RESUMEN
Mutations in MYBPC3 gene, encoding cardiac myosin-binding protein C (cMyBP-C), frequently cause hypertrophic cardiomyopathy (HCM), which affects 0.2 % of the general population. This myocardial autosomal-dominant disorder is the leading cause of sudden cardiac death particularly in young athletes. The current pharmacological and surgical treatments of HCM focus on symptoms relief, but do not address the cause of the disease. With the development of novel strategies targeting the endogenous mutation, causal HCM therapy is now possible. This review will discuss the current knowledge on HCM from the identification of MYBPC3 gene mutations to potential RNA-based correction.
Asunto(s)
Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/terapia , Proteínas Portadoras/genética , Terapia Genética/métodos , ARN/uso terapéutico , Animales , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , Exones , Mutación del Sistema de Lectura , Humanos , Ratones , Oligonucleótidos Antisentido/uso terapéutico , ARN/genética , Eliminación de Secuencia , Empalmosomas/fisiología , Trans-EmpalmeRESUMEN
Exon skipping mediated by antisense oligoribonucleotides (AON) is a promising therapeutic approach for genetic disorders, but has not yet been evaluated for cardiac diseases. We investigated the feasibility and efficacy of viral-mediated AON transfer in a Mybpc3-targeted knock-in (KI) mouse model of hypertrophic cardiomyopathy (HCM). KI mice carry a homozygous G>A transition in exon 6, which results in three different aberrant mRNAs. We identified an alternative variant (Var-4) deleted of exons 5-6 in wild-type and KI mice. To enhance its expression and suppress aberrant mRNAs we designed AON-5 and AON-6 that mask splicing enhancer motifs in exons 5 and 6. AONs were inserted into modified U7 small nuclear RNA and packaged in adeno-associated virus (AAV-U7-AON-5+6). Transduction of cardiac myocytes or systemic administration of AAV-U7-AON-5+6 increased Var-4 mRNA/protein levels and reduced aberrant mRNAs. Injection of newborn KI mice abolished cardiac dysfunction and prevented left ventricular hypertrophy. Although the therapeutic effect was transient and therefore requires optimization to be maintained over an extended period, this proof-of-concept study paves the way towards a causal therapy of HCM.
