Telomere recapping via gene therapy as a therapeutic strategy for cardio-renal syndromes type 4

Cardio-renal syndromes type 4 (CRS4) is defined as heart failure driven by chronic kidney disease (CKD). Cardiovascular mortality is the leading cause of mortality in advanced CKD patients. Current medical treatments exhibit limited efficacy. This study demonstrates that telomere shortening in cardiomyocytes is characteristic of CRS4. We engineered an adeno-associated virus9 (AAV9) gene therapy overexpressing catalytic inactive and nuclear localized human telomerase reverse transcriptase (modhTERT) under cardiac troponin T (cTnT) promotor. Overexpression of modhTERT recapped myocardial telomeres, reversed cardiac dysfunction, cardiac hypertrophy, cardiac fibrosis and mitochondrial dysfunction in two CRS4 animal models: 5/6 nephrectomy and Angiotensin II-high salt-uninephrectomy murine models. Overall design: Sham mice (mice were treated with sham operation for 12 weeks and injected with saline) Sham and injected with JV001 mice (mice were treated with sham operation for 12 weeks and injected with JV001) CKD mice (mice were treated with AngII + high salt diet + uninephrectomy and injected with saline) CKD and injected with JV001 mice (mice were treated with AngII + high salt diet + uninephrectomy for 12 weeks and injected with JV001) RNA-seq of isolated cardiomyocytes