Industry Matters: NervGen targets glial scars to treat Alzheimer’s.

NervGen is a biotech company dedicated to discovering and developing treatments for patients suffering from medical conditions related to nerve damage.

NervGen’s core technology targets protein tyrosine phosphatase sigma (PTPσ), a neural receptor that impedes nerve regeneration, remyelination and plasticity. Inhibition of the PTPσ receptor has been shown to promote regeneration of damaged nerves and improvement of nerve function in animal models for various indications.

The company’s president and CEO, Paul Brennan, set aside some time to discuss NervGen’s technology and bright future with SCINQ.


There’s a very personal story at the heart of NervGen’s formation. Can you discuss why and how the company was created?

In March 2016, Codi, the daughter-in-law of Dr. Harold Punnett, one of NervGen’s co-founders, became a complete T-11 paraplegic after a tragic fall. She has no sensation or function below the level of her belly button and the devastating injury changed the lives of Codi, and the rest of the family.

In response to this terrible injury, Dr. Punnett began a personal quest to learn about spinal cord injury. Through his research, he discovered a revolutionary nerve regeneration technology of deep biological logic in Dr. Jerry Silver’s work at Case Western Reserve University (“CWRU”). Dr. Silver and Dr. Punnett began a conversation that resulted in the formation of NervGen Pharma Corp.

Although the company was initially founded upon looking for a treatment in spinal cord injury, we now see that the technology can potentially be applied any time there is nerve damage, whether as part of an acute injury, or a neurodegenerative disease, and we’re very excited to try to recognize the full potential of the technology for help patients with nerve damage.

Treating permanent nerve damage is at the heart of NervGen’s focus. Can you briefly describe the science behind nerve damage, in particular the role of protein tyrosine phosphates sigma?

Injury or disease to the central nervous system (“CNS”) results in multifaceted cellular and molecular responses; the type of response depends upon the type of nerve damage that occurs (i.e. is it a result of trauma or a neurodegenerative disease).

In the case of spinal cord injury, the response is the formation of a glial scar, which is a structural formation of reactive glia (cells) around an area of severe tissue damage. The purpose of the scar is to encapsulate the site of the injury to prevent further damage and to begin the healing process, but it ultimately inhibits the body’s reparative mechanisms.

The lead inventor of NervGen’s technology, Dr. Silver, discovered that a constituent of these scars, a glycoprotein called chondroitin sulfate proteoglycan (“CSPG”), is a major inhibitor of the body’s natural ability to regrow and regenerate the CNS. Dr. Silver, together with scientists at Harvard University, identified protein tyrosine phosphatase sigma (“PTPσ”) as a key neural receptor that binds with the CSPGs in the glial scar (Shen et al., 2009, Science). Dr. Silver’s research showed that PTPσ impedes nerve regeneration through its activation upon binding to CSPGs in the glial scar.

As we learn more about the role of CSPGs and PTPσ we see that CSPGs are not just present in glial scars in spinal cord injuries, but they are also present in most types of nerve damage, including around the scar tissue that forms around demyelinated axons in multiple sclerosis, and around the neurofibrillary tangles and senile plaques found in Alzheimer’s disease.

NVG-291 is the primary drug candidate in NervGen’s pipeline. How was it discovered and what is its promise as a nerve damage therapeutic?

NVG-291 was discovered in the labs of Dr. Silver through a rational design process. It’s designed with two components; the first component, a peptide mimetic of the wedge domain of the PTPs receptor, was designed to inhibit the activity of PTPσ. The second component is a transporter, designed specifically to facilitate translocation across the blood brain barrier and the cell membrane of neuronal tissue.

The promise of NVG-291 as a nerve damage therapeutic is very exciting. As a PTPs inhibitor, NVG-291 was designed to inhibit the interaction between PTPs and CSPGs. As mentioned above, the inhibition of the interaction between PTPσ and CSPGs was originally hypothesized to promote nerve growth in systems where nerve growth is inhibited, such as in damage to the spinal cord. However, since then we have discovered that PTPs inhibition has several additional modes of action, including remyelination, increased plasticity, increased autophagy, and promoting a non-inflammatory phenotype in the innate immune system.

