Abstract
Purpose :
The Janus kinase (JAK) pathway plays key roles in inflammatory cell regulation, cytokine production, and proinflammatory signal transduction. VVN461 is a first-in-class pharmaceutically active small molecule that selectively targets both Janus kinase 1 (JAK1) and tyrosine [CL1] kinase 2 (TYK2). The purpose of this study is to investigate the ocular therapeutic effects of topically administered VVN461 for suppressing inflammation in the rabbit EAU model.
Methods :
Dutch-Belted rabbits were preimmunized twice, seven days apart, by subcutaneous injections of 0.5 ml Mycobacterium Tuberculosis (MTB) H37 RA antigen. Uveitis was induced in the right eye unilaterally by intravitreal injection of 20 µl 0.2% MTB antigen 21 days after the 1st systemic preimmunization. Standardization of Uveitis Nomenclature (SUN) scores was used to grade uveitis by an ophthalmologist using slit lamp biomicroscope. After ocular inflammation reached maximum, 25 eyes (5 eyes per group) were selected and treatments were given for 21 days (Day 1-Day 21). The therapeutic effects of 0.1% and 0.5% VVN461 Ophthalmic solution were evaluated in comparison with topical steroid, 0.1% Dexamethasone (Dex), a non-steroidal anti-inflammatory drug (NSAID), 0.5% Pranoprofen (Pran), and without treatment (Control).
Results :
Uveitis was developed in all animals. Maximum ocular inflammation was reached 2 days after MTB antigen injection, with moderate to severe SUN scores of anterior chamber cells (AC cell, grade > 2+, see Table 1). AC cell scores showed significant reduction from the peak for 0.5% VVN461 and 0.1% Dex groups on day 7 and 14, respectively, and reached the lowest (grade 0.5+) on day 21 of the treatment. However, 0.1% VVN461 and 0.5% Pran groups, as well as the Control, showed minimal reduction in inflammation.
Conclusions :
In conclusion, topical 0.5% VVN461 eyedrop significantly reduces AC cells in eyes of the rabbit EAU model. This finding suggests the potent JAK inhibitor VVN461 has a potential role in reducing the inflammation of Uveitis. The current experimental data also imply that VVN461 has the potential to substitute corticosteroid for the treatment of uveitis, which is an urgent need in the field.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.