Cardiovascular RNA interference therapy: the broadening tool and target spectrum.
Understanding of the roles of noncoding RNAs (ncRNAs) within complex organisms has fundamentally changed. It is increasingly possible to use ncRNAs as diagnostic and therapeutic tools in medicine. Regarding disease pathogenesis, it has become evident that confinement to the analysis of protein-coding regions of the human genome is insufficient because ncRNA variants have been associated with important human diseases. Thus, inclusion of noncoding genomic elements in pathogenetic studies and their consideration as therapeutic targets is warranted. We consider aspects of the evolutionary and discovery history of ncRNAs, as far as they are relevant for the identification and selection of ncRNAs with likely therapeutic potential. Novel therapeutic strategies are based on ncRNAs, and we discuss here RNA interference as a highly versatile tool for gene silencing. RNA interference-mediating RNAs are small, but only parts of a far larger spectrum encompassing ncRNAs up to many kilobasepairs in size. We discuss therapeutic options in cardiovascular medicine offered by ncRNAs and key issues to be solved before clinical translation. Convergence of multiple technical advances is highlighted as a prerequisite for the translational progress achieved in recent years. Regarding safety, we review properties of RNA therapeutics, which may immunologically distinguish them from their endogenous counterparts, all of which underwent sophisticated evolutionary adaptation to specific biological contexts. Although our understanding of the noncoding human genome is only fragmentary to date, it is already feasible to develop RNA interference against a rapidly broadening spectrum of therapeutic targets and to translate this to the clinical setting under certain restrictions.
Department of Cardiology and Pneumology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany. wolfgang.poller@charite.de
Wolfgang
W
Poller
Juliane
J
Tank
Carsten
C
Skurk
Martina
M
Gast
D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005544:Forecasting; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D055106:Genome-Wide Association Study; D006801:Humans; D035683:MicroRNAs / Q000009:adverse effects / Q000276:immunology / Q000502:physiology / Q000627:therapeutic use; D058990:Molecular Targeted Therapy / Q000009:adverse effects / Q000379:methods*; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D034741:RNA, Small Interfering / Q000009:adverse effects / Q000276:immunology / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use; D022661:RNA, Untranslated / Q000009:adverse effects / Q000145:classification / Q000276:immunology / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use*; D013379:Substrate Specificity; D059467:Transcriptome; D057170:Translational Research, Biomedical
D035683:MicroRNAs; D034741:RNA, Small Interfering; D022661:RNA, Untranslated
RNA interference; RNA, long untranslated; RNA, short untranslated; cardiovascular diseases; genetic therapy; immunity, innate; nanoparticles