From Animal Models to Humans: Strategies for Promoting CNS Axon Regeneration and Recovery of Limb Function after Spinal Cord Injury

Journal of Neurologic Physical Therapy,  Jun 2005  by Moon, Lawrence,  Bunge, Mary Bartlett

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ABSTRACT

There are currently no fully restorative therapies for human spinal cord injury (SCI). Here, we briefly review the different types of human SCI pathology as well as the most commonly used rodent and nonhuman primate models of SCI that are used to simulate these pathologies and to test potential therapies. We then discuss various high profile (sometimes controversial) experimental strategies that have reported CNS axon regeneration and functional recovery of limb movement using these animal models of SCI. We particularly focus upon strategies that have been tested both in rodents and in nonhuman primates, and highlight those which are currently transitioning to clinical tests or trials in humans. Finally we discuss ways in which animal studies might be improved and what the future may hold for physical therapists involved in rehabilitation of humans with SCI.

Key Words: plasticity, SCI, regeneration, animal, human, therapies, functional recovery

INTRODUCTION

Spinal cord injury (SCI) affects hundreds of thousands of people worldwide, with massive associated health care and other socioeconomic costs.1 Damage to the spinal cord results most notoriously in flaccid paralysis and loss of normal sensation in the limbs below the level of the lesion. Spinal cord injury may also lead to debilitating pain, spasticity, impairments in breathing and coughing, bowel or bladder problems, and reduced reproductive ability or sexual sensation. ' People with SCI may suffer from autonomic dysreflexia and may be at increased risk for stroke, decubitus ulcers, fractures, and depression. There are no fully restorative clinical therapies for SCI.

In attempts to develop therapeutic strategies for overcoming each of these sequelae, researchers often rely upon animal models of SCI. These enhance our understanding of the cellular and molecular response of the mammalian spinal cord to injury, and they allow us to evaluate the safety and efficacy of potential therapies for improving outcome. Use of animal models has shown that dysfunction following SCI results from interruption of descending and ascending spinal axons and loss of both myelin and cells including neurons, oligodendrocytes, and astrocytes. Many axons regenerate following injury to the peripheral nervous system (PNS) but few, if any axons regenerate long distances following injury to the central nervous system (CNS).1 This review will discuss strategies for promoting regeneration of CNS axon tracts and recovery of limb function in animal models of SCI.

Although beyond the scope of this review, there are other extremely important efforts aimed at restoring normal function after SCI. For example, following the initial insult to the spinal cord, further structure and function is lost through active secondary processes.2 Substantial effort has been devoted to limiting this secondary damage through development of neuroprotective measures.3 Substantial effort also has been dedicated to improving upon the small degree of endogenous repair that proceeds spontaneously in the spinal cord.4,5 For example, strategies for improving conduction through spared axons have been tested in animals and in humans.6 Strategies for treating pain and sexual, bladder, or bowel dysfunction and autonomie dysreflexia are also beyond the remit of this article. Readers are directed to excellent recent reviews of these fields in this volume and elsewhere.1,3,6,7

The present review will first outline different types of human SCI and will discuss how contemporary animal models of SCI attempt to simulate these pathologies. Next, we will discuss cellular and molecular strategies for improving CNS axon regeneration and recovery of limb function after SCI. Special consideration will be given to experimental strategies that have been evaluated in nonhuman primates and/or are currently transitioning to clinical studies or trials.7 We will highlight where strategies remain controversial, and where safety or efficacy barriers to translating experimental strategies exist. The aim is to inform readers of exciting laboratory advances, but to temper this with a realistic understanding of the challenges that remain in developing effective and safe therapies for humans.

HUMAN SCI IS PATHOLOGICALLY HETEROGENEOUS

The response of the human spinal cord to injury has been studied using imaging techniques as well as by histological staining and inspection of autopsy material.8 These studies reveal 4 classes of lesion. In one study of 48 specimens,8 in 33% of cases, contusion injuries resulted in cavity and cyst formation, typically with some sparing of white matter (or glial tissue) but with the external glial limiting membrane (the glia limitans) remaining intact. In 29% of cases, massive compression or maceration occurred due to vertebral displacement whereas in 21% of cases, laceration occurred due to cord penetration by foreign bodies or bony fragments. After compression, maceration or laceration, substantial breaks in the glia limitans led to the epicenter being filled predominantly with connective tissue; cysts and cavities were less prominent. In 17% of cases, solid core injuries manifested as either central cord syndrome (with loss of myelin and axons, but with preservation of gray matter), or as chronic cord compression (with loss of myelin and/or motor neurons in the epicenter, but with preservation of axonal integrity). The extent of demyelination, the invasion of host cells and the deposition of growthinhibitory molecules (see below) at sites of human SCI also have been documented.9,10