Key result
A single-dose injection of PLN-targeting LNA-ASO significantly improved fractional shortening by 6.5%, whereas scrambled LNA-ASO decreased it by 4.0% in mice with pressure overload.
Why the study?
Does a single-dose injection of PLN-targeting LNA-ASO improve cardiac contractility in mice with pressure overload-induced systolic dysfunction?
Does a single-dose injection of PLN-targeting LNA-ASO improve cardiac contractility in mice with pressure overload-induced systolic dysfunction?
A single-dose injection of PLN-targeting LNA-ASO improved cardiac contractility in a mouse model of pressure overload-induced cardiac dysfunction, suggesting potential as a novel therapeutic approach for heart failure.
Animal data support single-dose LNA-ASO PLN inhibition in HF; leaves open translation to human therapy.
BACKGROUND: Phospholamban (PLN) inhibition enhances calcium cycling and is a potential novel therapy for heart failure (HF). Antisense oligonucleotides (ASOs) are a promising tool for unmet medical needs. Nonviral vector use of locked nucleic acid (LNA)-modified ASOs (LNA-ASOs), which shows strong binding to target RNAs and is resistant to nuclease, is considered to have a potential for use in novel therapeutics in the next decades. Thus, the efficacy of a single-dose injection of LNA-ASO for cardiac disease needs to be elucidated. We assessed the therapeutic efficacy of a single-dose LNA-ASO injection targeting PLN in pressure overload-induced cardiac dysfunction. METHODS AND RESULTS: Mice intravenously injected with Cy3-labeled LNA-ASO displayed Cy3 fluorescence in the liver and heart 24 hours after injection. Subsequently, male C57BL/6 mice were subjected to sham or transverse aortic constriction surgery; after 3 weeks, these were treated with PLN-targeting LNA-ASO (0.3 mg/kg) or scrambled LNA-ASO. Cardiac function was measured by echocardiography before and 1 week after injection. Phospholamban-targeting LNA-ASO treatment significantly improved fractional shortening (FS) by 6.5%, whereas administration of the scrambled LNA-ASO decreased FS by 4.0%. CONCLUSION: Our study revealed that a single-dose injection of PLN-targeting LNA-ASO improved contractility in pressure overload-induced cardiac dysfunction, suggesting that LNA-ASO is a promising tool for hypertensive HF treatment.
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Morihara et al. (2016) studied Pressure overload-induced cardiac dysfunction. PLN-targeting LNA-ASO vs. scrambled LNA-ASO was evaluated on Fractional shortening (FS). A single-dose injection of PLN-targeting LNA-ASO significantly improved fractional shortening by 6.5%, whereas scrambled LNA-ASO decreased it by 4.0% in mice with pressure overload.
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