Aberrantly spliced cardiac ion channel pre-messenger RNA

Aberrantly spliced pre-messenger RNA (pre-mRNA) of cardiac ion channel genes refers to intermediate RNA transcripts that undergo incorrect processing due to genetic mutations or pathological signaling, leading to dysfunctional ion transport in the heart. These splicing errors, such as the inclusion of poison exons or the skipping of constitutive exons, are frequently implicated in hereditary arrhythmias like Brugada syndrome and Long QT syndrome (Karam et al., 2015, Circulation: Cardiovascular Genetics). By targeting these specific pre-mRNA sequences, therapeutic agents like splice-switching oligonucleotides (SSOs) can sterically block splice sites or regulatory elements to restore the production of functional, full-length proteins (Choudhary et al., 2020, JCI Insight). This strategy is particularly promising for addressing haploinsufficiency in genes like SCN5A, which encodes the primary cardiac sodium channel. Restoring correct splicing aims to normalize the cardiac action potential and reduce the risk of sudden cardiac death (Lara-Pezzi et al., 2013, Nature Reviews Cardiology). Current drug development efforts, such as those involving PRAX-020, are focused on optimizing the delivery of these RNA-targeted therapies to cardiomyocytes while minimizing off-target effects (Praxis Precision Medicines, 2023). This approach represents a precision medicine paradigm for treating channelopathies at the genetic level rather than just managing symptoms.

Other names

Mis-spliced cardiac ion channel transcriptsCardiac ion channel pre-mRNA splice variantsPoison exon-containing cardiac pre-mRNACryptic splice site-derived cardiac mRNA

Splice modulation via steric hindrance of splicing regulatory elements to promote correct exon inclusion or skip deleterious pseudo-exons.