GDNF gene delivery via the p75NTR receptor rescues injured motor neurons

Barati, Shahram; Hurtado, Plinio R; Zhang, Shu H; Tinsley, Rogan B.; Ferguson, Ian; Rush, Robert A.

doi:10.1016/j.expneurol.2006.05.027

Cited by 41 publications

(30 citation statements)

References 46 publications

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“…The neurotrophic action of GDNF on spinal motor neurons is widely recognized, 6 and the effectiveness of GDNF in SCI treatment has been extensively investigated. 4,5 In this study, we have documented that greater functional recovery was obtained using UCB-MCmediated gene therapy than using direct gene delivery, an effect that clearly depends on UCB-MCs.…”

Section: Discussionmentioning

confidence: 99%

“…Exploiting the stimulatory effects of neurotrophic factors on neuroregeneration appears to also be useful for SCI treatment, and one neurotrophic factor that is particularly suitable for SCI treatment is glial cell-derived neurotrophic factor (GDNF). GDNF is a member of the TGF-β superfamily that binds to the receptor GFRα1 and upregulates several signaling pathways; these pathways include those involving intracellular RAS/extracellular signalregulated kinase, phosphatidylinositol 3-kinase/AKT, p38 mitogenactivated protein kinase, c-Jun N-terminal kinase 1 and Src family kinases, 2,3 which promote neuronal survival and axon regrowth [4][5][6][7] by, for instance, increasing the expression of regeneration-associated genes such as βIII-tubulin and GAP-43 in chronically injured rubrospinal tract neurons. 8 In a previous study, nonviral GDNF gene delivery through a receptor-mediated mechanism rescued motor neurons after axotomy, and the gene was demonstrated to be expressed in motor neurons for up to 8 weeks.…”

Section: Introductionmentioning

confidence: 99%

“…8 In a previous study, nonviral GDNF gene delivery through a receptor-mediated mechanism rescued motor neurons after axotomy, and the gene was demonstrated to be expressed in motor neurons for up to 8 weeks. 6 However, compared with nonviral delivery, cell-based gene delivery or direct gene therapy is more often used for stimulating neuroregeneration. These approaches can be used for increasing the expression of neurotrophic factors and anti-apoptotic, cell adhesion and other biologically active molecules at injury sites.…”

Section: Introductionmentioning

confidence: 99%

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Adenoviral vector carrying glial cell-derived neurotrophic factor for direct gene therapy in comparison with human umbilical cord blood cell-mediated therapy of spinal cord injury in rat

et al. 2015

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Study design: Experimental study. Objective: To evaluate the treatment of spinal cord injury with glial cell-derived neurotrophic factor (GDNF) delivered using an adenoviral vector (AdV-GDNF group) in comparison with treatment performed using human umbilical cord blood mononuclear cells (UCB-MCs)-transduced with an adenoviral vector carrying the GDNF gene (UCB-MCs+AdV-GDNF group) in rat. Setting: Kazan, Russian Federation. Methods: We examined the efficacy of AdV-GDNF and UCB-MCs+AdV-GDNF therapy by conducting behavioral tests on the animals and morphometric studies on the spinal cord, performing immunofluorescence analyses on glial cells, investigating the survival and migration potential of UCB-MCs, and evaluating the expression of the recombinant GDNF gene. Results: At the 30th postoperative day, equal positive locomotor recovery was observed after both direct and cell-based GDNF therapy. However, after UCB-MCs-mediated GDNF therapy, the area of preserved tissue and the number of spared myelinated fibers were higher than those measured after direct GDNF gene therapy. Moreover, we observed distinct changes in the populations of glial cells; expression patterns of the specific markers for astrocytes (GFAP, S100B and AQP4), oligodendrocytes (PDGFαR and Cx47) and Schwann cells (P0) differed in various areas of the spinal cord of rats treated with AdV-GDNF and UCB-MCs+AdV-GDNF. Conclusion: The differences detected in the AdV-GDNF and UCB-MCs+AdV-GDNF groups could be partially explained by the action of UCB-MCs. We discuss the insufficiency and the advantages of these two methods of GDNF gene delivery into the spinal cord after traumatic injury. INTRODUCTIONSpinal cord injury (SCI) leads to complex pathological changes that include the death of neurons and glial cells and the demyelination and degeneration of nerve fibers. The limited growth capacity of mature central nervous system (CNS) neurons and the non-permissive environment of the CNS for axon regrowth are the main factors responsible for the little or no regeneration toward targets displayed by injured axons and for the permanent functional deficit observed after SCI. One promising approach for preventing neurodegeneration involves locally treating the site of injury in order to increase the expression of neurotrophic factors. Exploiting the stimulatory effects of neurotrophic factors on neuroregeneration appears to also be useful for SCI treatment, and one neurotrophic factor that is particularly suitable for SCI treatment is glial cell-derived neurotrophic factor (GDNF). GDNF is a member of the TGF-β superfamily that binds to the receptor GFRα1 and upregulates several signaling pathways; these pathways include those involving intracellular RAS/extracellular signalregulated kinase, phosphatidylinositol 3-kinase/AKT, p38 mitogen-

