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Published on: August 11, 2023
Histamine H4 receptor as a new therapeutic target for choroidal neovascularization in age-related macular
Hiroki Kaneko1, Fuxiang Ye, Ryo Ijima
1Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Background And Purpose:
The present treatment for choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD) is not sufficient. Hence, we examined the therapeutic efficacy of reducing histamine H4 receptor expression on CNV in mice.
Experimental Approach:
H4 receptor expression was examined in CNVs from patients with AMD. In mice, laser photocoagulation was performed in the retina to induce experimental CNV (laser CNV). Protein and mRNA expression levels were determined and CNV volume measured in wild-type and Hrh4(-/-) mice with laser CNV. The effects of JNJ7777120, an H4 receptor antagonist, administered intravitreously, on CNV volume and pathological vessel leakage were determined in mice with laser CNV and controls. Fundus imaging, retinal histology and electroretinography were performed on eyes injected with JNJ7777120 to evaluate retinal toxicity.
Key Results:
Human H4 receptors were only confirmed in CNV samples from AMD patients and not in the other subretinal tissues. Mouse H4 receptors were expressed in retinal pigment epithelium only after inducing laser CNV in wild-type mice, and were co-localized with the macrophage marker F4/80. Laser CNV volume was reduced in Hrh4(-/-) mice compared with that in wild-type mice, and JNJ7777120 suppressed laser-induced CNV volume and pathological CNV leakage in wild-type mice. Also eyes injected with JNJ7777120 did not show retinal degeneration.
Conclusions And Implications:
H4 receptors are expressed in macrophages that accumulate around CNVs. Suppressing H4 receptor expression prevented the pathological vessel leakage without showing retinal toxicity, indicating that the H4 receptor has potential as a novel therapeutic target in AMD.
Insights
Targeting histamine H4 receptors may treat age-related macular degeneration. Reducing H4 receptor expression in mice decreased choroidal neovascularization (CNV) and leakage without toxicity, suggesting a new therapeutic approach for AMD.
Area of Science:
- Ophthalmology
- Immunology
- Pharmacology
Background:
- Current treatments for choroidal neovascularization (CNV) in age-related macular degeneration (AMD) are insufficient.
- Histamine H4 receptors are implicated in inflammatory processes relevant to AMD.
Purpose of the Study:
- To investigate the therapeutic potential of targeting histamine H4 receptors in a mouse model of CNV.
- To assess the efficacy of reducing H4 receptor expression on CNV development and progression.
Main Methods:
- Examined H4 receptor expression in human AMD CNV samples and in laser-induced CNV in wild-type and Hrh4(-/-) mice.
- Measured CNV volume, protein and mRNA expression, and pathological vessel leakage.
- Administered an H4 receptor antagonist (JNJ7777120) intravitreously and evaluated retinal toxicity.
Main Results:
- H4 receptors were found in human AMD CNV and expressed in mouse retinal pigment epithelium and macrophages after laser-induced CNV.
- Hrh4(-/-) mice exhibited reduced laser CNV volume compared to wild-type mice.
- JNJ7777120 suppressed laser-induced CNV volume and leakage without causing retinal toxicity.
Conclusions:
- Histamine H4 receptors are present on macrophages associated with CNV.
- Inhibition of H4 receptor signaling effectively reduced pathological CNV and leakage.
- The H4 receptor represents a promising novel therapeutic target for AMD treatment.
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