siRNAs are used to treat diseases by silencing genes, and in the case of autoimmune skin diseases like vitiligo, blocking the production of the IFN-γ receptor gene may prevent disease-causing immune responses in the skin.
- Small interfering RNAs (siRNAs) are being used to treat diseases by silencing gene expression.
- In autoimmune skin diseases such as vitiligo, IFN-γ signaling is a central mechanism underlying disease.
- Blocking production of the gene for the IFN-γ receptor effectively prevents immunoregulatory cascades in the skin.
Autoimmune skin conditions like vitiligo are caused by inflammatory cascades and autoreactive T cell activity, which break down melanocytes and lead to tissue damage. CD8+ T cells both produce and are stimulated by IFN-γ, causing the release of harmful chemokines and attracting more T cells. Because IFN-γ is an early activator in this pathway, it has become the target for a new class of drugs that selectively interrupt gene expression known as small interfering RNAs (siRNAs).
IFN-γ Signaling and the JAK/STAT Pathway
IFN-γ activates the JAK/STAT immunoregulatory pathway by binding to the IFN-γ-receptor. Previous drugs have interfered with this pathway by blocking JAK signaling, but recent evidence has found more effective results using siRNAs against the IFN-γ receptor. After testing a panel of candidate siRNAs, two modifications showed effective blocking of mRNA expression of the receptor itself as well as chemokines resulting from receptor binding.
siRNAs Suppress IFN-γ Receptor Gene
siRNAs prevent the IFN-γ receptor gene from being generated in target tissue and decrease its protein expression for at least 4 weeks after injection. In a mouse model, injection into the tail vein recovered pigmentation and decreased the production of the chemokines responsible for carrying out the immune response and recruiting and activating immune cells.
siRNAs Hold Potential to Improve Treatments for Autoimmune Skin Diseases
siRNAs targeting the IFN-γ receptor effectively reduced immune signaling cascades and recovered skin pigmentation, and the effect on protein expression was fairly long-lasting. Interfering with IFN-γ-receptor gene expression could have unwanted systemic effects, but more research must be done to determine the safest ways to administer an IFN-γ receptor siRNA. Nevertheless, siRNA therapies are establishing an initial path to improved treatments for autoimmune skin diseases.
Tang, Q., Sousa, J., Echeverria, D., Fan, X., Hsueh, Y. C., Afshari, K., MeHugh, N., Cooper, D. A., Vangjeli, L., Monopoli, K., Okamura, K., Biscans, A., Clauss, A., Harris, J. E., & Khvorova, A. (2022). RNAi-based modulation of IFN-γ signaling in skin. Molecular Therapy, 30(8), 2709-2721. https://doi.org/10.1016/j.ymthe.2022.04.019