Favorable Efficacy and Reduced Acute Neurotoxicity by Antisense Oligonucleotides with 2',4'-BNA/LNA with 9-(aminoethoxy)phenoxazine
March 19, 2024
Abstract
An increasing number of antisense oligonucleotides (ASOs) have been approved for clinical use. However, improvements of both efficacy and safety in the central nervous system (CNS) are crucial for the treatment with CNS diseases. We aimed to overcome the crucial issues by our development of various gapmer ASOs with a novel nucleoside derivative including a 2′,4′-BNA/LNA with 9-(aminoethoxy)phenoxazine (BNAP-AEO). The various gapmer ASOs with BNAP-AEO were evaluated for thermal stability, in vitro and in vivo efficacy, and acute CNS toxicity. Thermal stability analysis of the duplexes with their complementary RNAs showed that ASOs with BNAP-AEO had a higher binding affinity than those without BNAP-AEO. In vitro assays, when transfected into neuroblastoma cell lines, demonstrated that ASOs with BNAP-AEO, had a more efficient gene silencing effect than those without BNAP-AEO. In vivo assays, involving intracerebroventricular injections into mice, revealed ASOs with BNAP-AEO potently suppressed gene expression in the brain. Surprisingly, the acute CNS toxicity in mice, as assessed through open field tests and scoring systems, was significantly lower for ASOs with BNAP-AEO than for those without BNAP-AEO. This study underscores the efficient gene-silencing effect and low acute CNS toxicity of ASOs incorporating BNAP-AEO, indicating the potential for future therapeutic applications.
Journal Article
JOURNAL：Molecular Therapy-Nucleic Acids
TITLE：Favorable Efficacy and Reduced Acute Neurotoxicity by Antisense Oligonucleotides with 2',4'-BNA/LNA with 9-(aminoethoxy)phenoxazine
DOI:https://doi.org/10.1016/j.omtn.2024.102161
TITLE：Favorable Efficacy and Reduced Acute Neurotoxicity by Antisense Oligonucleotides with 2',4'-BNA/LNA with 9-(aminoethoxy)phenoxazine
DOI:https://doi.org/10.1016/j.omtn.2024.102161
Correspondence to
Takanori, Yokota, Professor
Department of Neurology and Neurological Science,
Graduate School of Medical and Dental Sciences,
Tokyo Medical and Dental University(TMDU)
E-mail:tak-yokota.nuro(at)tmd.ac.jp
＊Please change (at) in e-mail addresses to @ on sending your e-mail to contact personnels.