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Mervyn Rothstein




Cory R. Nicholas Ph.D.






Cory R. Nicholas, Ph.D., is a Founder and the Chief Executive Officer of Neurona Therapeutics. He is also an adjunct Assistant Professor at the University of California, San Francisco. Before co-founding Neurona, Dr. Nicholas was a faculty member in the Department of Neurology at the University of California, San Francisco, where he studied brain development.

Dr. Nicholas pioneered methods to obtain inhibitory nerve cells, or interneurons, from human stem cells that were capable of being transplanted into multiple animal models of neurological disease. Neurona was conceived in 2008 to investigate the potential of inhibitory interneuron cell-based therapy to treat chronic disorders of the nervous system, including neuropathic pain. Dr. Nicholas and his co-founders, John Rubenstein, M.D., Ph.D., Arturo Alvarez-Buylla, Ph.D., and Arnold Kriegstein, M.D.,Ph.D., were the first to discover that this type of cell therapy could inhibit and rebalance hyper-excitable neural networks in animal models of relevant neurological disorders – that the injected interneuron precursor cells could integrate into neural circuitry, allowing for stable repair of the injured nervous system.

The Facial Pain Research Foundation recently agreed to finance a cooperative research project between Neurona and the University of Florida’s McKnight Brain Institute to test whether the Neurona interneuron cell therapy can stop neuropathic facial pain in animals. The study should take from 12 to 24 months. If it is successful, Neurona plans to work toward Food and Drug Administration approval to begin clinical trials in humans in the future. 

Dr. Nicholas spoke by telephone from California with Mervyn Rothstein, who was an editor and writer at The New York Times for nearly 30 years before retiring in 2010. Mr. Rothstein has also written for Playbill Magazine, and now, since 1991. He currently writes the Stage Directions column for the Playbill web site. He was diagnosed with Trigeminal Neuralgia in 2005. Dr. Nicholas spoke about his research, Neurona, the agreement with the Facial Pain Foundation, and his future hopes.

Why did you decide to focus on pain in your career?

I’m a neurobiologist and I was studying brain development, specifically the development of inhibitory nerve cells that are the basis of the collaborative work with the Foundation. We have a close colleague at the University of California at San Francisco, Allan Basbaum, Ph.D., who was very interested in seeing if these inhibitory cells could be applied to the treatment of neuropathic pain. So our groups joined forces, and Dr. Basbaum’s laboratory pioneered the application of the inhibitory interneuron transplants that we were studying in the rodent brain and applied them to the spinal cord in rodent models of neuropathic pain. And he was able to show that the transplantation of those neurons could ameliorate and in some cases completely reverse the experimental pain hypersensitivities in animal models. In part because the results were so exciting, we decided to launch a neuropathic pain program at the company.

What is the importance of this Trigeminal Neuralgia research study?

I think this is a tremendous opportunity to build upon the work from Dr. Basbaum and our group, to leverage the resources and expertise from the Foundation and translational savvy Neurona, and to determine whether the human interneuron cell therapy is feasible, safe, and effective in an animal model of Trigeminal Neuralgia. One of the reasons we weren’t able to do this on our own is that we didn’t have access to an animal model of this disease. These animal models are quite nuanced and can be difficult to establish from scratch. Then, we were introduced by the Foundation to Dr. John Neubert at the University of Florida, who has this model established in his laboratory and developed behavioral tests to measure experimental facial pain in rodents. Thankfully Michael Pasternak and the Foundation were able to make that introduction.

We submitted a proposal to the Foundation that was just funded where we will do three things. Number one, we can see if the pain phenotype – the observable pain characteristics – can be extended to an animal that does not have an active immune system. We need an animal model that does not have a functioning immune system to allow for the long-term persistence of the human cell therapy in a rat. So we had to change the animal strain – that is the first aim, to see if we can produce a stable pain phenotype in an immunodeficient animal model of Trigeminal Neuralgia.

The second aim is to see whether our human interneuron cells could be delivered into the rat model using neurosurgical stereotaxis – a method of locating points within the nervous system – specifically into the regions where we think the pain triggers are in this disease, to see if those cells will persist long-term in the rodents, and whether the human cell therapy is safe.

