ISIS 626112 sodium (ION-626112 sodium) is a blood-brain barrier-permeable MOE-gapmer antisense oligonucleotide and also an inhibitor of the Malat1 long non-coding RNA. ISIS 626112 sodium triggers RNase H1-mediated cleavage and degradation of complementary Malat1 RNA. ISIS 626112 sodium dose-dependently reduces Malat1 RNA levels in all tested central nervous system regions and major central nervous system cell types in mice, with glial cells showing higher sensitivity than neurons [1] [2].
In Vivo, ISIS 626112 (0-1000 μg, intracerebroventricular injection; single bolus administration) sodium achieves widespread distribution across all major central nervous system regions and cell types in mice, and reduces Malat1 RNA levels in a dose-dependent manner; among these, astrocytes exhibit the highest sensitivity (ED50 = 17 μg), while neurons show the lowest sensitivity (ED50 = 206 μg)[2]. ISIS 626112 (administered via a single intraspinal bolus injection at doses of 10–3000 μg) sodium achieves widespread distribution across most regions of the rat central nervous system and reduces Malat1 RNA levels in a dose-dependent manner, with the striatum showing the least pronounced target downregulation[2]. ISIS 626112 (25 mg; intrathecal injection; single bolus on Days 1, 14 and 28) sodium achieves widespread distribution across most central nervous system regions and ganglia in non-human primates, and reduces Malat1 RNA levels by 80%-90%[2].
References:
[1]. Kawanobe T, et al. Improved efficacy and tolerability of antisense oligonucleotide with Guanidine-bridged nucleic acid[J]. bioRxiv, 2026: 2026.01. 08.698310.
[2]. Jafar-Nejad P, et al. The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration. Nucleic acids research. 2021 Jan 25;49(2):657-673.
In Vivo, ISIS 626112 (0-1000 μg, intracerebroventricular injection; single bolus administration) sodium achieves widespread distribution across all major central nervous system regions and cell types in mice, and reduces Malat1 RNA levels in a dose-dependent manner; among these, astrocytes exhibit the highest sensitivity (ED50 = 17 μg), while neurons show the lowest sensitivity (ED50 = 206 μg)[2]. ISIS 626112 (administered via a single intraspinal bolus injection at doses of 10–3000 μg) sodium achieves widespread distribution across most regions of the rat central nervous system and reduces Malat1 RNA levels in a dose-dependent manner, with the striatum showing the least pronounced target downregulation[2]. ISIS 626112 (25 mg; intrathecal injection; single bolus on Days 1, 14 and 28) sodium achieves widespread distribution across most central nervous system regions and ganglia in non-human primates, and reduces Malat1 RNA levels by 80%-90%[2].
References:
[1]. Kawanobe T, et al. Improved efficacy and tolerability of antisense oligonucleotide with Guanidine-bridged nucleic acid[J]. bioRxiv, 2026: 2026.01. 08.698310.
[2]. Jafar-Nejad P, et al. The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration. Nucleic acids research. 2021 Jan 25;49(2):657-673.