Exploring the Potential of Symmetric Exon Deletion to Treat Non-Ischemic Dilated Cardiomyopathy by Removing Frameshift Mutations in TTN

Rodríguez-Polo, Ignacio; Behr, Rüdiger

doi:10.3390/genes13061093

Cited by 3 publications

(1 citation statement)

References 83 publications

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“…Given that ASOs have already been approved for the treatment of other diseases ( Crooke et al, 2021 ), such as Duchenne’s muscular dystrophy, ASO-based exon skipping strategies represent an accessible strategy to treat DCM caused by certain disruptive variants in titin. It has been predicted that upwards of 94 exons in titin may be suitable for therapeutic deletion to treat DCM-associated titin variants ( Rodriguez-Polo and Behr, 2022 ). More recently, CRISPR-Cas9 genome editing was used to correct TTNtvs in human iPSC-CMs ( Romano et al, 2022 ).…”

Section: Future Perspectives: Targeting Titin In Heart Diseasementioning

confidence: 99%

Titin: roles in cardiac function and diseases

Stroik,

Gregorich,

Raza

et al. 2024

Front. Physiol.

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The giant protein titin is an essential component of muscle sarcomeres. A single titin molecule spans half a sarcomere and mediates diverse functions along its length by virtue of its unique domains. The A-band of titin functions as a molecular blueprint that defines the length of the thick filaments, the I-band constitutes a molecular spring that determines cell-based passive stiffness, and various domains, including the Z-disk, I-band, and M-line, serve as scaffolds for stretch-sensing signaling pathways that mediate mechanotransduction. This review aims to discuss recent insights into titin’s functional roles and their relationship to cardiac function. The role of titin in heart diseases, such as dilated cardiomyopathy and heart failure with preserved ejection fraction, as well as its potential as a therapeutic target, is also discussed.

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Section: Future Perspectives: Targeting Titin In Heart Diseasementioning

confidence: 99%

Titin: roles in cardiac function and diseases

Stroik,

Gregorich,

Raza

et al. 2024

Front. Physiol.

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Systematic deletion of symmetrical CFTR exons reveals new therapeutic targets for exon skipping antisense oligonucleotides

Pena-Rasgado,

Rodriguez-Manriquez,

Dundr

et al. 2024

NAR Molecular Medicine

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There is a major need for therapeutics that treat disease caused by premature termination codons (PTCs). Splice-switching antisense oligonucleotides (ASOs) can be directed to block splicing and cause exon skipping, a process that can effectively remove PTCs from an mRNA. This ASO-induced exon skipping can restore protein coding potential when the exons on either side of the skipped exon are in the same reading frame, or symmetrical. We demonstrate this approach using the cystic fibrosis (CF) transmembrane regulator (CFTR) gene, which has CF-associated, PTC-causing variants in all 27 of its exons. We functionally screened all CFTR isoforms that can be generated by the deletion of symmetrical exons and identify four that are functionally responsive to CFTR modulators. We screened for ASOs that induce skipping of these exons and show that they recover CFTR function in airway cells derived from individuals with CFTR PTC variants. This study demonstrates that systematic functional analysis of in-frame exon-deleted protein isoforms can successfully identify targets for ASO-based splice-switching therapies, a therapeutic concept that can be broadly applied to any multi-exon protein-coding gene disrupted by PTCs.

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Identification of BMP10 as a Novel Gene Contributing to Dilated Cardiomyopathy

Yang

Ding

et al. 2023

Diagnostics

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Dilated cardiomyopathy (DCM), characterized by left ventricular or biventricular enlargement with systolic dysfunction, is the most common type of cardiac muscle disease. It is a major cause of congestive heart failure and the most frequent indication for heart transplantation. Aggregating evidence has convincingly demonstrated that DCM has an underlying genetic basis, though the genetic defects responsible for DCM in a larger proportion of cases remain elusive, motivating the ongoing research for new DCM-causative genes. In the current investigation, a multigenerational family affected with autosomal-dominant DCM was recruited from the Chinese Han population. By whole-exome sequencing and Sanger sequencing analyses of the DNAs from the family members, a new BMP10 variation, NM_014482.3:c.166C > T;p.(Gln56*), was discovered and verified to be in co-segregation with the DCM phenotype in the entire family. The heterozygous BMP10 variant was not detected in 268 healthy volunteers enrolled as control subjects. The functional measurement via dual-luciferase reporter assay revealed that Gln56*-mutant BMP10 lost the ability to transactivate its target genes NKX2.5 and TBX20, two genes that had been causally linked to DCM. The findings strongly indicate BMP10 as a new gene contributing to DCM in humans and support BMP10 haploinsufficiency as an alternative pathogenic mechanism underpinning DCM, implying potential implications for the early genetic diagnosis and precision prophylaxis of DCM.

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Exploring the Potential of Symmetric Exon Deletion to Treat Non-Ischemic Dilated Cardiomyopathy by Removing Frameshift Mutations in TTN

Cited by 3 publications

References 83 publications

Titin: roles in cardiac function and diseases

Titin: roles in cardiac function and diseases

Systematic deletion of symmetrical CFTR exons reveals new therapeutic targets for exon skipping antisense oligonucleotides

Identification of BMP10 as a Novel Gene Contributing to Dilated Cardiomyopathy

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