Broad-acting therapeutic effects of miR-29b-chitosan on hypertension and diabetic complications

• Published in: Molecular therapy Vol. 30; no. 11; pp. 3462 - 3476
• Main Authors: Jensen, David M., Han, Peng, Mangala, Lingegowda S., Lopez-Berestein, Gabriel, Sood, Anil K., Liu, Jing, Kriegel, Alison J., Usa, Kristie, Widlansky, Michael E., Liang, Mingyu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.11.2022; American Society of Gene & Cell Therapy
• Subjects: albuminuria; aneurysm; Angiotensin II - adverse effects; Animals; atherosclerosis; Chitosan; Diabetes Complications; Diabetes Mellitus; diabetic complications; Disease Models, Animal; Fibrosis; heart; Humans; hypertension; Hypertension - genetics; Hypertension - therapy; kidney; Mice; Mice, Inbred Strains; Mice, Knockout, ApoE; microRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Original; therapeutics; Thiolester Hydrolases; diabetic complications; atherosclerosis; kidney; aneurysm; albuminuria; therapeutics; microRNA; fibrosis; hypertension; heart
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2022.08.007

MicroRNA miR-29 promotes endothelial function in human arterioles in part by targeting LYPLA1 and increasing nitric oxide production. In addition, miR-29 is a master inhibitor of extracellular matrix gene expression, which may attenuate fibrosis but could also weaken tissue structure. The goal of this study was to test whether miR-29 could be developed as an effective, broad-acting, and safe therapeutic. Substantial accumulation of miR-29b and effective knockdown of Lypla1 in several mouse tissues were achieved using a chitosan-packaged, chemically modified miR-29b mimic (miR-29b-CH-NP) injected systemically at 200 μg/kg body weight. miR-29b-CH-NP, injected once every 3 days, significantly attenuated angiotensin II-induced hypertension. In db/db mice, miR-29b-CH-NP treatment for 12 weeks decreased cardiac and renal fibrosis and urinary albuminuria. In uninephrectomized db/db mice, miR-29b-CH-NP treatment for 20 weeks significantly improved myocardial performance index and attenuated proteinuria. miR-29b-CH-NP did not worsen abdominal aortic aneurysm in ApoE knockout mice treated with angiotensin II. miR-29b-CH-NP caused aortic root fibrotic cap thinning in ApoE knockout mice fed a high-cholesterol and high-fat diet but did not worsen the necrotic zone or mortality. In conclusion, systemic delivery of low-dose miR-29b-CH-NP is an effective therapeutic for several forms of cardiovascular and renal disease in mice. [Display omitted] Liang and colleagues developed a chitosan-packaged, chemically modified miR-29b mimic (miR-29b-CH-NP). Using five models of disease, they demonstrated that systemic delivery of low-dose miR-29b-CH-NP was an effective, broad-acting, and safe therapeutic for several forms of cardiovascular and renal disease in mice.