Efficacy of herpes simplex virus vector encoding the human preproenkephalin gene for treatment of facial pain in mice

Fei Ma; Chunmei Wang; William E. Yoder; Karin N. Westlund; Charles R. Carlson; Craig S. Miller; Robert J. Danaher

doi:10.11607/ofph.1512

Efficacy of herpes simplex virus vector encoding the human preproenkephalin gene for treatment of facial pain in mice

Fei Ma, Chunmei Wang, William E. Yoder, Karin N. Westlund, Charles R. Carlson, Craig S. Miller, Robert J. Danaher

Research output: Contribution to journal › Article › peer-review

7 Citations (SciVal)

Abstract

Aims: To determine whether herpes simplex virus-based vectors can efficiently transduce mouse trigeminal ganglion (TG) neurons and attenuate preexisting nerve injury-induced whisker pad mechanical hypersensitivity in a trigeminal inflammatory compression (TIC) neuropathic pain model. Methods: Tissue transduction efficiencies of replication-conditional and replication-defective vectors to mouse whisker pads after topical administration and subcutaneous injection were assessed using quantitative real-time PCR (qPCR). Tissue tropism and transgene expression were assessed using qPCR and reverse-transcriptase qPCR following topical application of the vectors. Whisker pad mechanical sensitivities of TIC-injured mice were determined using graduated von Frey fibers before and after application of human preproenkephalin expressing replicationconditional vector (KHPE). Data were analyzed using one-way analysis of variance (ANOVA) and post hoc tests. Results: Transduction of target TGs was 8- to 50- fold greater after topical application than subcutaneous injection and = 100-fold greater for replication-conditional than replication-defective vectors. Mean KHPE loads remained constant in TGs (4.5-9.8 × 104 copies/TG) over 3 weeks but were below quantifiable levels (10 copies/tissue) within 2 weeks of application in other nontarget cephalic tissues examined. Transgene expression in TGs was maximal during 2 weeks after topical application (100-200 cDNA copies/mL) and was below quantifiable levels (1 cDNA copy/mL) in all nontarget tissues. Topical KHPE administration reduced TIC-related mechanical hypersensitivity on whisker pads 4-fold (P < .05) for at least 1 week. Conclusion: Topically administered KHPE produced a significant antinociceptive effect in the TIC mouse model of chronic facial neuropathic pain. This is the first report in which a gene therapeutic approach reduced trigeminal pain-related behaviors in an established pain state in mice.

Original language	English
Pages (from-to)	42-50
Number of pages	9
Journal	Journal of Oral and Facial Pain and Headache
Volume	30
Issue number	1
DOIs	https://doi.org/10.11607/ofph.1512
State	Published - 2016

Bibliographical note

Funding Information:
The authors thank Hejab Malik, Michael Rechtin, and Dr Li Ping Zhang for their help in this research, and Matt Hazzard for creating the Fig 5 illustration. The investigation was supported by NIH COBRE grant 2P20RR020145-06 and from internal institutional sources from the University of Kentucky President's Research Professorship Fund (KNW) and the College of Medicine Dean's Start-up Fund (KNW). The authors report no conflicts of interest related to this study.

Publisher Copyright:
© 2016 by Quintessence Publishing Co Inc.

Keywords

Gene therapy
Mechanical allodynia
Nerve injury
Neuropathic pain
Trigeminal ganglia

ASJC Scopus subject areas

Dentistry (miscellaneous)
Clinical Neurology
Anesthesiology and Pain Medicine

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10.11607/ofph.1512

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title = "Efficacy of herpes simplex virus vector encoding the human preproenkephalin gene for treatment of facial pain in mice",

abstract = "Aims: To determine whether herpes simplex virus-based vectors can efficiently transduce mouse trigeminal ganglion (TG) neurons and attenuate preexisting nerve injury-induced whisker pad mechanical hypersensitivity in a trigeminal inflammatory compression (TIC) neuropathic pain model. Methods: Tissue transduction efficiencies of replication-conditional and replication-defective vectors to mouse whisker pads after topical administration and subcutaneous injection were assessed using quantitative real-time PCR (qPCR). Tissue tropism and transgene expression were assessed using qPCR and reverse-transcriptase qPCR following topical application of the vectors. Whisker pad mechanical sensitivities of TIC-injured mice were determined using graduated von Frey fibers before and after application of human preproenkephalin expressing replicationconditional vector (KHPE). Data were analyzed using one-way analysis of variance (ANOVA) and post hoc tests. Results: Transduction of target TGs was 8- to 50- fold greater after topical application than subcutaneous injection and = 100-fold greater for replication-conditional than replication-defective vectors. Mean KHPE loads remained constant in TGs (4.5-9.8 × 104 copies/TG) over 3 weeks but were below quantifiable levels (10 copies/tissue) within 2 weeks of application in other nontarget cephalic tissues examined. Transgene expression in TGs was maximal during 2 weeks after topical application (100-200 cDNA copies/mL) and was below quantifiable levels (1 cDNA copy/mL) in all nontarget tissues. Topical KHPE administration reduced TIC-related mechanical hypersensitivity on whisker pads 4-fold (P < .05) for at least 1 week. Conclusion: Topically administered KHPE produced a significant antinociceptive effect in the TIC mouse model of chronic facial neuropathic pain. This is the first report in which a gene therapeutic approach reduced trigeminal pain-related behaviors in an established pain state in mice.",

keywords = "Gene therapy, Mechanical allodynia, Nerve injury, Neuropathic pain, Trigeminal ganglia",

