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 Sigma 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
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.
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