Therapeutic repair for spinal cord injury: combinatory approaches to address a multifaceted problem

Abstract

The recent years saw the advent of promising preclinical strategies that combat the devastating effects of a spinal cord injury (SCI) that are progressing towards clinical trials. However, individually, these treatments produce only modest levels of recovery in animal models of SCI that could hamper their implementation into therapeutic strategies in spinal cord injured humans. Combinational strategies have demonstrated greater beneficial outcomes than their individual components alone by addressing multiple aspects of SCI pathology. Clinical trial designs in the future will eventually also need to align with this notion. The scenario will become increasingly complex as this happens and conversations between basic researchers and clinicians are required to ensure accurate study designs and functional readouts.

Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury

“…The regeneration of the human CNS, however, is more complex and challenging. More and more scholars propose that SCI may require comprehensive therapies and management to maximize recovery (Courtine and Sofroniew, 2019;Yu and Gu, 2019;Griffin and Bradke, 2020). Strategies targeting the glial scar may also require complementary strategies, because: (1) satisfactory spinal cord regeneration may need a combination of several key factors (Anderson et al, 2018) and (2) strategies targeting the glial scar may provide a permissive microenvironment for axonal regeneration, but several studies indicate that robust axonal regeneration may be insufficient to result in significant functional improvement because it also requires synaptic reorganization and use-dependent plasticity provided by rehabilitation or other engineering strategies (Zukor et al, 2013;Du et al, 2015;Anderson et al, 2018;Courtine and Sofroniew, 2019).…”

“…Strategies targeting the glial scar may also require complementary strategies, because: (1) satisfactory spinal cord regeneration may need a combination of several key factors (Anderson et al, 2018) and (2) strategies targeting the glial scar may provide a permissive microenvironment for axonal regeneration, but several studies indicate that robust axonal regeneration may be insufficient to result in significant functional improvement because it also requires synaptic reorganization and use-dependent plasticity provided by rehabilitation or other engineering strategies (Zukor et al, 2013;Du et al, 2015;Anderson et al, 2018;Courtine and Sofroniew, 2019). As a relatively mature strategy targeting the glial scar, chondroitinase ABC has been used in many studies to investigate combination therapies (Griffin and Bradke, 2020). By removing the inhibitory microenvironment, chondroitinase ABC treatments amplify the effects of other treatments, leading to better recovery (Alilain et al, 2011;DePaul et al, 2015;Suzuki et al, 2017;Warren et al, 2018).…”

Combined Supra- and Sub-Lesional Epidural Electrical Stimulation for Restoration of the Motor Functions after Spinal Cord Injury in Mini Pigs

“…Spinal cord injury (SCI) remains one of the most difficult problems in biomedical science [ 1 , 2 , 3 ]. Currently, the quality of life and life expectancy of patients with SCI largely depend on symptomatic treatment [ 4 , 5 , 6 ].…”

Cellular and Molecular Mechanisms of Spinal Cord Vascularization

“…CNS pathologies are multifaceted and complex pathologies characterized by cell death, axon damage/degeneration, loss of vascular integrity, disruption of the BBB and blood-spinal cord barrier (BSCB), inflammation, and ECM (extracellular matrix) remodeling (Griffin and Bradke, 2020). The BBB and BSCB are sophisticated barrier systems in which ECs and their tight junctions play a central part in association with astrocyte end-feet, perivascular macrophages, pericytes, and basement lamina (Bartanusz et al, 2011).…”