Translational spinal cord injury research: preclinical guidelines and challenges

As in many areas of biomedical research, “translational” and “preclinical” are now commonplace terminology in the neurosciences. Spinal cord injury (SCI) is a more recent area in which an active dialogue on translation has evolved (Sipski, 2003; Steeves et al., 2004; Blight and Tuszynski, 2006; Fawcett et al., 2007; Longbrake et al., 2007), following impressive advances in our understanding of the cellular and molecular biology of spinal cord trauma, the models and functional outcomes, and the therapeutic targets that have been identified (Tator, 2002; Hall and Springer, 2004; Kleitman, 2004; Kwon et al., 2005; Tsai and Tator, 2005; Rossignol et al., 2007; Eftekharpour et al., 2008). As with other neurological conditions, translational emphasis in SCI research underscores a growing sense of urgency for moving experimental strategies forward (Tator, 2006). Inherent in bench-to-bedside translational research has been the premise that preclinical (i.e., laboratory animal) studies can provide predictive indices of therapeutic potential in human subjects, although this issue has been contested for many years (for reviews see Bracken, 2009a; van der Worp et al., 2010). An often cited example is the clinical disappointment of neuroprotective strategies which showed significant benefits in animal studies but not in human subjects (Hugenholtz, 2003; Lammertse, 2004; Hawryluk et al., 2008). Translational difficulties, however, are not unique to the SCI field and have been experienced with far more extensive endeavors in other neurological disorders, including stroke, traumatic brain injury, and amyotrophic lateral sclerosis (Tolias and Bullock, 2004; Kazanis, 2005; O'Collins et al., 2006; Benatar, 2007; Walmsley and Mir, 2007; Margulies and Hicks, 2009). A common message is that experimental designs must be improved to obtain the most relevant data possible to warrant future clinical applications (Bracken, 2009b; van der Worp et al., 2010). A recent survey of opinions from SCI investigators indicates the field is still defining what constitutes ideal preclinical–translational designs and the level of evidence required to justify advancement of novel treatments to humans (Kwon et al., 2010a, 2011a). The following discussion expands upon several salient considerations related to translational–preclinical experimentation in acute and chronic SCI as presented in this volume by Dietz and Curt (see Chapter 29) and elsewhere by others (Steeves et al., 2004; Dobkin, 2007; Kwon et al., 2010a, 2011a, b; Tetzlaff et al., 2011). In that respect, this review is not to prescribe a specific roadmap for designing clinically relevant laboratory investigations. Rather, the objective is to raise further awareness of the fundamental challenges and complexities of translational SCI research by exploring general preclinical design issues, as well as others more specific to pharmacological and cellular interventions for acute and chronic SCI. In this review, discussion is limited to single treatment approaches though it is widely recognized that optimal benefits are more likely to result from multiple strategies combined with rehabilitation. Periodic reappraisal of the preclinical process is vital for further refinement and improved implementation of bench-to-beside, as well as beside-to-bench, experiences in SCI.