TrkB gene therapy by adeno-associated virus enhances recovery after cervical spinal cord injury

Gabriel Martínez-Gálvez, Juan M. Zambrano, Juan C. Diaz Soto, Wen Zhi Zhan, Heather M. Gransee, Gary C Sieck, Carlos Bernardo Mantilla

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Unilateral cervical spinal cord hemisection at C2 (C2SH) interrupts descending bulbospinal inputs to phrenic motoneurons, paralyzing the diaphragm muscle. Recovery after C2SH is enhanced by brain derived neurotrophic factor (BDNF) signaling via the tropomyosin-related kinase subtype B (TrkB) receptor in phrenic motoneurons. The role for gene therapy using adeno-associated virus (AAV)-mediated delivery of TrkB to phrenic motoneurons is not known. The present study determined the therapeutic efficacy of intrapleural delivery of AAV7 encoding for full-length TrkB (AAV-TrkB) to phrenic motoneurons 3 days post-C2SH. Diaphragm EMG was recorded chronically in male rats (n=26) up to 21 days post-C2SH. Absent ipsilateral diaphragm EMG activity was verified 3 days post-C2SH. A greater proportion of animals displayed recovery of ipsilateral diaphragm EMG activity during eupnea by 14 and 21 days post-SH after AAV-TrkB (10/15) compared to AAV-GFP treatment (2/11; p=0.031). Diaphragm EMG amplitude increased over time post-C2SH (p2=0.82), with increased motoneuron NMDA expression evident in animals treated with AAV-TrkB and that displayed recovery after C2SH. Overall, gene therapy using intrapleural delivery of AAV-TrkB to phrenic motoneurons is sufficient to promote recovery of diaphragm activity, adding a novel potential intervention that can be administered after upper cervical spinal cord injury to improve impaired respiratory function.

Original languageEnglish (US)
Pages (from-to)31-40
Number of pages10
JournalExperimental Neurology
Volume276
DOIs
StatePublished - Feb 1 2016

Fingerprint

Dependovirus
Diaphragm
Spinal Cord Injuries
Genetic Therapy
Motor Neurons
Cervical Cord
tropomyosin kinase
Brain-Derived Neurotrophic Factor
N-Methylaspartate

Keywords

  • Diaphragm muscle
  • Glutamatergic
  • Neuroplasticity
  • Neurotransmitter
  • Neurotrophin
  • Phrenic motoneuron
  • Respiratory
  • Serotonergic
  • Spinal hemisection

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Cite this

Martínez-Gálvez, G., Zambrano, J. M., Diaz Soto, J. C., Zhan, W. Z., Gransee, H. M., Sieck, G. C., & Mantilla, C. B. (2016). TrkB gene therapy by adeno-associated virus enhances recovery after cervical spinal cord injury. Experimental Neurology, 276, 31-40. https://doi.org/10.1016/j.expneurol.2015.11.007

TrkB gene therapy by adeno-associated virus enhances recovery after cervical spinal cord injury. / Martínez-Gálvez, Gabriel; Zambrano, Juan M.; Diaz Soto, Juan C.; Zhan, Wen Zhi; Gransee, Heather M.; Sieck, Gary C; Mantilla, Carlos Bernardo.

In: Experimental Neurology, Vol. 276, 01.02.2016, p. 31-40.

Research output: Contribution to journalArticle

Martínez-Gálvez G, Zambrano JM, Diaz Soto JC, Zhan WZ, Gransee HM, Sieck GC et al. TrkB gene therapy by adeno-associated virus enhances recovery after cervical spinal cord injury. Experimental Neurology. 2016 Feb 1;276:31-40. https://doi.org/10.1016/j.expneurol.2015.11.007
Martínez-Gálvez, Gabriel ; Zambrano, Juan M. ; Diaz Soto, Juan C. ; Zhan, Wen Zhi ; Gransee, Heather M. ; Sieck, Gary C ; Mantilla, Carlos Bernardo. / TrkB gene therapy by adeno-associated virus enhances recovery after cervical spinal cord injury. In: Experimental Neurology. 2016 ; Vol. 276. pp. 31-40.
@article{355ff9e8c1984238b05ec7adff46839b,
title = "TrkB gene therapy by adeno-associated virus enhances recovery after cervical spinal cord injury",
abstract = "Unilateral cervical spinal cord hemisection at C2 (C2SH) interrupts descending bulbospinal inputs to phrenic motoneurons, paralyzing the diaphragm muscle. Recovery after C2SH is enhanced by brain derived neurotrophic factor (BDNF) signaling via the tropomyosin-related kinase subtype B (TrkB) receptor in phrenic motoneurons. The role for gene therapy using adeno-associated virus (AAV)-mediated delivery of TrkB to phrenic motoneurons is not known. The present study determined the therapeutic efficacy of intrapleural delivery of AAV7 encoding for full-length TrkB (AAV-TrkB) to phrenic motoneurons 3 days post-C2SH. Diaphragm EMG was recorded chronically in male rats (n=26) up to 21 days post-C2SH. Absent ipsilateral diaphragm EMG activity was verified 3 days post-C2SH. A greater proportion of animals displayed recovery of ipsilateral diaphragm EMG activity during eupnea by 14 and 21 days post-SH after AAV-TrkB (10/15) compared to AAV-GFP treatment (2/11; p=0.031). Diaphragm EMG amplitude increased over time post-C2SH (p2=0.82), with increased motoneuron NMDA expression evident in animals treated with AAV-TrkB and that displayed recovery after C2SH. Overall, gene therapy using intrapleural delivery of AAV-TrkB to phrenic motoneurons is sufficient to promote recovery of diaphragm activity, adding a novel potential intervention that can be administered after upper cervical spinal cord injury to improve impaired respiratory function.",
keywords = "Diaphragm muscle, Glutamatergic, Neuroplasticity, Neurotransmitter, Neurotrophin, Phrenic motoneuron, Respiratory, Serotonergic, Spinal hemisection",
author = "Gabriel Mart{\'i}nez-G{\'a}lvez and Zambrano, {Juan M.} and {Diaz Soto}, {Juan C.} and Zhan, {Wen Zhi} and Gransee, {Heather M.} and Sieck, {Gary C} and Mantilla, {Carlos Bernardo}",
year = "2016",
month = "2",
day = "1",
doi = "10.1016/j.expneurol.2015.11.007",
language = "English (US)",
volume = "276",
pages = "31--40",
journal = "Experimental Neurology",
issn = "0014-4886",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - TrkB gene therapy by adeno-associated virus enhances recovery after cervical spinal cord injury

