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.
Statement of Benefit to California:
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.
This proposal focuses on the development of a stem cell (SC) therapy to treat temporal lobe epilepsy (TLE). The applicant proposes to use human embryonic stem cells (hESCs) to derive neurons that resemble GABAergic inhibitory neuron precursors from the medial ganglionic eminence (MGE). Preliminary data indicate that mouse MGE cell transplants are an effective treatment in a mouse model of TLE. Specifically the applicant proposes to (i) develop an intracerebral transplantation method for human MGE cells (hMGEs) into rodents and preclinical models; (ii) test the safety and viability of hMGE cell transplants in a preclinical model; and (iii) test the long-term efficacy of hMGE transplants in a mouse model of TLE.
The reviewers agreed that this proposal addresses a large unmet clinical need. Epilepsy afflicts over 3 million Americans and is often treated suboptimally by medication and surgery. Reviewers felt that the applicant provided strong rationale for the transplantation of inhibitory GABAergic neuron precursors as a treatment for TLE. This rationale included preliminary data showing a decrease in EEG seizure activity in a mouse model of TLE after MGE transplant. Reviewers also appreciated that the research could impact other neurological diseases. Specifically the proposed electrophysiological studies of transplanted brain regions could provide valuable information for the treatment of diseases such as Parkinson’s, in which modulation of neural circuits is required. Reviewers noted that intractable TLE is an attractive target for stem cell therapy because surgical resection of the transplanted region is an acceptable outcome if the cell transplant is not effective or causes side effects, such as teratoma formation. One reviewer did question the rationale for Specific Aim 1, which focuses on the development of a delivery device for intracerebral transplantation in humans. This reviewer noted that a number of neurosurgical groups have been implanting cells in patients with a variety of disorders for over twenty years and was not convinced of the need to develop better or safer cell implantation devices for this particular application. Another reviewer was worried about the possibility of transplanted inhibitory neurons suppressing inhibitory circuits and causing excitation, a possibility not addressed in the application.
Reviewers raised a number of concerns about the design of the research plan and the feasibility of the proposal. Primary was the lack of preliminary data showing that the applicant or his/her collaborators are able to differentiate hESCs into MGE cells. Reviewers noted that the entire research plan depends upon the success of this procedure. Reviewers also noted a lack of experimental detail and outcome measures throughout the proposal. For instance, only the genus of the preclinical animal model is provided but not the species, age or gender of these animals. One reviewer felt that the large number of analyses proposed for the tissue from preclinical animal models (immunohistochemistry with 24 animals, electrophysiology and electron microscopy) was excessive, and an n of 2 animals per group was not enough to provide statistical power for these studies. This reviewer also commented that the goal of identifying 25 differentiated GABAergic neurons for electrophysiology is quite ambitious. Reviewers noted the limitations of the chosen preclinical animal model for testing in this context, given the absence of a disease model for TLE. They cautioned that optimization of transplantation approaches in the rodent may not translate to the preclinical models and vice versa. Finally, reviewers felt that Specific Aims 2 and 3 are out of order. They commented that safety studies in preclinical animal models (Aim 2) are premature prior to testing in the mouse model of TLE (Aim 3).
Reviewers had strong praise for the principal investigator (PI) and assembled research team. They noted that the group has considerable experience with basic neurobiology as well as translational and clinical research and has demonstrated the ability to run large, integrated projects. However, reviewers were concerned that the team lacks a dedicated investigator with hESC expertise. They noted the participation of an expert consultant on the east coast, but worried that the geographic distance might be detrimental to the success of the study. Reviewers raised some concerns about the budget, noting the large portion devoted to consumables (over $1M for 3 years) and the large number of post-doctoral fellows and technicians, which they felt could have been justified more thoroughly.
Overall, while reviewers were impressed with the scientific team, the experimental design, and the potential impact of this proposal, they raised questions about its feasibility given the lack of preliminary data on the generation hMGEs from hESCs.
During programmatic review, the Grants Working Group was instructed to consider the specific rank order of applications as an indicator of priority for funding. A motion was made to move this application to the second position from the top in Tier 2, placing it at the top in the Recommended for Funding if Funding is Available category. The panelist noted that epilepsy is underrepresented in the CIRM portfolio and is an excellent candidate for cell therapy given its pathology (selective loss of inhibitory interneurons) and the ability to resect tissue if necessitated by teratoma formation. One reviewer concurred, noting that cell therapy was particularly attractive for left TLE given the reluctance to perform surgery in this region. Another reviewer reiterated that knowledge derived from this proposal could be applied to other neurological disorders involving overexcitation, including spasticity. The motion carried.