PTPσ and Spinal Cord Injury

Protein tyrosine phosphatase sigma (PTPσ) is a key neural receptor that inhibits nerve regeneration resulting in a loss of function in patients with spinal cord injury (SCI) and other medical conditions. Activation of the PTPσ receptor through the binding of chondroitin sulfate proteoglycan (CSPG – an extracellular molecule upregulated at sites of neuronal injury) is a key mediator of regeneration and remyelination failure of damaged nerves. Inhibition of PTPσ causes a cascade of downstream effects resulting in activation of growth-promoting pathways and the release of enzymes that break up inhibitory CSPGs, resulting in new and enhanced nerve growth, significant improvements of nerve function, and clinically relevant sensorimotor recovery in animal models for various indications.

The scientific evidence of PTPσ as the target for nerve regeneration following axonal damage, and the potential for NVG-291 treatment to reverse it, is well supported from nonclinical efficacy models.

Rodent animal models of SCI in three independent labs all showed that binding of NVG-291-R (a close analog to NVG-291) to PTPσ led to blockage of the signaling cascade associated with CSPG binding in turn leading to alleviation of the symptoms of SCI such as return of locomotor and urinary functions1–4. The findings in SCI models were bolstered with similar reversal of nerve injury and enhanced physiological recovery in acute myocardial infarction 5–7  ventral nerve root avulsion8, dorsal nerve root crush9, enhanced remyelination in a rodent MS models 10,11 and SCI model 12, and immune modulation in SCI models13.  NVG-291-R’s modulation of PTPσ also has effects within the peripheral nervous system (PNS). The root avulsion and root crush models data as well as the acute myocardial infarction data support the ability of NVG-291-R to facilitate nerve regeneration and functional recovery following peripheral nerve injury. 

Notable NVG-291-R results and attributes from these preclinical studies include:

  • Locomotive recovery with a significant subset of spinal cord injured animals achieving near complete recovery
  • 100% of spinal cord injured animals experienced partial to complete recovery of bladder function at the higher doses tested
  • The results were reproduced in multiple studies, labs and preclinical models, including several separate spinal cord injury studies
  • Functional improvement in locomotive and bladder functions was lasting and durable, even after a finite period of daily injections
  • NVG-291-R was found to be relatively simple and non-invasive to administer

 

Illustrative samples of the peer reviewed preclinical data collected using the PTPσ inhibitor, ISP, are shown below:

Figure 1 – Improvements in the BBB score. Two Different Doses of NVG-291-R Compared to Placebo

The Basso, Beattie, Bresnahan (“BBB”) rating score14 is an objective locomotor measures commonly used to assess locomotor recovery in preclinical models.   This assessment measures the ability for the rodent to move their hindlimbs, support their weight, and walk.  A locomotor BBB score of 21, corresponding to normal locomotion, were recorded in rodents prior to injury.  With no treatment, animals recover to a BBB score of about 7 after twelve weeks of recovery, corresponding to no weight support stepping of the hindlimbs.  After seven weeks of daily treatment with NVG-291-R, animals displayed weight bearing and coordinated locomotion, corresponding to a BBB score of 15-19. Compared to non-treated rodents, the treated animals had remarkable improvement in BBB scores of 8-12 points4. It should be noted that even though the treatments were halted on week 7, improvements continued and were persistent to the end of the experiment on week 12. Error bars show standard deviation. * and # P < 0.05

Figure 2 – Improvements in Gridwalk Locomotor Test,  NVG-291-R Compared to Placebo

The Gridwalk test15 is an objective locomotor measurement commonly used to assess locomotor recovery in preclinical models. This assessment measures the ability for rodents to accurately walk and balance on an elevated wire grid. Non-injured animals walk and balance on the wire grid with few to no missteps. Twelve weeks following injury non-treated animals typically made an average of over 5 missteps per meter traveled.  After 7 weeks of daily treatment with NVG-291-R, treated animals displayed significantly fewer missteps at 12 weeks post injury.  Error bars show s.e.m. ****P < 0.0001

Figure 3 – Bladder Function in Response to Treatment with NVG-291-R

Recovery of urinary bladder function is a critical issue in the management of paralyzed patients. Eliminating or reducing catheterization may reduce urinary tract infections, hospitalizations, morbidity and healthcare cost. Improvement in bladder function was observed in a dose dependent manner as published in Nature in 2015.2 In the two highest dose groups, improvements were observed in 100% of the animals. Improvement in bladder function was also observed in the Rink et al study from 2018.5 

A list of select scientific publications that give a robust overview of the effects of NVG-291 seen in animal models is provided in Notitia, or date center, which can be accessed here.

