@article{c29a08f8f6914b1a86297d1767cb413c,
title = "Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood–brain barrier and knock down genes in the rodent CNS",
abstract = "Achieving regulation of endogenous gene expression in the central nervous system (CNS) with antisense oligonucleotides (ASOs) administered systemically would facilitate the development of ASO-based therapies for neurological diseases. We demonstrate that DNA/RNA heteroduplex oligonucleotides (HDOs) conjugated to cholesterol or α-tocopherol at the 5′ end of the RNA strand reach the CNS after subcutaneous or intravenous administration in mice and rats. The HDOs distribute throughout the brain, spinal cord and peripheral tissues and suppress the expression of four target genes by up to 90% in the CNS, whereas single-stranded ASOs conjugated to cholesterol have limited activity. Gene knockdown was observed in major CNS cell types and was greatest in neurons and microglial cells. Side effects, such as thrombocytopenia and focal brain necrosis, were limited by using subcutaneous delivery or by dividing intravenous injections. By crossing the blood–brain barrier more effectively, cholesterol-conjugated HDOs may overcome the limited efficacy of ASOs targeting the CNS without requiring intrathecal administration.",
author = "Tetsuya Nagata and Dwyer, {Chrissa A.} and Kie Yoshida-Tanaka and Kensuke Ihara and Masaki Ohyagi and Hidetoshi Kaburagi and Haruka Miyata and Satoe Ebihara and Kotaro Yoshioka and Takashi Ishii and Kanjiro Miyata and Kenichi Miyata and Berit Powers and Tomoko Igari and Syunsuke Yamamoto and Naoto Arimura and Hideki Hirabayashi and Toshiki Uchihara and Hara, {Rintaro Iwata} and Takeshi Wada and Bennett, {C. Frank} and Seth, {Punit P.} and Frank Rigo and Takanori Yokota",
note = "Funding Information: We thank A. Oda, Y. Kakoi and A. Kunugi (Research, Takeda Pharmaceutical Company) for conducting the in vivo studies, and S. Matsumoto and I. Chisaki (Research, Takeda Pharmaceutical Company) for quantifying the ASO and conducting PK analyses. We also thank N. Post (Ionis Pharmaceuticals) for the quantification of the ASO, M. Jackson and M. Afetian (Ionis Pharmaceuticals) for valuable technical assistance, S. Klein (Ionis Pharmaceuticals) and A. Nakamura (TMDU) for histopathological studies and A. Abe and Y. Okamoto (WDB) for their care of the laboratory animals. This research was supported by the Basic Science and Platform Technology Programs for Innovative Biological Medicine (18am0301003h0005) and Advanced Biological Medicine (20am0401006h0002) to T.Y., a Research Project on the Elucidation of Chronic Pain (19ek0610013h0003) to T.Y. and T.N. from the Japan Agency for Medical Research and Development (AMED), JST CREST (JPMJCR12L4 to T.Y.) and a JSPS KAKENHI Grant-in-Aid for Scientific Research (S) (17H06109 to T.Y. and T.N.), (A) (19H01016 to T.N. and T.Y.) and (B) (16H05221 to T.N.) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (Tokyo). Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = dec,
doi = "10.1038/s41587-021-00972-x",
language = "English",
volume = "39",
pages = "1529--1536",
journal = "Nature Biotechnology",
issn = "1087-0156",
publisher = "Nature Publishing Group",
number = "12",
}