NervGen’s core technology was developed in the laboratory of Dr. Jerry Silver, a renowned spinal cord injury and regenerative medicine researcher and Professor of Neurosciences at Case Western Reserve University (CWRU) in Cleveland, Ohio. Dr. Silver’s research focuses on the glial scar which forms at sites of a physical injury such as spinal cord injury, as well as sites of inflammatory damage from neurodegenerative diseases such as multiple sclerosis and Alzheimer’s disease.
Dr. Jerry Silver
Listen to inventors Drs. Jerry Silver and Bradley Lang describe their groundbreaking work at CWRU
The Glial Scar and Chondroitin Sulfate Proteoglycans (CSPGs)
Injury or disease to the central nervous system (CNS) results in multifaceted cellular and molecular responses. One such response, the glial scar, 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 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.
Pictorial Representation of the Glial Scar
Cregg et al., 2014, Experimental Neurology1
The Neural Receptor for CSPGs – Protein Tyrosine Phosphatase Sigma (PTPσ)
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.
NVG-291-R (also known as ISP)
Multiple studies with animal models for several diseases and medical conditions have shown that treatment targeting PTPσ receptors with a compound developed by Dr. Silver and his research team, NVG-291-R (also called intracellular sigma peptide, or ISP in publications), 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; Luo et al. 2018, Nature Communications ). NervGen licenced the intellectual property underpinning this research from Case Western Reserve University and is now developing NVG-291-R as the basis for its core technology. NervGen’s lead product, NVG-291, is a close analog to NVG-291-R.
Since the original discovery of NVG-291-R, the compound has been studied further by Dr. Silver and his collaborators, by NervGen and by a number of independent laboratories. There is now a large body of evidence to indicate that NVG-291-R’s mechanism for nerve repair is mediated by a number of endogenous repair mechanisms, including regeneration, plasticity, remyelination, immune modulation and synapse formation. Furthermore, these repair mechanisms seem to be helpful in treating nerve damage associated with both nerve injury (spinal cord injury, peripheral nerve injury, traumatic brain injury, and stroke) and with neurodegenerative diseases (multiple sclerosis, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson’s disease).
- Cregg, J.M., DePaul, M.A., Filous, A.R., Lang, B.T., Tran, A., and Silver, J. (2014). Functional regeneration beyond the glial scar. Experimental Neurology 253, 197–207.
- Shen, Y., Tenney, A.P., Busch, S.A., Horn, K.P., Cuascut, F.X., Liu, K., He, Z., Silver, J., and Flanagan, J.G. (2009). PTPσ Is a Receptor for Chondroitin Sulfate Proteoglycan, an Inhibitor of Neural Regeneration. Science 326, 592–596.
- Lang, B.T., Cregg, J.M., DePaul, M.A., Tran, A.P., Xu, K., Dyck, S.M., Madalena, K.M., Brown, B.P., Weng, Y.-L., Li, S., et al. (2015). Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury. Nature 518, 404–408.
- Gardner, R.T., Wang, L., Lang, B.T., Cregg, J.M., Dunbar, C.L., Woodward, W.R., Silver, J., Ripplinger, C.M., and Habecker, B.A. (2015). Targeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias. Nature Communications 6, 6235.
- Li, H., Wong, C., Li, W., Ruven, C., He, L., Wu, X., Lang, B.T., Silver, J., and Wu, W. (2015). Enhanced regeneration and functional recovery after spinal root avulsion by manipulation of the proteoglycan receptor PTPσ. Scientific Reports 5, 1–14.
- Rink, S., Arnold, D., Wöhler, A., Bendella, H., Meyer, C., Manthou, M., Papamitsou, T., Sarikcioglu, L., and Angelov, D.N. (2018). Recovery after spinal cord injury by modulation of the proteoglycan receptor PTPσ. Experimental Neurology 309, 148–159.
- Luo, F., Tran, A.P., Xin, L., Sanapala, C., Lang, B.T., Silver, J., and Yang, Y. (2018). Modulation of proteoglycan receptor PTPσ enhances MMP-2 activity to promote recovery from multiple sclerosis. Nature Communications 9, 1–16.