New Pharmacologic and Minimally Invasive Therapies for the Overactive Bladder

Michael Franks, MD, Emmanuel Chartier-Kastler, MD, Michael B. Chancellor, MD

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Future Treatment of OAB

While new oral drugs, intravesical RTX, intrathecal clonidine, and SNS are exciting now, the real excitement may lie just around the corner. The field of urology, along with all specialties of medicine, is on the brink of a revolution called molecular medicine. While traditional medicine treats symptoms, gene therapy addresses the deficiency that causes the symptoms. With improved understanding of the human genome and techniques evolving to construct gene therapy vectors that manipulate our genetic patterns, the way we practice medicine will be forever changed.

Drug delivery technologies will allow us to get the drug or a gene to a specific target organ and thus limit side effects. The bladder is very accessible to these therapies. Through gene therapy, we will replace, supplement, or suppress a protein or cytokine to correct a disease process. Gene therapy in urology may not be that far away. For example, a sensory neurogenic bladder (diabetic cystopathy) develops in many persons who have diabetes within 10 years of disease onset. The symptoms are progressive and include decreasing bladder sensation and increasing bladder capacity. The end result is a large and acontractile bladder that is treated by catheterization or urinary diversion. There are no medical treatment options for diabetic sensory neuropathy.

We believe that there is a way to prevent the inevitable deterioration of diabetic cystopathy through organ-specific gene therapy. In a rat model of diabetic cystopathy, the bladder wall is injected with a specially constructed nonreplicating human simplex virus (HSV) vector. This recombinant herpes vector mediates expression of b-nerve growth factor (b-NGF), a neurotrophic factor that in experiment conditions have been shown to prevent and reverse diabetic neuropathy. When the safe nonreplicating, latent HSV vector is used, expression of b-NGF occurs not only in the bladder but also in the dorsal root ganglion of the pelvic nerve. We have exciting data suggesting that overexpression of b-NGF in the bladder and dorsal root ganglia can prevent diabetic cystopathy.

All this animal work is obviously very preliminary. In the future, we can imagine patients coming into the cystoscopy suite of a university urologist for cystoscopic-based gene therapy. A man with benign prostatic hyperplasia (BPH) will have a gene for the expression of prostate apotosis factor injected into his prostate instead of undergoing a formal resection. A woman with diabetes will have NGF-mediated vectors injected into her bladder. A man with impotence will receive a penile injection of genes such as vascular endothelial growth factor or nitric oxide synthase to promote normal erectile function. Through a single injection, these 3 patients will be cured of BPH, diabetic cystopathy, and impotency, respectively. This form of treatment is not available today, but perhaps it is not as far away as it once seemed.

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