And then finally, if we succeed with the first two aims, to next determine whether the human interneuron cell therapy can exhibit disease-modifying activity and compelling pain reduction in this rodent model. If we successfully accomplish these aims, then I think we can justify the pursuit of a future clinical trial in humans for treatment of drug-resistant, intractable Trigeminal Neuralgia. And of course we then have to work with the Food and Drug Administration to run a battery of safety and toxicology studies before we could consider proposing a first clinical trial. But those would be the next steps.

How would you describe the work being done at Neurona and its future and its progress?

Neurona is a pre-clinical stage biotechnology company developing neural cell therapies for the treatment of chronic diseases affecting the nervous system. Our lead product is a cellular therapeutic comprised of inhibitory nerve cells that we are developing for chronic focal epilepsies, neuropathic pain syndromes, and neurodegenerative diseases such as Parkinson’s. We are planning to launch our first clinical trial for epilepsy next year. Neurona now has ~50 employees who are passionately working around the clock to advance our novel cell therapies into the clinic. We are fully committed to creating safe and effective cell therapies for chronic disorders of the nervous system through rigorous science, collaborative innovation, and groundbreaking regenerative technology. 

When do you envision (or hope) that cell-replacement treatments for neuropathic pain (including Trigeminal Neuralgia) will be tested on humans and eventually be ready for use in humans?

The first study in rodents with Dr. Neubert is between one and two years long. And then it would probably be another two to three years of working with the FDA before a first-in-human clinical trial could be considered.

What are the biggest obstacles that you face in translating your preclinical findings to the clinic?

That’s a really good question. It’s one that is common not just to pain but to just about any disease, especially in the neurological space because rodents are different from humans in many aspects. There are different anatomies, different neural circuitries, and the added difficulty with studying pain in animals, where you don’t typically know how an animal such as a rodent is feeling. Since a rodent can’t tell us if they are in pain, we use surrogate measures of aversive behavior or hypersensitivities, such as how the animals are moving their limbs or responding to stimuli. Those surrogates are of course never the same thing as asking a person if they’re experiencing pain.

The Facial Pain Research Foundation is moving forward with a sense of urgency to find cures for Trigeminal Neuralgia and related neuropathic pain.  Why have you linked your efforts to such a new organization in the field of pain research?

We were looking for ways to apply our regenerative cell technology as a therapeutic for people living with devastating, treatment-resistant diseases. Pain had been an important potential indication for the company. Through the Foundation, we then heard the stories of people who are suffering with Trigeminal Neuralgia. It really pulls at your heartstrings, and you want to do whatever you can to help. Additionally, Trigeminal Neuralgia may be a rational indication for a restorative cell therapy. Neurona’s cell therapy is administered locally. In Trigeminal Neuralgia, there’s a focus of pain in the facial region that may be triggered in the trigeminal ganglion and may serve as a good target for local injection of the cell therapy.

However, the causes of chronic neuropathic pain are still quite controversial in the field and nobody knows for sure. It gets back to your question about what makes it difficult to translate preclinical research to humans. Another important aspect as to why this is a tough bridge is that it is challenging to establish a relevant and predictive animal model when we don’t really know yet what causes this disease. It is therefore not surprising that most drugs that work in animal testing often do not work in humans.

Every day many people are contacting the Facial Pain Research Foundation asking if it is truly possible to find a cure for Trigeminal Neuralgia. How would you respond to their questions?

Absolutely I think it’s possible. And I think the Foundation is funding some tremendous work. The Foundation has wisely spent its dollars on leading-edge research to understand the causes of the disease, looking very carefully at human genetics, and complementing this basic understanding with attempts at a cure using gene therapy, and cell therapy approaches, like ours. So I think there have been very rationally thought-out efforts to try to better understand and treat the disease, and we remain hopeful that a cure is possible.

What keeps you awake at night?

Other than the global pandemic now upon us, fundraising is paramount. Drug development is a slow and expensive business, especially for cell therapies. This is why we are so grateful to the Foundation for supporting the proof-of-concept study with John Neubert to determine whether the inhibitory neuron cell therapy can be efficacious in rodents. The Foundation has done a terrific job in seeding projects like these to take that important first step. If successful, we will need to raise additional funds to march this therapy toward a potential first clinical trial in human.

Beyond fundraising anxiety, it is always whether or not we will be able to build safe and effective therapies that can truly make a difference to significantly improve quality of life and revolutionize medical treatment for those living with chronic diseases. To achieve this ultimate goal, it will take all stakeholders working together, from researchers and clinicians, to investors and regulatory bodies, to patient advocates like you. I sincerely hope and expect that we will succeed.


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