BERKELEY, CA (UroToday.com) - Overexpression of nerve growth factor NGF in the bladder has been established as a key molecular mediator in the lower urinary tract symptoms associated with overactive bladder.[1, 2, 3] Therefore it makes sense to develop therapeutic interventions that are directed at blocking the NGF expression or its function. Recently attempts have been made to block NGF function by systemic administration of anti-NGF antibodies, with mixed results.[4] Studies have shown that overexpression of NGF does not happen system wide in animal models of OAB, but is restricted to certain bladder tissue regions, like urothelium.[5] Studies employing transgenic mice with urothelium-specific overexpression of NGF have been able to reproduce symptoms of OAB.[6] Basic research has also shown that overexpression of NGF in bladder is able to alter the molecular phenotype of dorsal root ganglion neurons innervating bladder.[7] Other studies have demonstrated that products from bladder urothelium may alter nerves in the periphery and in the central nervous system.[8]
The region-specific overexpression of NGF in the urothelium questions the need for system-wide blockade of NGF function. Generalized blockade of NGF function in the body may be related to the incidence of paresthesia, hypoesthesia, and arthralgia in patients treated with systemic anti-NGF therapy4. Therefore, in the present study, we sought to exploit the anatomical external access for the urinary bladder to develop a local treatment for OAB based on suppression of NGF expression. A similar approach used has been successfully demonstrated previously in the treatment of bladder cancer.[9]
Antisense sequence targeting coding sequence of rat NGF mRNA was used to downregulate NGF expression in bladder.[10] An 18-nucleotide-long oligo was custom synthesized that was complexed with cationic liposomes in 1:10 ratio prior to animal experiments. Bladder uptake was demonstrated by the uptake of fluorescent tag conjugated to oligo. Functional efficacy of antisense treatment was demonstrated by acetic acid cystometry and effect on NGF expression measured by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. Experiments with NGF antisense also uncovered the NGF-associated signaling mechanisms in acetic acid-induced model of bladder overactivity. Intravesical route can allow selective exposure of high concentration of antisense ODN to the NGF-producing cells in urothelium and avoid systemic side effects from genetic manipulation of NGF expression.
References:
- Lamb, K., Gebhart, G. F., Bielefeldt, K.: Increased nerve growth factor expression triggers bladder overactivity. J Pain, 5: 150, 2004
- Liu, H. T., Chancellor, M. B., Kuo, H. C.: Decrease of urinary nerve growth factor levels after antimuscarinic therapy in patients with overactive bladder. BJU Int, 103: 1668, 2009
- Liu, H. T., Chancellor, M. B., Kuo, H. C.: Urinary nerve growth factor levels are elevated in patients with detrusor overactivity and decreased in responders to detrusor botulinum toxin-A injection. Eur Urol, 56: 700, 2009
- Evans, R. J., Moldwin, R. M., Cossons, N. et al.: Proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis. J Urol, 185: 1716, 2011
- Zhang, Q. L., Qiao, L. Y.: Regulation of IGF-1 but not TGF-beta1 by NGF in the smooth muscle of the inflamed urinary bladder. Regul Pept, 177: 73, 2012
- Schnegelsberg, B., Sun, T. T., Cain, G. et al.: Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function. Am J Physiol Regul Integr Comp Physiol, 298: R534, 2010
- Girard, B. M., Merrill, L., Malley, S. et al.: Increased TRPV4 Expression in Urinary Bladder and Lumbosacral Dorsal Root Ganglia in Mice with Chronic Overexpression of NGF in Urothelium. J Mol Neurosci, 2013
- Birder, L. A., Wolf-Johnston, A. S., Chib, M. K. et al.: Beyond neurons: Involvement of urothelial and glial cells in bladder function. Neurourol Urodyn, 29: 88, 2010
- Nogawa, M., Yuasa, T., Kimura, S. et al.: Intravesical administration of small interfering RNA targeting PLK-1 successfully prevents the growth of bladder cancer. J Clin Invest, 115: 978, 2005
- Kashyap, M., Kawamorita, N., Tyagi, V. et al.: Downregulation of NGF Expression in the Bladder by Antisense Oligoucleotides as New Treatment for Overactive Bladder. J Urol, 2013
Written by:
Pradeep Tyagi, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Department of Urology, University of Pittsburgh, Pittsburgh, PA USA
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