Chemically modified small interfering RNA targeting Hedgehog signaling pathway for rheumatoid arthritis therapy

• Published in: Molecular therapy. Nucleic acids Vol. 31; pp. 88 - 104
• Main Authors: Lin, Lang, Zhu, Shangling, Huang, Hongyu, Wu, Lin-Ping, Huang, Jianlin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.03.2023; American Society of Gene & Cell Therapy; Elsevier
• Subjects: chemical modification; Hedgehog signaling; MT: Oligonucleotides: therapies and applications; Original; rheumatoid arthritis; small interfering RNA; Smoothened; Hedgehog signaling; MT: Oligonucleotides: therapies and applications; Smoothened; small interfering RNA; rheumatoid arthritis; chemical modification
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2022.12.008

Rheumatoid arthritis (RA) is an inflammatory disease that leads to disability; however, existing therapies are still unsatisfactory. Activated fibroblast-like synoviocytes (FLSs) play an essential role in synovitis formation and joint destruction in RA. The Hedgehog signaling pathway is aberrantly activated and contributes to the aggressive phenotype of RA-FLSs. However, it remains uncertain whether inhibiting Smoothened (SMO), a critical component of the Hedgehog signaling pathway, is an effective treatment for RA. Here, we design a series of small interfering RNAs (siRNAs) that specifically target the SMO gene. With precise chemical modifications, siRNAs’ efficacy and stability are significantly improved, and the off-target effects are minimized. The optimized chemically modified siRNA (si-S1A3-Chol) decreases RA-FLS proliferation and invasiveness without the transfection reagent. Furthermore, si-S1A3-Chol injected intra-articularly effectively alleviates joint destruction and improves motor function in collagen-induced arthritis mouse models. Consequently, our results demonstrate that chemically modified siRNA targeting the Hedgehog signaling pathway may be a potential therapy for RA. [Display omitted]