Systemic and local treatment with TG101209, a combined JAK2 and bromodomain BRD4-1 inhibitor, can diminish ocular disease progression in a murine model of graft-versus-host disease

Abstract

Purpose : To test the local or systemic use of TG101209, a combined JAK2 and bromodomain BRD4-1 inhibitor, in the prevention of disease development in a mouse model of graft-versus-host disease (GVHD)

Methods : In mice, an allogeneic GVHD model was established by transferring bone marrow (BM) and purified splenic T cells from C57BL/6J mice into irradiated C3-SW.H2b mice. Diseased groups consisted of: (1) No treatment (BM+T); (2) subconjunctival (SC) TG101209; (3) intraperitoneal (IP) TG101209; and (4) mice that received BM only (BMO). Mice were assessed for systemic and ocular disease across the 21-day post-transplantation period. Systemic disease was assessed using a composite score (0-12) of weight loss, activity, posture, fur texture, alopecia, skin integrity, and diarrhea. Ocular disease was assessed using eyelid edema (0-2), meibomian gland (MG) atrophy (% atrophy), and corneal epitheliopathy (staining fluorescence).

Results : Mice were assessed across the 21-day post-transplant period (n=12/group). Compared to BM+T mice, a significantly reduced median systemic disease score was noted on day 21 for the IP TG101209 and the BMO groups (4.25 and 0 vs 7.75, respectively; p<0.05) but not the SC TG101209 group (8 vs 7.75, p>0.1). Regarding ocular disease on day 21, compared to BM+T mice, a significantly reduced median eyelid edema score was noted for the BMO (0 vs 3), SC TG101209 (1.5 vs 3), and IP TG101209 (1.25 vs 3) groups (all p<0.05). Median fluorescein corneal staining index on day 21 was significantly lower for the BMO (4 vs 22), SC TG101209 (12.5 vs 22), and IP TG101209 (12 vs 22) groups compared to BM+T mice (all p<0.05). An MG atrophy of more than 50% was noted in 10/12 (80%) of the BM+T mice, significantly higher than that of the BMO (0%), SC TG101209 (3/12, 25%), and the IP TG101209 (2/12, 16.6%) (all p<0.05). No treatment complications were noted.

Conclusions : Systemic treatment with TG101209 reduced systemic and ocular GVHD development compared to no treatment. Despite not affecting systemic disease development, local treatment with TG101209 reduced ocular GVHD progression compared to no treatment. These findings highlight the safety and therapeutic potential of JAK2 with BRD4-1 inhibition in the treatment of ocular surface immune conditions. Additional testing is required for a more standardized comparison.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.