The topical drug regenerates and restores the function of the erectile nerves damaged by radical prostatectomy
Researchers at Albert Einstein College of Medicine have developed a topical drug that regenerates and restores the function of erectile nerves damaged by radical prostatectomy, the most common treatment for localized prostate cancer. The drug was tested on rats and the results were published online today in JCI Insight.
Erectile dysfunction (ED) after radical prostatectomy has a significant impact on the lives of many patients and their partners. Because rats are reliable animal models in urological research, our drug offers real hope of normal sexual function to the tens of thousands of men who undergo this surgery each year. “
David J. Sharp, Ph.D., Study Co-Leader, Professor of Physiology and Biophysics, and Ophthalmology and Visual Sciences, and Professor in the Dominick P. Purpura Department of Neuroscience at Einstein
Radical prostatectomy – an operation to remove the prostate gland – is considered the definitive treatment for localized prostate cancer. “Despite the emergence of so-called nerve-sparing procedures, surgery can damage the cavernous nerves that control erectile function by regulating blood flow to the penis,” said study co-director Kelvin P. Davies, Ph.D., professor of the Urology and Physiology & Biophysics at Einstein. He notes that around 60% of patients have ED 18 months after surgery and less than 30% have erections that are firm enough for sexual intercourse after five years. Viagra and similar ED treatments are rarely effective in these patients, he said.
A decade ago, Dr. Sharp and colleagues found that the enzyme fidgetin-like 2 (FL2) slows down skin cells as they migrate towards wounds to heal them. To accelerate wound healing, the researchers developed an “anti-FL2” drug: small disruptive RNA molecules (siRNAs) that inhibit the gene that codes for FL2. Packaged in gel nanoparticles and sprayed onto mice, the siRNAs not only healed wounds twice as fast as untreated wounds, but also regenerated damaged tissue. A study in rats from February 2021 found that the siRNAs also aided in healing alkaline burns to the cornea.
Dr. Sharp, Dr. Davies and her teams realized that injured nerves could be particularly suitable for this gene silencing drug: For unknown reasons, the FL2 gene becomes overactive after an injury to nerve cells, causing the cells to produce copious amounts of the FL2 enzyme.
The Einstein team evaluated the drug using rat models of peripheral nerve injury, in which the cavernous nerves were either crushed or severed, and mimicked the nerve damage associated with radical prostatectomy. The siRNA gel was applied to the nerves immediately after the injury.
When the treatment was used after a nerve crush injury, the siRNA treatment improved nerve regeneration (regrowth) and restored nerve function, as shown by cavernosometry, a test that measures blood pressure in the penile shaft after the cavernous nerves are electrically stimulated. Three and four weeks after therapy, the treated animals had significantly better erectile function compared to the controls. After one month, the blood pressure response of the treated animals was comparable to that of normal animals.
Remarkably, even after severing the nerves, drug treatment induced nerve regeneration and partial restoration of erectile function. Regenerated nerves were observed in 7 of 8 treated animals, but not in any of the control animals (severed nerves treated with non-functioning siRNAs). The siRNA drug was able to heal gaps of several millimeters between severed nerve endings – a result that Dr. Sharp has so far only been achieved through nerve transplantation. “Functionally, the result of the siRNA treatment was equal to or better than the nerve transplant,” he added.
The researchers also found that penile shafts from treated animals had higher levels of the enzyme nitric oxide synthase compared to controls. The enzyme produces the nitric oxide needed to start the series of events that lead to erections. “This is important because drugs like Viagra won’t work unless there’s nitric oxide to get things going,” said Dr. Sharp. “But if we can restore even some of the nitric oxide in these nerves, Viagra and other ED drugs may have their effect.”
Dr. Sharp is currently investigating whether the siRNAs can promote nerve regeneration after spinal cord injuries.
Albert Einstein College of Medicine
Baker, L. et al. (2021) Fidgetin-like 2 negatively regulates axonal growth and can be used specifically to promote functional nerve regeneration. JCI Insight. doi.org/10.1172/jci.insight.138484.