Key result
In silico screening identifies ~150 candidate exons across TTN and OBSCN for therapeutic deletion.
Why the study?
Genome editing therapies for cardiac diseases remain immature, prompting exploration of whether TTN-specific gene structure permits myoediting via symmetric exon deletion to reframe TTN truncating variants in non-ischemic DCM.
Does symmetric exon deletion provide a viable therapeutic approach to reframe truncating mutations in giant sarcomeric proteins for dilated cardiomyopathy?
Does symmetric exon deletion provide a viable therapeutic approach to reframe truncating mutations in giant sarcomeric proteins for dilated cardiomyopathy?
CRISPR/Cas9-mediated symmetric exon deletion provides a theoretically sound strategy for treating non-ischemic dilated cardiomyopathy caused by frameshift mutations in giant modular proteins.
Does not yet support clinical exon deletion for TTN cardiomyopathy; leaves open in vivo feasibility of CRISPR reframing.
Non-ischemic dilated cardiomyopathy (DCM) is one of the most frequent pathologies requiring cardiac transplants. Even though the etiology of this disease is complex, frameshift mutations in the giant sarcomeric protein Titin could explain up to 25% of the familial and 18% of the sporadic cases of DCM. Many studies have shown the potential of genome editing using CRISPR/Cas9 to correct truncating mutations in sarcomeric proteins and have established the grounds for myoediting. However, these therapies are still in an immature state, with only few studies showing an efficient treatment of cardiac diseases. This publication hypothesizes that the Titin (TTN)-specific gene structure allows the application of myoediting approaches in a broad range of locations to reframe TTNtvvariants and to treat DCM patients. Additionally, to pave the way for the generation of efficient myoediting approaches for DCM, we screened and selected promising target locations in TTN. We conceptually explored the deletion of symmetric exons as a therapeutic approach to restore TTN’s reading frame in cases of frameshift mutations. We identified a set of 94 potential candidate exons of TTN that we consider particularly suitable for this therapeutic deletion. With this study, we aim to contribute to the development of new therapies to efficiently treat titinopathies and other diseases caused by mutations in genes encoding proteins with modular structures, e.g., Obscurin.
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Rodríguez-Polo et al. (2022) studied Non-ischemic dilated cardiomyopathy. Symmetric exon deletion (CRISPR/Cas9) was evaluated on Identification of candidate exons suitable for therapeutic deletion. In silico analysis identified 94 candidate exons in TTN and 59 in OBSCN that are symmetric, highly conserved, and ≤300 bp, making them suitable targets for therapeutic deletion.
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