Dr. Jerry Silver on Spinal Cord Injury and Emerging Treatments

July 8, 2019

Imagine an injectable peptide that allows a paralyzed rat to walk again! What sounds like science fiction is here today with a new treatment for spinal cord injuries discovered by Dr. Jerry Silver, Professor of Neurosciences at Case Western Reserve University’s School of Medicine and advisor for NervGen PharmaClick to see a video featuring paralyzed rats, treated with NervGen’s proprietary peptides, that are able to walk again.

Dr. Jerry Silver

We sat down with Salonpas Wellness Warrior, Dr. Jerry Silver, advisor to NervGen Pharma, to learn more about his work in the spinal cord injury arena:

What is the core mission of NervGen Pharma?

NervGen Pharma is restoring life’s potential by creating innovative solutions for the treatment of nerve damage.

NervGen’s core technology focuses on the protein tyrosine phosphatase sigma (PTPσ), a key neural receptor that inhibits nerve regeneration resulting in a loss of function in patients with spinal cord injury and other medical conditions.  Inhibition of the PTPσ receptor has been shown to promote regeneration of damaged nerves and improvement of nerve function in animal models for various medical conditions.  A series of receptor antagonists have been identified including a lead candidate ready for clinical development.  NervGen plans to advance the lead candidate into the clinic initially for the treatment of spinal cord injury while exploiting the technology to identify additional therapeutic candidates for other related medical conditions. 

How many people suffer from spinal cord injuries (SCI) and peripheral nerve damage in the United States?

Injuries to the spinal cord can cause permanent paralysis and even lead to death with little to no hope of regaining lost functions once the trauma has occurred. Every year, from 12-17,000 people suffer a debilitating spinal cord injury in the United States with about 300,000 people living with permanent paralysis.  Every year about 1.4 million people suffer a traumatic peripheral nerve injury in the United States. The intricate, delicate structures that make up the nervous system, the body’s command center, — the brain, spinal cord and peripheral nerves — are vulnerable to injury ranging from trauma to neurodegenerative diseases that cause progressive deterioration: Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), multiple sclerosis and multiple system atrophy.

Due to the complexity of the brain and spinal cord, little spontaneous regeneration, repair or healing occurs. Therefore, brain damage, paralysis from spinal cord injury and peripheral nerve damage can be permanent and debilitating.

Nerve damage, from loss of sensation to paralysis, occurs with physical traumas such as car accidents and combat injuries as well as medical procedures such as surgery. It also occurs with multiple sclerosis, heart attack induced arrythmia, Alzheimer’s disease, stroke and other diseases and traumas in which the nerves are damaged. Millions of individuals are affected globally and hundreds of billions of healthcare dollars are spent to manage medical conditions arising from nerve injury. There are currently no drugs available to regenerate injured nerves and allow the individual to regain or improve key bodily functions.

What is the origination of NervGen Pharma’s spinal cord regeneration technology?

The protein tyrosine phosphatase sigma (PTPs) inhibitor technology originated from my research at Case Western Reserve University (CWRU).   Over several decades, my team and I have been researching the glial scar and the inability of axons to regenerate across scar areas following nerve damage.  We identified the role of chondroitin sulphate proteoglycan (CSPG) in stopping nerve growth across scar tissue and then, in collaboration with Dr. Flanagan at Harvard, identified PTPs as the neural receptor which binds to the CSPG in the scar.  My research team then identified a series of peptide antagonists that block the CSPG signaling through this receptor resulting in axon regrowth and functional improvement in animal models.

Multiple studies with animal models for several diseases and medical conditions have shown that treatment targeting PTPσ receptors with the compound we developed known as Intracellular Sigma Peptide (“ISP”), promoted regeneration of damaged nerves and improvement in function (Lang et al, 2015, Nature), (Gardner et al, 2015, Nature Communications),  (Li, H. , 2015, Scientific Reports),  (Rink et al. 2018, Experimental Neurology),  and (Luo et al. 2018, Nature Communications). This work has been replicated independently numerous times by other researchers.

What is protein tyrosine phosphatase sigma (PTPσ)?

Protein tyrosine phosphatases (PTPs) form a large and diverse molecular family and have a structure typical of transmembrane cell-surface receptors. They are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins. PTPs regulate the phosphorylation state of many important signaling molecules.

