Antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) are both recognized therapeutic agents for the silencing of specific genes at the posttranscriptional level. Chemical modifications, particularly 2'-O-(2-Methoxyethyl)- oligoribonucleotides (2'-O-MOE bases) and 2'-O-Methyl bases are commonly used to confer nuclease resistance to an oligo designed for anti-sense, siRNA or aptamer-based research, diagnostic or therapeutic purposes, when specific 2'-OH is not required.
Nuclease resistance can be further enhanced by phosphorothiolation of appropriate phosphodiester linkages within the oligo. These modifications confers nuclease resistance, high binding affinity towards complementary RNA, reduced unspecific protein binding and extended half-life in tissues.
Gapmers.
Currently, the mainstream of the ASO is gapmer design ASOs. Gapmer design oligonucleotides, contain two to five chemically modified nucleotides'(LNA, 2'-O methyl or 2'-O-MOE RNA) as 'wings' at each terminus flanking a central 5- to 10-base 'gap' of DNA, enable cleavage of the target mRNA by RNase H, which recognizes DNA/RNA heteroduplexes. Usually all the phosphodiester linkages are converted to phosphorothioate.
ASO's and siRNA Modifications.
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ASO's and siRNA Delivery.
The development of effective delivery systems for antisense oligonucleotides is essential for their clinical therapeutic application. The most common delivery system involves a relatively hydrophobic molecule that can cross the lipid membrane. Cholesterol TEG, alpha-Tocopherol TEG ( a natural isomer of vitamin E), stearyl and GalNAc modifications have been shown to effective for delivery of ASO's and siRNA in addition to cell penetrating peptides.
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