Journal
MOLECULES
Volume 26, Issue 24, Pages -Publisher
MDPI
DOI: 10.3390/molecules26247662
Keywords
antisense oligonucleotide; conjugation; bile acid; ursodeoxycholic acid; solid support; solid phase synthesis; exon-skipping; dystrophin
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The study found that ASO oligonucleotides conjugated with ursodeoxycholic acid (UDCA) showed better performance in targeting human DMD exon 51 compared to unconjugated ones, with an average 9.5-fold increase in exon skipping efficiency.
Steric blocking antisense oligonucleotides (ASO) are promising tools for splice modulation such as exon-skipping, although their therapeutic effect may be compromised by insufficient delivery. To address this issue, we investigated the synthesis of a 20-mer 2 '-OMe PS oligonucleotide conjugated at 3 '-end with ursodeoxycholic acid (UDCA) involved in the targeting of human DMD exon 51, by exploiting both a pre-synthetic and a solution phase approach. The two approaches have been compared. Both strategies successfully provided the desired ASO 51 3 '-UDC in good yield and purity. It should be pointed out that the pre-synthetic approach insured better yields and proved to be more cost-effective. The exon skipping efficiency of the conjugated oligonucleotide was evaluated in myogenic cell lines and compared to that of unconjugated one: a better performance was determined for ASO 51 3 '-UDC with an average 9.5-fold increase with respect to ASO 51.
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