دانلود رایگان مقاله انگلیسی درمان RNA برای بیماری های قلبی - الزویر 2018

ABSTRACT

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.

6. RNA therapeutics: hurdles towards clinical application

RNA-based drugs have conceptual and practical advantages compared to conventional small chemistry-based drugs or therapeutic antibodies directed against a target protein product. For example, small chemistry-based medicinal products lack absolute target speci ficity and require expensive drug screening procedures before lead compounds can be re fined towards an acceptable drug substance with su fficient speci ficity [63]. Antibodies can only recognize targets that are both druggable and secreted or extracellular, because there is no good strategy to deliver them inside cells [64]. By contrast, siRNAs and ASOs can in principle suppress any gene, even if it is highly expressed, including non-coding genes, which conventional chemical therapeutics or antibodies cannot [7]. Unlike antibodies, RNAs can be chemically synthesized, thus leading to cheaper and more easily manufactured drugs than biologics, which can su ffer from batch-to-batch variability. Antibodies need to be administered every few weeks, and patients often develop immunological responses, which can limit the e ffectiveness of antibody therapy with continued use. Thus far, there is no evidence of adaptive immune responses against RNA therapeutics [65]. A final potential advantage of RNA drugs that utilize a Watson-Crick targetbinding motif, compared to antibodies, is that an antisense oligo is straightforward to design using the complementary sequence to speci- fically bind and inactivate the target sequence, being either a mRNA, a ncRNA or a ssDNA [7,65] .