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

Nagata, Tetsuya; Dwyer, Chrissa A.; Yoshida-Tanaka, Kie; Ihara, Kensuke; Ohyagi, Masaki; Kaburagi, Hidetoshi; Miyata, Haruka; Ebihara, Satoe; Yoshioka, Koshiro; Ishii, Takashi; Miyata, Kanjiro; Miyata, Kenichi; Powers, Berit; Igari, Tomoko; Yamamoto, Satoshi; Arimura, Naoto; Hirabayashi, Hideki; Uchihara, Toshiki; Hara, Rintaro Iwata; Wada, Takehiko; Bennett, C. Frank; Seth, Punit P.; Rigo, Frank; Yokota, Takanori

doi:10.1038/s41587-021-00972-x

Cited by 87 publications

(74 citation statements)

References 53 publications

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“…Among ASOs’ advantages for treatment of human brain diseases is the possibility of efficient, low-immunogenic delivery of ASOs to cells in the human brain. While brain delivery of chemically modified ASOs following injection to meninges or intravenously has been shown in rodents [9] , this has yet to be emulated in humans, however progress is still being made [87] . Alternative approaches such as transient permeabilisation of the BBB are also being explored [88] .…”

Section: Discussionmentioning

confidence: 99%

Antisense oligonucleotides for Alzheimer's disease therapy: from the mRNA to miRNA paradigm

et al. 2021

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Section: Discussionmentioning

confidence: 99%

Antisense oligonucleotides for Alzheimer's disease therapy: from the mRNA to miRNA paradigm

et al. 2021

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“…A 2021 study reported that cholesterol-functionalized DNA–RNA heteroduplexes were capable of crossing the blood–brain barrier in mice and rats after systemic administration. Once again, the chemical structure of the lipid and conjugate was critical for cell targeting, gene silencing and pharmacokinetics 194 . RNA aptamers, which are RNAs that fold into defined three-dimensional structures 195 , have also emerged as ligands for specific cell-targeted delivery of RNAi-based therapeutics.…”

Section: Active Versus Passive Tissue Targetingmentioning

confidence: 99%

Drug delivery systems for RNA therapeutics

2022

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RNA-based gene therapy requires therapeutic RNA to function inside target cells without eliciting unwanted immune responses. RNA can be ferried into cells using non-viral drug delivery systems, which circumvent the limitations of viral delivery vectors. Here, we review the growing number of RNA therapeutic classes, their molecular mechanisms of action, and the design considerations for their respective delivery platforms. We describe polymer-based, lipid-based, and conjugate-based drug delivery systems, differentiating between those that passively and those that actively target specific cell types. Finally, we describe the path from preclinical drug delivery research to clinical approval, highlighting opportunities to improve the efficiency with which new drug delivery systems are discovered.

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“…The same group recently reported in an in vitro study that HDOs are distinctly released from early endosomes [ 22 ]. Overall, HDOs might hold potential for delivery of ASOs to difficult-to-access cells and tissues [ 23 , 24 ].…”

Section: Innovative Developments In Nucleic Acid Therapeuticsmentioning

confidence: 99%

Innovative developments and emerging technologies in RNA therapeutics

et al. 2022

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RNA-based therapeutics are emerging as a powerful platform for the treatment of multiple diseases. Currently, the two main categories of nucleic acid therapeutics, antisense oligonucleotides and small interfering RNAs (siRNAs), achieve their therapeutic effect through either gene silencing, splicing modulation or microRNA binding, giving rise to versatile options to target pathogenic gene expression patterns. Moreover, ongoing research seeks to expand the scope of RNA-based drugs to include more complex nucleic acid templates, such as messenger RNA, as exemplified by the first approved mRNA-based vaccine in 2020. The increasing number of approved sequences and ongoing clinical trials has attracted considerable interest in the chemical development of oligonucleotides and nucleic acids as drugs, especially since the FDA approval of the first siRNA drug in 2018. As a result, a variety of innovative approaches is emerging, highlighting the potential of RNA as one of the most prominent therapeutic tools in the drug design and development pipeline. This review seeks to provide a comprehensive summary of current efforts in academia and industry aimed at fully realizing the potential of RNA-based therapeutics. Towards this, we introduce established and emerging RNA-based technologies, with a focus on their potential as biosensors and therapeutics. We then describe their mechanisms of action and their application in different disease contexts, along with the strengths and limitations of each strategy. Since the nucleic acid toolbox is rapidly expanding, we also introduce RNA minimal architectures, RNA/protein cleavers and viral RNA as promising modalities for new therapeutics and discuss future directions for the field.

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

Cited by 87 publications

References 53 publications

Antisense oligonucleotides for Alzheimer's disease therapy: from the mRNA to miRNA paradigm

Antisense oligonucleotides for Alzheimer's disease therapy: from the mRNA to miRNA paradigm

Drug delivery systems for RNA therapeutics

Innovative developments and emerging technologies in RNA therapeutics

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