Embryonic stem cell-derived neural cells have been used by researchers to treat nervous system disorders in animal models. In the case of spinal cord injuries, neural cells derived from animal embryonic stem cells and injected into the spinal cord injury site produced significant recovery of the animal's ability to move and bear weight.
To apply those observations to humans, we have derived oligodendrocyte progenitor cells (GRNOPC1) from hESCs. Oligodendrocytes are naturally occurring cells in the nervous system that have several functions. Oligodendrocytes produce myelin (insulating layers of cell membrane) that wraps around the axons of neurons to enable them to conduct electrical impulses. Myelin enables efficient conduction of nerve impulses in the same manner as insulation prevents 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 (biologicals that enhance neuronal survival and function) to support the maintenance of nerve cells. Oligodendrocytes are lost in spinal cord injury, resulting in myelin and neuronal loss that cause paralysis in many patients with spinal cord injuries.
In our collaboration with researchers at the University of California, Irvine, we have shown in animal models that GRNOPC1 can improve functional locomotor behavior after implantation in the injury site seven days after injury. Histological analysis also provided evidence for the engraftment and function of these cells. These data were first published in May 2005 in the Journal of Neuroscience. In additional studies, the lesion site of animals nine months after injury and subsequent injection of GRNOPC1 was observed to be essentially filled with GRNOPC1 and myelinated rat axons crossing the lesion. These animal observations serve as the rationale for the use of GRNOPC1 in treating spinal cord injuries in man.
We have developed a functional cryopreserved formulation of GRNOPC1 for use in clinical trials and have initiated current Good Manufacturing Practices (cGMP) production of GRNOPC1 in our qualified manufacturing facilities.
We completed extensive animal toxicology testing that included 24 separate studies in rats and mice requiring more than five billion GRNOPC1 cells. In those preclinical IND-enabling studies, we had observed the occurrence of occasional epithelial cysts in animals transplanted with GRNOPC1. These cysts were non-proliferative, confined to the injury site, smaller than the injury cavity and were not associated with adverse effects on the animals. Data from these animal and in vivo studies were included in the IND filed with the FDA.
In January 2009, we received clearance from the FDA to begin the first human clinical trial of an embryonic stem cell-based therapy using GRNOPC1 for acute spinal cord injury. The study is a Phase I multi-center trial designed to assess the safety and tolerability of GRNOPC1 in patients with complete ASIA (American Spinal Injury Association) Impairment Scale grade A thoracic spinal cord injuries.
Since clearance of the IND, Geron has been performing a series of preclinical studies to expand the clinical program (preclinical expansion studies) for spinal cord injury beyond patients with complete thoracic injuries. Our goal is to test the safety and utility of GRNOPC1 in patients with complete and incomplete (less severe) injuries in both thoracic and cervical regions.
In one of the preclinical expansion studies, a higher frequency of animals developed cysts in the injury site than had been seen in numerous foregoing preclinical studies with clinical grade GRNOPC1, including the IND-enabling studies. We notified the FDA of the findings from this animal study and the trial was put on clinical hold in August 2009. As part of ongoing work to optimize GRNOPC1 manufacturing and product release, we developed new candidate markers and assays as additional release specifications for GRNOPC1. We completed an additional confirmatory preclinical animal study to test the new markers and assays, and subsequently submitted a request to the FDA for the clinical hold to be lifted.
In July 2010, the FDA notified us that the clinical hold placed on our IND application has been lifted and Geron's Phase I clinical trial of GRNOPC1 in patients with acute spinal cord injury may proceed.
Click here for information on the planned clinical trial in patients with acute spinal cord injury.
In addition to spinal cord injury, GRNOPC1 may have therapeutic utility for other central nervous system indications, such as Alzheimer's disease, Canavan disease and multiple sclerosis. We have established three separate collaborations with academic groups to test GRNOPC1 in animal models of these diseases.
Embryonic stem cell-derived neural cells have been used by researchers to treat nervous system disorders in animal models. In the case of spinal cord injuries, neural cells derived from animal embryonic stem cells and injected into the spinal cord injury site produced significant recovery of the animal's ability to move and bear weight.
