Preclinical Studies Identify a Novel Target for Nerve Regeneration and Recovery of Erectile Function following Prostatectomy
By: Kelvin P. Davies, MSc, PhD | Posted on: 01 Jan 2022
Over the course of their lifetime, approximately 15% of all men will be diagnosed with prostate cancer, with prostatectomy being the most commonly employed strategy to treat localized prostatic cancer. Although the long-term oncologic outcomes following prostatectomy are good, patients commonly suffer postsurgical lower urinary tract complications, such as incontinence and erectile dysfunction (ED).
The cavernous nerves innervating erectile tissue are responsible for the release of neuronal signals that initiate an erection, and their injury during the surgical procedures of prostatectomy is believed to be a major factor in the development of ED. The loss of neuronal signals to erectile tissue is accompanied by progressive changes in penile architecture, involving a decrease in the density of nitrergic nerves and an increase in apoptosis and fibrosis of the cavernous smooth muscle. With increasing time, these changes become more difficult to reverse, such that even when there is recovery of nerve integrity, ED may persist. Avoiding chronic ED following prostatectomy can be considered a race between the time for functional cavernous nerve regeneration and permanent changes in penile architecture.
Recognizing this, several investigators have sought to enhance nerve regeneration following prostatectomy. The majority of these strategies have only been tested in animal models, or are prohibitively costly and technically challenging for widespread clinical use. Although none of these treatments has yet to be approved by the U.S. Food and Drug Administration, the majority of these investigations demonstrate the feasibility of this approach.
Because microtubules are known to play a key role in regulating axonal growth, therapeutic strategies that modulate microtubule dynamics have been proposed as possible treatments to accelerate nerve regeneration after injury. Dr. David Sharp’s laboratory, in the Department of Physiology and Biophysics at Albert Einstein College of Medicine, has pioneered our understanding of the fundamental molecular mechanisms that govern the formation and function of the microtubule cytoskeleton and in a recent paper identified Fidgetin-Like 2 (FL2) gene as a novel regulator of microtubule dynamics inhibiting axonal growth.1 Genetic knockout of FL2 in cultured adult dorsal root ganglion neurons resulted in longer axons, which were able to cross an inhibitory substrate composed of aggrecans (see figure). Aggrecans are abundant in glial scar tissue, which forms at the site of central nervous system injury, and are considered to be a major impediment to nerve regeneration by limiting axonal growth.
Recognizing that FL2 depletion in vitro had positive effects on axonal growth, the investigators went on to determine if targeting FL2 expression in vivo might promote peripheral nerve regeneration following injury. For these studies, an interdisciplinary collaboration was established with the laboratory of Dr. Kelvin Davies (in the Department of Urology at Albert Einstein College of Medicine), which for the past 2 decades has been at the forefront of research aimed at understanding the underlying mechanisms leading to ED. A novel formulation was developed in which FL2-siRNA was embedded into hardened chondroitin sulfate microgels. This “wafer-like” material adheres to tissue on application and slowly dissolves onto the injury site, confining treatments to the site of application. This formulation was applied at the site and time of bilateral transection of rat cavernous nerves, which is a commonly used animal model of iatrogenic nerve injury. Two weeks later, animals treated with FL2-siRNA demonstrated significantly enhanced nerve regeneration compared to controls. Remarkably, there was visible nerve regeneration in 7 out of 8 animals treated with FL2-siRNA. Electron microscopy confirmed that there was no qualitative difference in the myelin sheaths of regenerated and uninjured nerve tissue. Furthermore, electrical stimulation of regenerated nerves distal to the site of injury resulted in a significant erectile response. These results demonstrate that FL2 depletion at the time of cavernous injury results in sufficiently rapid nerve regeneration and that any changes in penile architecture that occur in this time frame are not to a level preventing an erectile response.
Overall, these studies identify FL2 as a promising therapeutic target for mitigating neurogenic ED after prostatectomy, and potentially to enhance regeneration following any type of peripheral nerve injury. Dr. Sharp’s group has also published studies describing that FL2 depletion accelerates the rate of wound healing, suggesting there could be beneficial pleiotropic effects that improve patient outcomes following the surgical procedures of prostatectomy. Investigations to support clinical translation of these findings are currently ongoing, supported by funding through a recently awarded National Institutes of Health small business grant (R41 DK112476, Principal Investigators: Baker L, Davies KP and Sharp D).
- Baker L, Tar M, Villegas G et al: Fidgetin-like 2 negatively regulates axonal growth and can be targeted to promote functional nerve regeneration. JCI Insight 2021; 6: e138484.
- Charafeddine RA, Makdisi J, Schairer D et al: Fidgetin-like 2: a microtubule-based regulator of wound healing. J Invest Dermatol 2015; 135: 2309.