Extracellular vesicle-based senotherapeutics for aging diabetic kidneydisease

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Project Summary The rise in an aging population plagued by obesity and diabetes mellitus is projected to render exponential growth in diabetic kidney disease (DKD). Hence, therapeutic interventions that halt aging-related kidney changes and DKD must be rigorously pursued. Maladaptive inflammation drives DKD onset, and proinflammatory cytokines and chemokines activate macrophages leading to kidney infiltration and poor renal prognosis. Yet, inflammation remains a major unaddressed injurious pathway in DKD. We and others demonstrated that maladaptive inflammation in DKD patients and animal models is associated with increased cellular senescence and kidney dysfunction. Thus, decreasing senescence through senotherapeutics, such as, small molecule drugs or cell-derived components, may halt DKD and age-related kidney deterioration. Therefore, there is an urgent need to develop a therapeutic armamentarium targeting the multifaceted pathogenesis (inflammation and cell senescence) of DKD to extend healthy lifespan. We and others demonstrated that mesenchymal stromal cells (MSCs) suppress inflammatory responses through secretion of extracellular vesicles (EVs) containing biologically active cargo, primarily microRNAs (miRNAs), and reduce senescent burden and extend lifespan in aging mouse models. Although the therapeutic activity of MSC-EVs has previously been assessed in aging and inflammatory disease models, the effects of these biotherapeutics on inflammation and senescence in aging DKD remain unexplored. Our preliminary results indicate that MSC-EVs: (i) reduce senescence pathways, macrophage infiltration, and kidney injury in murine DKD and (ii) can be loaded with small molecule drugs for combination therapy. Additionally, our recent study demonstrated, for the first time, that senolytic drugs, dasatinib and quercetin, reduce senescent cell abundance in humans and improve kidney injury following senescent cell clearance in mouse models. We hypothesize that EVs have anti-inflammatory and senotherapeutic effects in aging DKD, that can be further enhanced by co-delivery of senolytic drugs. To address this central hypothesis, we will determine the effects of EV miRNAs on senescence and inflammation in vitro (Aim 1), assess the effects of EVs from several sources in a mouse model of aging DKD (Aim 2), and evaluate the performance of EVs as drug delivery vehicles for dasatinib and quercetin (Aim 3). To ensure the technical success of this study, we have assembled a team with complementary expertise in aging, DKD, extracellular vesicles, senolytics, and drug delivery. Novel approaches encompassing unique EV sources, EV isolation methods, and immunoprofiling technology will enhance knowledge of EV-mediated therapeutic mechanisms in DKD and may advance clinical translation of EVs as novel senotherapeutics, delivery vehicles for senolytics, and/or combination therapies to reduce inflammatory and senescence pathways in diabetic and age-related kidney dysfunction. These novel therapeutics hold potential to alter disease trajectory and extend the healthy lifespan in those with aging DKD.