Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy

Area of Science:

• Cardiology
• Molecular Medicine
• Pharmacology

Background:

• Heart failure (HF) is a significant global health burden with limited treatment options.
• Dysfunctional calcium (Ca2+) handling is a hallmark of HF pathophysiology.
• Targeting Ca2+ regulatory proteins presents a viable therapeutic strategy.

Purpose of the Study:

• To investigate antisense oligonucleotides (ASOs) targeting phospholamban (PLN) mRNA as a potential HF treatment.
• To evaluate the efficacy of PLN-ASO in preclinical models of genetic and acquired heart failure.

Main Methods:

• Development and administration of PLN-ASO in murine models of dilated cardiomyopathy (DCM) and in rats with myocardial infarction.
• Assessment of PLN protein aggregation, cardiac function, and survival rates.
• Evaluation of left ventricular remodeling and contractility.

Main Results:

• PLN-ASO prevented PLN protein aggregation and reversed cardiac dysfunction in a PLN R14del DCM model, increasing survival by threefold.
• PLN-ASO treatment improved cardiac function in a separate genetic DCM model (Cspr3/Mlp-/-).
• In rats with myocardial infarction, PLN-ASO mitigated left ventricular dilatation and enhanced contractility.

Conclusions:

• Antisense inhibition of PLN is a promising therapeutic strategy for diverse HF etiologies.
• PLN-ASO demonstrates efficacy in preclinical models of genetic cardiomyopathy and ischemia-induced HF.
• This approach offers a novel therapeutic avenue for heart failure management.