author = "Fei Ma and Chunmei Wang and Yoder, {William E.} and Westlund, {Karin N.} and Carlson, {Charles R.} and Miller, {Craig S.} and Danaher, {Robert J.}",

note = "Funding Information: The authors thank Hejab Malik, Michael Rechtin, and Dr Li Ping Zhang for their help in this research, and Matt Hazzard for creating the Fig 5 illustration. The investigation was supported by NIH COBRE grant 2P20RR020145-06 and from internal institutional sources from the University of Kentucky President's Research Professorship Fund (KNW) and the College of Medicine Dean's Start-up Fund (KNW). The authors report no conflicts of interest related to this study. Publisher Copyright: {\textcopyright} 2016 by Quintessence Publishing Co Inc.",

year = "2016",

doi = "10.11607/ofph.1512",

language = "English",

volume = "30",

pages = "42--50",

number = "1",

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TY - JOUR

T1 - Efficacy of herpes simplex virus vector encoding the human preproenkephalin gene for treatment of facial pain in mice

AU - Ma, Fei

AU - Wang, Chunmei

AU - Yoder, William E.

AU - Westlund, Karin N.

AU - Carlson, Charles R.

AU - Miller, Craig S.

AU - Danaher, Robert J.

N1 - Funding Information: The authors thank Hejab Malik, Michael Rechtin, and Dr Li Ping Zhang for their help in this research, and Matt Hazzard for creating the Fig 5 illustration. The investigation was supported by NIH COBRE grant 2P20RR020145-06 and from internal institutional sources from the University of Kentucky President's Research Professorship Fund (KNW) and the College of Medicine Dean's Start-up Fund (KNW). The authors report no conflicts of interest related to this study. Publisher Copyright: © 2016 by Quintessence Publishing Co Inc.

PY - 2016

Y1 - 2016

N2 - Aims: To determine whether herpes simplex virus-based vectors can efficiently transduce mouse trigeminal ganglion (TG) neurons and attenuate preexisting nerve injury-induced whisker pad mechanical hypersensitivity in a trigeminal inflammatory compression (TIC) neuropathic pain model. Methods: Tissue transduction efficiencies of replication-conditional and replication-defective vectors to mouse whisker pads after topical administration and subcutaneous injection were assessed using quantitative real-time PCR (qPCR). Tissue tropism and transgene expression were assessed using qPCR and reverse-transcriptase qPCR following topical application of the vectors. Whisker pad mechanical sensitivities of TIC-injured mice were determined using graduated von Frey fibers before and after application of human preproenkephalin expressing replicationconditional vector (KHPE). Data were analyzed using one-way analysis of variance (ANOVA) and post hoc tests. Results: Transduction of target TGs was 8- to 50- fold greater after topical application than subcutaneous injection and = 100-fold greater for replication-conditional than replication-defective vectors. Mean KHPE loads remained constant in TGs (4.5-9.8 × 104 copies/TG) over 3 weeks but were below quantifiable levels (10 copies/tissue) within 2 weeks of application in other nontarget cephalic tissues examined. Transgene expression in TGs was maximal during 2 weeks after topical application (100-200 cDNA copies/mL) and was below quantifiable levels (1 cDNA copy/mL) in all nontarget tissues. Topical KHPE administration reduced TIC-related mechanical hypersensitivity on whisker pads 4-fold (P < .05) for at least 1 week. Conclusion: Topically administered KHPE produced a significant antinociceptive effect in the TIC mouse model of chronic facial neuropathic pain. This is the first report in which a gene therapeutic approach reduced trigeminal pain-related behaviors in an established pain state in mice.

AB - Aims: To determine whether herpes simplex virus-based vectors can efficiently transduce mouse trigeminal ganglion (TG) neurons and attenuate preexisting nerve injury-induced whisker pad mechanical hypersensitivity in a trigeminal inflammatory compression (TIC) neuropathic pain model. Methods: Tissue transduction efficiencies of replication-conditional and replication-defective vectors to mouse whisker pads after topical administration and subcutaneous injection were assessed using quantitative real-time PCR (qPCR). Tissue tropism and transgene expression were assessed using qPCR and reverse-transcriptase qPCR following topical application of the vectors. Whisker pad mechanical sensitivities of TIC-injured mice were determined using graduated von Frey fibers before and after application of human preproenkephalin expressing replicationconditional vector (KHPE). Data were analyzed using one-way analysis of variance (ANOVA) and post hoc tests. Results: Transduction of target TGs was 8- to 50- fold greater after topical application than subcutaneous injection and = 100-fold greater for replication-conditional than replication-defective vectors. Mean KHPE loads remained constant in TGs (4.5-9.8 × 104 copies/TG) over 3 weeks but were below quantifiable levels (10 copies/tissue) within 2 weeks of application in other nontarget cephalic tissues examined. Transgene expression in TGs was maximal during 2 weeks after topical application (100-200 cDNA copies/mL) and was below quantifiable levels (1 cDNA copy/mL) in all nontarget tissues. Topical KHPE administration reduced TIC-related mechanical hypersensitivity on whisker pads 4-fold (P < .05) for at least 1 week. Conclusion: Topically administered KHPE produced a significant antinociceptive effect in the TIC mouse model of chronic facial neuropathic pain. This is the first report in which a gene therapeutic approach reduced trigeminal pain-related behaviors in an established pain state in mice.

KW - Gene therapy

KW - Mechanical allodynia

KW - Nerve injury

KW - Neuropathic pain

KW - Trigeminal ganglia

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Efficacy of herpes simplex virus vector encoding the human preproenkephalin gene for treatment of facial pain in mice

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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