This grant application is by Ion Channel Innovations, LLC, (ICI) a company dedicated to the development of naked DNA transfer to treat the unmet needs of people with common smooth muscle diseases that negatively impact the quality of life of millions. Overactive bladder syndrome (OAB), characterized by symptoms of urinary urgency, frequency, and incontinence, is one of such diseases. OAB affects 17% of the adult US population and there are no satisfactory medical therapies available. ICI's therapy uses the increased expression of the hSlo gene splice variant, called hMaxiK, which codes for the pore forming subunit of the large conductance potassium channel. Prior studies by ICI have shown that hMaxiK improves urogenital pathophysiology in rodent and nonhuman primate models of aging, diabetes and atherosclerosis. ICI views its method of targeted, localized administration, safety, and 6-month duration of action as strengths of hMaxiK therapy contributing to its potential as a major advance in medicine. The current proposal will test the hypothesis that localized bladder wall injection of hMaxiK is a safe and efficacious treatment of OAB. Urodynamic studies in previous clinical trials using bladder lumen instillation of hMaxiK showed no transfer-related serious adverse events and yielded evidence that the mean number of detrusor overactivity contractions (a presumptive clinical correlate of urinary urgency and incontinence) was diminished up to 24 weeks after transfer (P<0.0508). Indeed the 5000 mcg treated group showed a 70% reduction of contractions from baseline compared to placebo (P<0.0217);although this did not result in improved continence. However, direct bladder wall injection of hMaxiK may be more efficacious with a similar safety profile. The current grant proposal will test this hypothesis in two phases. In Phase I, in collaboration with the Consortium PI Dr. Kelvin Davies, ICI will conduct studies in an animal model to optimize the method of direct injection of the plasmid to ensure the safe and efficient expression of hMaxiK by a sufficient number of bladder smooth muscle cells to result in significant physiological effects on bladder function. In Phase II, in collaboration with the consortium CE3, Inc. ICI will conduct a sequential double blind placebo controlled clinical trial in women with moderate to severe OAB to evaluate the safety and efficacy of direct injection of hMaxiK into the bladder wall. ICI has already identified potential investors from both industry and the private equity community. However, they require further efficacy data before additional investments are made. Upon completion of the proposed Phase II safety and efficacy trial, ICI will be positioned to partner with investors to bring its innovative technology to market.
This proposal is designed to demonstrate that naked DNA-based gene transfer with the direct bladder wall injection of the gene encoding the calcium sensitive potassium channel known as hMaxiK can correct in humans, as has been shown to do in animal models, the syndrome of urinary urgency, frequency and incontinence known as overactive bladder or OAB. The study, with a placebo control, in a small number of participants is designed to show both safety and efficacy. Such proof would be a major step forward for both the advancement of the company and for medical care as there are no existent satisfactory therapies for that syndrome that affects 17% of the adult population in the United States.