Therapeutic Strategies Targeting Respiratory Recovery after Spinal Cord Injury: From Preclinical Development to Clinical Translation

Abstract

High spinal cord injuries (SCIs) lead to permanent functional deficits, including respiratory dysfunction. Patients living with such conditions often rely on ventilatory assistance to survive, and even those that can be weaned continue to suffer life-threatening impairments. There is currently no treatment for SCI that is capable of providing complete recovery of diaphragm activity and respiratory function. The diaphragm is the main inspiratory muscle, and its activity is controlled by phrenic motoneurons (phMNs) located in the cervical (C3–C5) spinal cord. Preserving and/or restoring phMN activity following a high SCI is essential for achieving voluntary control of breathing. In this review, we will highlight (1) the current knowledge of inflammatory and spontaneous pro-regenerative processes occurring after SCI, (2) key therapeutics developed to date, and (3) how these can be harnessed to drive respiratory recovery following SCIs. These therapeutic approaches are typically first developed and tested in relevant preclinical models, with some of them having been translated into clinical studies. A better understanding of inflammatory and pro-regenerative processes, as well as how they can be therapeutically manipulated, will be the key to achieving optimal functional recovery following SCIs.

Updating perspectives on spinal cord function: motor coordination, timing, relational processing, and memory below the brain

“…The consequent dysregulation causes systemic immune and metabolic dysfunction that can impact multiple major organ systems, including the liver, lungs, gut, and urinary tract, increasing susceptibility to urinary and lung infections, gut dysbiosis, and a disruption in lipid metabolism (metabolic syndrome; Kopp et al, 2017 ; Holmes and Blanke, 2019 ; Kigerl et al, 2020 ; Rodgers et al, 2022 ). Pneumonia and urinary tract infections are among the leading causes of mortality after SCI ( Schwab et al, 2014 ; DiSabato et al, 2023 ; Michel-Flutot et al, 2023 ). Further, immune dysregulation and an increase in circulating pro-inflammatory cytokines can promote depression and pain ( Maier and Watkins, 1998 ; Slavich and Irwin, 2014 ; Lees et al, 2015 ).…”

Glycolytic metabolism modulation on spinal neuroinflammation and vital functions following cervical spinal cord injury

“…Cervical SCIs are the most prevalent, and patients living with these injuries often have to rely on mechanical ventilation to survive, and are thus more susceptible to respiratory infections (Ahuja et al, 2017). To date, no effective treatments that induce complete functional recovery are available, making the development of new therapeutics critical (Randelman et al, 2021;Locke et al, 2022;Michel-Flutot et al, 2023a).…”

Recovery of Forearm and Fine Digit Function After Chronic Spinal Cord Injury by Simultaneous Blockade of Inhibitory Matrix Chondroitin Sulfate Proteoglycan Production and the Receptor PTPσ

“…8,[10][11][12][13]15,16,21,22 The regulatory effects of CSPGs on both myelin and axon regeneration as well as neuronal plasticity after an acute 9,17,[23][24][25][26][27][28][29] or sub-chronic SCI, 5,17,23,26,30 and in the context of many other conditions have been well documented. 8,10,[31][32][33][34][35][36][37] The glycosaminoglycan (GAG) side chains, especially those containing 4-O-sulfated CS-E, 38,39 are known to bind with highest affinity to their receptor protein tyrosine phosphatase PTPσ (rPTPσ) 38 and provide much of the inhibitory properties of CSPGs. [39][40][41] Their effects can be greatly decreased by enzymatic digestion using the bacterial enzyme, Chondroitinase ABC (ChABC).…”