References

  1. Lang BT, Cregg JM, DePaul MA, Tran AP, Xu K, Dyck SM, et al. Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury.
  2. Ham TR, Pukale DD, Hamrangsekachaee M, Leipzig ND. Subcutaneous priming of protein-functionalized chitosan scaffolds improves function following spinal cord injury. Materials Science and Engineering: C. 2020 May 1;110:110656.
  3. Ham TR, Farrag M, Soltisz AM, Lakes EH, Allen KD, Leipzig ND. Automated Gait Analysis Detects Improvements after Intracellular σ Peptide Administration in a Rat Hemisection Model of Spinal Cord Injury. Ann Biomed Eng. 2019 Mar 1;47(3):744–53.
  4. Rink S, Arnold D, Wöhler A, Bendella H, Meyer C, Manthou M, et al. Recovery after spinal cord injury by modulation of the proteoglycan receptor PTPσ. Experimental Neurology. 2018 Nov 1;309:148–59.
  5. Johnsen D, Olivas A, Lang B, Silver J, Habecker B. Disrupting protein tyrosine phosphatase σ does not prevent sympathetic axonal dieback following myocardial infarction. Experimental Neurology. 2016 Feb;276:1–4.
  6. Gardner RT, Wang L, Lang BT, Cregg JM, Dunbar CL, Woodward WR, et al. Targeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias. Nature communications. 2015 Feb;6(1):6235.
  7. Sedaghat G, Gardner RT, Kabir MM, Ghafoori E, Habecker BA, Tereshchenko LG. Correlation between the High-Frequency Content of the QRS on Murine Surface Electrocardiogram and the Sympathetic Nerves Density in Left Ventricle after Myocardial Infarction: Experimental Study. J Electrocardiol. 2017;50(3):323–31.
  8. Li H, Wong C, Li W, Ruven C, He L, Wu X, et al. Enhanced regeneration and functional recovery after spinal root avulsion by manipulation of the proteoglycan receptor PTPσ. Scientific Reports. 2015 Oct 14;5(1):1–14.
  9. Yao M, Sun H, Yuan Q, Li N, Li H, Tang Y, et al. Targeting proteoglycan receptor PTPσ restores sensory function after spinal cord dorsal root injury by activation of Erks/CREB signaling pathway. Neuropharmacology. 2019 Jan 1;144:208–18.
  10. Luo F, Tran AP, Xin L, Sanapala C, Lang BT, Silver J, et al. Modulation of proteoglycan receptor PTPσ enhances MMP-2 activity to promote recovery from multiple sclerosis. Nature Communications. 2018 Oct 8;9(1):1–16.
  11. Niknam P, Raoufy MR, Fathollahi Y, Javan M. Modulating proteoglycan receptor PTPσ using intracellular sigma peptide improves remyelination and functional recovery in mice with demyelinated optic chiasm. Molecular and Cellular Neuroscience. 2019 Sep 1;99:103391.
  12. Dyck S, Kataria H, Akbari‐Kelachayeh K, Silver J, Karimi‐Abdolrezaee S. LAR and PTPσ receptors are negative regulators of oligodendrogenesis and oligodendrocyte integrity in spinal cord injury. Glia. 2018;67(1):125–45.
  13. Dyck S, Kataria H, Alizadeh A, Santhosh KT, Lang B, Silver J, et al. Perturbing chondroitin sulfate proteoglycan signaling through LAR and PTPσ receptors promotes a beneficial inflammatory response following spinal cord injury. Journal of Neuroinflammation. 2018 Mar 20;15(1):90.
  14. Basso DM, Beattie MS, Bresnahan JC. A sensitive and reliable locomotor rating scale for open field testing in rats. Journal of neurotrauma. 1995 Feb;12(1):1–21.
  15. Prakriya M, McCabe PM, Holets VR. A computerized grid walking system for evaluating the accuracy of locomotion in rats. J Neurosci Methods. 1993 Jun;48(1–2):15–25.