Gene Editing for the Heart
Correcting Dystrophin Mutations
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- clustered regularly interspaced short palindromic repeats
- gene editing
Gene editing is moving rapidly from a highly useful laboratory-based tool toward human clinical application. In vivo gene editing has been documented in mouse models of Duchenne muscular dystrophy (DMD), where skeletal and cardiac muscle editing produces internally truncated dystrophin. A recent report now demonstrates that editing the dystrophin gene in the heart improves cardiac function, paving the path to in vivo application of cardiac gene correction.
Article, see p 923
Mutations in the gene encoding dystrophin cause DMD and its associated cardiomyopathy. Large deletions, which span multiple exons, are the most common cause of DMD, and these deletions disrupt dystrophin’s reading frame and ablate its expression. Dystrophin binds actin at its N-terminus and with its C-terminus, dystrophin connects to the plasma membrane of myocytes. The central portion of dystrophin is composed of multiple spectrin repeat domains, and mutations that interrupt the internal spectrin repeat domains and leave intact the N- and C-terminus result in a milder form of disease called Becker muscular dystrophy.1 A major therapeutic approach for DMD aims to restore the reading frame by converting DMD-associated frame-disrupting mutations into those that produce internally deleted but more functional BMD-associated dystrophins. In 2016, the Food and Drug Administration granted approval for eteplirsen, which uses antisense technology to restore dystrophin’s reading frame.2 Antisense treatments act on RNA and, therefore, require regular repeated dosing to induce the expected molecular effect. In contrast, gene editing corrects DNA, and if directed to the correct cell type, it can afford a permanent treatment with a single application.
Gene editing using CRISPR/Cas9 induces double-stranded breaks in DNA, which typically rejoin at predictable sites using nonhomologous end joining.3 Alternatively, when CRISPR/Cas9 is activated in the presence of a corrective template, homology-directed repair can generate specific base pair changes, like those required to fully …