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Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin

ABSTRACT: Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin

PROVIDER: PRJNA979262 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24809120_1.fastq.gz	Fastqsanger.gz
	SRR24809120_2.fastq.gz	Fastqsanger.gz
	SRR24809121_1.fastq.gz	Fastqsanger.gz
	SRR24809121_2.fastq.gz	Fastqsanger.gz
	SRR24809122_1.fastq.gz	Fastqsanger.gz

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Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin

Project description:Inhibition of Janus kinase (JAK) family enzymes has surged as a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, current available small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting their variable selectivity for JAK subtypes. Nonselective inhibition of multiple JAK enzymes is associated with increased side effects and has resulted in FDA-mandated black box warnings. Developing therapeutics to enable absolute JAK subtype selectivity is challenging and has not yet been achieved. Here, we harness RNA interference (RNAi) for rationally designing small interfering RNA (siRNA) therapeutics that offer sequence-specific gene silencing of JAK1, thus narrowing the spectrum of action on JAK-dependent cytokine signaling pathways to maintain efficacy and improve safety. We developed a fully chemically modified siRNA that supports efficient silencing of JAK1 expression in human skin explant and functional modulation of JAK1-dependent inflammatory signaling. A single injection of the JAK1 siRNA into mouse skin enables JAK1 silencing for 5 weeks in vivo. 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 outlines a robust framework for designing targeted RNAi-based therapies and establishes a path toward novel siRNA treatments for inflammatory and autoimmune skin diseases.

2023-10-18 | GSE234070 | GEO

Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin.

Project description: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.

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