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

Markosyan, Vage; Safiullov, Zufar Z.; Izmailov, Andrei; Fadeev, Filip; Sokolov, Mikhail; Kuznetsov, M. S.; Trofimov, D. A.; Kim, Evgeny; Kundakchyan, Grayr; Gibadullin, Airat; Салафутдинов, И. И.; Нуруллин, Л. Ф.; Bashirov, Farid Vagizovich; Islamov, R. R.

doi:10.3390/ijms21186858

Cited by 14 publications

(14 citation statements)

References 57 publications

(67 reference statements)

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“…The simultaneous intrathecal delivery of 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, showed positive effects on the preservation and recovery of the brain in rats after stroke modeling. The obtained data might add an additional knowledge for ischemic stroke treatment as a novel, and potentially successful, approach [193].…”

Section: Other Treatment Perspectivesmentioning

confidence: 82%

The Genetic Basis of Strokes in Pediatric Populations and Insight into New Therapeutic Options

Janković

Petrović²,

Novaković

et al. 2022

IJMS

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Strokes within pediatric populations are considered to be the 10th leading cause of death in the United States of America, with over half of such events occurring in children younger than one year of life. The multifactorial etiopathology that has an influence on stroke development and occurrence signify the importance of the timely recognition of both modifiable and non-modifiable factors for adequate diagnostic and treatment approaches. The early recognition of a stroke and stroke risk in children has the potential to advance the application of neuroprotective, thrombolytic, and antithrombotic interventions and rehabilitation strategies to the earliest possible timepoints after the onset of a stroke, improving the outcomes and quality of life for affected children and their families. The recent development of molecular genetic methods has greatly facilitated the analysis and diagnosis of single-gene disorders. In this review, the most significant single gene disorders associated with pediatric stroke are presented, along with specific therapeutic options whenever they exist. Besides monogenic disorders that may present with stroke as a first symptom, genetic polymorphisms may contribute to the risk of pediatric and perinatal stroke. The most frequently studied genetic risk factors are several common polymorphisms in genes associated with thrombophilia; these genes code for proteins that are part of the coagulation cascade, fibrolysis, homocystein metabolism, lipid metabolism, or platelets. Single polymorphism frequencies may not be sufficient to completely explain the stroke causality and an analysis of several genotype combinations is a more promising approach. The recent steps forward in our understanding of the disorders underlying strokes has given us a next generation of therapeutics and therapeutic targets by which to improve stroke survival, protect or rebuild neuronal connections in the brain, and enhance neural function. Advances in DNA sequencing and the development of new tools to correct human gene mutations have brought genetic analysis and gene therapy into the focus of investigations for new therapeutic options for stroke patients.

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Section: Other Treatment Perspectivesmentioning

confidence: 82%

The Genetic Basis of Strokes in Pediatric Populations and Insight into New Therapeutic Options

Janković

Petrović²,

Novaković

et al. 2022

IJMS

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“…VEGF, the most important pro-angiogenic factor, was shown to function directly as a neurotrophic and neuroprotective factor for glial cells and neurons. [36][37][38] Muratori et al reported a modulation mechanism for VEGF and its family members under degenerative and regenerative conditions. They concluded that VEGF could influence the migration of Schwann cells.…”

Section: Discussionmentioning

confidence: 99%

Biocompatible Polyurethane Conduit Grafted with Vascular Endothelial Growth Factor‐Loaded Hydrogel Repairs the Peripheral Nerve Defect in Rats

Zhang

Lü

et al. 2021

Macromolecular Bioscience

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Artificial nerve guidance conduits (NGCs) can be potentially used to address the problems of peripheral nerve defects. The biomaterial polyurethane (PU) has already been used to construct NGCs. However, the use of a combination of PU-based NGCs and other bioactive cues, such as extracellular matrix proteins and growth factors, has not been reported yet. A PU conduit grafted with a vascular endothelial growth factor (VEGF)-loaded hydrogel (abbreviated as PU/Gel/VEGF conduit) is fabricated. The leachate generated during the use of the PU/Gel/VEGF conduit could facilitate the proliferation, migration, and expression of the neural marker S100𝜷 in RSC96 cells (in vitro). The walking track and target muscle are analyzed, and it is observed that PU/Gel/VEGF conduits promote the functional recovery of the injured side. Various histological staining analyses are carried out, and the results reveal that the PU/Gel/VEGF conduit effectively improves the extent of nerve regeneration achieved. The number of blood vessels developed during the regeneration of the axons in the PU/Gel/VEGF group (attributable to the pro-angiogenic effect of the functional NGC) is higher than the number of blood vessels developed in the PU/Gel conduit. Overall, the results indicate that PU/Gel/VEGF conduits could promote the process of peripheral nerve regeneration.

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“…Markosyan et al (2020) tested adenoviral vectors carrying VEGF in combination with GDNF and neural cell adhesion molecule as a preventative option for ischemic stroke in rats. Intrathecal delivery reduced infarct size and brought about functional recovery of neurons, though neurogenesis was not observed 84 . Acute upregulation of VEGF is associated with disruption of the BBB, which must be considered for clinical trials and could be mitigated by combining VEGF with other angiogenic factors 85 .…”

Section: Neurotrophic Factors In Gene Therapymentioning

confidence: 94%

Neurogenesis: Gene-Based Strategies for Treating Ischemic Stroke

Bhagwat¹,

Bronstein²,

Bhatt³

et al. 2022

bptjm

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Stroke is one of the predominant causes of long-term disability and death, and is characterized by the cessation of blood flow to part of the brain, preventing it from accessing oxygen and nutrients needed for ATP production and proper function. Ischemic stroke, the most prevalent type of stroke, involves an obstruction such as a blood clot in a blood vessel. Current treatments seek to remove the obstruction and restore blood flow, but are time-limited and do not reverse tissue damage once it has occurred. The endogenous response to ischemic stroke involves an increase in neurogenesis but falls short in producing functional recovery. Gene therapy that enhances neurogenesis has provided encouraging results in animal models. Preclinical studies in this area have utilized neurotrophic factors that can promote migration of cells from the subventricular zone (SVZ). The transcription factor NeuroD1 converts reactive glial cells, which increase during ischemia, into neurons that integrate into the existing circuits of the brain. The clinical value of gene therapy depends upon the development of safe and efficient administration methods. In this review, we draw from scientific literature to evaluate the relevant genes and vectors for treating ischemic stroke through neurogenesis, and discuss strategies to overcome current limitations of gene therapy in human patients.

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

Cited by 14 publications

References 57 publications

The Genetic Basis of Strokes in Pediatric Populations and Insight into New Therapeutic Options

The Genetic Basis of Strokes in Pediatric Populations and Insight into New Therapeutic Options

Biocompatible Polyurethane Conduit Grafted with Vascular Endothelial Growth Factor‐Loaded Hydrogel Repairs the Peripheral Nerve Defect in Rats

Neurogenesis: Gene-Based Strategies for Treating Ischemic Stroke

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