Background: There is a critical need for a reliable and clinically-relevant non-human primate model of spinal cord injury (SCI) for translating therapies developed in rodents to human clinical trials. The California Primate Spinal Cord Consortium has made substantial progress in developing a cervical hemisection model of SCI that has multiple neurological and physiological outcomes along with sophisticated anatomical measures of lesion size, cortico-spinal tract sprouting, and endogenous repair. Endogenous repair and sprouting in the hemisection model predict recovery of forelimb function. Plasticity in the non-human primate spinal cord after injury is remarkable, and may exceed that in rodent models. There is thus a compelling reason to extend this model to a more clinically relevant contusion injury. Objective: Based on extensive experience in both rodent and rhesus monkey SCI research, we propose to use pilot funding to develop a reliable unilateral partial cervical contusion lesion model that can be used to test emerging therapies prior to advancement to clinical trials.
Specific aims :
Aim 1 is to develop a new injury device to produce unilateral cervical contusion in monkeys based on 1) extensive experience in the rat at cervical and thoracic levels, and in thoracic spinal cord injuries in monkeys (Bresnahan et al 1976;Bresnahan, 1978) and 2) a finite element analysis (Sparrey et al 2008) that will translate lesion parameters in the rat cervical contusion injury model to the larger cord of the rhesus monkey.
In aim 2, we will then test the selected contusion lesion parameters on a small number of animals and use anatomical measures of the lesion at 3 weeks after injury to evaluate the effects of the biomechanical variables selected.
In aim 3, we will then establish the reproducibility of the selected optimal injury protocol in a second small cohort of animals sustaining the same injury and surviving for 4 months. Selecting from the battery of behavioral and physiological outcome measures that we have already developed to assess recovery after hemisection injury (e.g. Courtine et al, 2005), we will characterize the long term functional consequences of this contusion injury. Basic histological studies will be performed on the tissue from these subjects to assess lesion consistency (e.g. lesion size, extent of scar, white and gray matter damage, motor neuron loss) and more detailed studies will be planned for future analysis using this tissue. Finally, we will correlate the anatomical changes with the functional outcomes in this injury paradigm using principle components analysis and compare these results with those already available from the hemisection model. Impact: The model will provide a clinically relevant contusion lesion model of partial cervical injury in non- human primates that produces a reliable and sustained neurological deficit that exhibits partial recovery. This moderate lesion will be sensitive to both positive and negative effects of treatments.
STATEMENT Spinal cord injury (SCI) is a devastating condition that affects at least 10,000 new patients each year, with new estimates of incidence from the Reeve Foundation showing that there may be as many as 1,275,000 people living with SCI. Most injuries are from motor vehicle accidents, and military personnel are especially affected by the increased use of roadside IEDs. There have been many recent exciting innovations in the neurobiology of injury and repair, and many new treatment strategies have emerged in the past 10 years. As interesting as all these findings may be, there is a translational gap between studies of therapies in rodents and clinical trials in man. As a means to fill that gap, we propose to develop a unilateral spinal cord contusion model in the primate to address issues of scaling as well as to address the pathobiological and behavioral differences between rats and humans.