High-throughput screening of uterine smooth muscle contractility towards therapies to prevent pre-term birth

SUMMARYABSTRACT Preterm birth is the leading cause of infant mortality and morbidity for which efficacious preventative treatments are essentially absentPre term labor occurring prior toweeks of gestation is associated with up toof all births and significantly increases the risks for a slew of health complicationsand medical costs associated with pre term births have exceeded $BTreatments preventing pre term birth are extremely limitedThe only approved prophylactic treatment is weekly injection with the hormone progesterone beginning around weekthrough the end of gestation indicated specifically for at risk mothers which benefits only ideal candidates who meet the risk criteria and promptly and faithfully receive treatmentTocolytics are helpful in delaying delivery for a typically a few days allowing additional treatments to be administered to minimize riskbut they are not consistently effective nor are they able to postpone delivery until full termThere is a need for new therapies that halt pre term labor at its onset and delay delivery indefinitely untilweeks are reachedForce generation by uterine cellswhich is a central event in laboris a logical and appropriate therapeutic target for preventing pre term birthsForcyte Biotechnologies is an early stage bio pharmaceutical company in Los Angeles that has partnered with advanced high throughput screening and laboratory automation as well as nanofabrication facilities at UCLAthat is leveraging a microtechnology known as FLECSa highthroughput screeningHTSplatform that measures contractility of single cells in awellplate formatto identify and bring to market new compound classes that act on force generating pathways within cellsThis is the first and only reported assay that obtains functional force generation data for single cellsat HTS scalesOur existing programs have focused on treatment resistant asthma and hypertensionand have already had success in discovering novel phenotypic modulators relating to these indicationsThis proposal aims to develop a functional assay for screening and developing novel therapeutics that are able to halt uterine contraction during pre term labor and return it to quiescent state to prevent pre term birthswhich are the leading cause of infant mortality and morbidityand lack efficacious treatmentOur approach implements a target agnostic functional screen directly evaluating cell force generationa hallmark of laborwith a miniaturized and fully automated cell contractility assay implemented in thewellplate formatSuch a transformative improvement will enable us to rapidly screen entire compound libraries and greatly improving the probability of successful discoveryFurthermorethe proposed assay would offer high throughput functional pre clinical follow up to other target based affinity assays that cannot predict phenotypic activityFurthermorethe proposed assay would offer high throughput functional follow up to other target based affinity assays that cannot predict phenotypic activityA follow on Phase II proposal will perform screens of an expanded library in commercially available and patient derived cellsas well as cell lines derived from smooth muscle in pregnant womenSelectivity counter screens will also be performed in other contractile cell types to establish a deep safety profile for the discovered hitsto facilitate transitions to later stages of drug developmentThe completed assay will also be distributed through our commercial partners NARRATIVE In the proposed workwe will build off our platform technologythe first high throughput single cell contractility screening platform based on fluorescently labeled elastomeric contractible surfacesFLECSto develop a functional assay for screening for force generation in uterine smooth muscle and developing novel therapeutics that are able to halt uterine contraction during pre term labor and return it to quiescent state to prevent pre term birthswhich are the leading cause of infant mortality and morbidityand lack efficacious treatmentOur approach implements a target agnostic functional screen directly evaluating cell force generationa hallmark of laborwith a miniaturized and fully automated cell contractility assay implemented in thewellplate formatSuch a transformative improvement will enable us to rapidly screen entire compound libraries and greatly improving the probability of successful discoveryFurthermorethe proposed assay would offer high throughput functional pre clinical follow up to other target based affinity assays that cannot predict phenotypic activityThe completed assay will be distributed through our commercial partners