An Automated Platform for High-throughput Network Electrophysiology

DESCRIPTION (provided by applicant): Calista Therapeutics has discovered a first-in-class, proprietary PDZ1-2 lead drug, AT010, that is being optimized and developed as an inhaled daily therapy for cystic fibrosis (CF). CF is a deadly inherited genetic disorder that disrupts chloride channel function, resulting in the buildup of sticky mucus in patient's lungs and other organs.CF patients have a life expectancy of 37 years and need intensive therapeutic interventions for chronic co-morbidities and symptoms.Critically, there are no approved disease-modifying treatments for 96% of CF patients, resulting in a very high unmet clinical need. Preliminary AT010 results already show proof of efficacy in the restoration of the chloride channel in human CF bronchialepithelium. In addition, AT010 can be delivered through CF mucus following topical apical dosing. PDZ1-2 is a well-validated therapeutic target in CF that influences both the CF chloride channels trafficking and anchoring at the cell membrane, and its activation. The high level of restoration we have already observed with AT010 is established to be predictive of clinical efficacy. The novel and distinct PDZ1-2 mechanism of action in CF also suggests it will have a beneficial additive effect with other CF drugs. We have built a world-class team of CF and drug development experts and our results demonstrate technical competence and the environment to successfully achieve the project's aims: Aim 1. Synthesis of an optimized clinical lead AT010-derived peptidelibrary: AT010 analogs designed to have stability, efficacy, low cost of manufacture, simple predicted CMC, non-immunogenicity, bioavailability, mucus penetration and target specificity will be synthesized in sufficient quantity and purity for Aim 2. Aim 2. Stability and efficacy testing of candidate compounds in human CF models. Aim 2.1: We will test and percentage rank the library for stability in human CF epithelial lining fluid. Peptides wil be eliminated from further development only if they show low solubility or a half-life lt30 minutes because this will lead to unacceptable bioavailability. Aim 2.2: We will assess efficacy of the peptide drug library using CF patient tissues and samples and gold standard pre-clinical models that provide the best predictive power for clinical success: (1) Restoration of human delta-F508-CFTR chloride current gt10%, (2) Restoration of normal airway surface liquid (ASL) height and (3) Unimpaired diffusion through CF mucus. This will provide a percentage ranked peptide drug library for CF-relevant in vitro stability and efficacy endpoints that will identify clinical lead nd back-up peptide drugs ready for toxicity assessments. Milestone 2: Upon completion we will solicit a Pre-IND meeting to allow rapid lead drug progression to IND studies and clinical trials. An expert team, substantially validated target, proprietary novel drug class (AT010), compelling preliminary data and an outstanding environment combine to ensure successful commercialization. Calista therapeutics hasplanned IND enabling studies and clinical trials that project completion of Phase1 and 2a trials in Year 4 post-grant award with a pivotal Phase 2b/3 trial prior to New Drug Application for approval. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE:Cystic Fibrosis is the commonest lethal inherited disease among Caucasian Americans. Calista Therapeutics has discovered a novel 'corrector' therapeutic strategy for Cystic Fibrosis that has already proven very effective in cystic fibrosis patient lung tissue. This therapy is intended to effectively treat all Cystic Fibrosis patients, preventing death and disablement of the 30,000 patients.