Stealth attraction techniques summarized for free

To circumvent this challenge, major advances have been made in the development of RNA delivery vehicles, including viral and non-viral delivery systems. The use of viral delivery systems, such as lentiviral vectors and adeno-associated viral vectors, has been successfully applied in the efficient systemic delivery of RNAs. However, unwanted immune responses to viral vectors hinder their wide application in clinic. Integration of the lentiviral vector close to or within a coding region of the host genome may also result in undesirable effects such as loss of gene function or overexpression, stimulation of oncogenesis, or cell death.

Therefore, non-viral systems have attracted increasing attention for their potential safety and flexibility. Non-viral vectors, such as nanocarriers, have high gene-packaging capacity, can be designed to have low immunogenicity and are relatively simple and less costly to manufacture. Currently, four RNAi therapeutics delivered by non-viral strategies have been approved by the FDA and EMA for delivering RNAi into livers in clinics. Patisiran, the first approved RNAi (in 2018) for the treatment of hereditary transthyretin-mediated amyloidosis (hTTR), acts by targeting the untranslated region of TTR mRNA, reducing translation of its protein. The lipid nanoparticle formulation directs it to the main TTR production site, which is the liver ( Figure 1). The second approved RNAi drug, Givosiran, has the siRNA molecule conjugated to Alnylam’s Enhanced Stabilization Chemistry N-acetylgalactosamine (ESC-GalNAc) residues, which binds to specific receptors mainly found on hepatocytes. It is used in the treatment of acute hepatic porphyria (AHP) and acts by degrading 5-aminolevulinic acid synthase 1 (ALAS1) mRNA, resulting in reduced levels of intermediates associated with AHP attacks. The third approved RNAi drug, Lumasiran, was developed for the treatment of Hyperoxaluria type 1 and, similar to Givosiran, is conjugated to ESC-GalNAc.

It degrades glycolate oxidase mRNA, reducing hepatic production of oxalate. Inclisiran, the most recently approved drug, targets mRNA coding for hepatic proprotein convertase subtilisin-kexin type 9 and utilises the GalNAc tail. It results in a reduction of low-density lipoprotein cholesterol and is used for the treatment of atherosclerotic cardiovascular disease.

Stealth attraction techniques summarized for free