Chronic diseases of aging account for a significant proportion of healthcare spending and result in a painful and limiting existence for many tens of millions of Americans and hundreds of millions of people around the world. Recursion Pharmaceuticals has developed a drug discovery platform that re-purposes known drugs for the treatment of such diseases. The platform consists of high content fluorescent image analysis using machine-learning algorithms to identify relevant and on-target changes induced in human cells in which diseases and treatments have been modeled. This system has been adapted to screen for drugs which may preferentially destroy senescent cells, as this may result in improved tissue function and decreases in pathology and mortality related to aging. In this SBIR fast-track proposal we will: PHASE I Identify a morphological profile of senescence in a variety of human cell types. Progression to Phase II will depend on our ability to demonstrate the power of our morphological approach to identify senescent cells independent of any known senescent markers. PHASE II Identify known drugs which preferentially destroy senescent cells, without affecting healthy cells, as identified by morphometric means. Evaluate the efficacy of identified senolytic agents in a variety of tissue function and health-span models in mice. *Evaluate the effect of identified senolytic agents in a murine model of age-associated cardiovascular disease. Recursion Pharmaceuticals has the experience, tools, and drive to execute this Phase I/Phase II Fast-track SBIR proposal, and to accelerate commercial development of any compounds we identify as a result.
Public Health Relevance Statement: Public Health Relevance: Chronic diseases of aging affect a significant proportion of Americans. Cellular senescence, a useful biological program which prevents replication of cells exposed to various stresses that may be at risk of initiating tumors, has long-term deleterious inflammatory effects. We will combine biological, imaging, and computational approaches to identify complex morphological profiles associated with senescence, to identify senescence- killing effects of known drugs, and to evaluate any hits in relevant models of aging.
Project Terms: Accounting; Affect; Age; Age of Onset; age related; aged; Aging; Aging-Related Process; Algorithms; American; Attenuated; base; beta-Galactosidase; Biological; Biology; Cardiovascular Diseases; Cardiovascular system; CDKN2A gene; Cell Aging; cell type; Cells; Cellular Morphology; Cellular Stress; Chemicals; Chronic Disease; Chronic Obstructive Airway Disease; Clinical Trials; Complex; Computer Vision Systems; cost; Cytokine Activation; Data; Development; Disease; Disease model; DNA Damage; drug development; drug discovery; Economics; Elderly; Excision; experience; fluorescence imaging; functional disability; Functional disorder; Future; Genetic Engineering; Health; Healthcare; Hereditary Disease; Human; Hydrogen Peroxide; Image; Image Analysis; improved; improved functioning; in vivo; Individual; Inflammatory; Killings; Length; Life; Long-Term Effects; Machine Learning; Mammals; Measures; Methodology; Methods; Modeling; Morbidity - disease rate; mortality; mouse model; Mus; Mutate; Non-Insulin-Dependent Diabetes Mellitus; novel; novel strategies; Organ; Oxidants; Oxidative Stress; Pain; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Phenotype; Population; Pre-Clinical Model; Preclinical Drug Evaluation; prevent; Process; Production; programs; public health relevance; response; Risk; Risk Factors; screening; senescence; Signal Transduction; Small Business Innovation Research Grant; social; Specificity; Stress; success; System; Systems Biology; Telomere Shortening; Time; Tissues; tool; Translations; tumor; Tumor Suppression; tumorigenesis
