A Therapeutic Small-Interfering RNA Potentiates Janus Kinase 1 Modulation for the Treatment of Dog Inflammatory Diseases

Inflammatory cytokine signaling pathways share notable similarities between humans and dogs. Janus kinase (JAK) family enzymesJAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) are popular therapeutic targets for inflammatory diseases in human clinics. While more than a dozen JAK inhibitors are available for human use, the only FDA-approved JAK inhibitor for dogs is oclacitinib. Oclacitinib targets multiple JAK subtypes (i.e., JAK1/2/3 and TYK2) and requires daily oral administration, raising concerns about its long-term safety. There is a growing demand for safer and longer-lasting JAK inhibitors to improve the treatment of dog inflammatory diseases. Small-interfering RNAs (siRNAs) are an emerging class of medicines that offer mRNA sequence-specific target selectivity and sustained durability. In this work, we developed a fully chemically modified siRNA that supports efficient gene silencing of dog JAK1. We show that dog JAK1 siRNA offers more than 90% target silencing <i>in vitro</i>. The partial homology of the siRNA targeting site between dog and mouse mRNAs allowed us to validate the compound's preclinical <i>in vivo</i> activity in mouse skin and muscle tissues. In <i>ex vivo</i> models using surgically discarded dog tissues from veterinary clinics, we show that dog JAK1 siRNA supports approximately 65% JAK1 silencing in the skin after intradermal injection and about 51% silencing in the muscle after intramuscular injection. This siRNA potentiates the treatment of inflammatory skin conditions and myopathies in dogs. Further engineering of siRNA may extend its utility to additional tissues, opening up new avenues for the development of immunomodulatory therapies for dogs.