Our goal is to develop a human neuronal cell line that can modulate aberrant brain activity in the treatment of neurological disorders. Our initial focus is on epilepsy, a seizure disorder. In 20-30% of these patients, seizures are unresponsive to drugs requiring invasive surgical resection of regions of their brains with aberrant activity. The candidate cells we propose to develop, after implantation into the damaged brain can inhibit hyperactive neural circuits. As such these cells could provide an effective treatment for epilepsy and other neurological conditions like Parkinson’s disease, traumatic brain injury and spasticity after spinal cord injury. We propose to bring a development candidate, a neuronal cell therapy, to the point of preclinical development. We have determined that the neurons that normally inhibit brain circuits originate from a specific region of the developing brain: the medial ganglionic eminence (MGE). When MGE cells are grafted into the postnatal or adult brain they disperse seamlessly and form inhibitory neurons that modulate local circuits. This is a robust property of MGE cells that has not been shown for any other type of neural precursor. Our recent pre-clinical studies demonstrate that MGE cells grafted into an animal model for epilepsy can significantly decrease the number and severity of seizures. Other “proof-of-principle” studies suggest that these progenitor cells can be effective treatments in Parkinson’s disease. Recently, a group of collaborators in New York has developed method to purify large numbers of human MGE (hMGE) cells from embryonic stem (hES) cells. Methods to directly derive hMGE cells from hES cells are being perfected in our laboratories. To translate this therapy to humans, we need to develop new cell injection strategies and determine that the procedure is safe in the more complex mammalian brain. In addition, therapeutic efficacy of hMGE cells needs to be tested in animal models that more closely mimic the clinical condition. At present, these issues hinder development of this cell-based therapy in California and worldwide. We propose: (i) to develop new needles and delivery methods compatible with human transplantation; (ii) to test cell transplantation safety, neuronal migration, and functional integration in a preclinical model; and (iii) to test cell transplantation efficacy for the long-term suppression of seizures in a well-established animal model of chronic epilepsy. Our application takes advantage of an established multi-lab collaboration between basic scientists, neurosurgeons and epilepsy neurologists. If a safe cell-based therapy to replace lost inhibitory interneurons can be developed and validated, then clinical trials in patients destined for invasive neurosurgical resections could proceed.
This proposal is designed to accelerate progress toward development of a novel cell based therapy with potentially broad benefit for the treatment of epilepsy. The potential to translate our basic science findings into a treatment that could benefit patients is our primary focus. This work will provide benefits to the State of California in the following areas:
• California epilepsy patients will benefit from improved therapies. The numbers of patients refractory to available medications is significant: a recent report from the Center for Disease Control and Prevention [www.cdc.gov/epilepsy/] estimates that 1 out of 100 adults have epilepsy and up to one-third of these patients are not receiving adequate treatment. In California, it is one of the most common disabling neurological conditions, with approximately 140,000 affected individuals. In most states, including California, people with epilepsy whose seizures aren't well controlled cannot obtain a driver's license or work certain jobs -- truck driving, air traffic control, firefighting, law enforcement and piloting. The annual cost estimates to treat epilepsy range from $12 to $16 billion in the U.S. Current therapies curb seizures through pharmacological management but are not designed to modify brain circuits that are damaged or dysfunctional. The goals of our research program is to develop a novel cell-based therapy with the potential for eliminating seizures and improving the quality of life for this patient population, as well as decrease the financial burden to the patients' families, private insurers and state agencies.
• Technology transfer in California. Historically, California institutions have developed and implemented a steady flow of technology transfer. Based on these precedents, and the translational potential of our research goals both to provide a cell “delivery” system and a potentially useful “cell line”, this program is likely to result in licensing of further technology to the corporate sector. This will have an impact on the overall competitiveness of our state's technology sector and the resulting potential for creation of new jobs.
• Enhanced ability of California institutions to recruit stem cell scientists. Across California, we have seen a number of recruits from students to senior faculty as a result of CIRM funding, and this is likely to be enhanced by additional funding. Moreover, because of the translational nature of the research and resulting technology transfer to industry partners, the proposed disease-oriented proposal should have a similar impact on our local biotechnology or pharmaceutical partners.