The long-term goal of Atropos Therapeutics Inc. is development of a therapeutic drug for progeria and other aging-related disorders based on their ability to regulate the senescence process. At the end of Phase 1 SBIR, we anticipate having two to five scaffolds that have utility slowing or preventing cellular senescence in tissue culture. In phase 2 we anticipate moving scaffolds toward lead selection, to enable a subsequent clinical development phase, the last of which should follow an expedited path for debilitating orphan indications. The first indication we will pursue is the ultra-orphan disease, progeria. Progeroid syndromes, including HGPS or progeria, are rare human genetic diseases of accelerated aging, which likely arise from dysregulation of normal aging process. Aging is thought to be at least in part due to the accumulation of senescent cells, which have irreversibly exited the cell cycle and have elaborated a cell type-specific secretory program known as SASP. While accumulation of senescent cells can lead to sterile inflammation and tissue damage, they are also important for wound repair and stem cell reprogramming. Senescent cells accumulate in the tissues of aged normal and progeric humans and mice. In some tissues of progeric or aged normal mice, eliminating senescent cells can lessen tissue damage and mitigate organ dysfunction. A number of commercial efforts are underway to eliminate senescent cells as a way to lessen the comorbidities of aging processes. We suspect that many of these so called âsenolyticsâ will run into the same types of hurdles that have plagued our ability to control cancer. Studies of CDK4/6 inhibitor therapy-induced senescence (CDK4i TIS) revealed that cancer cells could enter senescence directly from a quiescent state. This new biologic transition, now termed senescence after growth arrest or SAGA, is akin to geroconversion and presents a novel approach to interfere with the accumulation of senescent cells in aged normal and progeric tissue. We have determined genes and mechanisms required for SAGA using genetically-stable cancer cell lines. Some, but not all, of these are conserved and necessary in other models of senescence. Since we have shown that senescence cells can arise directly from quiescent cells, it opens the possibility that slowing SAGA will not cause aberrant proliferation. During Phase 1 of this program, we propose to carry out high-throughput/high-content screens (HTS/HCS) to identify small molecule scaffolds that inhibit the formation of ATRX foci, an event both necessary and specific to cells embarking on the path to senescence.
Public Health Relevance Statement: Public Health Relevance The long-term goal of this SBIR project is development of a drug for the ultra-orphan disease progeria. Our approach is to prevent cellular senescence. Findings from this work may also lead to identification of compounds to treat other age-related diseases.
Project Terms: age related; aged; Aging; Aging-Related Process; Appearance; ATRX gene; base; Biological Assay; cancer cell; Cancer cell line; Cancer Control; CDK4 gene; Cell Aging; Cell Cycle; Cell Line; cell type; Cells; clinical development; Clinical Trials; Comorbidity; Data; Development; Disease; Doxycycline; Epithelial; Event; Excision; Family; Fibroblasts; Functional disorder; Genes; Genetic Diseases; Goals; Gray unit of radiation dose; Growth; Human; Human Genetics; Immunofluorescence Immunologic; Inflammation; inhibitor/antagonist; innovation; Knowledge; Lead; Mesenchymal; Modality; Modeling; Molecular; Mus; normal aging; novel strategies; novel therapeutics; Organ; Orphan; Patients; Pharmaceutical Preparations; Phase; prevent; Process; Progeria; programs; public health relevance; Rare Diseases; Resolution; Running; SAGA; scaffold; senescence; Small Business Innovation Research Grant; small molecule; small molecule libraries; Stem cells; Sterility; Syndrome; Testing; Therapeutic; Time; tissue culture; Tissues; Validation; Work; Wound Heal
