Gene Therapy for Overactive Bladder: A Review of BK-Channel α-Subunit Gene Transfer

Abstract

A need exists for local (ie, bladder-specific) interventions to treat overactive bladder (OAB) with low risk of unwanted postprocedural outcomes. Gene therapy targeted to leverage endogenous physiology in bladder cells may assist in restoring normal cell and organ function. Herein, we review the potential promise of gene therapy for treating OAB, focusing on gene transfer of URO-902, a non-viral naked plasmid DNA expressing the big potassium (BK) channel. We searched PubMed for articles concerning functional aspects of the BK channel and its potential use for gene transfer as local OAB treatment. Results from preclinical, phase 1, and phase 2 studies of URO-902 for erectile dysfunction and phase 1 studies of URO-902 for OAB are included. The BK channel has been extensively studied; however, URO-902 is the first gene therapy used in clinical trials directed toward treating OAB via the BK channel. In both URO-902 studies, there were no serious adverse events considered treatment related and no adverse events leading to early withdrawal. Both studies included secondary efficacy endpoints with promising results suggesting improvement in OAB symptoms, and quality of life, with use of URO-902 versus placebo. Gene therapy involving the BK channel, such as gene transfer with URO-902, has demonstrated promising safety and efficacy results in women with OAB. Findings warrant further investigation of the use of URO-902 for OAB treatment.

Overactive Bladder and Cognitive Impairment: The American Urogynecologic Society and Pelvic Floor Disorders Research Foundation State-of-the-Science Conference Summary Report

“…Gap junctions are important to facilitate the conductance and permeability to calcium. Smooth muscle cells can function as 1 coordinated unit, or syncytium, due to gap junctions to facilitate cellular activation 172 …”

“…Micturition and storage of urine in the bladder is conducted via an intricate interworking between nerve stimulation and downregulation of the smooth muscle, lamina propria, and the urothelium. There is significant signal complexity in the bladder wall to include smooth muscle cell interactions with excitatory motor neurons (acetylcholine) and inhibitory motor neurons (nitric oxide and ATP) 172 . Calcium mobilization or sensitization through ion channels can affect changes to contractility.…”

“…Smooth muscle cells can function as 1 coordinated unit, or syncytium, due to gap junctions to facilitate cellular activation. 172 Phase 1 and 2 randomized controlled trials of targeted gene therapy conducted by injecting URO-902 (also known as hMaxi-K) in patients with OAB symptoms and detrusor overactivity revealed favorable results with significant reduction in urgency, UI, and number of voids compared with placebo without adverse effects noted. 173 These 2 early phase 1 studies of targeted gene therapy appear favorable for treatment of OAB symptoms; however, more robust research is necessary to determine true benefit as well as specific studies in older women.…”

“…Calcium mobilization or sensitization through ion channels can affect changes to contractility. Because the smooth muscle cells in the bladder are in a partially constricted state, it is imperative to maintain a fine balance between contraction and relaxation of the bladder for functionality 172 . Gap junctions are important to facilitate the conductance and permeability to calcium.…”

BK channels in microglia

“…Large-conductance calcium-and voltage-dependent potassium (BK) channels are composed of pore-forming α subunits (Slo1, KCNMA1) and auxiliary subunits, including β1 through β4 (KCNMB1 through KCNMB4), γ1 through γ4 (LRRC26, LRRC52, LRRC55, LRRC38), and LINGO1 through LINGO4 [1][2][3][4][5][6][7]. BK channels are ubiquitously distributed in the body and play vital roles in various physiological and pathological processes [8,9]. In the brain, cells including neurons, astrocytes, and microglia all express BK channels on both their plasma membranes and intracellular organelle membranes [10][11][12][13].…”