PTPσ and Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune-mediated disease characterized by the loss of oligodendrocytes, demyelination, nerve damage, and irreversible neurological disability. Although remyelination can occur spontaneously, it ultimately fails in regions that develop scar-like plaques1. The underlying mechanisms of incomplete remyelination are still not fully understood; however, recent studies have identified the negative effects of chondroitin sulfate proteoglycans (CSPGs) that are upregulated during the scaring process in the central nervous system (CNS)2-3. CSPGs have been identified as a negative regulator of regeneration and remyelination in many different CNS pathologies, including MS4-6.

Within the CNS, CSPGs bind to and signal predominantly through the receptor protein tyrosine phosphatase sigma (PTPσ). PTPσ is expressed in neural stem cells, progenitor cells, including oligodendrocyte progenitor cells (OPCs), oligodendrocytes, astrocytes, and neurons7,9. CSPG activation of PTPσ inhibits remyelination, plasticity, and neural repair in MS and other CNS indications7,8,10.

NVG-291-R (also known as intracellular signalling peptide, or ISP) is a potent inhibitor of PTPσ. Inhibition of PTPσ with NVG-291-R in rodent models of multiple sclerosis and spinal cord injury was observed by researchers at Case Western Reserve University (CWRU) and their collaborators to

  • stimulate the production of OPCs11,
  • allow remyelination and regeneration of damaged nerves, and
  • increase specific proteases that digest and break down the glial scar tissue (CSPGs) that otherwise keep nerves from regenerating and oligodendrocytes from remyelinating7.

Remyelination and functional recovery following NVG-291-R treatment were tested in the experimental autoimmune encephalomyelitis (EAE) model of MS7. NVG-291-R or placebo was administered at the onset of clinical symptoms (onset group) or at the peak of clinical symptoms (peak group) until experimental endpoint at day 48. Significant improvements in functional recovery was initially observed in the onset group when compared to placebo after approximately 10–12 days of NVG-291-R treatment. Animals in the peak group also improved significantly with NVG-291-R treatment; however, NVG-291-R given at the onset of disease allowed for better recovery.

Figure 1 – Delayed NVG-291-R treatment or treatment at symptom
onset promotes functional recovery in EAE model7

Clinical score of disease severity in MOG-induced EAE mice treated daily with NVG-291-R
or vehicle beginning at either the onset (approximately day 9) or the peak (approximately day 17)
of disease determined by clinical score.

In a MS demyelination experiment following a lysophosphatidylcholine (LPC) administration, enhanced remyelination was observed with NVG-291-R treated lesion of the dorsal column compared to vehicle, as measured by Luxol fast blue staining in the spinal cord and myelin basic protein levels of lesions detected by Western blot.

Figure 2 – Histological Evidence of Remyelination7

Luxol fast blue stained sections of LPC lesions from
the spinal cords of vehicle or NVG-291-R-treated mice.

In a separate independent experiment, remyelination following an LPC lesion was also observed when demyelinating the optic chiasm of the visual pathway8. Mice were administered NVG-291-R or placebo for 3, 7, or 14 days post lesion. NVG- 291-R treated mice remyelinated at a faster rate compared to vehicle treated mice as measured by myelin staining. To functionally investigate the effect of PTPσ inhibition on optic chiasm demyelination and repair, visual evoked potentials (VEP) were recorded from the visual cortex of mice at 0, 7, and 14 days post-injury. VEP recording reflects the functional integrity of the visual pathway up to the visual cortex. LPC administration significantly increased the latency in VEP at both 7 and 14 days post-injury. In animals treated with NVG-291- R, a lower level of VEP delay was observed when compared to the group, and at 14 days post-injury, no significant difference was observed between the NVG-291-R treated animals and their baseline records.

To determine if mice functionally recover visual acuity, a visual cliff behavioral task was conducted. This test effectively measures the visual depth perception in animals using an optical illusion of a cliff. At baseline levels prior to injury, mice avoided the cliff more than 85% of the total time. LPC lesion significantly increased the time spent on the cliff at 7 and 14 days post-injury, whereas animals treated with NVG-291-R spent significantly less time on the cliff.

A list of select scientific publications that give a robust overview of the effects of NVG-291-R seen in animal models is provided in Notitia – Our Data Center, which can be accessed here.

References

1. Franklin, R. J. M. & French-Constant, C. Remyelination in the CNS: from biology to therapy. Nat.Rev. Neurosci. 9, 839–855 (2008).
2. Keough, M. B. et al. An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination. Nat Commun 7, 1–12 (2016).
3. Pendleton, J. C. et al. Chondroitin sulfate proteoglycans inhibit oligodendrocyte myelinationthrough PTPσ. Exp. Neurol. 247, 113–121 (2013).
4. Lau, L. W. et al. Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination. Ann. Neurol. 72, 419–432 (2012).
5. Mohan, H. et al. Extracellular matrix in multiple sclerosis lesions: Fibrillar collagens, biglycan and decorin are upregulated and associated with infiltrating immune cells. Brain Pathol. 20, 966–975 (2010).
6. Sobel, R. A. & Ahmed, A. S. White Matter Extracellular Matrix Chondroitin Sulfate/Dermatan Sulfate Proteoglycans in Multiple Sclerosis. J Neuropathol Exp Neurol 60, 1198–1207 (2001).
7. Luo, F. et al. Modulation of Proteoglycan Receptor PTPσ Enhances MMP-2 Activity to Promote Recovery from Multiple Sclerosis. Nature Communications 9 (1): 1–16 (2018)
8. Niknam, P., Raoufy, M. R., Fatholahi, 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 103391 (2019)
9. Kirkham, D. L. et al. Neural stem cells from protein tyrosine phosphatase sigma knockout mice generate an altered neuronal phenotype in culture. BMC Neurosci 7, 50 (2006).
10. Shen, Y. et al. PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration. Science 326, 592–596 (2009)
11. Dyck, Scott, Hardeep Kataria, Khashayar Akbari‐Kelachayeh, Jerry Silver, and Soheila Karimi‐Abdolrezaee. 2018. “LAR and PTPσ Receptors Are Negative Regulators of Oligodendrogenesis and Oligodendrocyte Integrity in Spinal Cord Injury.” Glia 67 (1): 125–45