Therapeutic efficacy of AAV-mediated restoration of PKP2 in arrhythmogenic cardiomyopathy.

Autor: Kyriakopoulou E; Hubrecht Institute-KNAW and Utrecht University Medical Center, Utrecht, the Netherlands., Versteeg D; Hubrecht Institute-KNAW and Utrecht University Medical Center, Utrecht, the Netherlands., de Ruiter H; Hubrecht Institute-KNAW and Utrecht University Medical Center, Utrecht, the Netherlands., Perini I; Hubrecht Institute-KNAW and Utrecht University Medical Center, Utrecht, the Netherlands., Seibertz F; Institute of Pharmacology and Toxicology, University Medical Center Gottingen (UMG), Göttingen, Germany.; German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany.; Nanion Technologies GmbH, Munich, Germany., Döring Y; Institute of Pharmacology and Toxicology, University Medical Center Gottingen (UMG), Göttingen, Germany.; German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany., Zentilin L; International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy., Tsui H; Hubrecht Institute-KNAW and Utrecht University Medical Center, Utrecht, the Netherlands., van Kampen SJ; Hubrecht Institute-KNAW and Utrecht University Medical Center, Utrecht, the Netherlands., Tiburcy M; Institute of Pharmacology and Toxicology, University Medical Center Gottingen (UMG), Göttingen, Germany.; German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany., Meyer T; Institute of Pharmacology and Toxicology, University Medical Center Gottingen (UMG), Göttingen, Germany.; German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany., Voigt N; Institute of Pharmacology and Toxicology, University Medical Center Gottingen (UMG), Göttingen, Germany.; German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany., Tintelen VJP; Department of Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands., Zimmermann WH; Institute of Pharmacology and Toxicology, University Medical Center Gottingen (UMG), Göttingen, Germany.; German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany.; German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Göttingen, Germany., Giacca M; International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.; British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, King's College London, London, UK., van Rooij E; Hubrecht Institute-KNAW and Utrecht University Medical Center, Utrecht, the Netherlands.; Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
Jazyk: angličtina
Zdroj: Nature cardiovascular research [Nat Cardiovasc Res] 2023; Vol. 2 (12), pp. 1262-1276. Date of Electronic Publication: 2023 Dec 07.
DOI: 10.1038/s44161-023-00378-9
Abstrakt: Arrhythmogenic cardiomyopathy is a severe cardiac disorder characterized by lethal arrhythmias and sudden cardiac death, with currently no effective treatment. Plakophilin 2 ( PKP2 ) is the most frequently affected gene. Here we show that adeno-associated virus (AAV)-mediated delivery of PKP2 in PKP2 c.2013delC/WT induced pluripotent stem cell-derived cardiomyocytes restored not only cardiac PKP2 levels but also the levels of other junctional proteins, found to be decreased in response to the mutation. PKP2 restoration improved sodium conduction, indicating rescue of the arrhythmic substrate in PKP2 mutant induced pluripotent stem cell-derived cardiomyocytes. Additionally, it enhanced contractile function and normalized contraction kinetics in PKP2 mutant engineered human myocardium. Recovery of desmosomal integrity and cardiac function was corroborated in vivo, by treating heterozygous Pkp2 c.1755delA knock-in mice. Long-term treatment with AAV9-PKP2 prevented cardiac dysfunction in 12-month-old Pkp2 c.1755delA/WT mice, without affecting wild-type mice. These findings encourage clinical exploration of PKP2 gene therapy for patients with PKP2 haploinsufficiency.
Competing Interests: Competing interestsE.v.R. is a consultant for Tenaya Therapeutics and Novo Nordisk and is Chief Scientific Officer of Phlox Therapeutics. M.T., T.M. and W.H.Z. are inventors of patents related to the EHM technology and scientific advisors to myriamed GmbH. W.H.Z. is founder and shareholder of myriamed GmbH. M.G. is founder, consultant, member of the Board and equity holder in Purespring Therapeutics, Forcefield Therapeutics and Heqet Therapeutics. All other authors declare that they have no competing interests.
(© The Author(s) 2023.)
Databáze: MEDLINE
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