TY - JOUR
T1 - Effect of 2'-O-methyl/thiophosphonoacetate-modified antisense oligonucleotides on huntingtin expression in patient-derived cells
AU - Matsui, Masayuki
AU - Threlfall, Richard N.
AU - Caruthers, Marvin H.
AU - Corey, David R.
PY - 2014/12/15
Y1 - 2014/12/15
N2 - Optimizing oligonucleotides as therapeutics will require exploring how chemistry can be used to enhance their effects inside cells. To achieve this goal it will be necessary to fully explore chemical space around the native DNA/RNA framework to define the potential of diverse chemical modifications. In this report we examine the potential of thiophosphonoacetate (thioPACE)-modified 2'-O-methyl oligoribonucleotides as inhibitors of human huntingtin (HTT) expression. Inhibition occurred, but was less than with analogous locked nucleic acid (LNA)-substituted oligomers lacking the thioPACE modification. These data suggest that thioPACE oligonucleotides have the potential to control gene expression inside cells. However, advantages relative to other modifications were not demonstrated. Additional modifications are likely to be necessary to fully explore any potential advantages of thioPACE substitutions.
AB - Optimizing oligonucleotides as therapeutics will require exploring how chemistry can be used to enhance their effects inside cells. To achieve this goal it will be necessary to fully explore chemical space around the native DNA/RNA framework to define the potential of diverse chemical modifications. In this report we examine the potential of thiophosphonoacetate (thioPACE)-modified 2'-O-methyl oligoribonucleotides as inhibitors of human huntingtin (HTT) expression. Inhibition occurred, but was less than with analogous locked nucleic acid (LNA)-substituted oligomers lacking the thioPACE modification. These data suggest that thioPACE oligonucleotides have the potential to control gene expression inside cells. However, advantages relative to other modifications were not demonstrated. Additional modifications are likely to be necessary to fully explore any potential advantages of thioPACE substitutions.
KW - Huntington's disease
KW - antisense oligonucleotides
KW - huntingtin
KW - locked nucleic acids
KW - phosphate modification
KW - thiophosphonoacetate
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U2 - 10.1080/1949095X.2016.1146391
DO - 10.1080/1949095X.2016.1146391
M3 - Article
C2 - 26865404
AN - SCOPUS:85015141889
SN - 1949-095X
VL - 5
SP - e1146391
JO - Artificial DNA, PNA & XNA
JF - Artificial DNA, PNA & XNA
IS - 3
ER -