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

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

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Co-author 1

Danshu Xie xie_danshu@shsmu.edu.cn Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine Department of Nephrology Shanghai China *

Co-author 2

Chenguang Wang sunshine3632@163.com Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine Department of Cardiology and Shanghai Institute of Precision Medicine Shanghai China -

Co-author 3

Xin Wan wanxin19950321@163.com Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine Department of Cardiology and Shanghai Institute of Precision Medicine Shanghai China -

Co-author 4

Longyu Wang wanglongyu77@163.com Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine Department of Nephrology Shanghai China -

Co-author 5

Yinlong Zhao zhaoyinlong@foxmail.com Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine Department of Cardiology and Shanghai Institute of Precision Medicine Shanghai China -

Co-author 6

Jianan Pan panja0428@163.com Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine Department of Cardiology and Shanghai Institute of Precision Medicine Shanghai China -

Co-author 7

Jiaying Ji jiayingamyji@163.com Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine Department of Cardiology and Shanghai Institute of Precision Medicine Shanghai China -

Co-author 8

Jiaolun Li jiaolun_li@163.com Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine Department of Nephrology Shanghai China -

Co-author 9

Feng Ding dingfeng@sjtu.edu.cn Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine Department of Nephrology Shanghai China -

Co-author 10

Alex C Y Chang alexchang@shsmu.edu.cn Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine Department of Cardiology and Shanghai Institute of Precision Medicine Shanghai China -

Co-author 11

Wei Ding dingwei@shsmu.edu.cn Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine Department of Nephrology Shanghai China -

Co-author 12

Co-author 13

Co-author 14

Co-author 15

Introduction

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.

Methods

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 (JV001).

Results

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. Surprisingly, JV001 ameliorated kidney function, measured by blood urea nitrogen levels, in Angiotensin II-high salt-uninephrectomy murine models. Transcriptomic analysis of isolated mouse cardiomyocytes revealed differentially expressed genes that were highly enriched in mitochondrial dysfunction. In human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) co-cultured with patients’ serum or indoxyl sulfate toxin, hiPSC-CMs exhibited contractile dysfunction. Overexpression of modhTERT also blocked further telomere shortening and reversed contractile dysfunction in hiPSC-CMs.

Conclusion

Our results provide proof-of-concept evidence for treating CRS4 by telomere recapping gene therapy.

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