Researchers have successfully designed a JAK1-specific siRNA that offers a novel, precise, and safer approach to treating autoimmune skin diseases, including vitiligo.
Background — The Challenge of Treating Autoimmune Skin Diseases
Autoimmune skin diseases, such as vitiligo, result from immune system dysfunction leading to skin depigmentation and other inflammatory symptoms. Current treatments often rely on JAK inhibitors, such as ruxolitinib, which effectively block inflammatory signaling pathways but lack specificity. This non-selectivity frequently results in adverse effects, including immunosuppression and infections, due to the inhibition of multiple JAK family members. A more targeted therapeutic strategy is urgently needed to address these limitations.
Research Aim & Objectives — Aiming for Precision: The JAK1-Specific Solution
To address these challenges, researchers aimed to develop a small interfering RNA (siRNA) capable of selectively silencing JAK1, a key driver of inflammatory pathways in autoimmune skin diseases. The study was conducted by a team of scientists from the University of Massachusetts Chan Medical School and LEO Pharma, with findings published in Nature Communications in October 2023.
Research Method — The Science Behind the Innovation
The team used computational screening to identify siRNA sequences targeting JAK1 mRNA. After screening 150 candidates, they selected a lead compound, siRNA 3033, which demonstrated cross-species reactivity with human, mouse, and primate JAK1 transcripts.
To enhance its therapeutic potential, siRNA 3033 underwent full chemical stabilization and was conjugated to docosanoic acid (DCA), a molecule promoting retention in the skin. These modifications ensured prolonged activity and effective gene silencing with minimal off-target effects.
Results — A Breakthrough in Autoimmune Skin Therapy
Key findings of the study include:
1. Selective Gene Silencing
siRNA 3033 selectively silenced JAK1 without affecting other JAK family members, such as JAK2, JAK3, or TYK2.
- In human skin explants, siRNA 3033 reduced JAK1 mRNA levels by approximately 62% while significantly decreasing the expression of IFN-γ-induced chemokines CXCL9, CXCL10, and CXCL11.
2. Efficacy in Vitiligo Models
In a mouse model of vitiligo, siRNA 3033 reduced CD8+ T-cell infiltration into the skin and prevented epidermal depigmentation. A single injection achieved up to 5 weeks of sustained JAK1 silencing with a 20–30% reduction in mRNA expression.
3. Safety Profile
The siRNA demonstrated good tolerance in animal models. No significant systemic toxicity was observed, although transient platelet count reductions were noted at high doses.
These results highlight siRNA 3033’s ability to modulate inflammation with fewer side effects compared to non-specific JAK inhibitors.
Conclusion — Towards a Safer Treatment Future
This research highlights the potential of siRNA 3033 as a selective and effective therapy for autoimmune skin diseases. By specifically targeting JAK1, siRNA 3033 reduces inflammation with a promising safety profile and long-lasting effects, as demonstrated in preclinical models. The researchers recommend future work to address critical steps for clinical translation, including evaluating safety and pharmacokinetics in animal models with human-like skin characteristics, optimizing delivery mechanisms for skin-targeted applications, and testing in milder autoimmune models to better simulate human disease progression. These steps are expected to refine siRNA 3033 for potential human use and expand its application to other JAK1-related inflammatory disorders.
Reference:
Tang, Qi, et al. “Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin.” Nature Communications 14.1 (2023): 7099.