All these modes of action suggest that NVG-291 has the potential to have an effect any time there is nerve damage, whether it’s a result of trauma, such as in spinal cord injury, traumatic brain injury or stroke, or as a result of neurodegenerative diseases, such as Alzheimer’s disease, multiple sclerosis, motor neuron disease (for example, ALS), and Parkinson’s disease.

One of the potential uses of NVG-291 is in treating Alzheimer’s Disease. Would its activity be against plaque formation or neurofibrillary tangles? How could it potentially help?

The potential for NVG-291 in Alzheimer’s disease is really exciting and is based on both the pharmacodynamic response seen with NVG-291 in preclinical studies, and observations that have been seen regarding the role of CSPGs and the PTPσ receptor in Alzheimer’s disease studies.

The pharmacodynamic effects of nerve regeneration, remyelination, increased plasticity and autophagy (a natural cellular mechanism that removes unnecessary or dysfunctional components) and promotion of a non-inflammatory phenotype of the microglia in the CNS are all responses that would be expected to be beneficial for Alzheimer’s disease patients. 

Additionally, the role of both CSPGs and PTPs in Alzheimer’s disease have been directly demonstrated in patients and in preclinical studies. For example, an upregulation of CSPGs has been demonstrated in Alzheimer’s disease patients and is correlated with cognitive decline. In preclinical studies, CSPGs have been demonstrated to form around the senile plaques that are characteristic of Alzheimer’s disease patients and breaking down the CSPGs improves cognitive function. Knockout models of PTPσ demonstrate that PTPσ deficiency results in fewer amyloid beta plaques and PTPσ deficiency rescues cognitive deficits in Alzheimer’s disease mice models.

Although we have a lot of evidence suggesting that PTPσ inhibition will be beneficial in Alzheimer’s disease patients, we haven’t yet completed any studies with NVG-291. Last year we prioritised Alzheimer’s disease as one of our development indications; we intend to report results from our first preclinical results in Alzheimer’s disease models in 2021.

NervGen and NVG-291 are currently in the pre-clinical stage. As a CEO leading his company through the challenges of not just the scientific aspects of R&D but also the administrative and financial, do you find it difficult juggling the various hot potatoes that could make or break the company?

In a small company there are definitely a lot of balls in the air, and you have to be able to quickly switch between thinking about financing strategies, clinical design, manufacturing, intellectual property, legal, accounting and then the science behind your target and the related diseases.

Fortunately, I’m lucky to have had a diverse career where I’ve been exposed to all these issues, working first in international regulatory affairs at AstraZeneca, and then in business development at Astra and various biotech companies. Also, it really helps that we have great people at NervGen that drive these issues and who are the real experts. 

The clinical trials process and various regulatory steps post-trials are notoriously expensive and at times labyrinthine. How do you prepare for an obstacle course that is clearly in the horizon?

Having access to capital is key to financing our Phase 2 trials. There are three approaches that we will explore: (i) grants from governments and non-profit organizations, (ii) partnerships with pharma, and (iii) equity financings. Each approach has its pros and cons; for example, grants can be a great source of cash, but they can also slow your program considerably, and are generally not advised for critical path activities. The approach that we take will likely be a combination of two or more of the above, and will be weighed based on the opportunities presented to us, the speed that each opportunity provides for development, and the value each opportunity provides to shareholders 

You are at the helm of a company that can potentially contribute a drug that can help ease a debilitating disease to society. Is this where you’ve always imagined yourself?

I’ve been lucky in my career to be involved in several truly impactful drugs that have gone from development stage to approval, including foscavir, one of the first HIV drugs, budesonide nebulising suspension, the first nebulizable steroid which provided for administration of inhaled steroids to newborns and children under 3 years old, and Mozobil®, a stem cell mobiliser, that greatly improved a patient’s probability of being able to undergo stem cell transplants. It’s very gratifying to be involved in the process, and success is always is a team effort with several key players.

After I left big pharma, I always had the goal of leading a biotech company as one of my ambitions. However, even with the great experiences that I’ve had to date, I feel really lucky to be leading a company that could truly redefine therapy in the field of nerve damage.

Lastly, science and business are two areas with tremendous highs but also trench-deep lows. Is it all worth it?

Absolutely. Science is the antidote to the curios and rational mind, and business is a way to apply scientific discoveries to practical application. I’ve been working in the business of science for my entire career and can’t imagine doing anything else that would be as satisfying.

For more information, visit NervGen.


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