Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin.
Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin.
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DOI：
10.1038/s41467-023-42714-4
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发表时间：
2023-11-04
影响因子：
16.6
通讯作者：
Harris, John E.
中科院分区：
文献类型：
--
作者：
Tang, Qi;Fakih, Hassan H.;Ul Abideen, Mohammad Zain;Hildebrand, Samuel R.;Afshari, Khashayar;Gross, Katherine Y.;Sousa, Jacquelyn;Maebius, Allison S.;Bartholdy, Christina;Sogaard, Pia Pernille;Jackerott, Malene;Hariharan, Vignesh;Summers, Ashley;Fan, Xueli;Okamura, Ken;Monopoli, Kathryn R.;Cooper, David A.;Echeverria, Dimas;Bramato, Brianna;Mchugh, Nicholas;Furgal, Raymond C.;Dresser, Karen;Winter, Sarah J.;Biscans, Annabelle;Chuprin, Jane;Haddadi, Nazgol-Sadat;Sherman, Shany;Yildiz-Altay, Ummugulsum;Rashighi, Mehdi;Richmond, Jillian M.;Bouix-Peter, Claire;Blanchard, Carine;Clauss, Adam;Alterman, Julia F.;Khvorova, Anastasia;Harris, John E.
抑制Janus激酶(JAK)家族酶是治疗炎症性和自身免疫性皮肤病的常用策略。在临床上，小分子JAK抑制剂显示出不同的有效性和安全性，可能反映了JAK亚型的不同选择性。JAK亚型的绝对选择性尚未达到。在这里，我们合理地设计小干扰RNA(SiRNAs)，提供JAK1的序列特异性基因沉默，缩小JAK依赖的细胞因子信号的作用范围，以保持有效性和提高安全性。我们的完全化学修饰的siRNA支持有效地沉默人类皮肤外植体中JAK1的表达，并调节JAK1依赖的炎症信号。一次小鼠皮肤注射就能持续五周的效果。在白癜风小鼠模型中，局部应用JAK1 siRNA显著减少皮肤自身反应性CD8+T细胞的渗透，防止表皮脱色。这项工作为siRNA治疗作为炎症性和自身免疫性皮肤病的一种新的治疗方式奠定了道路。Janus激酶家族酶的治疗调节是治疗炎症性和自身免疫性皮肤病的既定方法。在这里，作者合理地设计了小干扰RNA来实现单个Janus激酶的靶向，并在皮肤病模型中测试了这种新的治疗方法，以保持有效性和提高选择性。
Inhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting variable selectivity for JAK subtypes. Absolute JAK subtype selectivity has not yet been achieved. Here, we rationally design small interfering RNAs (siRNAs) that offer sequence-specific gene silencing of JAK1, narrowing the spectrum of action on JAK-dependent cytokine signaling to maintain efficacy and improve safety. Our fully chemically modified siRNA supports efficient silencing of JAK1 expression in human skin explant and modulation of JAK1-dependent inflammatory signaling. A single injection into mouse skin enables five weeks of duration of effect. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8+ T cells and prevents epidermal depigmentation. This work establishes a path toward siRNA treatments as a new class of therapeutic modality for inflammatory and autoimmune skin diseases. Therapeutic modulation of Janus kinase family enzymes is an established approach for inflammatory and autoimmune skin diseases. Here the authors rationally design small interfering RNAs to enable single Janus kinase targeting and test this new therapeutic approach in a skin disease model for maintaining efficacy and improving selectivity.
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影响因子：
6.5
作者：
Hsueh, Ying-Chao;Wang, Yuzhen;Harris, John E.
通讯作者：
Harris, John E.
影响因子：
32.4
作者：
Groom JR;Richmond J;Murooka TT;Sorensen EW;Sung JH;Bankert K;von Andrian UH;Moon JJ;Mempel TR;Luster AD
通讯作者：
Luster AD
DOI：
10.1016/j.omtn.2022.06.009
发表时间：
2022-09-13
期刊：
MOLECULAR THERAPY NUCLEIC ACIDS
影响因子：
--
作者：
Davis, Sarah M.;Hariharan, Vignesh N.;Lo, Agnes;Turanov, Anton A.;Echeverria, Dimas;Sousa, Jacquelyn;McHugh, Nicholas;Biscans, Annabelle;Alterman, Julia F.;Karumanchi, S. Ananth;Moore, Melissa J.;Khvorova, Anastasia
通讯作者：
Khvorova, Anastasia
影响因子：
13.8
作者：
Damsky W;King BA
通讯作者：
King BA
影响因子：
4
作者：
Coles, Andrew H.;Osborn, Maire F.;Khvorova, Anastasia
通讯作者：
Khvorova, Anastasia