April 2010 Fact Sheet

Geron, a pharmaceutical company based in California, announced in January 2009 that they had received clearance from the FDA to begin the first human clinical trial of embryonic stem-cell based therapy in the treatment of acute spinal cord injury. This was planned to be a Phase 1 clinical trial to assess safety and tolerability in patients with subacute (injury occurrence within 7 to 14 days), complete ASIA grade A thoracic spinal cord injury.  However, in subsequent animal studies, an increase of cysts at the site of injury after injection of the Geron product was observed.  Thus, the clinical trial has been postponed until the second half of 2010. Once positive results are obtained in the additional preclinical studies, the clinical trial in humans will begin.  Although the primary endpoint of the trial will be safety, the protocol will include secondary endpoints to assess efficacy, such as improved neuromuscular control or sensation in the trunk or lower extremities. Once safety in this patient population has been established and the FDA reviews clinical data in conjunction with additional data from ongoing animal studies, Geron plans to seek FDA approval to extend the study to increase the dose of GRNOPC1, enroll subjects with complete cervical injuries and expand the trial to include patients with severe incomplete (ASIA grade B or C) injuries to enable access to the therapy for a broad population of spinal cord-injured patients.

Background

The Geron stem-cell based product for spinal cord injury is known as GRNOPC1.  It is a population of living cells containing oligodendrocyte progenitor cells (OPCs) that have been derived from human embryonic stem cells.  OPCs mature into oligodendrocytes, which are naturally occurring cells in the nervous system responsible for the production of myelin (insulating cells that wrap around nerve axons) as well as for the production of neurotrophic factors that support the survival and function of neurons.  Myelin enables the efficient conduction of nerve impulses. Without myelin, the brain and spinal cord cannot function properly.  In most spinal cord injuries there is bruising to the nerve tissue that results in a severe inflammation at the site of injury. This inflammation is very toxic to oligodendrocytes and results in loss of myelin and nerve cells which may result in paralysis below the level of injury.

Geron scientists and scientists from the University of California, Irvine published a paper in Journal of Neuroscience in which they describe their methodology to produce OPCs from animal embryonic stem cells.  These OPCs (GRNOPC1) were then tested in an animal model of spinal cord injury.  This validated animal model, which mimics what occurs in humans after suffering a spinal cord injury, results in a loss of truncal muscle function, bladder control and hind limb function.  Their controlled experiment involved injecting GRNOPC1 at the site of injury within 7 days of contusion.  The treated animals showed both functional (significant hind limb locomotor control) and histological (increased remyelination of axons at injury site) improvement as compared to the control group.  In additional studies, nine months after injury and a subsequent injection of GRNOPC1, the lesion site was filled with GRNOPC1 and myelinated nerve axons crossed the lesion.  Taken together, these findings, that 1)embryonic stem cell derived OPCs were present at the injury site and 2)that there was increased axonal remyelination at the injury site nine months post injury, and 3) there was  functional improvement in the experimental group compared to the control group, are the basis for the clinical trial in humans.

Could be GRNOPC1  be effective for the treatment of motor dysfunction associated with CP?

Human periventricular white matter injury (PWMI) is the predominant form of brain damage and the leading cause of life-long neurological disability from cerebral palsy in survivors of premature birth. The two major causes of PWMI are thought to be: chorioamnionitis, which can induce fetal inflammatory response, and hypoxia/ischemia (H/I),  both of which can cause acute degeneration of oligodendrocyte progenitors (OPCs)resulting in chronic myelination disturbances of neuronal axons. As with spinal cord injury, the loss of myelin causes loss of motor function and control.

The Geron GRNOPC1 SCI protocol requires that the injection be precisely at the point of injury. In cerebral palsy the injury is likely diffuse throughout the brain.  So a major issue would be how to get the OPCs to all of the sites of injury in CP.  Further, Geron has found that the GRNOPC1 product is ineffective 14 days post injury due to scarring around the lesion.  Cerebral palsy may not be diagnosed for up to 2 years post injury.  Geron plans to further study the effectiveness of their human embryonic stem cell derived OPCs in other neurological conditions resulting from white matter injury including Alzheimer’s disease, stroke and multiple sclerosis. There are currently no plans to test this product in cerebral palsy. However, this is a significant advance in the treatment of incurable neurological conditions and the results of this trial may provide important insights on the short and long term effectiveness of stem cell therapy for all neurological conditions. To learn more about Geron and their research program go to http://www.geron.com/products/