Rationale: Senescent cells accumulate as people age but they can also be induced by various types of stress including treatments for cancer and chronic inflammation. In any given tissue or organ there will be some cells that are senescent and some normal cells. Senescent cells do not function normally and can interfere with the function of surrounding normal, nonsenescent cells. Thus, accumulation of senescent cells is associated with poor function of multiple organs including the heart and blood vessels, kidneys, muscles, bone, and brain. In the past few years, drugs targeting senescent cells (senolytic drugs) have been identified, and treatment of animals with these drugs have led to the clearance of senescent cells from organs and improved organ function. Interferon beta, a protein made to fight viral infections but also a protein markedly upregulated in lupus, is one of the factors that promotes cellular senescence. We have recently found that patients with lupus and high levels of interferon beta in their blood have senescent cells in their bone marrow. These bone marrow cells, called mesenchymal stem cells (MSC), play an important role in repair from injury and downregulation of inflammation. We hypothesize that patients with lupus have an accelerated accumulation of senescent cells and that treatment with senolytic drugs will clear these cells and improve organ function. We are especially interested in lupus nephritis. In other types of chronic kidney disease, senescent cells have been identified but these studies did not include patients with lupus. We already have MSC cell lines from over 20 patients with lupus and controls matched for sex and age.

Aim 1. A series of senolytic drugs will be tested on MSC cell lines from SLE patients and from lupus-prone mice. Sensitivity of lupus cell lines will be compared to control cell lines from healthy individuals and healthy strains of mice.

Aim 2. We will assess the accumulation of senescent cells in kidneys of SLE patients and in kidneys from lupus-prone mice compared to kidney specimens from patients without inflammatory disease of the kidney (healthy tissue from kidneys removed because of small tumors) and from healthy strains of mice.

Relationship of proposed work to specific Focus Area(s): Focus Area #3. Determine the pathobiology of lupus in target human tissue. The principal aim of the study will be to evaluate accumulation of senescent cells in lupus target tissue and to see if senescent cells from lupus patients can be targeted by drugs that have been successfully used to target senescent cells in animal models of aging.

What type of patients will it help and how will it help them? We anticipate that patients who have had lupus for a long time will accumulate more senescent cells and have more organ dysfunction, e.g., patients who have lupus kidney disease and whose kidneys are beginning to fail. We expect that these patients with chronic disease and the start of organ failure are the patients who will most likely be helped.

What are the potential clinical applications, benefits, and risks? Many of the drugs that target senescent cells are already approved for use in patients with certain type of cancers. Radiation and many of the drugs traditionally used to treat cancers actually increase accumulation of senescent cells. (Indeed, cyclophosphamide, which is often used in lupus, is one of those cancer drugs that can induce accumulation of senescent cells.) Some of these drugs have significant toxicity; some others are available over the counter as nutraceuticals. In animal models, short-term treatment appears to be effective. Therefore, any toxicity of senolytic drugs will be mitigated by the short duration of treatment.

What is the projected time it may take to achieve a patient-related outcome? The proposed grant is for a 1-year period. At the end of the grant, we will have determined whether senolytic drugs can target cells from lupus patients and which senolytic drugs are most potent. We will also have established whether kidneys from patients with lupus nephritis accumulate senescent cells and which types of cells in lupus kidneys have accelerated senescence. Parallel studies in a murine model of lupus will tell us whether this model can be used to further test these drugs. We anticipate another year (and another grant) will be needed to test promising senolytic drugs in a murine model of lupus.

What is the likely impact of the study on the understanding, prevention, diagnosis, and/or treatment of lupus? Clearance of the senescent cells that accumulate within target organs in the chronic inflammation so often seen in lupus patients will allow rejuvenation and repopulation with healthy cells, leading to improved function of tissues and organs. Thus, clearance of senescent cells may reverse some of the abnormalities seen in SLE patients, e.g., in kidneys, hearts, blood vessels, bone, and nervous tissue, leading to improved recovery from lupus.