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