Modified hTERT treatment ameliorates pressure overload-induced heart failure

Area of Science:

• Cardiovascular Research
• Gene Therapy
• Molecular Biology

Background:

• Heart failure (HF) is a significant risk factor for stroke and sudden cardiac death.
• Shortened telomeres in cardiomyocytes are linked to HF development.
• Telomere reprotection is a promising strategy for novel HF therapies.

Purpose of the Study:

• To design a gene therapy for pan-heart failure using modified human telomerase (modhTERT) driven by the cardiac troponin promoter.
• To evaluate the cardiac protective effects of this novel gene therapy.

Main Methods:

• Quantitative fluorescence in situ hybridization (Q-FISH) to assess telomere length in human and monkey cardiomyocytes.
• Bioengineering of AAV9-modhTERT Y707F, D868A for gene therapy delivery.
• Evaluation in transverse aortic constriction (TAC)-induced HF mouse models and Ang II-stimulated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using various assays.

Main Results:

• AAV9-modhTERT reversed cardiac dysfunction and prevented fibrosis in HF mice.
• modhTERT alleviated cardiomyocyte contractile dysfunction and prevented hypertrophy in hiPSC-CMs.
• Overexpression of modhTERT blocked DNA damage response, reduced inflammation and ROS, and restored mitochondrial function and ATP production.

Conclusions:

• Telomere reprotection via gene therapy confers significant cardiac protection.
• This approach may represent a potential therapeutic option for treating heart failure.