Potential therapeutic target for erectile dysfunction following prostate cancer surgery
Researchers have identified a nerve regeneration pathway that could be targeted to reverse erectile dysfunction (ED) caused by surgery. ED is a condition in which one is unable to get or maintain a penile erection firm enough for satisfactory sexual activity. Notably, many men experience ED after prostate cancer surgery. ED may occur if nerves that regulate blood flow to the penis, called cavernous nerves, are inadvertently damaged or removed during surgery. Unfortunately, existing treatments are rarely effective for men with ED following prostate cancer surgery.
Investigators recently described a series of experiments in male rodents that highlight the important role of a protein called fidgetin-like 2 (FL2) in the regeneration of neurons, or nerve cells. One way to assess neuronal regeneration is to measure growth of the axon, a specialized cellular extension neurons use to transmit signals throughout the body. The researchers found that mouse neurons genetically engineered to no longer produce FL2 protein had significantly longer axon growth compared to neurons with normal levels of FL2. This finding suggested that FL2 acts as a negative regulator of axon growth and that its absence might facilitate neuron growth. To test this, the researchers used a technique employing small interfering RNAs (siRNAs)— short strips of genetic material—to effectively “turn off” the Fl2 gene in a rat model of cavernous nerve injury that mimics what can occur in human prostate cancer surgery. In this experiment, Fl2-siRNAs, packaged in nanoparticles, were topically applied to crushed cavernous nerves immediately after injury. After 4 weeks, the erectile response of the rats treated with Fl2-siRNAs was significantly improved compared to that of animals treated with controls (no Fl2-siRNAs). In addition, applying Fl2-siRNA treatment to rats with severed cavernous nerves resulted in seven of eight animals exhibiting visible nerve regeneration and erectile response 2 weeks later, whereas rats treated with scrambled siRNA had no visible nerve regrowth.
These findings demonstrate that depleting FL2 protein in neurons enhances their regeneration potential and suggest that approaches targeting production of this protein may lead to promising therapeutic strategies for ED caused by prostate cancer surgery.
Baker L, Tar M, Kramer AH,…Sharp DJ. Fidgetin-like 2 negatively regulates axonal growth and can be targeted to promote functional nerve regeneration. JCI Insight 6: e138484, 2021.