新しい遺伝子編集システムが複雑な疾患に挑む(A New Gene-Editing System Tackles Complex Diseases)

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2024-05-21 カリフォルニア大学サンディエゴ校(UCSD)

人間のゲノムは約30億塩基対で構成されており、人間は99.6%が遺伝的に同一です。この0.4%の違いが個々の差異を生じさせます。カリフォルニア大学サンディエゴ校の研究者たちは、複数の点突然変異を同時にゲノムに導入する効率的な編集ツール「MOBE(多重直交ベースエディター)」を開発しました。この技術は、従来のCRISPR-Cas9に比べ、細胞へのダメージを減らしながら高効率で編集を行うことができます。MOBEはアプタマーを使用して特定の遺伝子編集酵素を誘導し、多くの病気モデルの研究に応用されています。

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多重化直交ベースエディター(MOBE)システムの開発 Development of multiplexed orthogonal base editor (MOBE) systems

Quinn T. Cowan,Sifeng Gu,Wanjun Gu,Brodie L. Ranzau,Tatum S. Simonson & Alexis C. Komor
Nature Biotechnology  Published:21 May 2024
DOI:https://doi.org/10.1038/s41587-024-02240-0

新しい遺伝子編集システムが複雑な疾患に挑む(A New Gene-Editing System Tackles Complex Diseases)

Abstract

Base editors (BEs) enable efficient, programmable installation of point mutations while avoiding the use of double-strand breaks. Simultaneous application of two or more different BEs, such as an adenine BE (which converts A·T base pairs to G·C) and a cytosine BE (which converts C·G base pairs to T·A), is not feasible because guide RNA crosstalk results in non-orthogonal editing, with all BEs modifying all target loci. Here we engineer both adenine BEs and cytosine BEs that can be orthogonally multiplexed by using RNA aptamer–coat protein systems to recruit the DNA-modifying enzymes directly to the guide RNAs. We generate four multiplexed orthogonal BE systems that enable rates of precise co-occurring edits of up to 7.1% in the same DNA strand without enrichment or selection strategies. The addition of a fluorescent enrichment strategy increases co-occurring edit rates up to 24.8% in human cells. These systems are compatible with expanded protospacer adjacent motif and high-fidelity Cas9 variants, function well in multiple cell types, have equivalent or reduced off-target propensities compared with their parental systems and can model disease-relevant point mutation combinations.

細胞遺伝子工学
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