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Nonviral Therapeutic Approaches for Modulation of Gene Expression: Nanotechnological Strategies to Overcome Biological Challenges
Published in Ana Rute Neves, Salette Reis, Nanoparticles in Life Sciences and Biomedicine, 2018
Ana M. Cardoso, Ana L. Cardoso, Maria C. Pedroso de Lima, Amalia S. Jurado
The first approach was used to improve the stability of ONs whose function does not require their recognition and loading onto intracellular enzyme complexes. This particularity allows for extensive chemical modifications and can be applied to antisense oligonucleotides (ASOs) (reviewed in “RNA Therapeutics: Beyond RNA Interference and Antisense Oligonucleotides” [16]). ASOs are designed to bind to a specific mRNA sequence and are usually based on a phosphorothioate backbone, whose resistance to nuclease degradation is increased by nucleotide replacement by 2’-O-methoxyethyl (2’-MOE)- or 2’-O-methyl (2’-OMe)-modified residues on each end. These heavily modified portions flank an unmodified “gap,” which is recognized by ribonuclease H (RNase H), an endonuclease that specifically degrades the RNA strand of an RNA-DNA hybrid. However, the introduction of flanking 2’-OMe residues can also prevent RNase H from binding to the ASO-target mRNA duplex [36]. Alternatively, the entire ASO molecule can be 2’-MOE or 2’-OMe modified, its strong binding to the target mRNA being enough to prevent mRNA translation. Due to the increased stability of the ASO-mRNA hybrid, these molecules can act through a steric block mechanism (reviewed in “RNA Therapeutics: Beyond RNA Interference and Antisense Oligonucleotides” [16]), resulting in reduced off-target effects [36].
The roadmap towards cure of chronic hepatitis B virus infection
Published in Journal of the Royal Society of New Zealand, 2022
The two platforms for translation inhibition are short interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), both nucleic acid derivatives that harness natural cellular mechanisms to regulate the expression of host or viral messenger RNA transcripts. siRNAs are small double stranded RNA sequences typically 19–27 base pairs in length with an antisense strand that is complimentary to the unwanted mRNAs. After entering the hepatocytes, the siRNA duplex unwinds and is loaded into the cytoplasmic RNA-induced silencing complex (RISC). The antisense strand directs site-specific cleavage of the complementary target RNA sequence, resulting in RNA degradation, thereby silencing the parent gene. In contrast, ASOs are single-stranded oligonucleotides typically 18–30 base pairs in length. They hybridise directly with complementary mRNA and are destroyed through cytoplasmic RNase H-mediated cleavage.