Preterm birth is the leading cause of infant mortality and morbidity for which efficacious preventative treatments are essentially absent. Pre-term labor occurring prior to 37 weeks of gestation is associated with up to 18% of all births and significantly increases the risks for a slew of health complications, and medical costs associated with pre-term births have exceeded $26B. Treatments preventing pre-term birth are extremely limited. The only approved prophylactic treatment is weekly injection with the hormone progesterone beginning around week 16 through 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 treatment. Tocolytics are helpful in delaying delivery for a typically a few days allowing additional treatments to be administered to minimize risk, but they are not consistently effective nor are they able to postpone delivery until full term. There is a need for new therapies that halt pre-term labor at its onset and delay delivery indefinitely until 37 weeks are reached. Force generation by uterine cells, which is a central event in labor, is a logical and appropriate therapeutic target for preventing pre-term births. Forcyte 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 UCLA, that is leveraging a microtechnology known as FLECS ? a high- throughput screening (HTS) platform that measures contractility of single-cells in a 384-wellplate format ? to identify and bring to market new compound classes that act on force-generating pathways within cells. This is the first and only reported assay that obtains functional force generation data for single cells, at HTS scales. Our existing programs have focused on treatment resistant asthma and hypertension, and have already had success in discovering novel phenotypic modulators relating to these indications. This 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 births, which are the leading cause of infant mortality and morbidity, and lack efficacious treatment. Our approach implements a target-agnostic functional screen directly evaluating cell force generation ? a hallmark of labor ? with a miniaturized and fully automated cell-contractility assay implemented in the 384-wellplate format. Such a transformative improvement will enable us to rapidly screen entire compound libraries and greatly improving the probability of successful discovery. Furthermore, the proposed assay would offer high-throughput functional pre-clinical follow-up to other target-based affinity assays that cannot predict phenotypic activity. Furthermore, the proposed assay would offer high-throughput functional follow-up to other target-based affinity assays that cannot predict phenotypic activity. A follow-on Phase II proposal will perform screens of an expanded library in commercially available and patient-derived cells, as well as cell lines derived from smooth muscle in pregnant women. Selectivity counter-screens will also be performed in other contractile cell types to establish a deep safety profile for the discovered hits, to facilitate transitions to later stages of drug development. The completed assay will also be distributed through our commercial partners.
In the proposed work, we will build off our platform technology, the first high-throughput single-cell contractility screening platform based on fluorescently-labeled elastomeric contractible surfaces (?FLECS?), to 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 births, which are the leading cause of infant mortality and morbidity, and lack efficacious treatment. Our approach implements a target-agnostic functional screen directly evaluating cell force generation ? a hallmark of labor ? with a miniaturized and fully automated cell-contractility assay implemented in the 384-wellplate format. Such a transformative improvement will enable us to rapidly screen entire compound libraries and greatly improving the probability of successful discovery. Furthermore, the proposed assay would offer high-throughput functional pre-clinical follow-up to other target-based affinity assays that cannot predict phenotypic activity. The completed assay will be distributed through our commercial partners.
