title: HSV delivery of a ligand-regulated endogenous ion channel gene to sensory neurons results in pain control following channel activation.
abstract: Persistent pain remains a tremendous health problem due to both its prevalence and dearth of effective therapeutic interventions. To maximize pain relief while minimizing side effects, current gene therapy-based approaches have mostly exploited the expression of pain inhibitory products or interfered with pronociceptive ion channels. These methods do not enable control over the timing or duration of analgesia, nor titration to analgesic efficacy. Here, we describe a gene therapy strategy that potentially overcomes these limitations by providing exquisite control over therapy with efficacy in clinically relevant models of inflammatory pain. We utilize a herpes simplex viral (HSV) vector (vHGlyRα1) to express a ligand-regulated chloride ion channel, the glycine receptor (GlyR) in targeted sensory afferents; the subsequent exogenous addition of glycine provides the means for temporal and spatial control of afferent activity, and therefore pain. Use of an endogenous inhibitory receptor not normally present on sensory neurons both minimizes immunogenicity and maximizes therapeutic selectivity.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Goss
authors.forename: Michael
authors.initials: M
authors.lastname: Cascio
authors.forename: William F
authors.initials: WF
authors.lastname: Goins
authors.forename: Shaohua
authors.initials: S
authors.lastname: Huang
authors.forename: David M
authors.initials: DM
authors.lastname: Krisky
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Clarke
authors.forename: Jon W
authors.initials: JW
authors.lastname: Johnson
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yokoyama
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoshimura
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gold
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Glorioso
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D023061:Gene Order; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D005998:Glycine / Q000378:metabolism / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D059408:Pain Management; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism; D018139:Simplexvirus / Q000235:genetics
chemical_list: D008024:Ligands; D018009:Receptors, Glycine; D005998:Glycine