Our principal goal is to develop medial ganglionic eminence (MGE) inhibitory nerve cell transplantation as a safe and effective therapy for medically intractable, focal temporal lobe epilepsy (TLE). There is a substantial unmet need for effective alternatives to surgery for TLE patients who do not respond to current anti-epileptic drug therapy. We have previously documented that mouse MGE cell transplants (precursors to inhibitory nerve cells) reduce seizures in animal models of epilepsy, demonstrating proof of concept for the transplantation of human MGE cells to treat patients with epilepsy. Over the past three years via CIRM basic and translational grant funding, we have developed technology to generate human MGE cells from human embryonic stem (ES) cell lines with remarkable efficiency and purity. With lead clinical candidate in hand, we now propose four specific aims to advance this candidate into a phase I clinical trial for TLE patients who are resistant to drug therapy and candidates for surgical temporal lobe removal. These patient candidates will therefore have a safety net that involves surgical removal of the brain region containing transplanted cells in the event that stem cell therapy is not effective or causes adverse side effects.
Over the course of four years, we will create clinical-grade human MGE cells from human ES cells using good manufacturing practice (GMP) methods. We will then test these cells to ensure that they are free from disease causing agents, not contaminated or genetically altered, and that they are of acceptable purity. We will next examine the cell product following transplantation into mouse and primate brain in order to make certain that the cells are safe. We will also test the cell product for its ability to suppress seizures in epileptic animals. If the cells prove to be safe and effective, we will submit an IND application for FDA regulatory approval to begin a phase I clinical trial in patients with TLE.
The purpose of this proposal is to assemble an interdisciplinary team of scientists, technicians, industry experts, and physicians who will work together to create a pathway leading to a novel cell-based therapy for medically refractory epilepsy. Approximately 48,000 citizens in California are suffering from pharmaco-resistant seizures, and many of them will have no option other than temporal lobectomy, surgical removal of part of the temporal lobe of the brain. This procedure does not work for all patients, and many are ineligible for surgery due to the location of their seizure focus. The therapeutic cells developed in this proposal will first be tested in patients with intractable temporal lobe epilepsy who are candidates for temporal lobectomy. If the cells prove safe and effective, they could be used to treat other forms of seizure disorders, including those that are not treatable with surgery as well as the intractable childhood epilepsies. The potential benefits to California in terms of reduced medical care costs and increased productivity would be considerable for temporal lobe epilepsy patients alone, and would be much greater if other conditions associated with epilepsy can eventually be treated as well. The production facilities for generating, banking, and testing the cells are all within the state of California, and if effective therapeutically, the cells could become a world-wide resource bringing economic benefits in the form of patent income, job creation, and tax revenue. In the course of pursuing the aims of this grant, a medical team will be assembled that will become expert in delivering cell therapy to specific brain regions. This expertise will help make California a leading site for the trial and therapeutic delivery of cutting edge cell-based therapeutics for diseases that could range from epilepsy to stroke, Parkinson’s disease, Alzheimer’s disease, cerebral palsy, and brain tumors.