30

The overall goals for the treatment of SCI might be summarized as a series of temporally overlapping targets or goals to preserve or improve functional capacity (Table 30.1). At this time there is limited human efficacy data; thus, the timelines for effective neuroprotective, reparative, regenerative, and recovery treatments are necessarily vague. It is not the intent of this chapter to review the mechanisms underlying experimental treatment strategies. Instead, the focus is on the principled pathway for translation of discoveries, as well as the factors that may influence outcomes or confound the accurate interpretation of clinical trial results.

Therapeutic Goals after Spinal Cord Injury

Protection strategies are directed against the mechanical, pathological, and inflammatory effects on spinal cord tissues immediately following the primary injury and throughout the first few weeks when secondary cell death processes are most active. Surgical decompression of the cord and mechanical stabilization of the spine constitute standard acute care to ensure the spinal column does not impinge on the cord and cause further damage. The maintenance of adequate vascular perfusion of the spinal cord is also a current standard of care, whereas the reduction of spinal edema and minimization of secondary cell death (e.g., apoptosis) are research goals for acute treatments.1,2

Table 30.1 Overall Goals for Improving Functional Capacity after Spinal Cord Injury

Repair includes endogenous cellular and tissue responses that are spontaneously activated after injury or need appropriate stimulation to provide a benefit. For example, stimulation of appropriate angiogenesis or decreasing widespread demyelination is likely to be beneficial.3,4 Current thinking also suggests astrogliosis after SCI is maladaptive to functional recovery, and limiting such responses by astrocytes may be a worthy therapeutic target.^5–7 Interventions that enhance the expression of required growth factors, stimulate the proliferation and differentiation of resident neural progenitors, or activate endogenous “developmental programs” to facilitate intrinsic neuronal outgrowth are also areas of active preclinical investigation.^1,8

Regeneration is often used as a synonym for repair, but here the emphasis is on exogenous interventions that specifically stimulate or facilitate outgrowth from severed axons, as well as strategies, such as cell and biocompatible material transplants, that replace lost tissue or provide scaffolds for neural growth.⁹ Obvious approaches include transplantation of autologous or allograft neural stem cells or neural progenitors.¹⁰ Although cell transplantation is a most promising therapeutic intervention, at this time there is little scientific consensus as to what are the most appropriate cellular candidates for transplantation after SCI. In addition, different therapeutic goals may require different cell transplant phenotypes. Further preclinical studies are essential before this approach will have a meaningful and widespread clinical application.

Recovery of a clinically meaningful functional capacity is the ultimate goal and may necessarily involve all the above approaches, but activity-dependent rehabilitation alone can provide benefit. The underlying basis is collectively referred to as neuroplasticity, which includes a variety of mechanisms, such as the formation of novel synaptic connections by axonal sprouts from existing (i.e., preserved) fibers, to alterations in synaptic strength, or the rewiring of functional circuits within intact (uninjured) spinal and brain regions.11 Treatments, such as bodyweight-supported walking, robot-assisted training, and functional electric stimulation, capitalize on and facilitate plasticity.^12,13 Activity-dependent efforts are also important to consolidate any functional anatomical repair induced by a biological intervention that protects, repairs, or regenerates the injured cord.

SCI is a complex disorder, and functional recovery will undoubtedly require more than one type of intervention. Many pre-clinical investigations are examining the combined or sequential manipulations of promoters, inhibitors, intracellular modulators of axonal growth, cell transplants, and activity-dependent training.^14,15 The steps for the clinical translation of combinatorial therapies are necessarily more involved because each individual component, as well as the proposed combination, must be examined for safety at both the preclinical and the clinical level before any evaluation for efficacy can begin.

Preclinical Translation of Discoveries

A disconnect between preclinical and clinical results is undesirable, especially considering the extensive investment of time and money in a translation process. Thus, the adoption of high-quality preclinical protocols, with blinded assessments, adequate power, and the incorporation of “functional” outcome measures similar to those used in a human study, provide increased confidence. Likewise, most scientists would agree that the optimal pre-clinical translation process would include independent replication of promising pre-clinical strategies.¹⁶ Furthermore, in the case of SCI, independent replication efforts might involve the use of different SCI models (e.g., severe vs moderate injury, lacerating vs contusive SCI) or variations of the treatment paradigms. This would establish both the relevance and the robustness of the initial discovery. In addition, finding similar beneficial outcomes of the experimental intervention after SCI in different species would demonstrate the fundamental nature of the therapeutic target and increase the likelihood that the treatment would benefit humans. Finally, if a therapy purports to be a useful acute treatment, it should be demonstrated to have benefit in animals when administered within a clinically relevant time frame (in most circumstances, at least several hours after the initial spinal injury). If an intervention is suggested to benefit people living with chronic SCI, then it should be shown to be effective in a chronic animal model.

As outlined in Table 30.2, there are several characteristics of an experimental treatment that should be established prior to beginning a human study. Nevertheless, some experimental interventions enter into clinical trials without being directly studied in a preclinical animal model of the human disorder. This may occur, for example, if the treatment has a previous clinical use for a different disorder but involves a related clinical therapeutic target. The advantages for such a translational path include a prior understanding of the safety and toxicology of the treatment in humans. Thus, when translated to SCI, there is reduced risk that the intervention might deteriorate neurological function or have other adverse effects (Fig. 30.1).

Spinal Cord Injury Clinical Trial Process

Initial guidelines for the conduct of valid SCI clinical trials have become progressively more important. The development of basic cell culture and surgical transplant technologies is relatively inexpensive and requires only modest biological or surgical expertise. Thus there has been a rapid expansion of “for-profit” clinics offering such treatments. The increasing attractiveness of these transplantation practices has understandable appeal to patients when presented as a “cure,” but patients’ desperation can be exploited. The claims of beneficial outcomes are often based on media reports that are powerfully emotive, but unsubstantiated, and usually rely on anecdotal testimonials from hopeful patients or biased practitioners who stand to profit.

Table 30.2 Necessary Characterization and Development of an Experimental Treatment Prior to Human Study

To ensure public safety, most countries in the developed world have regulatory agencies that have established criteria for an experimental therapy to enter a clinical trial program. Unfortunately, regulatory requirements are only as good as their enforcement, and this has not been uniform across the globe. To provide some objective assistance to a complex series of decisions weighing the possible risks and benefits for a human study, an initial set of SCI clinical trial guidelines was recently developed and published by an international panel of scientists and clinicians. This series of papers detailed the degree of spontaneous recovery after SCI,17 outlined approaches for trial outcome measures,¹⁸ discussed inclusion/exclusion criteria and ethics,¹⁹ and outlined various trial designs and protocols.²⁰ In addition, the same authors created a document written for the general public and allied health care professionals (www.icord.org).

Each phase of a clinical trial program has distinct goals and thus different parameters, protocols, outcome measures, and end points that can govern the conduct for each stage of investigation. The overall translational path for an experimental intervention through the various stages of preclinical and clinical study might be summarized as shown in Fig. 30.1.

Related posts:

Principles of Surgical Management of Spinal Trauma Associated with Spinal Cord Injury Posttraumatic Syringomyelia: Pathophysiology and Management Glial Scar and Monocyte-Derived Macrophages Are Needed for Spinal Cord Repair: Timing, Location, and Level as Critical Factors Electrophysiological Predictors of Lower Limb Motor Recovery: The Rehabilitation Perspective Management of Central Cord Syndrome Neuroimaging after Spinal Cord Injury: Evaluating Injury Severity and Prognosis Using Magnetic Resonance Imaging

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