Small Molecule Drug Discovery for Cardiac Fibrosis using AI/ML and iPSC-Derived Organoids

About This Grant

Duchenne muscular dystrophy (DMD) is a rare X-linked genetic disorder affecting 1 in 3,500 male births worldwide. In DMD, cardiomyopathies are highly prevalent and the leading cause of death in the disease. DMDassociated cardiomyopathies include myocardial fibrosis and dilated cardiomyopathy that subsequently results in heart failure. Corticosteroids may increase the life expectancy of a DMD patient until the age of 30 by postponing heart failure, but more than 25% of DMD patients are unable to be treated with corticosteroids due to side effects or lack of response. To date, there are no specific treatments available for myocardial fibrosis and dilated cardiomyopathy in DMD. This proposal for the NHLBI Catalyze (R61/R33) will build on promising preliminary studies by Greenstone Biosciences to advance drug discovery for myocardial fibrosis in two phases. The R61 Phase will be to (i) perform unbiased proteomics to elucidate pathogenic crosstalk in DMD induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and cardiac fibroblasts (iPSC-FBs) as alternative testing models to identify drug targets, (ii) utilize artificial intelligence (AI) with molecular docking and molecular dynamics simulations to computationally screen a large library of compounds that bind to the drug target, (iii) apply a new generative AI SyntheMol to generate novel and easily synthesizable compounds out of a chemical space of ~30 billion molecules, and (iv) perform a drug screen using bioactive compound library that includes different nutritional and dietary supplements using DMD iPSCs that may prevent cardiac fibrosis. The R33 Phase will be to (v) synthesize and evaluate compounds to characterize physicochemical properties, including lipophilicity, pKa, and solubility, (vi) perform validation and replication studies to confirm the safety and efficacy of drug candidates identified from AI/ML and small molecule drug screen using DMD iPSCderived cardiac organoids for the prevention of myofibroblast activation, and (vii) evaluate the safety and efficacy in vivo using DMD mouse model (D2-mdx) along with an assessment of initial pharmacokinetic parameters for absorption, distribution, metabolism, excretion, and toxicity (ADMET). The successful outcome of this proposal will advance a drug candidate for cardiac fibrosis into the next stages of preclinical studies, including Investigational New Drug (IND) enabling studies and ultimately into clinical trials to address an unmet need for DMD patients. This drug would also be anticipated to be broadly applicable to dilated cardiomyopathies and other diseases with prevalent myocardial fibrosis. In doing so, our approach utilizes in silico (i.e., AI) and in vitro (i.e., iPSCs) approaches as New Alternative Methods (NAMs) and testing models, which will advance the replacement, reduction, and refinement of animal studies and clinical trials, especially to address urgent health needs and chronic health issues that affect many Americans, such as chronic childhood diseases like DMD.