Histamine Receptor H4 as a New Therapeutic Target for Choroidal Neovascularization in Age-related Macular Degeneration

Abstract

Purpose: To examine the therapeutic ability of reducing histamine receptor H4 (HRH4) expression in choroidal neovascularization (CNV) for the treatment of age-related macular degeneration (AMD).

Methods: HRH4 expression was examined in the CNV from the patient with AMD. In mice, laser photocoagulation was performed in the retina to induce experimental CNV (laser-CNV). Protein and mRNA expression were examined and CNV volume was measured in wild-type and Hrh4-/- mice after inducing laser-CNV. JNJ7777120, HRH4 antagonist, was administrated intravitreously after inducing laser-CNV, and CNV volume and pathological vessel leakage were compared with those injected with control. Fundus image and retinal histology, and electroretinography were examined from the eye injected with JNJ7777120 to evaluate the retinal toxicity.

Results: Human HRH4 was confirmed only in CNV sample from the AMD patient but not in the other subretinal tissue. Mouse Hrh4 was expressed in the retinal pigment epithelium (RPE) only after inducing laser-CNV in wild-type mice, and it was co-localized with macrophage marker F4/80. Laser-CNV volume was reduced in Hrh4-/- mice compared with that in wild-type mice, and JNJ7777120 successfully suppressed laser-induced CNV volume and pathological CNV leakage in wild-type mice. The eyes injected with JNJ7777120 did not show retinal degeneration in mice.

Conclusions: Hrh4 expressed in macrophage that accumulated around the CNV. Suppressing Hrh4 expression lead to prevent pathological vessel leakage without showing retinal toxicity, indicating that HRH4 showed potential as a novel therapeutic target in AMD.

Keywords: 675 receptors: pharmacology/physiology • 453 choroid: neovascularization • 412 age-related macular degeneration