Senescence After Growth Arrest a new therapeutic modality for progeria

Abstract The long term goal of Atropos Therapeutics Incis development of a therapeutic drug for progeria and other aging related disorders based on their ability to regulate the senescence processAt the end of PhaseSBIRwe anticipate having two to five scaffolds that have utility slowing or preventing cellular senescence in tissue cultureIn phasewe anticipate moving scaffolds toward lead selectionto enable a subsequent clinical development phasethe last of which should follow an expedited path for debilitating orphan indicationsThe first indication we will pursue is the ultra orphan diseaseprogeriaProgeroid syndromesincluding HGPS or progeriaare rare human genetic diseases of accelerated agingwhich likely arise from dysregulation of normal aging processAging is thought to be at least in part due to the accumulation of senescent cellswhich have irreversibly exited the cell cycle and have elaborated a cell type specific secretory program known as SASPWhile accumulation of senescent cells can lead to sterile inflammation and tissue damagethey are also important for wound repair and stem cell reprogrammingSenescent cells accumulate in the tissues of aged normal and progeric humans and miceIn some tissues of progeric or aged normal miceeliminating senescent cells can lessen tissue damage and mitigate organ dysfunctionA number of commercial efforts are underway to eliminate senescent cells as a way to lessen the comorbidities of aging processesWe suspect that many of these so calledsenolyticswill run into the same types of hurdles that have plagued our ability to control cancerStudies of CDKinhibitor therapy induced senescenceCDK i TISrevealed that cancer cells could enter senescence directly from a quiescent stateThis new biologic transitionnow termed senescence after growth arrest or SAGAis akin to geroconversion and presents a novel approach to interfere with the accumulation of senescent cells in aged normal and progeric tissueWe have determined genes and mechanisms required for SAGA using genetically stable cancer cell linesSomebut not allof these are conserved and necessary in other models of senescenceSince we have shown that senescence cells can arise directly from quiescent cellsit opens the possibility that slowing SAGA will not cause aberrant proliferationDuring Phaseof this programwe propose to carry out high throughput high content screensHTS HCSto identify small molecule scaffolds that inhibit the formation of ATRX focian event both necessary and specific to cells embarking on the path to senescence Public Health Relevance The long term goal of this SBIR project is development of a drug for the ultra orphan disease progeriaOur approach is to prevent cellular senescenceFindings from this work may also lead to identification of compounds to treat other age related diseases