United States and 900,000 in Europe and Japan are affected by Parkinson's Disease. The most effective drug therapy, L-dopa, partially relieves the symptoms in Parkinson's patients, but loses efficacy
over time. Cell transplants of human fetal tissue have been performed on more than 200 Parkinson's patients, providing proof of concept for cell replacement strategies. In addition to Parkinson's Disease, cell replacement strategies are being tested in other
neurodegenerative diseases such as Huntington's Disease and spinal cord injury. Currently, these approaches require the transplantation of primary fetal tissue. This approach requires tissue from multiple donors for each patient, which is logistically problematic and
cannot be scaled. Because of the unlimited growth potential of hES cells and the capacity to extend the replicative capacity of differentiated cells with telomerase, Geron's approach to the production of cells for transplantation can occur in large-batch manufacturing
lots. This means that for the first time, cell therapy products can be scalably produced in much the same way as monoclonal antibodies or protein biologicals are manufactured. This could translate into scalable, low cost manufacturing and distribution that previously
has been unachievable with traditional individualized cell therapies.

In addition to cell therapy applications, the generation of enriched populations of neurons also provides cells for other applications. The unique capacity of hES cells to replicate indefinitely and generate substantial numbers of functional neurons makes this
population of cells appropriate for toxicological screening and drug discovery research.

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, dependence on
collaborative partners, 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 September 30, 2001.

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