Skip to main content
Top
Published in: Current Bladder Dysfunction Reports 1/2024

15-01-2024 | Overactive Bladder | REVIEW

Gene Therapy and Overactive Bladder

Authors: Stephen Patrick, Eric Rovner

Published in: Current Bladder Dysfunction Reports | Issue 1/2024

Login to get access

Abstract

Purpose of Review

Within the last decade, a number of gene therapies have been developed as a treatment option for monogenic diseases. Overactive bladder is a multifactorial syndrome with likely many underlying causes and regulatory components. The goal of this paper is to review current gene therapy in and outside of the genitourinary system, review the pathophysiology and genetics of OAB, and discuss recent advances in application of this technology for OAB treatment.

Recent Findings

Various genes have been found to be upregulated in OAB patients including receptors involved in purinergic signaling, gap junctions between detrusor smooth muscle cells, proteins involved in detrusor myocyte cytoskeletal dynamics, cholinergic receptors, and some types of membrane channels. Fewer genes are downregulated but include receptors in purinergic signaling and a channel critical for detrusor smooth muscle cell relaxation. Results of a recent phase 2 trial exploiting a gene coding for a portion of a potassium channel suggest that gene therapy may have emerging relevance in OAB therapy.

Summary

OAB is a syndrome, and the pathophysiology is incompletely understood but likely is due to a combination of altered afferent signaling at the level of the bladder modified by a constant hyper- or hypo-excitability of the detrusor myocyte. Understanding the complex pathways underlying OAB as well as the related genetic components of the normal and abnormal bladder may provide novel therapeutic options for this widespread condition.
Literature
6.
go back to reference Fantl JA, Wyman JF, McClish DK, Harkins SW, Elswick RK, Taylor JR, et al. Efficacy of bladder training in older women with urinary incontinence. JAMA. 1991;265(5):609–13.CrossRefPubMed Fantl JA, Wyman JF, McClish DK, Harkins SW, Elswick RK, Taylor JR, et al. Efficacy of bladder training in older women with urinary incontinence. JAMA. 1991;265(5):609–13.CrossRefPubMed
10.
go back to reference Chapple C, Sievert K-D, MacDiarmid S, Khullar V, Radziszewski P, Nardo C, et al. OnabotulinumtoxinA 100 U significantly improves all idiopathic overactive bladder symptoms and quality of life in patients with overactive bladder and urinary incontinence: a randomised, double-blind, placebo-controlled trial. Eur Urol. 2013;64(2):249–56. https://doi.org/10.1016/j.eururo.2013.04.001.CrossRefPubMed Chapple C, Sievert K-D, MacDiarmid S, Khullar V, Radziszewski P, Nardo C, et al. OnabotulinumtoxinA 100 U significantly improves all idiopathic overactive bladder symptoms and quality of life in patients with overactive bladder and urinary incontinence: a randomised, double-blind, placebo-controlled trial. Eur Urol. 2013;64(2):249–56. https://​doi.​org/​10.​1016/​j.​eururo.​2013.​04.​001.CrossRefPubMed
19.
go back to reference Day JW, Finkel RS, Chiriboga CA, Connolly AM, Crawford TO, Darras BT, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021;20(4):284–93. https://doi.org/10.1016/s1474-4422(21)00001-6.CrossRefPubMed Day JW, Finkel RS, Chiriboga CA, Connolly AM, Crawford TO, Darras BT, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021;20(4):284–93. https://​doi.​org/​10.​1016/​s1474-4422(21)00001-6.CrossRefPubMed
22.
go back to reference • Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: A single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107–17. https://doi.org/10.1016/s1470-2045(20)30540-4. First FDA-approved gene therapy in the genitourinary system demonstrating reduction in recurrence of bladder cancer after instillation of adenovirus containing interferon alpha-2b. • Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: A single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107–17. https://​doi.​org/​10.​1016/​s1470-2045(20)30540-4. First FDA-approved gene therapy in the genitourinary system demonstrating reduction in recurrence of bladder cancer after instillation of adenovirus containing interferon alpha-2b.
29.
go back to reference O’Reilly BA, Kosaka AH, Knight GF, Chang TK, Ford AP, Rymer JM, et al. P2X receptors and their role in female idiopathic detrusor instability. J Urol. 2002;167(1):157–64.CrossRefPubMed O’Reilly BA, Kosaka AH, Knight GF, Chang TK, Ford AP, Rymer JM, et al. P2X receptors and their role in female idiopathic detrusor instability. J Urol. 2002;167(1):157–64.CrossRefPubMed
35.•
