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GRNOPC1 – Oligodendrocyte Progenitors to Address CNS Disorders

The major neural cells of the central nervous system (CNS) typically do not regenerate after injury. If a nerve cell is damaged due to disease or injury, there is no treatment at present to restore lost function. Patients worldwide suffer from injury to the nervous system or disorders associated with its degeneration.

About Spinal Cord Injury

Spinal cord injury is caused by trauma to the spinal cord that results in a loss of control of muscles, a loss of sensatory perception, loss of bowel and bladder control, or numerous other voluntary or involuntary body functions. A traumatic blow to the spine can fracture or dislocate vertebrae (the bones or segments of the spine) causing bone fragments or disc material to damage the nerve fibers and cells of the central nervous system that protect the nerve fibers in the spinal cord. Most human spinal cord injuries are contusions (bruises) rather than lacerations to the cord. Every year approximately 12,000 people in the U.S. sustain spinal cord injuries.

About GRNOPC1

GRNOPC1 is a population of cells containing oligodendrocyte progenitor cells (OPCs) that have been derived from human embryonic stem cells (hESCs).

Oligodendrocytes produce myelin, an insulating layer made up of protein and fatty substances that forms around nerves in the CNS to enable them to conduct electrical signals. Myelin behaves the same way insulation does in preventing short circuits in an electrical wire. Without myelin, many of the nerves in the brain and spinal cord cannot function properly.

Oligodendrocytes also produce neurotrophic factors - proteins that are responsible for the growth and survival of developing nerve cells and the maintenance of mature nerve cells. Oligodendrocytes are lost in spinal cord injury, due to the injury itself and the inflammatory environment that ensues, resulting in myelin and nerve cell loss that causes paralysis in many patients with spinal cord injuries.

Preclinical Safety Data

Extensive preclinical toxicology testing was conducted using GRNOPC1 to support the IND (Investigational New Drug) application to begin human clinical trials. Data from the testing includes:

• No evidence of teratomas one year after the injection of clinical grade GRNOPC1.
• Small cysts lined by human epithelial cells were found at the injection site in some rodents, but there was no evidence of any adverse effects on the animals.
• No systemic toxicity or cell migration outside of the central nervous system (CNS) was observed in rodents with spinal cord injury that received GRNOPC1.
• No evidence of allodynia (pain induced by normally non-noxious stimuli) was detected following injection of GRNOPC1 in a rat model of spinal cord injury.
• No major susceptibility of GRNOPC1 to direct humoral or cell-mediated alloimmune attack in vitro.

These preclinical animal studies provided the rationale for the use of GRNOPC1 in treating spinal cord injuries in humans.

Phase 1 Clinical Trial in Spinal Cord Injury

A Phase 1 clinical trial was initiated to evaluate the safety of GRNOPC1 in patients with spinal cord injury. Although Geron is not enrolling any additional patients in this Phase 1 study, patients who had been treated with GRNOPC1 are being followed for up to 15 years in accordance with pre-established clinical protocols.

Indication	Trial Design Summary
Spinal cord injury (ASIA A, T3-11)	Open label, single agent Learn more

Patients with neurologically complete, thoracic spinal cord injuries received the lowest intended dose level of GRNOPC1 (2 million cells). In this trial, GRNOPC1 has been well tolerated. Data presented at the October 2011 ACRM – ASRN annual meeting noted the following:

• No surgical complications reported during or after surgeries.
• No serious adverse events (SAEs) reported.
• No adverse events reported related to the injection procedures or GRNOPC1.
• Few mild and adverse events reported related to the immunosuppressive drug tacrolimus (nausea and low magnesium).
• No evidence of adverse changes or cavitation in the spinal cord at the injury site observed on MRI.
• No unexpected neurological changes observed.
• No evidence of immune responses to GRNOPC1 through Day 90 (30 days after complete withdrawal of immune-suppression) detected.

Other Potential Applications

In addition to spinal cord injury, GRNOPC1 may have therapeutic utility for the treatment of other CNS diseases, such as Alzheimer’s disease, multiple sclerosis, leukodystrophies and stroke, due to the multiple functional properties of the cells.

Related Publications

• Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, Steward O. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci. 2005 May 11;25(19):4694-705.
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• Yi Wei Zhang, Jerrod Denham, R. Scott Thies. Oligodendrocyte Progenitor Cells Derived from Human Embryonic Stem Cells Express Neurotrophic Factors. Stem Cells & Development 15(6):943-952,2006
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• Ross M. Okamura, Jane Lebkowski, Melinda Au, Catherine A. Priest, Jerrod Denham, Anish S. Majumdar. Immunological properties of human embryonic stem cell-derived oligodendrocyte progenitor cells. Journal of Neuroimmunology 192(1-2):134-144, 2007.
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