مقاله انگلیسی رایگان در مورد درمان RNA برای بیماری های قلبی – الزویر 2018

The majority of the human genome encodes non-coding RNAs (ncRNAs), species of RNA without protein-coding potential but with powerful regulatory functions in disease onset and progression. Functional studies demonstrate that both coding and ncRNAs underlie various mechanisms in heart disease and that molecules targeting RNA species show promising efficacy in preclinical development. Accompanying the exciting developments in basic RNA biology, an equally provocative field has flourished for the design of RNA-based strategies to generate innovative types of therapeutics against these new “druggable” targets, going beyond our current repertoire of small chemistry or biologics. Here, we review the (bio)chemical basis of RNA-based drug design, provide examples that show promise as translatable drug products in preclinical studies, give an insight in the current barriers that hamper straight-forward clinical translation and discuss future directions that may overcome these hurdles to expand the current pharmacotherapy for myocardial disorders.

RNA avenues for heart disease

Heart diseases are a major cause of morbidity and death in Western societies with little recent progress to reduce their high mortality and are now also steeply on the rise in the developing world [1]. The diseases are preceded by ventricular remodelling and changes in left ventricular mass and volume of the myocardium in response to alterations in loading conditions [2,3]. The molecular events that underlie myocardial remodelling still remain poorly understood. Another major hurdle towards improved therapeutics is that currently cardiovascular disease therapy mainly follows a generic ‘one-size-fits-all’ approach, ignoring the inter-individual differences caused by underlying genetic susceptibility, age, gender or stages of disease. This calls for better disease stratification and introduction of medical breakthroughs to address the key biological mechanisms that derail in subsets of patients, an approach that will likely signal the end of the big block-buster treatments for vast numbers of patients, introducing the concept of “Precision Medicine”. With “Precision Medicine” is meant medical decisions, practices, and interventions tailored to the individual patient who will benefit, sparing expenses and side effects for those who will not. Heart diseases are most commonly provoked by the acute and chronic loss of cardiomyocyte function secondary to coronary artery disease, hypertension, diabetes or combinations thereof, which places a volume load or a pressure load, respectively, on the surviving portion of the myocardium. Chronic “load” causes quite generic responses in the myocardium, such as hypertrophy of cardiac myocytes, cardiac dilatation and interstitial fibrosis. These structural cardiac changes are preceded by changes in the “genomics” of the heart: changes in transcript abundance of protein-coding or non-coding genes and the re-expression of genes that are normally only observed in the embryonic heart [4]. These complex forms of heart disease are referred to as “acquired heart diseases” [5]. Acquired forms of heart disease are contrasted by monogenetic forms of heart disease caused by mutations in single genes identified using candidate gene studies or linkage analysis, leading to hereditary, familial dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) [5]. Since cardiovascular disease mechanisms are typically genomic in nature (hereditary cardiovascular diseases comprise a very small subset of the patient population), new developments will likely derive from a better understanding of our genome. The results of the Encyclopedia of DNA Elements (ENCODE) project demonstrate that at least 80% of our genome is functional, has a regulatory role and is transcribed into various classes of non-coding, regulatory RNAs.