Basic advances and new avenues in therapy of spinal cord injury

Abstract

The prospects for successful clinical trials of neuroprotective and neurorestorative interventions for patients with acute and chronic myelopathies depend on preclinical animal models of injury and repair that reflect the human condition. Remarkable progress continues in the attempt to promote connections between the brain and the sensory and motor neurons below a spinal cord lesion. Recent experiments demonstrate the potential for biological therapies to regenerate or remyelinate axons and to incorporate new neural cells into the milieu of a traumatic spinal cord injury. The computational flexibility and plasticity of the sensorimotor systems of the brain, spinal cord, and motor unit make functional use of new circuitry feasible in patients. To incorporate residual and new pathways, neural repair strategies must be coupled to rehabilitation therapies that drive activity-dependent plasticity for walking, for reaching and grasping, and for bowel and bladder control. Prevention of pain and dysautonomia are also clinical targets. Research aims to define the temporal windows of opportunity for interventions, test the safety and efficacy of delivery systems of agents and cells, and provide a better understanding of the cascades of gene expression and cell interactions both acutely and chronically after injury. These bench-to-bedside studies are defining the neurobiology of spinal cord injury rehabilitation.

Figure 1

Experimental strategies for SCI repair. At the site of this hypothetical cystic lesion, a cellular matrix or biopolymer bridge is injected to fill the cavity. The matrix contains neuronal or oligodendroglial precursors and neurotrophins. Chondroitinase is injected into the white matter above and below the cavity to lessen inhibitory proteoglycans. An inhibitor to the Nogo receptor is injected around white matter tracts near the cavity to prevent growth-cone collapse. Fibroblasts modified to secrete brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3) are placed intermittently along the white matter tracts below the injury site to help signal the growth cones of regenerating axons. Neurotrophins or other diffusible attractive cueing molecules are injected to lead regenerating axons into the ventral gray matter of the cord at the levels of targeted motoneuron pools. Task-oriented sensorimotor training promotes regeneration and specific neuronal targeting, incorporates the sensorimotor pools into functional units, and enhances cortical representational plasticity for the motor control needed to relearn functional skills.

Figure 2

Physical comparison of human and rodent spinal cord anatomy. The overall length of a rat brain and spinal cord, including the cauda equina, measure about 15 cm. The human cord alone, up to the cauda equina averages about 65 cm in a person who is 68 inches tall. The splay of roots of the cauda equina of the human cord reveals that 2–3 lumbar roots equal the diameter of the rat spinal cord. The differences in diameter of the cord sectioned at the lumbar enlargement are shown in the axial sections. Approximately 20 axial sections from the rat would fit within the human cord at this level. Relative distances necessary for targeting the cervical or lumbar motor pools for axonal regeneration from any level is at least four times greater in humans.