Radical prostatectomy (RP) is a commonly used treatment option for localized prostate cancer, which carries a
high risk for development of erectile dysfunction (ED) because of cavernous nerve (CN) injury. Even newer,
nerve-sparing, robotic procedures do not convincingly improve erectile function (EF) outcomes after RP. In
addition, ED resulting from RP is often refractory to treatment by orally administered phosphodiesterase type 5
inhibitors (PDE5i) leaving patients with poor treatment options that are invasive, associated with side-effects,
have limited efficacy, and treat symptoms rather than being curative. There is a real and urgent need to
identify new therapeutic strategies to treat ED associated with RP.
As a consequence of CN injury there is decreased neuronal nitric oxide (NO) release in corporal tissue, the
primary activator of the molecular pathways leading to an erection. Lower levels of NO release lead to a failure
in mechanisms that facilitate cavernosal oxygenation, resulting in fibrosis and cavernosal smooth muscle
apoptosis, which then act as potentially irreversible barriers to recovery of EF, even after CN regeneration. Since
EF is impacted within 48 hours of CN injury, a strategy called “penile rehabilitation” such as oral PDE5i
administration, is initiated as early as possible after RP with the goal of raising basal corporal blood flow and
preserving penile architecture until there is functional CN regeneration.
Based on the central role that CN injury plays in the development of ED following RP, our novel treatment
strategy uses siRNA technology to target expression of a newly discovered microtubule regulator, Fidgetin-like
2 (FL2) to enhance CN regeneration. Preliminary and published studies suggest FL2 is a negative regulator of
axon growth and wound repair; in Phase I studies a novel lead therapeutic formulation (a “wafer” releasing FL2-
siRNA; SiFi2) was identified that when administered to rats undergoing bilateral CN transection resulted in visible
CN regeneration and improved erectile function. Compared to other pre-clinical strategies under investigation
for CN regeneration, SiFi2 is exceptionally fast and effective in promoting CN regeneration, inducing reformation
of nerve tissue across a gap of several millimeters, and resulting in significant improvement in erectile function
as early as two weeks following transection. However, this and other preclinical strategies being explored for
CN regeneration may fail to recover optimal EF because irreversible changes may occur in penile architecture
during the time it takes for nerve regeneration. Therefore, we will explore a two-pronged approach enhancing
nerve regeneration and mitigating corporal tissue damage while the nerve is healing.
The goal for this Phase II proposal is to initiate steps towards an Investigational New Drug application (IND)
filing, over three specific aims: (1) evaluate the ability of orally administered PDE5i to enhance SiFi2 treatment;
(2) initiate a GMP start-up program at a contract manufacturing organization (CMO); and (3) evaluate toxicity of
SiFi2 produced at the CMO.
