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

Radical prostatectomyRPis a commonly used treatment option for localized prostate cancerUnfortunatelythe procedure carries a risk of post surgical complications including a high risk of erectile dysfunctionEDAccording to The Prostate Cancer Outcomes Studyvirtually all men experience ED after surgeryincluding a profound loss of nocturnal erectionsThe Prostate Cancer Outcomes Study further reveals thatof men experienced self reported EDmonths after RPand onlyof men reported erections firm enough for intercourse at ayear follow upThe main pathophysiological mechanism behind this is damage to the cavernous nervesCNConsequentlythe mechanisms that facilitate cavernosal oxygenation failfibrosis ensues and leads to cavernosal smooth muscle apoptosisWhereas neuropraxia may be reversiblethe penile fibrosis resulting from poor oxygenation permanently damages cavernosal function and produces chronic EDAccelerated wound healing and nerve growth would preserve penile anatomy and corporal smooth muscle and potentially reduce the time patients experience ED following RPHoweverthere are at present no clinically approved strategies for this procedureSeveral promising studies in animal models have used gene therapy approachesusually involving overexpression ofnerve growth factorsClinical translation of these gene therapy approaches will be hampered by safety issues over the use of viral vectors or transformed stem cells in abenign urological diseaseas well as concerns over the ease of applicationIn additionthere are no orally or topically administered therapeutics that reliably elicit an erection in men with RP induced EDOur goal is to develop a novel therapeutic that enhances EF after RP via RNAi mediated silencing of the microtubule severing enzymeFidgetin likeFLPreliminary results in an animal model of RP demonstrate that FLcan be targeted by nanoparticle delivered siRNA to dramatically and predictably recover EFFLacts through mechanisms dramatically different from other genes proteins factors currently being investigatedthe experiments presented in this application represent the first reported success of siRNA in treating ED associated with RPIn additionour recent preliminary findings indicate that a polyplex based carrierwaferof FLsiRNA is at least as effective as FLsiRNA np in restoring EF in an animal RP modelIn Specific Aimwe will compare a range of concentrations of FLsiRNA incorporated in a wafer formulation for efficacy in restoring EF following CN injurytransectionFinallyin Specific Aimwe will perform toxicity studies to provide evidence of safety for the different siRNA concentrationsThusat the end of the projectwe will have identified the siRNA wafer formulation that restores EF and is safe for further IND enabling studies Radical prostatectomyRPis a commonly used treatment option for localized prostate cancerUnfortunatelyaccording to The Prostate Cancer Outcomes Study virtually all men experience erectile dysfunctionEDafter surgeryAt present there is no orally or topically administered therapeutics that reliably elicits an erection in men with ED due to of RPOur goal is to develop and bring to the market a novel therapeutic that restores EF after RP via RNAi mediated silencing of the microtubule severing enzymeFidgetin likeFL