go back to reference Hristov KL, Afeli SA, Parajuli SP, Cheng Q, Rovner ES, Petkov GV. Neurogenic detrusor overactivity is associated with decreased expression and function of the large conductance voltage- and Ca(2+)-activated K(+) channels. PLoS One. 2013;8(7):e68052. https://doi.org/10.1371/journal.pone.0068052. Detrusor overactivity is associated with decreased BK channel expression. Hristov KL, Afeli SA, Parajuli SP, Cheng Q, Rovner ES, Petkov GV. Neurogenic detrusor overactivity is associated with decreased expression and function of the large conductance voltage- and Ca(2+)-activated K(+) channels. PLoS One. 2013;8(7):e68052. https://​doi.​org/​10.​1371/​journal.​pone.​0068052. Detrusor overactivity is associated with decreased BK channel expression.
40.•
go back to reference Isali I, McClellan P, Wong TR, Sun C, Stout AC, Schumacher FR, et al. A systematic review and in silico study of potential genetic markers implicated in cases of overactive bladder. Am J Obstet Gynecol. 2023;228(1):36–47.e3. https://doi.org/10.1016/j.ajog.2022.07.044. Review article analyzing upregulated OAB genes revealing overlap in calcium signaling pathways and neuroactive ligand-receptor interaction. Isali I, McClellan P, Wong TR, Sun C, Stout AC, Schumacher FR, et al. A systematic review and in silico study of potential genetic markers implicated in cases of overactive bladder. Am J Obstet Gynecol. 2023;228(1):36–47.e3. https://​doi.​org/​10.​1016/​j.​ajog.​2022.​07.​044. Review article analyzing upregulated OAB genes revealing overlap in calcium signaling pathways and neuroactive ligand-receptor interaction.
44.
go back to reference •• Rovner E, Chai TC, Jacobs S, Christ G, Andersson KE, Efros M, et al. Evaluating the safety and potential activity of URO-902 (hMaxi-K) gene transfer by intravesical instillation or direct injection into the bladder wall in female participants with idiopathic (non-neurogenic) overactive bladder syndrome and detrusor overactivity from two double-blind, imbalanced, placebo-controlled randomized phase 1 trials. Neurourol Urodyn. 2020;39(2):744–53. https://doi.org/10.1002/nau.24272. Intravesical administration or intradetrusor injection of URO-902 is safe and not associated with any significant adverse events with clinical significance in reduction of urgency episodes and number of voids in those receiving injection. •• Rovner E, Chai TC, Jacobs S, Christ G, Andersson KE, Efros M, et al. Evaluating the safety and potential activity of URO-902 (hMaxi-K) gene transfer by intravesical instillation or direct injection into the bladder wall in female participants with idiopathic (non-neurogenic) overactive bladder syndrome and detrusor overactivity from two double-blind, imbalanced, placebo-controlled randomized phase 1 trials. Neurourol Urodyn. 2020;39(2):744–53. https://​doi.​org/​10.​1002/​nau.​24272. Intravesical administration or intradetrusor injection of URO-902 is safe and not associated with any significant adverse events with clinical significance in reduction of urgency episodes and number of voids in those receiving injection.
45.
go back to reference • Andersson KE, Christ GJ, Davies KP, Rovner ES, Melman A. Gene therapy for overactive bladder: A review of BK-channel α-subunit gene transfer. Ther Clin Risk Manag. 2021;17:589–99. https://doi.org/10.2147/tcrm.S291798. Comprehensive review of BK-channel and studies in ED as well as URO-902. • Andersson KE, Christ GJ, Davies KP, Rovner ES, Melman A. Gene therapy for overactive bladder: A review of BK-channel α-subunit gene transfer. Ther Clin Risk Manag. 2021;17:589–99. https://​doi.​org/​10.​2147/​tcrm.​S291798. Comprehensive review of BK-channel and studies in ED as well as URO-902.
48.
go back to reference Arun N. Treatment of erectile dysfunction with hMaxi-K gene transfer: Safety report from phase IIA study. Eur Urol. 2018;12(2). Arun N. Treatment of erectile dysfunction with hMaxi-K gene transfer: Safety report from phase IIA study. Eur Urol. 2018;12(2).
49.
go back to reference •• Kenneth Peters EE, Susan Kalota, Kaiser Robertson, Sijian Ge, Jingmei Lu, Hanh Badger, Salim Mujais. Long-term efficacy and safety of URO-902 (PVAX/HSLO) in women with overactive bladder and urge urinary incontinence: Final results of a phase 2A trial. . Journal of Urology. 2023;209:e1184. Larger trial demonstrating reduced number of voids per day and urgency episodes at 12 weeks after intradetrusor injection of URO-902. •• Kenneth Peters EE, Susan Kalota, Kaiser Robertson, Sijian Ge, Jingmei Lu, Hanh Badger, Salim Mujais. Long-term efficacy and safety of URO-902 (PVAX/HSLO) in women with overactive bladder and urge urinary incontinence: Final results of a phase 2A trial. . Journal of Urology. 2023;209:e1184. Larger trial demonstrating reduced number of voids per day and urgency episodes at 12 weeks after intradetrusor injection of URO-902.
Metadata
Title
Gene Therapy and Overactive Bladder
Authors
Stephen Patrick
Eric Rovner
Publication date
15-01-2024
Publisher
Springer US
Published in
Current Bladder Dysfunction Reports / Issue 1/2024
Print ISSN: 1931-7212
Electronic ISSN: 1931-7220
DOI
https://doi.org/10.1007/s11884-023-00733-3

Other articles of this Issue 1/2024

Current Bladder Dysfunction Reports 1/2024 Go to the issue