Post–spinal cord injury astrocyte-mediated functional recovery in rats after intraspinal injection of the recombinant adenoviral vectors Ad5-VEGF and Ad5-ANG

Povysheva, T.V.; Шмаров, М. М.; Logunov, Denis Y.; Naroditsky, Boris S.; Shulman, Ilya; Ogurcov, Sergey; Kolesnikov, Pavel; Islamov, R. R.; Chelyshev, Yu. A.

doi:10.3171/2016.9.spine15959

Cited by 17 publications

(9 citation statements)

References 35 publications

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“…Similar to our study on mini pig, we found functional improvement in rats with SCI after intrathecal administration of adenoviral vectors or genetically engineered UCB-MCs with two combinations of therapeutic genes: (1) VEGF+GDNF+NCAM and (2) VEGF+ANG+NCAM that was demonstrated based on Basso-Beattie-Bresnahan (BBB) score. The pattern of motor recovery in gene-treated groups was consistent with our previous studies showing improvement after intraspinal injection of Ad5-VEGF+Ad5-ANG vectors on BBB score (Povysheva et al, 2017 ). Thus, intrathecal delivery of the therapeutic genes was found to be as effective as intraspinal approach of gene administration.…”

Section: Discussionsupporting

confidence: 90%

“…Simultaneous delivery of various therapeutic genes into post-traumatic spinal cord may not only support the viability of affected injury cells and stimulate their regeneration, but also influence different mechanisms of the SCI including inflammation, demyelination, astrogliosis, and others (Lim et al, 2010 ; Walthers and Seidlits, 2015 ). Currently, several therapeutic genes are considered to be effective for single gene therapy, i.e., encoding neurotrophic BDNF (Nakajima et al, 2007 ), NGF (Romero et al, 2001 ), GDNF (Chou et al, 2014 ), growth VEGF, FGF (De Laporte et al, 2011 ), Angiogenin (Povysheva et al, 2017 ), anti-apoptotic BCL-2, BCL-XL (Yukawa et al, 2002 ), and anti-inflammatory IL-10, IL-1RA (Zhou et al, 2009 ) factors, and cell adhesion NCAM and L1 molecules (Chaudhry et al, 2006 ; Thuret et al, 2006 ; Walthers and Seidlits, 2015 ). The search for the best single candidate or the optimal combinations of several therapeutic genes is particularly important for translation of the gene therapy strategy to clinic.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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 this relatively younger and wide spectrum of pre-middle age groups, anti-VEGF approaches have been proposed because the endogenous level of VEGF has not declined in the parenchyma adjacent to cerebral ventricles and in the cerebrospinal fluid (CSF). The neuroprotective effect of VEGF in cerebrovascular diseases is appreciated but the causal role of VEGF in the cerebral vasculature and ventricles has just begun to be revealed [ 8 , 12 , 16 , 18 , 19 , 20 , 22 , 24 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

Section: Vegf Signaling In Cerebrovascular Diseasesmentioning

confidence: 99%

“…However, such a clinical report alone displaying VEGF as a biomarker (total human sample size, 171) is not sufficient to determine an appropriate therapeutic approach of pro-VEGF or anti-VEGF drugs. As described in this section, for clinical decision making of pro-VEGF therapy, however, a methodological advancement of delivering VEGF [ 30 , 51 , 52 ] or inducing endogenous VEGF-like trophic factors [ 49 , 58 ] are expected to achieve a more effective modulatory outcome of neuroprotection in the cerebrovascular disease.…”

Section: Vegf Signaling In Cerebrovascular Diseasesmentioning

confidence: 99%

VEGF Signaling in Neurological Disorders

Shim

Madsen

2018

IJMS

117

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Vascular endothelial growth factor (VEGF) is a potent growth factor playing diverse roles in vasculogenesis and angiogenesis. In the brain, VEGF mediates angiogenesis, neural migration and neuroprotection. As a permeability factor, excessive VEGF disrupts intracellular barriers, increases leakage of the choroid plexus endothelia, evokes edema, and activates the inflammatory pathway. Recently, we discovered that a heparin binding epidermal growth factor like growth factor (HB-EGF)—a class of EGF receptor (EGFR) family ligands—contributes to the development of hydrocephalus with subarachnoid hemorrhage through activation of VEGF signaling. The objective of this review is to entail a recent update on causes of death due to neurological disorders involving cerebrovascular and age-related neurological conditions and to understand the mechanism by which angiogenesis-dependent pathological events can be treated with VEGF antagonisms. The Global Burden of Disease study indicates that cancer and cardiovascular disease including ischemic and hemorrhagic stroke are two leading causes of death worldwide. The literature suggests that VEGF signaling in ischemic brains highlights the importance of concentration, timing, and alternate route of modulating VEGF signaling pathway. Molecular targets distinguishing two distinct pathways of VEGF signaling may provide novel therapies for the treatment of neurological disorders and for maintaining lower mortality due to these conditions.

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“…Н.Ф. Гамалеи (Москва) [5]. В настоящем исследовании были исполь-зованы Ad5, несущие репортёрный ген зелё-ного флюоресцирующего белка (Ad5-GFP).…”

Section: экспериментальная медицинаunclassified

Experimental validation of gene therapy for ischemic stroke

et al. 2017

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Aim. To develop a protocol of direct and cell-mediated gene therapy for ischemic stroke. Methods. Viral vector carrying green fluorescent protein (GFP) reporter gene was created on the basis of human adenovirus serotype 5 (Ad5). The umbilical blood supply was preserved according to instructions of Kazan State Medical Uuniversity Stem cell bank. Umbilical cord blood mononuclear cells were isolated in a ficoll density gradient by standard procedure and transduced with Ad5-GFP. Ischemic cerebral stroke in rats was caused by distal occlusion of the middle cerebral artery through trephination hole in a temporal bone under surgical microscope. Within four hours after modeling stroke in the anesthetized animals laminectomy was performed at the L 4 -L 5 level, and (1) 0.9% sodium

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Post–spinal cord injury astrocyte-mediated functional recovery in rats after intraspinal injection of the recombinant adenoviral vectors Ad5-VEGF and Ad5-ANG

Cited by 17 publications

References 35 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

VEGF Signaling in Neurological Disorders

Experimental validation of gene therapy for ischemic stroke

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