AU - Martínez-Gálvez, Gabriel

AU - Zambrano, Juan M.

AU - Diaz Soto, Juan C.

AU - Zhan, Wen Zhi

AU - Gransee, Heather M.

AU - Sieck, Gary C

AU - Mantilla, Carlos Bernardo

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Unilateral cervical spinal cord hemisection at C2 (C2SH) interrupts descending bulbospinal inputs to phrenic motoneurons, paralyzing the diaphragm muscle. Recovery after C2SH is enhanced by brain derived neurotrophic factor (BDNF) signaling via the tropomyosin-related kinase subtype B (TrkB) receptor in phrenic motoneurons. The role for gene therapy using adeno-associated virus (AAV)-mediated delivery of TrkB to phrenic motoneurons is not known. The present study determined the therapeutic efficacy of intrapleural delivery of AAV7 encoding for full-length TrkB (AAV-TrkB) to phrenic motoneurons 3 days post-C2SH. Diaphragm EMG was recorded chronically in male rats (n=26) up to 21 days post-C2SH. Absent ipsilateral diaphragm EMG activity was verified 3 days post-C2SH. A greater proportion of animals displayed recovery of ipsilateral diaphragm EMG activity during eupnea by 14 and 21 days post-SH after AAV-TrkB (10/15) compared to AAV-GFP treatment (2/11; p=0.031). Diaphragm EMG amplitude increased over time post-C2SH (p2=0.82), with increased motoneuron NMDA expression evident in animals treated with AAV-TrkB and that displayed recovery after C2SH. Overall, gene therapy using intrapleural delivery of AAV-TrkB to phrenic motoneurons is sufficient to promote recovery of diaphragm activity, adding a novel potential intervention that can be administered after upper cervical spinal cord injury to improve impaired respiratory function.

AB - Unilateral cervical spinal cord hemisection at C2 (C2SH) interrupts descending bulbospinal inputs to phrenic motoneurons, paralyzing the diaphragm muscle. Recovery after C2SH is enhanced by brain derived neurotrophic factor (BDNF) signaling via the tropomyosin-related kinase subtype B (TrkB) receptor in phrenic motoneurons. The role for gene therapy using adeno-associated virus (AAV)-mediated delivery of TrkB to phrenic motoneurons is not known. The present study determined the therapeutic efficacy of intrapleural delivery of AAV7 encoding for full-length TrkB (AAV-TrkB) to phrenic motoneurons 3 days post-C2SH. Diaphragm EMG was recorded chronically in male rats (n=26) up to 21 days post-C2SH. Absent ipsilateral diaphragm EMG activity was verified 3 days post-C2SH. A greater proportion of animals displayed recovery of ipsilateral diaphragm EMG activity during eupnea by 14 and 21 days post-SH after AAV-TrkB (10/15) compared to AAV-GFP treatment (2/11; p=0.031). Diaphragm EMG amplitude increased over time post-C2SH (p2=0.82), with increased motoneuron NMDA expression evident in animals treated with AAV-TrkB and that displayed recovery after C2SH. Overall, gene therapy using intrapleural delivery of AAV-TrkB to phrenic motoneurons is sufficient to promote recovery of diaphragm activity, adding a novel potential intervention that can be administered after upper cervical spinal cord injury to improve impaired respiratory function.

KW - Diaphragm muscle

KW - Glutamatergic

KW - Neuroplasticity

KW - Neurotransmitter

KW - Neurotrophin

KW - Phrenic motoneuron

KW - Respiratory

KW - Serotonergic

KW - Spinal hemisection

UR - http://www.scopus.com/inward/record.url?scp=84949191102&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84949191102&partnerID=8YFLogxK

U2 - 10.1016/j.expneurol.2015.11.007

DO - 10.1016/j.expneurol.2015.11.007

M3 - Article

VL - 276

SP - 31

EP - 40

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

ER -