PTPσ is in the leukocyte antigen-related (LAR) subfamily of PTPs.  Collaboration between my Case Western lab and Dr. Flanagan’s Harvard lab (confirmed that PTPσ is the receptor for CSPG and is the inhibitory mechanism by which CSPG inhibits axonal regeneration.

What are the outstanding features of this technology?

The compelling features of the technology, as found in animal testing include:

  • The remarkable recovery of locomotion with a significant subset of animals recovering fully even in very severe spinal cord injury (SCI) models.
  • The animals recovered voluntary bladder function, a critical unmet medical problem associated with SCI.
  • The results were reproduced in multiple studies, labs and models – robust, reproducible data.
  • It is relatively simple and non-invasive to administer with a limited period of daily injections. The technology could be used days or weeks after injury which is a major advantage relative to many potential technologies under development in terms of competitive advantage and also in the execution of clinical trials. Chronic SCI injuries are also a target for NVG-291.
  • There is a clear mechanism of action with a validated target – inhibition of receptor signaling.
  • There are broad potential applications wherever nerve damage has occurred.
  • It is easy and relatively inexpensive to manufacture.

Have peptides been successfully used as drugs before?

Yes, peptides have been successfully developed and approved as drugs.  As of March 2017, 68 peptides have been approved in the United States, Europe, and Japan. 155 peptides are in active clinical development, just under half of which are currently in Phase 2 studies.  Peptides have been approved across multiple disease areas.  Examples of approved peptides include Carfilzomib (Kyprolis) which was approved in 2012 for cancer treatment, plecanatide which was approved in 2017 for chronic idiopathic constipation and abaloparatide which was approved in 2018 for osteoporosis. 

NervGen plans to manufacture its peptide through established chemical processes at GMP manufacturing facilities setup for peptide synthesis.

In addition to NVG-291, we have gained access to other peptides from CWRU and is also working to synthesize and evaluate new peptide inhibitors of PTPs.

What are the advantages and disadvantages of peptides as drugs?

Peptide therapeutics have played a notable role in medical practice since the advent of insulin therapy in the 1920s.  The utilization of peptides as therapeutics has evolved over time and continues to evolve with changes in drug development and treatment paradigms.  Peptides, such as insulin and ACTH were originally isolated from natural sources, providing life-saving medicines in the first half of the 20th century.  When sequence elucidation and chemical synthesis of peptides became feasible in the 1950s, synthetic peptides began to be developed and approved as drugs.  The genomic era allowed for the identification and molecular characterization of receptors for many important endogenous peptide hormones enabling scientists to pursue novel peptidic ligands for these receptors.  Peptidic drugs are well suited to match the peptide sequences within the binding sites of these receptors.  Peptide drug candidates are being generated against a range of molecular targets that reach beyond historically dominant extracellular receptors. Peptides have been shown to disrupt protein-protein interactions, target receptor tyrosine kinases and inhibit intracellular targets better.  Unlike small molecule drugs, issues such as CYP inhibition leading to drug-drug interactions (DDIs,) and side effects caused by off target binding, are less of an issue for peptides.

There are general disadvantages to peptidic drugs such as short plasma half-life and negligible oral bioavailability.  These drugs cannot be administered orally. The relatively short half-life compared to other drugs would suggest that they may not be suitable in cases where sustained maximum inhibition of a target is required.  However, novel synthetic strategies have allowed for the modulation of pharmacokinetic properties and target specificity of peptides through amino acid or backbone modification, incorporation of non-natural amino acids, and conjugation of moieties that extend half-life or improve solubility.  Novel formulation strategies allow for reduced injection frequency and improve stability and other positive physical properties. 

Are there any approved therapeutics to enhance nerve regeneration to-date?

There are currently no approved drugs that regenerate nerves.  Some medical devices or autogenic/allogenic grafts have been approved for treating nerve injury but there is no approved drug that is able to regenerate axons.  To our knowledge, no other agents have demonstrated the magnitude of nerve regeneration capability of this technology in so many different animal models of different diseases and medical conditions.  We believe this technology could revolutionize the treatment of nerve injury across multiple indications.