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adenoviral vector carrying glial cell-derived neurotrophic factor for direct gene therapy in comparison with human umbilical cord blood cell-mediated therapy of spinal cord injury in rat

et al. 2015

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“…Modular protein vectors have also been used for neuroprotection after acute peripheral nerve transection. For example, Barati and colleagues (Barati et al 2006) delivered a polylysine-based polyplex targeting p75 NTR positive cells accomplishing the plasmid encoding for GDNF after a peripheral nerve transection (see Table 1). They showed an almost complete reversal in neuronal death caused by GDNF transgene expression.…”

Section: Preclinical Studiesmentioning

confidence: 99%

Modular Multifunctional Protein Vectors for Gene Therapy

Peluffo¹

2011

Non-Viral Gene Therapy

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“…In contrast to the described viral mediated gene transfer methods, Barati et al [2006] used non-viral vector DNA to induce rat GDNF expression in hypoglossal motor neurons after nerve crush. In this study, gene delivery was achieved by coupling the plasmid DNA encoding for GDNF with an antibody to low-affinity nerve growth factor receptor (p75 LNGFR ) so that the foreign gene could be internalized to cells which expressed this receptor like the targeted motor neurons but also injury-activated SC.…”

Section: In Vivo Gene Therapy Approachesmentioning

confidence: 99%

Gene Therapy in Peripheral Nerve Reconstruction Approaches

Haastert¹,

Grothe

2007

CGT

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Gene transfer to a transected peripheral nerve or avulsed nerve root is discussed to be helpful where neurosurgical peripheral nerve reconstruction alone will not result in full recovery of function. Axonal regeneration is supposed to be facilitated by this new therapeutic approach via delivery of specific regeneration promoting molecules as well as survival proteins for the injured sensory and motor neurons. Therefore gene therapy aims in long-term and site-specific delivery of those neurotrophic factors. This paper reviews methods and perspectives for gene therapy to promote functional recovery of severely injured and thereafter reconstructed peripheral nerves. Experimental in vivo and ex vivo gene therapy approaches are reported by different groups. In vivo gene therapy generally uses direct injection of cDNA vectors to injured peripheral nerves. Ex vivo gene therapy is based on the isolation of autologous cells followed by genetic modification of these cells in vitro and re-transplantation of the modified cells to the patient as part of tissue engineered nerve transplants. Vectors of different origin are published to be suitable for peripheral nerve gene therapy and this review discusses the different strategies with regard to their efficiency in gene transfer, their risks and their potential relevance for clinical application.

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GDNF gene delivery via the p75NTR receptor rescues injured motor neurons

Cited by 41 publications

References 46 publications

Adenoviral vector carrying glial cell-derived neurotrophic factor for direct gene therapy in comparison with human umbilical cord blood cell-mediated therapy of spinal cord injury in rat

Adenoviral vector carrying glial cell-derived neurotrophic factor for direct gene therapy in comparison with human umbilical cord blood cell-mediated therapy of spinal cord injury in rat

Modular Multifunctional Protein Vectors for Gene Therapy

Gene Therapy in Peripheral Nerve Reconstruction Approaches

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