Gene therapy for bladder overactivity and nociception with herpes simplex virus vectors expressing preproenkephalin.
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a major challenge to treat. We studied the effect of targeted and localized expression of enkephalin in afferent nerves that innervate the bladder by gene transfer using replication-defective herpes simplex virus (HSV) vectors in a rat model of bladder hyperactivity and pain. Replication-deficient HSV vectors encoding preproenkephalin, which is a precursor for Met- and Leu-enkephalin, or control vector encoding the lacZ reporter gene, were injected into the bladder wall of female rats. After viral vector injection, quantitative polymerase chain reaction showed high preproenkephalin transgene levels in bladder and dorsal root ganglia innervating the bladder in enkephalin vector-treated animals. Functionally, enkephalin vector-treated animals showed reductions in bladder hyperactivity and nociceptive behavior induced by intravesical application of capsaicin; however, vector-mediated expression of enkephalin did not alter normal voiding. This antinociceptive effect of enkephalin gene therapy was antagonized by naloxone hydrochloride administration. Together, our results with HSV vectors encoding preproenkephalin demonstrated physiological improvement in visceral pain induced by bladder irritation. Thus, gene therapy may represent a potentially useful treatment modality for bladder hypersensitive disorders such as IC/PBS.
Yokoyama
Hitoshi
H
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Sasaki
Katsumi
K
Franks
Michael E
ME
Goins
William F
WF
Goss
James R
JR
de Groat
William C
WC
Glorioso
Joseph C
JC
Chancellor
Michael B
MB
Yoshimura
Naoki
N
D000818:Animals; D018856:Cystitis, Interstitial / Q000235:genetics / Q000628:therapy*; D004195:Disease Models, Animal; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D009475:Neurons, Afferent / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018139:Simplexvirus / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D001743:Urinary Bladder / Q000294:innervation / Q000473:pathology
D004745:Enkephalins; D011498:Protein Precursors; C033660:preproenkephalin