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

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) t...

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Autores principales: Sokolov, Mikhail E., Bashirov, Farid V., Markosyan, Vage A., Povysheva, Tatyana V., Fadeev, Filip O., Izmailov, Andrey A., Kuztetsov, Maxim S., Safiullov, Zufar Z., Shmarov, Maxim M., Naroditskyi, Boris S., Palotás, András, Islamov, Rustem R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818439/
https://www.ncbi.nlm.nih.gov/pubmed/29497380
http://dx.doi.org/10.3389/fphar.2018.00111
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author Sokolov, Mikhail E.
Bashirov, Farid V.
Markosyan, Vage A.
Povysheva, Tatyana V.
Fadeev, Filip O.
Izmailov, Andrey A.
Kuztetsov, Maxim S.
Safiullov, Zufar Z.
Shmarov, Maxim M.
Naroditskyi, Boris S.
Palotás, András
Islamov, Rustem R.
author_facet Sokolov, Mikhail E.
Bashirov, Farid V.
Markosyan, Vage A.
Povysheva, Tatyana V.
Fadeev, Filip O.
Izmailov, Andrey A.
Kuztetsov, Maxim S.
Safiullov, Zufar Z.
Shmarov, Maxim M.
Naroditskyi, Boris S.
Palotás, András
Islamov, Rustem R.
author_sort Sokolov, Mikhail E.
collection PubMed
description 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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spelling pubmed-58184392018-03-01 Triple-Gene Therapy for Stroke: A Proof-of-Concept in Vivo Study in Rats Sokolov, Mikhail E. Bashirov, Farid V. Markosyan, Vage A. Povysheva, Tatyana V. Fadeev, Filip O. Izmailov, Andrey A. Kuztetsov, Maxim S. Safiullov, Zufar Z. Shmarov, Maxim M. Naroditskyi, Boris S. Palotás, András Islamov, Rustem R. Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2018-02-15 /pmc/articles/PMC5818439/ /pubmed/29497380 http://dx.doi.org/10.3389/fphar.2018.00111 Text en Copyright © 2018 Sokolov, Bashirov, Markosyan, Povysheva, Fadeev, Izmailov, Kuztetsov, Safiullov, Shmarov, Naroditskyi, Palotás and Islamov. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Sokolov, Mikhail E.
Bashirov, Farid V.
Markosyan, Vage A.
Povysheva, Tatyana V.
Fadeev, Filip O.
Izmailov, Andrey A.
Kuztetsov, Maxim S.
Safiullov, Zufar Z.
Shmarov, Maxim M.
Naroditskyi, Boris S.
Palotás, András
Islamov, Rustem R.
Triple-Gene Therapy for Stroke: A Proof-of-Concept in Vivo Study in Rats
title Triple-Gene Therapy for Stroke: A Proof-of-Concept in Vivo Study in Rats
title_full Triple-Gene Therapy for Stroke: A Proof-of-Concept in Vivo Study in Rats
title_fullStr Triple-Gene Therapy for Stroke: A Proof-of-Concept in Vivo Study in Rats
title_full_unstemmed Triple-Gene Therapy for Stroke: A Proof-of-Concept in Vivo Study in Rats
title_short Triple-Gene Therapy for Stroke: A Proof-of-Concept in Vivo Study in Rats
title_sort triple-gene therapy for stroke: a proof-of-concept in vivo study in rats
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818439/
https://www.ncbi.nlm.nih.gov/pubmed/29497380
http://dx.doi.org/10.3389/fphar.2018.00111
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