Abstract
The contemporary strategy for spinal cord injury (SCI) therapy aims to combine multiple approaches to control pathogenic mechanisms of neurodegeneration and stimulate neuroregeneration. In this study, a novel regenerative approach using an autologous leucoconcentrate enriched with transgenes encoding vascular endothelial growth factor (VEGF), glial cell line-derived neurotrophic factor (GDNF), and neural cell adhesion molecule (NCAM) combined with supra- and sub-lesional epidural electrical stimulation (EES) was tested on mini-pigs similar in morpho-physiological scale to humans. The complex analysis of the spinal cord recovery after a moderate contusion injury in treated mini-pigs compared to control animals revealed: better performance in behavioural and joint kinematics, restoration of electromyography characteristics, and improvement in selected immunohistology features related to cell survivability, synaptic protein expression, and glial reorganization above and below the injury. These results for the first time demonstrate the positive effect of intravenous infusion of autologous genetically-enriched leucoconcentrate producing recombinant molecules stimulating neuroregeneration combined with neuromodulation by translesional multisite EES on the restoration of the post-traumatic spinal cord in mini-pigs and suggest the high translational potential of this novel regenerative therapy for SCI patients.
Highlights
We demonstrated the benefits of triple gene therapy after intrathecal injection of umbilical cord blood mononuclear cells (UCBC) simultaneously transduced with adenoviral vectors (Ad5) carrying the genes encoding for endothelial growth factor (VEGF), glial cell linederived neurotrophic factor (GDNF), and neural cell adhesion molecule (NCAM) [29,30]
For ex vivo gene therapy, we proposed using an autologous geneticallyenriched leucoconcentrate producing recombinant vascular endothelial growth factor (VEGF), glial cell line-derived neurotrophic factor (GDNF), and NCAM
Recombinant replication-defective viral vectors carrying vegf165, gdnf, ncam1, and green fluorescent protein genes were created based on the human adenovirus serotype
Summary
Proposed therapies for the spinal cord injury (SCI) include a combination of different therapies such as pharmacological treatment, neuromodulation, bioengineering, biotechnology strategies, and other approaches. Neuromodulation with electrical stimulation or neurochemical agents targets and activates proprioceptive feedback spinal circuits to respond to supraspinal signals and facilitate the formation of a translesional spinal neural network, thereby integrating interrupted SCI circuits. Innovative bioengineering strategies after SCI have the potential to facilitate the restoration of upper or lower limb movements [2]. Functional electrical stimulation of the peripheral nerves and skeletal muscles has been introduced to assist with recovery after injury, focusing on direct muscle activation. Spinal cord stimulation has further demonstrated significant effects on the restoration of volitional motor control after complete
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