Chronic pain is a major health concern affecting 80 million Americans at some time in their lives. Current pharmacotherapies are not effective long-term, which has led to the development and testing of gene therapy approaches. We and others have demonstrated that herpes simplex virus type 1 (HSV) based vectors can deliver highly effective pain-modulating transgenes to sensory neurons in vivo following inoculation of peripheral tissue. One major advantage of this approach is that painful tissue can be specifically targeted by local vector delivery. We believe that this advantage can be further extended by targeting specific neuron types responsible for chronic pain, thus enabling gene transfer to be tailored to specific types of pain, such as inflammatory or neuropathic pain, while simultaneously reducing deleterious side effects. We have recently shown that HSV-mediated transfer and long-term expression of the glycine receptor 11 subunit (GlyR11) can be used to control the timing and duration of afferent silencing with exogenous administration of glycine. Based on these findings and our recent success in the creation of highly efficient, fully retargeted HSV vectors, we hypothesize that we can selectively silence distinct subpopulations of primary afferents responsible for neuropathic and inflammatory pain, therefore providing injury specific pain relief. These studies will enable us to determine whether the same or different afferent populations underlie inflammatory and neuropathic pain and provide the rational basis for the future development of HSV-based gene transfer vectors designed to restrict analgesia to the relevant primary afferents. We anticipate that these studies will (i) provide a novel platform technology that will allow us to selectively express transgenes designed to modulate the function of sensory afferent subpopulations, a strategy that can be readily extended to other types of sensory nerve disorders;(ii) develop initial functional and physical maps of sensory afferent subtypes that upon silencing will block different persistent pain conditions, thereby providing essential information needed for targeted pain control;(iii) identify afferents that have been functionally altered to respond to painful stimuli providing further information on nerve fiber plasticity;and, (iv) identify potential risks associated with silencing of an inappropriate population of sensory neurons (e.g. altered proprioception). To achieve these goals, we have proposed a series of interrelated experiments described in 3 Specific Aims.
In Aim 1, the infectivity of HSV vectors will be retargeted to selectively transduce (a) A2 fibers, (b) peptidergic and (c) nonpeptidergic C fibers.
In Aim 2, we will complement transductional retargeting with transcriptional targeting using transgene promoters that will, when combined with transductional targeting, fine tune silencing specificity. The combination strategy is intended to create initial fine maps of subpopulations of sensory fibers within the larger transductionally targeted groups representing critical afferents for the response to different painful stimuli.
In Aim 3, the retargeted HSV vectors will be introduced into the DRG by peripheral inoculation of animal models of inflammatory and neuropathic pain and the analgesic efficacy and side effect profiles will be established following glycine-induced GlyR11-mediated silencing.

Public Health Relevance

Chronic pain is a major health concern affecting 80 million Americans at some time in their lives. Current treatments are not effective long-term, creating a substantial unmet medical need. Experiments described in this study are intended to develop insights into the role of specific nociceptor populations in chronic pain responses that may lead to methods to control pain by targeted delivery of a highly specific regulated pain silencing gene therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS064988-01A2
Application #
8186007
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Porter, Linda L
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$360,447
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Han, Fang; Miyagawa, Yoshitaka; Verlengia, Gianluca et al. (2018) Cellular Antisilencing Elements Support Transgene Expression from Herpes Simplex Virus Vectors in the Absence of Immediate Early Gene Expression. J Virol 92:
Shimizu, Nobutaka; Doyal, Mark F; Goins, William F et al. (2018) Corrigendum to 'Morphological Changes in Different Populations of Bladder Afferent Neurons Detected by Herpes Simplex Virus (HSV) Vectors with Cell-type-specific Promoters in Mice with Spinal Cord Injury' [Neuroscience 364 (2017) 190-201]. Neuroscience 381:161
Shimizu, Nobutaka; Doyal, Mark F; Goins, William F et al. (2017) Morphological changes in different populations of bladder afferent neurons detected by herpes simplex virus (HSV) vectors with cell-type-specific promoters in mice with spinal cord injury. Neuroscience 364:190-201
Verlengia, Gianluca; Miyagawa, Yoshitaka; Ingusci, Selene et al. (2017) Engineered HSV vector achieves safe long-term transgene expression in the central nervous system. Sci Rep 7:1507
Miyagawa, Yoshitaka; Verlengia, Gianluca; Reinhart, Bonnie et al. (2017) Deletion of the Virion Host Shut-off Gene Enhances Neuronal-Selective Transgene Expression from an HSV Vector Lacking Functional IE Genes. Mol Ther Methods Clin Dev 6:79-90
Reinhart, Bonnie; Goins, William F; Harel, Asaff et al. (2016) An HSV-based library screen identifies PP1? as a negative TRPV1 regulator with analgesic activity in models of pain. Mol Ther Methods Clin Dev 3:16040
Miyagawa, Yoshitaka; Marino, Pietro; Verlengia, Gianluca et al. (2015) Herpes simplex viral-vector design for efficient transduction of nonneuronal cells without cytotoxicity. Proc Natl Acad Sci U S A 112:E1632-41
Guedon, Jean-Marc G; Wu, Shaogen; Zheng, Xuexing et al. (2015) Current gene therapy using viral vectors for chronic pain. Mol Pain 11:27
Mazzacurati, Lucia; Marzulli, Marco; Reinhart, Bonnie et al. (2015) Use of miRNA response sequences to block off-target replication and increase the safety of an unattenuated, glioblastoma-targeted oncolytic HSV. Mol Ther 23:99-107
Guedon, J-M G; Zhang, M; Glorioso, J C et al. (2014) Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin. Gene Ther 21:694-702

Showing the most recent 10 out of 11 publications