Therapeutic inhibition of RBM20 improves diastolic function in a murine heart failure model and human engineered heart tissue

TY - JOUR

T1 - Therapeutic inhibition of RBM20 improves diastolic function in a murine heart failure model and human engineered heart tissue

AU - Radke, Michael H

AU - Badillo-Lisakowski, Victor

AU - Britto-Borges, Thiago

AU - Kubli, Dieter A

AU - Jüttner, René

AU - Parakkat, Pragati

AU - Carballo, Jacobo Lopez

AU - Hüttemeister, Judith

AU - Liss, Martin

AU - Hansen, Arne

AU - Dieterich, Christoph

AU - Mullick, Adam E

AU - Gotthardt, Michael

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Heart failure with preserved ejection fraction (HFpEF) is prevalent and deadly, but so far, there is no targeted therapy. A main contributor to the disease is impaired ventricular filling, which we improved with antisense oligonucleotides (ASOs) targeting the cardiac splice factor RBM20. In adult mice with increased wall stiffness, weekly application of ASOs over 2 months increased expression of compliant titin isoforms and improved cardiac function as determined by echocardiography and conductance catheter. RNA sequencing confirmed RBM20-dependent isoform changes and served as a sensitive indicator of potential side effects, largely limited to genes related to the immune response. We validated our approach in human engineered heart tissue, showing down-regulation of RBM20 to less than 50% within 3 weeks of treatment with ASOs, resulting in adapted relaxation kinetics in the absence of cardiac pathology. Our data suggest anti-RBM20 ASOs as powerful cardiac splicing regulators for the causal treatment of human HFpEF.

AB - Heart failure with preserved ejection fraction (HFpEF) is prevalent and deadly, but so far, there is no targeted therapy. A main contributor to the disease is impaired ventricular filling, which we improved with antisense oligonucleotides (ASOs) targeting the cardiac splice factor RBM20. In adult mice with increased wall stiffness, weekly application of ASOs over 2 months increased expression of compliant titin isoforms and improved cardiac function as determined by echocardiography and conductance catheter. RNA sequencing confirmed RBM20-dependent isoform changes and served as a sensitive indicator of potential side effects, largely limited to genes related to the immune response. We validated our approach in human engineered heart tissue, showing down-regulation of RBM20 to less than 50% within 3 weeks of treatment with ASOs, resulting in adapted relaxation kinetics in the absence of cardiac pathology. Our data suggest anti-RBM20 ASOs as powerful cardiac splicing regulators for the causal treatment of human HFpEF.

U2 - 10.1126/scitranslmed.abe8952

DO - 10.1126/scitranslmed.abe8952

M3 - SCORING: Journal article

C2 - 34851694

VL - 13

JO - SCI TRANSL MED

JF - SCI TRANSL MED

SN - 1946-6234

IS - 622

M1 - eabe8952

ER -