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March 26, 2026 • ✎ STRIA TECH

Discovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndrome

DF-003 reduces microglial infiltration in the retinas of ROSAH model mice

Topics:

Neuroinflammation

Ocular Inflammation and Immune-Mediated Eye Disease

Rare and Inherited CNS and Eye Disorders

Rare Disease

Retinal Ganglion Cell Pathology

Publication

Nature Communications (Sep 09, 2025) Discovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndrome

Fan J, Liu D, Ming Z, Yan C, Dang H, Pan Y, Wei X, Zhao Z, Wang W, Zhang S, Chen L, Cai S, Ke J, Luo Y, Rao L, Chen J, Chen Z, Zhou J, Chen F, Duan X, Ren B, Li TR, Melvin L, Yogaratnam J, Mahajan VB, Song H, Lichenstein H, Xu T, Xu C

DOI: 10.1038/s41467-025-63731-5 >>

Fan et al. identify DF-003, an oral small molecule that selectively blocks the enzyme ALPK1, which is overactive in ROSAH syndrome and drives chronic inflammation. In human immune cells and a mouse model carrying the ROSAH mutation, DF-003 lowers inflammatory signaling and chemokine production, and reduces activation of retinal microglia and astrocytes in the eye, optic nerve, and brain, supporting ALPK1 inhibition as a targeted treatment strategy. Visual function was monitored with an OptoDrum-based optokinetic setup from Striatech, which helped standardize assessment of vision in the ROSAH mice.

ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome is a rare genetic disease caused by variants in alpha-kinase 1 (ALPK1) resulting in downstream pro-inflammatory signaling mediated by the TIFA/TRAF6/NF-κB pathway. Here, we report the design of an ALPK1 inhibitor, DF-003, with pharmacokinetic properties suitable for daily oral dosing. In biochemical assays, DF-003 potently inhibits human ALPK1 (IC₅₀ = 1.5 nM) and the ROSAH disease-causing mutant ALPK1[T237M] (IC₅₀ = 16 nM). When tested against a panel of 394 human kinases, DF-003 exhibits ≥860-fold selectivity over the closest kinase. In cell-based assays, DF-003 suppresses inflammatory cytokine signaling mediated both by wild-type ALPK1 and the disease-causing ALPK1[T237M] mutant. Using mice heterozygous for wild-type human ALPK1 and ALPK1^T237M established to model ROSAH syndrome that exhibit retinal microglial infiltration, astrocyte activation, and inflammatory cytokine upregulation in the retina, optic nerve, and cortex, we show that orally administered DF-003 is sufficient to inhibit these inflammatory phenotypes.