Veterinary Science Collected Works - Theses
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ItemDevelopment of methods to evaluate therapy for spinal cord trauma in dogs( 2020)Spinal cord injury (SCI) is a common cause of neurological deficits in dogs and a major cause of morbidity and decreased quality of life in people. In dogs, the most common causes of SCI are intervertebral disc diseases, particularly 'type I' intervertebral disc herniation knowns as intervertebral disc extrusion (IVDE), which occurs predominantly in chondrodystrophic breeds. The IVDE commonly causes contusion and compression to the spinal cord, which in most severe cases leads to complete loss of voluntary motor functions, bladder control and pain sensation distal to the level of the lesion. For decades, researchers have used animal models in their studies of SCI. However, limited progress has been achieved in translating any beneficial findings from experimental animal models to human SCI. Moreover, experimental studies in rodent models may not closely represent clinical SCI in human and canine patients. Naturally occurring compressive and contusive lesion of SCI associated with IVDE in dogs may be more analogous to human disease than induced experimental animal models. Canine naturally occurring SCI could simulate the injury in human patients including; mechanism of damage, pathophysiological events, healing processes, functional recovery, measures of evaluating outcomes, and effectiveness of the candidate therapies. Therefore, recruiting dogs of naturally occurring IVDE associated with SCI has become a common practice in clinical research trials. To date, no therapeutic method has been shown to treat SCI successfully in dogs with severe lesions. Therefore, the long-term outcome in these cases is chronic paraplegia with loss of sensation distal to the level of the lesion. Since this is true in both human and canine patients, novel therapies must be investigated, including promising neural stem cells (NSCs) therapy. The principal objective of this thesis was to study canine SCI and develop a reliable and reproducible paradigm for evaluating the effect of candidate therapies, using human neural precursor cells (hNPCs) in dogs as an example. This was approached by; 1) evaluating different MRI measures to monitor the spinal cord lesion in putatively naturally occurring canine spinal cord trauma, pre- and post- surgical or non-surgical treatments of IVDE, 2) ex vivo examination of hNPCs’ impact on inflammatory factors in stimulated whole blood (WB) samples from healthy dogs, 3) evaluating methods to measure responses to transplant of hNPCs into the spinal cord of the paraplegic dog with grade 5 SCI, as a pilot clinical study, 4) exploring the fate of hNPCs at 18 months post-xenotransplantation into spinal cord tissue (SCT) of a dog with grade 5 SCI, and 5) investigating the possibility of isolate and culture of canine NSCs from SCT of the dog. The findings of this thesis showed that the pathological and morphometric alterations of the objective and quantifiable parameters of the MRI measures of the spinal cord and vertebral canal post-SCI and following treatments are important prognostic indicators. The interaction effect of time and surgery is an important factor in decreasing spinal cord compression and vertebral canal narrowing. The results of the ex vivo study suggested that hNPCs could modulate the inflammatory responses in stimulated WB by reducing the production of tumour necrosis factor-alpha. The in vivo clinical pilot study concluded that neither adverse effects nor immunological reactions were developed following transplantation of hNPCs into the spinal cord of the dog. Although recovery of the cutaneous trunci muscle reflex was identified, no improvements of the deep pain sensation or locomotion and urinary functions were shown at the end of the 6 months observation period post-therapy. The immunohistochemical findings revealed that the grafted hNPCs had survived and migrated, after xenotransplantation into SCT of the host dog. The gross and histopathological examination showed neither significant pathological changes nor tumour formation at 18 months following xenotransplantation in the dog with grade 5 SCI. This research work reported that it is possible to isolate, and culture canine derived NSCs from SCT. Therefore, this shows promise for future research using of dog-to-dog allotransplantation of canine derived NSCs, which may minimise the associated complications of xenotransplantation. In summary, the observations of the studies in this thesis offer insight into the methods developed to evaluate potential benefits of using hNPCs for transplantation therapy in dogs with grade 5 SCI. The current research work helps understanding of the pathological and morphometrics alterations of spinal cord lesion pre and post treatment of IVDE. The findings are of value in understanding the mechanism of potential therapeutic effects of hNPCs, including the anti-inflammatory effect and the fate of the cells following transplantation into the spinal cord of the host. Finally, this research represents an initial step towards investigating the efficacy and potential benefits of hNPCs in a preclinical study in a large number of dogs with naturally occurring SCI.