Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood–brain barrier and knock down genes in the rodent CNS

Autor: Kie Yoshida-Tanaka, Hidetoshi Kaburagi, Kotaro Yoshioka, Naoto Arimura, Takanori Yokota, Frank Rigo, Toshiki Uchihara, Takashi Ishii, Kensuke Ihara, Kenichi Miyata, Haruka Miyata, Takeshi Wada, Kanjiro Miyata, Chrissa A. Dwyer, Punit P. Seth, Tetsuya Nagata, Rintaro Iwata Hara, Syunsuke Yamamoto, Hideki Hirabayashi, Satoe Ebihara, Tomoko Igari, C. Frank Bennett, Masaki Ohyagi, Berit Powers
Rok vydání: 2021
Předmět:
Zdroj: Nature Biotechnology. 39:1529-1536
ISSN: 1546-1696
1087-0156
DOI: 10.1038/s41587-021-00972-x
Popis: 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. Genes in the rodent brain are knocked down by DNA/RNA heteroduplexes injected intravenously.
Databáze: OpenAIRE
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