Novel, Non-hormonal Therapeutic for Endometriosis

The goal of the project is to develop the first disease modifyingnon hormonal therapeutic for endometriosisEMSEMS is considered the greatest overlooked epidemic in womenandapos s healthaffecting approximatelyof women worldwideIt is the number one cause of infertility and disability among adolescents and women across all ethnicitiesShockinglyto datethere is no cure for this chronic and prevalent diseaseBecause it takes an average US womanyears to be diagnosed with EMSthe current management protocols of hormonalpain therapiesor surgical interventions which fail to reverse the disease or address the root cause are often insufficientHormone pills and GnRH antagonistscausingmedical menopauseprescribed to patients with EMS can induce many undesirable side effectsMany women who undergo EMS excision will have reoccurrence withinyears of surgeryHysterectomies are recommended for women who do not experience relief through less invasive methodsOur team has developed a novel therapeutic option for EMS by targeting a downstream component of a pathway known to contribute to endometriosis pathogenesis and endometrial migration and invasionOur panel of macrocyclic peptides specifically inhibits this downstream component and shows success in cell potency and proliferation assaysreporter assaysserum stabilitymembrane permeabilitytoxicity mouse studiesand exhibits great potential to act as an endometriosis therapeuticOther molecules targeting the pathway have reversed EMS progression in academic settingsbut have off target or upstream pathway targets that induce undesired side effectsIn this novel projectwe will identify the most promisingmacrocyclic peptides that inhibit the migration and invasion in EMS cells and confirm its efficacy in an EMS animal modelThe compounds will be evaluated for cellular potencyPK PDon target effectsconfirm lack of off target effectsinhibition of cellular invasion and migrationand efficacy using primary EMS cells donated by our collaborators at the Boston Center for EndometriosisThe cells have been excised from different patients and collected in accordance to the EPHECT standard protocols with accompanying clinical recordsThe PKefficacyand biodistribution of our macrocyclic peptides will also be evaluated an in vivo animal models of endometriosisand on target effects will be confirmed through qPCR of RNAimmunohistochemistryand western blot analysisMedicinal chemistry optimization will be performed on the lead candidate peptides to obtain an optimal clinical drug profile by becoming more unnaturalpeptidomimeticsmall molecule likeagentsOnce validated and optimizedthese compounds will enter into preclinical investigation and toxicity studies in Phase IIThese experiments will prepare us for a subsequent Phase IIB application to fund IND toxicity experiments in preparation for pre discussions with the FDA as we prepare for an IND for Phaseclinical trials The goal of this project is to develop a therapeutic capable of treating endometriosisEndometriosis is a high priority research area of NICHDCurrent management protocols for endometriosis including hormones and surgery do not address the root cause of the diseasefail to reverse disease progressionleave a chance of reoccurrenceand often present patients with undesirable side effectsWe have identified a set of compounds that can specifically target a downstream component of a pathway known to contribute to endometriosis pathogenesis and endometrial migration and invasionand we will develop the two most promising compound into endometriosis therapeutics