A pilot study of cell-mediated gene therapy for spinal cord injury in mini pigs

Islamov, R. R.; Sokolov, Mikhail; Bashirov, Farid Vagizovich; Fadeev, Filip; Шмаров, М. М.; Naroditskiy, B. S.; Povysheva, T.V.; Shaymardanova, G. F.; Yakupov, R. A.; Chelyshev, Yu. A.; Lavrov, Igor

doi:10.1016/j.neulet.2017.02.034

Cited by 25 publications

(22 citation statements)

References 21 publications

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“…Previously we reported positive results with a novel therapeutic strategy for SCI treatment in mini pigs with SCI where the intrathecal administration of gene modified UCB-MNs improved nervous tissue sparing and locomotor functional recovery (Islamov et al, 2017 ). In the present investigation we applied the same strategy using rat model of SCI.…”

Section: Discussionmentioning

confidence: 99%

“…In our recent study, along with other findings, we observed improvements and prolongation of lifespan in amyotrophic lateral sclerosis (ALS) mice after transplantation of the umbilical cord blood mononuclear cells (UCB-MCs) simultaneously transduced with three adenoviral vectors (Ad) encoding vascular endothelial growth factor (VEGF), glial derived neurotrophic factor (GDNF) and neural cell adhesion molecule (NCAM). Recently we also describe a positive effect of UCB-MC simultaneously transduced with three adenoviral vectors carrying VEGF, GDNF and NCAM for treatment of SCI in mini-pigs (Islamov et al, 2017 ) with earlier functional recovery. The role of each factor and their combination has to be further investigated.…”

Section: Introductionmentioning

confidence: 94%

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Spinal Cord Molecular and Cellular Changes Induced by Adenoviral Vector- and Cell-Mediated Triple Gene Therapy after Severe Contusion

et al. 2017

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The gene therapy has been successful in treatment of spinal cord injury (SCI) in several animal models, although it still remains unavailable for clinical practice. Surprisingly, regardless the fact that multiple reports showed motor recovery with gene therapy, little is known about molecular and cellular changes in the post-traumatic spinal cord following viral vector- or cell-mediated gene therapy. In this study we evaluated the therapeutic efficacy and changes in spinal cord after treatment with the genes encoding vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF), angiogenin (ANG), and neuronal cell adhesion molecule (NCAM) applied using both approaches. Therapeutic genes were used for viral vector- and cell-mediated gene therapy in two combinations: (1) VEGF+GDNF+NCAM and (2) VEGF+ANG+NCAM. For direct gene therapy adenoviral vectors based on serotype 5 (Ad5) were injected intrathecally and for cell-mediated gene delivery human umbilical cord blood mononuclear cells (UCB-MC) were simultaneously transduced with three Ad5 vectors and injected intrathecally 4 h after the SCI. The efficacy of both treatments was confirmed by improvement in behavioral (BBB) test. Molecular and cellular changes following post-traumatic recovery were evaluated with immunofluorescent staining using antibodies against the functional markers of motorneurons (Hsp27, synaptophysin, PSD95), astrocytes (GFAP, vimentin), oligodendrocytes (Olig2, NG2, Cx47) and microglial cells (Iba1). Our results suggest that both approaches with intrathecal delivery of therapeutic genes may support functional recovery of post-traumatic spinal cord via lowering the stress (down regulation of Hsp25) and enhancing the synaptic plasticity (up regulation of PSD95 and synaptophysin), supporting oligodendrocyte proliferation (up regulation of NG2) and myelination (up regulation of Olig2 and Cx47), modulating astrogliosis by reducing number of astrocytes (down regulation of GFAP and vimetin) and microglial cells (down regulation of Iba1).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Spinal Cord Molecular and Cellular Changes Induced by Adenoviral Vector- and Cell-Mediated Triple Gene Therapy after Severe Contusion

et al. 2017

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“…In our previous studies, we showed the positive effect of gene-modified umbilical cord blood mononuclear cells (UCB-MC), simultaneously producing three recombinant molecules—vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF) and neural cell adhesion molecule (NCAM)—in animal models of amyotrophic lateral sclerosis [ 23 ], spinal cord injury [ 24 ], and stroke [ 25 ]. The rationale of using a combination of two neurotrophic factors with cell adhesion molecules is based on the well-known neuroprotective effects of VEGF and GDNF [ 26 , 27 ], with the expression of NCAM increasing the homing and survivability of UCB-MC at the brain injury site [ 28 ] supporting local production of the therapeutic molecules.…”

Section: Introductionmentioning

confidence: 99%

Preventive Triple Gene Therapy Reduces the Negative Consequences of Ischemia-Induced Brain Injury after Modelling Stroke in a Rat

Markosyan

Safiullov

Izmailov

et al. 2020

IJMS

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Currently, the main fundamental and clinical interest for stroke therapy is focused on developing a neuroprotective treatment of a penumbra region within the therapeutic window. The development of treatments for ischemic stroke in at-risk patients is of particular interest. Preventive gene therapy may significantly reduce the negative consequences of ischemia-induced brain injury. In the present study, we suggest the approach of preventive gene therapy for stroke. Adenoviral vectors carrying genes encoding vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF) and neural cell adhesion molecule (NCAM) or gene engineered umbilical cord blood mononuclear cells (UCB-MC) overexpressing recombinant VEGF, GDNF, and NCAM were intrathecally injected before distal occlusion of the middle cerebral artery in rats. Post-ischemic brain recovery was investigated 21 days after stroke modelling. Morphometric and immunofluorescent analysis revealed a reduction of infarction volume accompanied with a lower number of apoptotic cells and decreased expression of Hsp70 in the peri-infarct region in gene-treated animals. The lower immunopositive areas for astrocytes and microglial cells markers, higher number of oligodendrocytes and increased expression of synaptic proteins suggest the inhibition of astrogliosis, supporting the corresponding myelination and functional recovery of neurons in animals receiving preventive gene therapy. In this study, for the first time, we provide evidence of the beneficial effects of preventive triple gene therapy by an adenoviral- or UCB-MC-mediated intrathecal simultaneous delivery combination of vegf165, gdnf, and ncam1 on the preservation and recovery of the brain in rats with subsequent modelling of stroke.

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“…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%

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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A pilot study of cell-mediated gene therapy for spinal cord injury in mini pigs

Cited by 25 publications

References 21 publications

Spinal Cord Molecular and Cellular Changes Induced by Adenoviral Vector- and Cell-Mediated Triple Gene Therapy after Severe Contusion

Spinal Cord Molecular and Cellular Changes Induced by Adenoviral Vector- and Cell-Mediated Triple Gene Therapy after Severe Contusion

Preventive Triple Gene Therapy Reduces the Negative Consequences of Ischemia-Induced Brain Injury after Modelling Stroke in a Rat

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

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