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GDNF Gene Therapy to Repair the Injured Peripheral Nerve

A spinal root avulsion is the most severe proximal peripheral nerve lesion possible. Avulsion of ventral root filaments disconnects spinal motoneurons from their target muscles, resulting in complete paralysis. In patients that undergo brachial plexus nerve repair, axonal regeneration is a slow proc...

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Autores principales: Eggers, Ruben, de Winter, Fred, Tannemaat, Martijn R., Malessy, Martijn J. A., Verhaagen, Joost
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673415/
https://www.ncbi.nlm.nih.gov/pubmed/33251197
http://dx.doi.org/10.3389/fbioe.2020.583184
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author Eggers, Ruben
de Winter, Fred
Tannemaat, Martijn R.
Malessy, Martijn J. A.
Verhaagen, Joost
author_facet Eggers, Ruben
de Winter, Fred
Tannemaat, Martijn R.
Malessy, Martijn J. A.
Verhaagen, Joost
author_sort Eggers, Ruben
collection PubMed
description A spinal root avulsion is the most severe proximal peripheral nerve lesion possible. Avulsion of ventral root filaments disconnects spinal motoneurons from their target muscles, resulting in complete paralysis. In patients that undergo brachial plexus nerve repair, axonal regeneration is a slow process. It takes months or even years to bridge the distance from the lesion site to the distal targets located in the forearm. Following ventral root avulsion, without additional pharmacological or surgical treatments, progressive death of motoneurons occurs within 2 weeks (Koliatsos et al., 1994). Reimplantation of the avulsed ventral root or peripheral nerve graft can act as a conduit for regenerating axons and increases motoneuron survival (Chai et al., 2000). However, this beneficial effect is transient. Combined with protracted and poor long-distance axonal regeneration, this results in permanent function loss. To overcome motoneuron death and improve functional recovery, several promising intervention strategies are being developed. Here, we focus on GDNF gene-therapy. We first introduce the experimental ventral root avulsion model and discuss its value as a proxy to study clinical neurotmetic nerve lesions. Second, we discuss our recent studies showing that GDNF gene-therapy is a powerful strategy to promote long-term motoneuron survival and improve function when target muscle reinnervation occurs within a critical post-lesion period. Based upon these observations, we discuss the influence of timing of the intervention, and of the duration, concentration and location of GDNF delivery on functional outcome. Finally, we provide a perspective on future research directions to realize functional recovery using gene therapy.
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spelling pubmed-76734152020-11-26 GDNF Gene Therapy to Repair the Injured Peripheral Nerve Eggers, Ruben de Winter, Fred Tannemaat, Martijn R. Malessy, Martijn J. A. Verhaagen, Joost Front Bioeng Biotechnol Bioengineering and Biotechnology A spinal root avulsion is the most severe proximal peripheral nerve lesion possible. Avulsion of ventral root filaments disconnects spinal motoneurons from their target muscles, resulting in complete paralysis. In patients that undergo brachial plexus nerve repair, axonal regeneration is a slow process. It takes months or even years to bridge the distance from the lesion site to the distal targets located in the forearm. Following ventral root avulsion, without additional pharmacological or surgical treatments, progressive death of motoneurons occurs within 2 weeks (Koliatsos et al., 1994). Reimplantation of the avulsed ventral root or peripheral nerve graft can act as a conduit for regenerating axons and increases motoneuron survival (Chai et al., 2000). However, this beneficial effect is transient. Combined with protracted and poor long-distance axonal regeneration, this results in permanent function loss. To overcome motoneuron death and improve functional recovery, several promising intervention strategies are being developed. Here, we focus on GDNF gene-therapy. We first introduce the experimental ventral root avulsion model and discuss its value as a proxy to study clinical neurotmetic nerve lesions. Second, we discuss our recent studies showing that GDNF gene-therapy is a powerful strategy to promote long-term motoneuron survival and improve function when target muscle reinnervation occurs within a critical post-lesion period. Based upon these observations, we discuss the influence of timing of the intervention, and of the duration, concentration and location of GDNF delivery on functional outcome. Finally, we provide a perspective on future research directions to realize functional recovery using gene therapy. Frontiers Media S.A. 2020-10-30 /pmc/articles/PMC7673415/ /pubmed/33251197 http://dx.doi.org/10.3389/fbioe.2020.583184 Text en Copyright © 2020 Eggers, de Winter, Tannemaat, Malessy and Verhaagen. 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(s) 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 Bioengineering and Biotechnology
Eggers, Ruben
de Winter, Fred
Tannemaat, Martijn R.
Malessy, Martijn J. A.
Verhaagen, Joost
GDNF Gene Therapy to Repair the Injured Peripheral Nerve
title GDNF Gene Therapy to Repair the Injured Peripheral Nerve
title_full GDNF Gene Therapy to Repair the Injured Peripheral Nerve
title_fullStr GDNF Gene Therapy to Repair the Injured Peripheral Nerve
title_full_unstemmed GDNF Gene Therapy to Repair the Injured Peripheral Nerve
title_short GDNF Gene Therapy to Repair the Injured Peripheral Nerve
title_sort gdnf gene therapy to repair the injured peripheral nerve
topic Bioengineering and Biotechnology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673415/
https://www.ncbi.nlm.nih.gov/pubmed/33251197
http://dx.doi.org/10.3389/fbioe.2020.583184
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