A Novel Therapeutic that Harnesses Microtubules to Promote Cavernous Nerve Regeneration after Radical Prostatectomy

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.Radical prostatectomy (RP), a commonly used treatment option for localized prostate cancer, often results in erectile dysfunction (ED) and, unfortunately, no orally or topically administered therapeutics exist which reliably restore erectile function in these afflicted men. Phase I studies have shown that when siRNA targeting the newly discovered microtubule regulator, Fidgetin-like 2 (FL2-siRNA-wafer; SiFi2), is administered to rats that underwent CN transection, visible CN regeneration and improved erectile function outcomes as early as two weeks post-transection were observed; these effects were both faster and more effective than other pre-clinical strategies. 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 the commonly prescribed, orally administered phosphodiesterase type 5 inhibitors (PDE5i) to enhance SiFi2 treatment; (2) initiate a good manufacturing process (GMP) start-up program at drug substance and drug product contract manufacturing organizations (CMO); and (3) evaluate toxicity of the CMO generated SiFi2.