Myocardial fibrosis refers to a variety of quantitative and qualitative changes in the interstitial myocardial collagen network that occur in response to cardiac ischaemic insults, systemic diseases, drugs, or any other harmful stimulus affecting the circulatory system or the heart itself. Myocardial fibrosis alters the architecture of the myocardium, facilitating the development of cardiac dysfunction, also inducing arrhythmias, influencing the clinical course and outcome of heart failure patients. Focusing on myocardial fibrosis may potentially improve patient care through the targeted diagnosis and treatment of emerging fibrotic pathways. The European Commission funded the FIBROTARGETS consortium as a multinational academic and industrial consortium with the primary aim of performing a systematic and collaborative search of targets of myocardial fibrosis, and then translating these mechanisms into individualized diagnostic tools and specific therapeutic pharmacological options for heart failure. This review focuses on those methodological and technological aspects considered and developed by the consortium to facilitate the transfer of the new mechanistic knowledge on myocardial fibrosis into potential biomedical applications.

The discovery of miRNAs as important regulatory agents for gene expression has expanded the therapeutic opportunities for oligonucleotides. In contrast to siRNA, miRNA-targeted therapy is able to i...

Therapeutic gene silencing promises significant progress in pharmacotherapy, including considerable expansion of the druggable target space and the possibility for treating orphan diseases. Technological hurdles have complicated the efficient use of therapeutic oligonucleotides, and siRNA agents suffer particularly from insufficient pharmacokinetic properties and poor cellular uptake. Intense development and evolution of delivery systems have resulted in efficient uptake predominantly in liver tissue, in which practically all nanoparticulate and liposomal delivery systems show the highest accumulation. The most efficacious strategies include liposomes and bioconjugations with N-acetylgalactosamine. Both are in early clinical evaluation stages for treatment of liver-associated diseases. Approaches for achieving knockdown in other tissues and tumors have been proven to be more complicated. Selective targeting to tumors may be enabled through careful modulation of physical properties, such as particle size, or by taking advantage of specific targeting ligands. Significant barriers stand between sufficient accumulation in other organs, including endothelial barriers, cellular membranes, and the endosome. The brain, which is shielded by the blood-brain barrier, is of particular interest to facilitate efficient oligonucleotide therapy of neurological diseases. Transcytosis of the blood-brain barrier through receptor-specific docking is investigated to increase accumulation in the central nervous system. In this review, the current clinical status of siRNA therapeutics is summarized, as well as innovative and promising preclinical concepts employing tissue- and tumor-targeted ligands. The requirements and the respective advantages and drawbacks of bioconjugates and ligand-decorated lipid or polymeric particles are discussed.

Insufficient pharmacokinetic properties and poor cellular uptake are the main hurdles for successful therapeutic development of oligonucleotide agents. The covalent attachment of various ligands de...

As part of the TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes) series to enhance regenerative medicine, here, we discuss the role of preclinical studies designed to advance stem cell therapies for cardiovascular disease. The quality of this research has improved over the past 10 to 15 years and overall indicates that cell therapy promotes cardiac repair. However, many issues remain, including inability to provide complete cardiac recovery. Recent studies question the need for intact cells suggesting that harnessing what the cells release is the solution. Our contribution describes important breakthroughs and current directions in a cell-based approach to alleviating cardiovascular disease.

Therapeutic gene silencing is a huge promise for the treatment of a variety of diseases. The translation of this widely used scientific technique toward clinical application has been hindered by insufficient ADME properties of antisense and siRNA oligonucleotides. Despite reasonable therapeutic response after local administration, reaching adequate concentrations at the site of action after systemic application is still a major hurdle and this has resulted in poor efficiency in preclinical and clinical situations. This review focuses on the influence on the ADME parameters of chemical modifications already tested in clinical trials, such as phosphorothioates (PSs), 2'-modified agents, including locked nucleic acids (LNA) and phosphorodiamidate morpholino oligomers (PMO). The dominating PS backbone modification, while conferring adequate nuclease resistance and improving biodistribution, has been shown to be involved in unspecific protein binding and off-target effects on apoptosis pathways. PS-free antisense agents such as PMO generally show poorer pharmacokinetic characteristics. In terms of pharmacokinetics and cell membrane permeation, there is currently no efficient alternative to PS, although doubts about long-term toxicity of this class still remain. Consequently, improved structural modifications or galenic formulations are deemed necessary to create entities with higher efficiency and lower toxicity.