Evaluation of direct and cell-mediated triple-gene therapy in spinal cord injury in rats

Islamov, R. R.; Izmailov, Andrei; Sokolov, Mikhail; Fadeev, Filip; Bashirov, Farid Vagizovich; Eremeev, Anton; Shaymardanova, G. F.; Шмаров, М. М.; Naroditskiy, B. S.; Chelyshev, Yu. A.; Lavrov, Igor; Palotás, András

doi:10.1016/j.brainresbull.2017.05.005

Cited by 14 publications

(14 citation statements)

References 28 publications

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“…In clinical trials, autologous cells isolated from bone marrow ( Jeong et al, 2014 ) or peripheral blood were preferentially used for post stroke transplantation ( Wang et al, 2013 ; Chernykh et al, 2016 ). Based on our previous studies we confirmed the rationale for using UCB-MC in the treatment of neurological disorders such as amyotrophic lateral sclerosis and SCI ( Islamov et al, 2016 , 2017a ). The reason for clinical application of UCB-MC is their suitability for human allo- and autotransplantation, as well as low immunogenicity, availability, ease of preparation, and storage ( Yang et al, 2010 ).…”

Section: Discussionsupporting

confidence: 74%

“…Previously we used the approach of ex vivo gene therapy for amyotrophic lateral sclerosis ( Islamov et al, 2015 , 2016 ) and SCI ( Chen et al, 2014 ; Islamov et al, 2017a ). Based on the data we proposed that UCB-MC transduced with adenoviral vectors carrying genes encoding growth and neurotrophic factors can rescue spinal neurons from cell death in those diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Cell-mediated gene delivery makes the viral antigens inside the ex vivo transduced cells invisible to the recipient immune system. Previously, we have shown that intravenous administration of UCB-MC transduced with three adenoviral vectors carrying VEGF, GDNF, and neural cell adhesion molecule (NCAM) improved symptomatic outcomes and increased life-span in transgenic ALS mice ( Islamov et al, 2016 ), in rat ( Islamov et al, 2017a ), and mini-pigs ( Islamov et al, 2017b ) with spinal cord injury (SCI) model. The beneficial neuroprotective effects of the chosen therapeutic molecules are based on their biological role in the regulation of neurogenesis and neuroregeneration by promoting neuron survival and maintaining their morphological and physiological plasticity.…”

Section: Introductionmentioning

confidence: 99%

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Triple-Gene Therapy for Stroke: A Proof-of-Concept in Vivo Study in Rats

et al. 2018

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Natural brain repair after stroke is extremely limited, and current therapeutic options are even more scarce with no clinical break-through in sight. Despite restricted regeneration in the central nervous system, we have previously proved that human umbilical cord blood mono-nuclear cells (UCB-MC) transduced with adenoviral vectors carrying genes encoding vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF), and neural cell adhesion molecule (NCAM) successfully rescued neurons in amyotrophic lateral sclerosis and spinal cord injury. This proof-of-principle project was aimed at evaluating the beneficial effects of the same triple-gene approach in stroke. Rats subjected to distal occlusion of the middle cerebral artery were treated intrathecally with a combination of these genes either directly or using our cell-based (UCB-MC) approach. Various techniques and markers were employed to evaluate brain injury and subsequent recovery after treatment. Brain repair was most prominent when therapeutic genes were delivered via adenoviral vector- or UCB-MC-mediated approach. Remodeling of brain cortex in the stroke area was confirmed by reduction of infarct volume and attenuated neural cell death, depletion of astrocytes and microglial cells, and increase in the number of oligodendroglial cells and synaptic proteins expression. These results imply that intrathecal injection of genetically engineered UCB-MC over-expressing therapeutic molecules (VEGF, GDNF, and NCAM) following cerebral blood vessel occlusion might represent a novel avenue for future research into treating stroke.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Triple-Gene Therapy for Stroke: A Proof-of-Concept in Vivo Study in Rats

et al. 2018

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“…At the same time, rodents compare to large mammals have a smaller brain and spinal cord sizes and shorter conductive pathways of neural fibers [ 38 ]. Several other metrics collected on rodents were found to be different from humans [ 42 , 43 , 44 ]. For example, activation of sensory feedback in rats may significantly improve the motor function after severe SCI, which is usually not a case in humans with severe SCI [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several other metrics collected on rodents were found to be different from humans [ 42 , 43 , 44 ]. For example, activation of sensory feedback in rats may significantly improve the motor function after severe SCI, which is usually not a case in humans with severe SCI [ 44 ]. Translational large animal models can facilitate the development and testing of new therapeutic techniques where the difference between rodents and humans should be considered [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Combined Supra- and Sub-Lesional Epidural Electrical Stimulation for Restoration of the Motor Functions after Spinal Cord Injury in Mini Pigs

et al. 2020

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This study evaluates the effect of combined epidural electrical stimulation (EES) applied above (C5) and below (L2) the spinal cord injury (SCI) at T8–9 combined with motor training on the restoration of sensorimotor function in mini pigs. The motor evoked potentials (MEP) induced by EES applied at C5 and L2 levels were recorded in soleus muscles before and two weeks after SCI. EES treatment started two weeks after SCI and continued for 6 weeks led to improvement in multiple metrics, including behavioral, electrophysiological, and joint kinematics outcomes. In control animals after SCI a multiphasic M-response was observed during M/H-response testing, while animals received EES-enable training demonstrated the restoration of the M-response and H-reflex, although at a lower amplitude. The joint kinematic and assessment with Porcine Thoracic Injury Behavior scale (PTIBS) motor recovery scale demonstrated improvement in animals that received EES-enable training compared to animals with no treatment. The positive effect of two-level (cervical and lumbar) epidural electrical stimulation on functional restoration in mini pigs following spinal cord contusion injury in mini pigs could be related with facilitation of spinal circuitry at both levels and activation of multisegmental coordination. This approach can be taken as a basis for the future development of neuromodulation and neurorehabilitation therapy for patients with spinal cord injury.

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