Neurona was conceived in 2008 to realize the therapeutic potential of neuronal cell-based therapy. The rationale for pursuing this translational effort was based on many years of rigorous scientific discovery. In the late 1990’s, co-founders John Rubenstein, MD, PhD, and Arturo Alvarez-Buylla, PhD, were among the first to demonstrate that interneurons, a type of nerve cell, in the cerebral cortex mostly originate from precursor cells in the medial ganglionic eminence (MGE), a transient structure during fetal brain development. In these early studies, MGE cells were isolated from fetal mouse brain and injected into the brains of post-natal mice. In contrast to other neural stem and progenitor cells from neighboring fetal brain regions that remained as large cellular masses post-injection, the MGE cells rapidly dispersed away from the injection site and appeared to seamlessly integrate into juvenile and adult mouse recipient brain tissue. The injected MGE cells appropriately matured into various sub-lineages of cortical interneurons that secreted GABA, the major inhibitory neurotransmitter in the central nervous system. Electrophysiology confirmed these cells to be functional neurons that both received and formed synapses, validating their integration post-transplant. The interneurons persisted long-term following transplantation. Moreover, the transplanted interneurons augmented functional inhibition in the brain regions where they were placed. Therefore, MGE interneuron precursor cells had unique properties that could be advantageous if developed into a transplantation cell-based therapeutic. These cells could potentially provide targeted inhibition to hyper-excitable neural networks in relevant neurological disorders. Rather than acting as a transient point source of GABA or a drug pump, the injected interneuron precursor cells integrated into neural circuitry, possibly allowing for stable repair of the injured nervous system.
To investigate the therapeutic potential of interneuron cell transplantation therapy, we first injected mouse MGE precursor cells into multiple rodent models of epilepsy, Parkinson’s, and Alzheimer’s disease. Although their etiologies are largely unknown and progression is divergent, these disorders can be associated with neural hyper-excitability and have overlapping co-morbidities. We collaborated with preclinical animal model experts in these disease areas, and, indeed, we found that the injected cells were effective. The injected MGE cells matured into inhibitory interneurons and virtually eliminated seizures, improved motor function, and reduced cognitive impairments, respectively.
In each of these animal models, the MGE cells were injected into forebrain regions where MGE-type interneurons would normally reside during endogenous brain development. To our surprise, the MGE cells also integrated into ectopic regions of the central nervous system, regions they do not normally populate during development. In collaboration with Allan Basbaum, PhD, mouse MGE cells were injected into the mouse spinal cord where they matured into inhibitory cortical-type interneurons and synapsed with resident spinal cord neurons. The mouse MGE cells were next injected into the mouse spinal cord after a sciatic nerve injury. Sciatic nerve injury produces chronic neuropathic pain that is associated with a loss of GABAergic inhibitory tone in key sensory pathways. This loss of inhibition leads to hyper-excitability of sensory neurons that send pain signals to the brain. The delivery of GABAergic inhibitory interneurons into the spinal cord was able to provide missing inhibition, rebalance sensory circuits, and suppress pain hypersensitivity. The transplanted interneurons achieved a complete rescue, reducing pain sensitivity to pre-injury levels without any observable side effects. Rather than a transient treatment of symptoms, the interneuron cell therapy was truly disease modifying by addressing the underlying pathophysiology of neuropathic pain following the administration of a single dose of cells. In addition, the disease modifying activity persisted long-term for six months post-transplantation, as long as was studied in a mouse. Dr. Basbaum’s laboratory has subsequently shown that interneuron cell therapy can be similarly effective at rescuing experimental pain hypersensitivity in mice following trigeminal nerve-injury or chemotherapy.
All of the studies above were performed with mouse MGE interneuron precursor cells. However, a human cell source is required to facilitate the translation of an interneuron therapeutic for patients. Since the MGE structure disappears before birth and human interneurons in the adult brain are not accessible, we turned to human pluripotent stem cell (hPSC) lines. These hPSC lines can be expanded to meet clinical demand and can be coaxed into becoming virtually any cell type in the body. We developed methods to direct hPSCs into the MGE-type interneuron lineage in petri dish cell cultures. These human interneurons produced in petri dishes were then isolated and provided to collaborators at UCSF for testing in many of the preclinical animal models described above. Encouragingly, Dr. Basbaum found that version 1.0 of the human interneurons also could reduce pain hypersensitivity in the sciatic nerve injury mouse model. Arnold Kriegstein, MD, PhD, in collaboration with another laboratory, next demonstrated that the human interneurons mitigated neuropathic pain and bladder dysfunction following spinal cord injury in mice.
Based on this body of work, Drs. Rubenstein, Alvarez-Buylla, Kriegstein, and I officially launched Neurona Therapeutics in early 2015 to develop neuronal cell-based therapeutics, starting with interneurons. We have assembled an all-star team of 35 researchers from around the world to advance this technology toward the clinic. We believe that multiple neurological disorders are associated with interneuron dysfunction and/or imbalances in neuronal activity. Because they do not innately regenerate, stem cell technology is required to generate inhibitory interneurons to re-balance the nervous system. Technology to produce human interneurons was developed at UCSF using research-grade stem cell lines, materials, and methods. The company is now tasked with extending this work and developing clinical-grade product candidates. We have made tremendous progress and continue to passionately pursue regenerative neuronal cell-based therapies with the potential to successfully treat patients who have neurological disorders.
The Facial Pain Research Foundation
Dr. Michael Pasternak and Elizabeth Cilker Smith introduced me to the Foundation. They were familiar with Neurona’s efforts from our collaboration with Dr. Basbaum. I was immediately impressed with the progress being made by the Foundation, its ability to raise important research dollars, and the selective investment of those funds into breakthrough facial pain research efforts that are making critical advances. I was equally struck by Michael and Beth’s passion, dedication, and determination to find a cure – attributes undoubtedly shared by all who contribute and volunteer at the Foundation and responsible for its success thus far.
Neurona and the FPRF share a bold vision to achieve pain-free disease modification. Neurona’s mission is, in part, an extension of Dr. Basbaum’s work funded by the FPRF. We continue to develop a human inhibitory interneuron therapeutic for the treatment of neuropathic pain syndromes. We are pleased to be formally acquainted with the Facial Pain Research Foundation and look forward to an ongoing relationship.
Cory R. Nicholas, PhD
Co-Founder and Chief Scientific Officer; Neurona Therapeutics
Assistant Professor, Adjunct; University of California, San Francisco
Dr. Cory Nicholas is Chief Scientific Officer at Neurona Therapeutics. Prior to co-founding Neurona, Dr. Nicholas was a faculty member in the Department of Neurology at the University of California, San Francisco where his research program was focused on investigating the ontogeny of human cortical interneurons. Dr. Nicholas pioneered methods to derive interneuron precursors from human pluripotent stem cells for transplantation into multiple animal models of neurological disease. He maintains an adjunct faculty appointment at the University. Dr. Nicholas’s post-doctoral studies were conducted at UCSF. His pre-doctoral work at both UCSF and Stanford University investigated germ cell development from primordial germline and pluripotent stem cells. He received his Bachelor’s degree from the University of California, Berkeley. Prior to his interest in stem cell and developmental biology, Dr. Nicholas was a member of the research team at Sugen.