Buck Institute for Research on Aging

Unity Biotechnology, Inc.

Mayo Foundation for Medical Education and Research

The Johns Hopkins University

Erasmus University Medical Center Rotterdam

Buck Institute for Research Aging

Remi-Martin Laberge

Judith Campisi

Marco Demaria

Nathaniel E David

James L Kirkland

Tamar Tchkonia

Yi Zhu

Jan M A Van Deursen

Alain Philippe Vasserot

Darren J Baker

Bennett G Childs

Albert Davalos

Jennifer H Elisseeff

Francis Rodier

Chaekyu Kim

Okhee Jeon

F Anthony Romero

Anne-Marie Beausoleil

Ryan Hudson

Jamie Dananberg

Daniel Marquess

Pam Tsuruda

Jill Hopkins

Harry Sweigard

Yan Poon

James Mitchell

Jan H J Hoeijmakers

Wendy Toussaint

Jan Ma Van Deursen

Jan MA Van Deursen

Claude Chapman

This invention establishes a new paradigm for treatment of Parkinson's disease (PD) by eliminating senescent cells that reside in or around the site of the disease pathophysiology. Exposure of test subjects to the herbicide paraquat (PQ) increases the risk for developing Parkinson's disease. The data in this disclosure show that PQ induces a senescence arrest and SASP in astrocytes, in culture and in vivo in mice, and senescent cell markers were present in astrocytes in midbrain tissue from PD patients. In a transgenic mouse model, senescent cell ablation protected against PQ-induced PD-like neuropathology. Removal of senescent cells from affected sites using small molecule agents that specifically target senescent cells can help prevent or ameliorate signs and symptoms of the disease.

Treatment of a senescence-associated ocular disease or disorder using a Bcl-xL selective inhibitor

Methods are provided herein for selectively killing senescent cells and for treating senescence-associated diseases and disorders by administering a senolytic agent. Senescence-associated diseases and disorders treatable by the methods using the senolytic agents described herein include cardiovascular diseases and disorders associated with or caused by arteriosclerosis, such as atherosclerosis; idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; osteoarthritis; senescence-associated ophthalmic diseases and disorders; and senescence-associated dermatological diseases and disorders.

Treating liver disease by selectively eliminating senescent cells

Treating cardiovascular disease by selectively eliminating senescent cells

Treating cognitive decline and other neurodegenerative conditions by selectively removing senescent cells from neurological tissue

The proteasome inhibitors of this invention include peptide-based compounds with a short linear sequence of amino acids. An oxo or thio group is attached to the N-terminal amino acid. A protein-reactive electrophilic group such as an epoxyketone, an aziridinylketone, or a beta-lactone is attached to the C-terminal amino acid. Upon contact with a proteasome complex in a target cell, the electrophilic group reacts with a functional group in or near a binding pocket or active site of the proteasome, forming a covalent bond and thereby inactivating the proteasome. These and other proteasome inhibitors can be screened for binding affinity and an ability to selectively eliminate senescent cells or cancer cells. Compounds that selectively remove senescent cells can be developed for the treatment of conditions such as osteoarthritis, ophthalmic disease, pulmonary disease, and atherosclerosis.

Peptide-based proteasome inhibitors for treating conditions mediated by senescent cells and for treating cancer

This disclosure provides non-human animal models for age-related disorders and age-sensitive traits, particularly those caused by senescence-inducing stimuli, wherein the models comprise transgenes selectively expressed by senescent cells. The disclosure further provides methods for identifying therapeutic agents effective for treating or preventing age-related disorders and age-sensitive traits using the animal models, therapeutic agents identified using such methods, pharmaceutical compositions comprising the identified therapeutic agents, and methods of treating or preventing age-related disorders and age-sensitive traits.

Nucleic acid construct with a p16 promoter that causes a prodrug converting enzyme to be expressed specifically in senescent cells

Removing senescent cells from a mixed cell population or tissue using a phosphoinositide 3-kinase (PI3K) inhibitor

Compositions of matter for treatment of ophthalmic conditions by selectively removing senescent cells from the eye

Unit dose of an aryl sulfonamide that is effective for treating eye disease and averting potential vision loss

Methods and compositions for killing senescent cells and for treating senescence-associated diseases and disorders using an inhibitor of Akt kinase

Foamy macrophages with senescence markers accumulate in the subendothelial space at the onset of atherosclerosis where they drive pathology by increasing expression of key atherogenic and inflammatory cytokines and chemokines. In advanced lesions, senescent cells promote features of plaque instability, including elastic fiber degradation and fibrous cap thinning, by heightening metalloprotease production. This invention provides methods and materials for treating arthritis by removing senescent cells in or around atherosclerotic plaques, thereby stabilizing the plaques, inhibiting rupture of the plaques and pathological sequelae that manifest as coronary artery disease.

Treating atherosclerosis by removing senescent foam cell macrophages from atherosclerotic plaques

Use of sulfonamide inhibitors of BCL-2 and BCL-xL to treat ophthalmic disease by selectively removing senescent cells

Treating pulmonary conditions by selectively removing senescent cells from the lung using an intermittent dosing regimen

Method of optimizing conditions for selectively removing a plurality of senescent cells from a tissue or a mixed cell population

Growing community of inventors

San Francisco, CA, United States of America

Remi-Martin Laberge