Recent progress and challenges in the treatment of spinal cord injury

Abstract

Spinal cord injury (SCI) disrupts the structural and functional connectivity between the higher center and the spinal cord, resulting in severe motor, sensory, and autonomic dysfunction with a variety of complications. The pathophysiology of SCI is complicated and multifaceted, and thus individual treatments acting on a specific aspect or process are inadequate to elicit neuronal regeneration and functional recovery after SCI. Combinatory strategies targeting multiple aspects of SCI pathology have achieved greater beneficial effects than individual therapy alone. Although many problems and challenges remain, the encouraging outcomes that have been achieved in preclinical models offer a promising foothold for the development of novel clinical strategies to treat SCI. In this review, we characterize the mechanisms underlying axon regeneration of adult neurons and summarize recent advances in facilitating functional recovery following SCI at both the acute and chronic stages. In addition, we analyze the current status, remaining problems, and realistic challenges towards clinical translation. Finally, we consider the future of SCI treatment and provide insights into how to narrow the translational gap that currently exists between preclinical studies and clinical practice. Going forward, clinical trials should emphasize multidisciplinary conversation and cooperation to identify optimal combinatorial approaches to maximize therapeutic benefit in humans with SCI.

Keywords: axon regeneration; clinical translation; functional recovery; spinal cord injury; therapeutic strategies.

Figure 1.

Neuronal regeneration following spinal cord injury involves multiple forms of axon growth. (1) The transected axons of supraspinal and propriospinal neurons regrow to pass through the scar borders and towards the lesion core, while failing to move beyond the injury site. (2) Long-distance regeneration of transected supraspinal axons across the lesion site to form functional connections with motor neurons via interneurons. (3) Sprouting of injured propriospinal neurons to bypass the lesion area to reach appropriate targets. (4) The sprouting axons of injured supraspinal neurons bypass the injury site to form new synaptic connectivity with interneurons. (5) The sprouting axons of injured supraspinal neurons make connections with the contralesional spared propriospinal neurons to relay supraspinal commands to motor neural network below the injury site. (6) Sprouting of intact supraspinal axons to cross the midline to regain control over the motor circuits below the lesion. These growth processes support certain degrees of functional restoration.

Figure 2.

Cellular and molecular mechanisms determining axon regeneration. The extrinsic and intrinsic determinants control the intrinsic regenerative ability of injured neurons following SCI.

Figure 3.

Therapeutic strategies for spinal cord repair. The illustration summarizes the promising interventions to improve functional recovery following SCI. Neuroprotective strategies counteract the progression of the secondary injury. Targeting intrinsic regenerative mechanism promotes neuroplasticity and axon regeneration. Eliminating inhibitory molecules and enhancing neurotrophic support provide a growth-permissive environment for axon regeneration. Cell transplantation facilitates the formation of neural relay circuits across the lesion site. Neuromodulation technology enables control over the activity of paralyzed legs and reorganization of spared circuits. Finally, combinatorial strategies contribute to maximize meaningful functional recovery by targeting multifaceted SCI pathology.