Epidural Stimulation Combined with Triple Gene Therapy for Spinal Cord Injury Treatment

Abstract

The translation of new therapies for spinal cord injury to clinical trials can be facilitated with large animal models close in morpho-physiological scale to humans. Here, we report functional restoration and morphological reorganization after spinal contusion in pigs, following a combined treatment of locomotor training facilitated with epidural electrical stimulation (EES) and cell-mediated triple gene therapy with umbilical cord blood mononuclear cells overexpressing recombinant vascular endothelial growth factor, glial-derived neurotrophic factor, and neural cell adhesion molecule. Preliminary results obtained on a small sample of pigs 2 months after spinal contusion revealed the difference in post-traumatic spinal cord outcomes in control and treated animals. In treated pigs, motor performance was enabled by EES and the corresponding morpho-functional changes in hind limb skeletal muscles were accompanied by the reorganization of the glial cell, the reaction of stress cell, and synaptic proteins. Our data demonstrate effects of combined EES-facilitated motor training and cell-mediated triple gene therapy after spinal contusion in large animals, informing a background for further animal studies and clinical translation.

New Therapy for Spinal Cord Injury: Autologous Genetically-Enriched Leucoconcentrate Integrated with Epidural Electrical Stimulation

“…Hind limb skeletal muscle contraction and the appearance of a consistent hematoma at the site exposed to the metal rod confirmed the onset of SCI. Moderate contusion injury in mini pigs has demonstrated consistent morphological and behavioural changes across our previous studies [ 28 , 29 , 32 , 36 ].…”

“…In our previous study, we reported the procedure of stimulating electrodes implantation at the C5 and L2 spinal cord segments in mini-pigs with subsequent spinal contusion at the Th9 segment [ 29 ]. It was shown that sublesional EES at L2 activates central pattern generators and facilitates hind limb movements on a treadmill.…”

“…A moderate contusion injury of the spinal cord was performed as described in our previous study [ 29 ], 14 days after implantation of the electrodes. After laminectomy at the Th8-Th9 vertebral level, the dura matter was exposed and a 50 g metal rod with a diameter of 9 mm of was centred.…”

“…Recently, we translated spinal cord epidural electrical stimulation (EES) to a porcine model and further demonstrated the efficacy of supra- and sublesional EES [ 27 , 28 ]. We also 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 line-derived neurotrophic factor (GDNF), and neural cell adhesion molecule (NCAM) [ 29 , 30 ]. Comparative analysis of EES in combination with cell-mediated gene therapy both in rats [ 27 ] and mini-pigs [ 29 ] demonstrated the advantages of this approach in severe SCI.…”

Spinal Cord Injury Management through the Combination of Stem Cells and Implantable 3D Bioprinted Platforms

“…Researchers have attempted to identify new treatments, such as drug administration, surgical decompression, hypothermia, and stem cells therapies, which could promote nerve cell regeneration, repair damaged parts, reduce the metabolic rate, and suppress acute inflammatory processes (to protect central nerve tissue from continued injury following traumatic damage) [5,6]. Recently, new therapeutic methods, such as cell/gene therapy, motor exercises, electrical stimulation, electrochemical neuromodulation therapy, and stem cell-based therapies, have been used, alone or in a combinatory approach, to achieve successful SCI therapy [7].…”