Targeting ECM-producing cells with CAR-T therapy alleviates fibrosis in chronic kidney disease

Abstract

Kidney fibrosis is a hallmark of chronic kidney disease (CKD) and a potential therapeutic target. However, clinical interventions and therapies targeting kidney fibrosis remain conceptual and practical challenges due to the complex origin, functional heterogeneity, and regulation of scar-forming cells. Here, we define fibroblasts, pericytes, and myofibroblasts as the major extracellular matrix (ECM)-producing cells in the kidney, highlighting their primary contribution to kidney fibrosis. We then identify platelet-derived growth factor receptor β (PDGFRβ) as a potential targeting surface antigen for anti-fibrotic chimeric antigen receptor (CAR)-T against CKD. In multiple mouse CKD models, both adoptive transfer and CD5-lipid nanoparticle (LNP)-mediated in vivo generation of PDGFRβ CAR-T cells significantly ameliorate fibrosis-associated pathologies, including kidney, myocardial interstitial, and perivascular fibrosis without notable toxicity, evoking an integrated therapeutic strategy for multi-organ fibrosis in mice with CKD and its cardiovascular complications. The anti-fibrotic effects are also demonstrated in the human kidney organoid CKD, further strongly supporting the therapeutic potential for the treatment of patients with CKD.