Recovery of forearm and fine digit function after chronic spinal cord injury by simultaneous blockade of inhibitory matrix CSPG production and the receptor PTPσ

Abstract

Spinal cord injuries, for which there are limited effective clinical treatments, result in enduring paralysis and hypoesthesia due, in part, to the inhibitory microenvironment that develops and limits regeneration/sprouting, especially during chronic stages. Recently, we discovered that targeted enzymatic modulation of the potently inhibitory chondroitin sulfate proteoglycan (CSPG) component of the extracellular and perineuronal net (PNN) matrix via Chondroitinase ABC (ChABC) can rapidly restore robust respiratory function to the previously paralyzed hemi-diaphragm after remarkably long times post-injury (up to 1.5 years) following a cervical level 2 lateral hemi-transection. Importantly, ChABC treatment at cervical level 4 in this chronic model also elicited rapid, albeit modest, improvements in upper arm function. In the present study, we sought to further optimize and elucidate the capacity for nerve sprouting and/or regeneration to restore gross as well as fine motor control of the forearm and digits at lengthy chronic stages post injury. However, instead of using ChABC, we utilized a novel and more clinically relevant systemic, non-invasive combinatorial treatment strategy designed to both reduce (via oral delivery of 4-methylumbelliferone) and overcome inhibitory CSPGs (via sub-cutaneous delivery of the PTPσ CSPG receptor blocking peptide ISP) simultaneously and spatially extensively. Following a three-month upper cervical spinal hemi-lesion, we show that the combined treatment has a profound effect on functional recovery of the chronically paralyzed forelimb and paw, specifically during walking as well as precision movements of the digits. Our exciting pre-clinical findings will begin to dramatically enhance our understanding of the basic mechanisms underlying functionally beneficial regenerative events occurring at chronic injury stages for clinically relevant translational benefits.

PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury

“…When peptide is delivered early after SCI (Urban et al 2019), axon growth inhibitory extracellular matrix, including CSPGs, is still in the process of increasing in density in the injured spinal cord, while it is already well-established in the present chronic protocol (Busch & Silver 2007), which further increases axon growth inhibition. We can hypothesize that, at this late time post-injury, the delivered PTPσ peptide is not effective in the face of these greater levels of neuronal-extrinsic inhibitory molecules (Milton et al 2023).…”

Collagen I is a critical organizer of scarring and CNS regeneration failure

“…Our laboratory has designed an intracellular sigma peptide (ISP) to modulate protein tyrosine phosphatase σ (PTPσ) and release CSPG-mediated axonal regeneration/sprouting inhibition after incomplete spinal cord injury (SCI) 12,25,26 . However, in the model of complete SCI caused by forceps compression, we have now learned that ISP rarely promotes the recovery of hindlimb motor function in both rats and mice, aligning with the outcome of a recent chondroitinase ABC (chABC) enzyme study 27 (Fig 1a, c).…”