Gene therapy strategies in the treatment of hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease with an estimated prevalence of 1:200 caused by mutations in sarcomeric proteins. It is associated with hypertrophy of the left ventricle, increased interstitial fibrosis, and diastolic dysfunction for heterozygous mutation carriers. Carriers of double heterozygous, compound heterozygous, and homozygous mutations often display more severe forms of cardiomyopathies, ultimately leading to premature death. So far, there is no curative treatment against HCM, as current therapies are focused on symptoms relief by pharmacological intervention and not on the cause of HCM. In the last decade, several strategies have been developed to remove genetic defects, including genome editing, exon skipping, allele-specific silencing, spliceosome-mediated RNA trans-splicing, and gene replacement. Most of these technologies have already been tested for efficacy and efficiency in animal- or human-induced pluripotent stem cell models of HCM with promising results. We will summarize recent technological advances and their implication as gene therapy options in HCM with a special focus on treating MYBPC3 mutations and its potential for being a successful bench to bedside example.

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Acknowledgements

We would like to thank Suellen Lopes Oliveira for graphic design of the figure.

Funding

This work was supported by the DZHK (German Centre for Cardiovascular Research) and the German Ministry of Research Education (BMBF).

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Correspondence to Lucie Carrier.

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L.C. and G.M. are co-applicants and holders of a provisional patent no. PCT/EP2014/057984 (WO 2014/170470 A1; EP2792742 A1; CA2944186 A1), Priority date Apr 17, 2013, Filling date Apr 17, 2014, publication date Oct 23, 2014. The authors declare no competing financial interests.

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Prondzynski, M., Mearini, G. & Carrier, L. Gene therapy strategies in the treatment of hypertrophic cardiomyopathy. Pflugers Arch - Eur J Physiol 471, 807–815 (2019). https://doi.org/10.1007/s00424-018-2173-5

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Keywords

  • Hypertrophic cardiomyopathy
  • Gene therapy
  • Exon skipping
  • trans-splicing
  • CRISPR/Cas9
  • MYBPC3
  • Gene replacement