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.

Keywords: axon regeneration; clinical trials; combination treatments; reproducibility; spinal cord injury.

Figure 1. The seven targets for therapeutic interventions following spinal cord injury

A horizontal plane view through a region of thoracic spinal cord injury depicting some of the features of the pathology. SCI leads to immediate and continued death of neural alongside disruption of descending and ascending fibres. Seven therapeutic targets are present which can improve functional recovery after SCI: neuroprotective strategies to limit ongoing secondary damage resulting in spared tissue; tissue and cellular transplants to replace lost cells and may provide trophic or growth‐permissive environments; removal of inhibitory factors such as CSPGs to allow for enhanced axonal growth; targeting neuron‐intrinsic mechanisms to enhance intrinsic regenerative response which could then be directed through the resupply of trophic support; and remyelination of demyelinated axons may improve axonal conduction. Finally, rehabilitation to function in circuit remodelling and strengthens beneficial connections.

Figure 2. Combinatory therapies for spinal cord injury

Experimental spinal cord injury research has resulted in a multitude of individual therapeutic possibilities yet recovery after injury remains incomplete. Combinatory approaches to address the seven targets will need to be a focus of translation studies. Tissue and cellular transplants will replace lost cells, among other regenerative functions. Removal of inhibitory factors such as CSPGs allows for enhanced axonal growth. Targeting neuron‐intrinsic mechanisms enhance intrinsic regenerative response which can then be directed through resupply of trophic support. Remyelination of demyelinated axons may improve axonal conduction and survival. Finally, rehabilitation functions in circuit remodelling and strengthens beneficial connections.