タンパク質ベースのホーミング・デバイスが標的ニューロンに薬剤を正確に送達(Protein-Based Homing Device Precisely Delivers Drugs to Target Neurons)

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2024-06-17 デューク大学(Duke)

デューク大学の生物医学エンジニアが、脳内の特定のニューロンに薬を届ける新しい方法を開発しました。この新しいアプローチは、従来の方法よりも100倍の精度を持ち、神経疾患の研究や標的薬治療の効率を高めます。研究は「Nature Methods」に掲載されました。この方法「DART.2」は、特定のニューロンに薬を集中させることで、副作用を最小限に抑えつつ、薬の効果を最大化します。マウスを用いた実験で、ガバジンという薬が安全に標的ニューロンに届けられることが示されました。DART.2は、脳全体に薬を循環させることで、簡便な投与経路も可能にします。

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DART.2:千倍の細胞特異性を持つ双方向シナプス薬理学 DART.2: bidirectional synaptic pharmacology with thousandfold cellular specificity

Brenda C. Shields,Haidun Yan,Shaun S. X. Lim,Sasha C. V. Burwell,Celine M. Cammarata,Elizabeth A. Fleming,S. Aryana Yousefzadeh,Victoria Z. Goldenshtein,Elizabeth W. Kahuno,Purav P. Vagadia,Marie H. Loughran,Lei Zhiquan,Mark E. McDonnell,Miranda L. Scalabrino,Mishek Thapa,Tammy M. Hawley,Greg D. Field,Court Hull,Gary E. Schiltz,Lindsey L. Glickfeld,Allen B. Reitz & Michael R. Tadross
Nature Methods  Published:14 June 2024
DOI:https://doi.org/10.1038/s41592-024-02292-9

タンパク質ベースのホーミング・デバイスが標的ニューロンに薬剤を正確に送達(Protein-Based Homing Device Precisely Delivers Drugs to Target Neurons)

Abstract

Precision pharmacology aims to manipulate specific cellular interactions within complex tissues. In this pursuit, we introduce DART.2 (drug acutely restricted by tethering), a second-generation cell-specific pharmacology technology. The core advance is optimized cellular specificity—up to 3,000-fold in 15 min—enabling the targeted delivery of even epileptogenic drugs without off-target effects. Additionally, we introduce brain-wide dosing methods as an alternative to local cannulation and tracer reagents for brain-wide dose quantification. We describe four pharmaceuticals—two that antagonize excitatory and inhibitory postsynaptic receptors, and two that allosterically potentiate these receptors. Their versatility is showcased across multiple mouse-brain regions, including cerebellum, striatum, visual cortex and retina. Finally, in the ventral tegmental area, we find that blocking inhibitory inputs to dopamine neurons accelerates locomotion, contrasting with previous optogenetic and pharmacological findings. Beyond enabling the bidirectional perturbation of chemical synapses, these reagents offer intersectional precision—between genetically defined postsynaptic cells and neurotransmitter-defined presynaptic partners.

有機化学・薬学
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