HBI-002 treatment improves retinal ischemia-reperfusion injury in mice

Abstract

Purpose : Retinal ischemia is a major cause of vision loss in a number of degenerative retinal diseases, including diabetic retinopathy (DR). The up-regulation of heme oxygenase (HO-1) has shown to be protective. The precise mechanism(s) by which HO-1 confers protection against cellular stress and tissue injury has not been defined, however, overwhelming evidence in the literature points to carbon monoxide (CO) generation. Low doses of CO have shown the potential for benefit in numerous disease paradigms. The impact of low dose CO therapy on conditions of the retina has not been widely evaluated. HBI-002 is an oral drug product containing precise amounts of CO. In the present study, we evaluated the therapeutic efficacy of HBI-002 in regulating retinal ischemia-reperfusion (I/R) in mice.

Methods : Male C57BL/6J mice (8-10 weeks old) were anesthetized and subjected to retinal ischemia by inserting a 32-gauge needle in the anterior chamber of the right eye to infuse sterile saline. The intraocular pressure was raised to 110 mm Hg and maintained for 40 min, after which reperfusion was begun by removing the needle. HBI-002 or vehicle (2 mg/kg) was orally administered to mice 60 minutes before I/R and then dosed daily for 7, 14, or 28 days with two doses of 2 mg/kg 60 min apart. Endpoint analyses included optokinetic tracking and electroretinogram (ERG) analysis as well as monitoring for changes in oxidative stress, inflammation, morphometric changes, and neurodegeneration by immunohistochemistry and Western blotting analysis.

Results : Oral treatment with HBI-002 significantly induced HO-1 expression thereby inducing a significant antioxidant response in the retinas of HBI-002 treated mice. The thickness of the total retina and of the inner nuclear layer was preserved as were ganglion cells in I/R-injured eyes of HBI-002 treated mice. Importantly, visual function was significantly better as evidenced by increases in spatial frequency threshold and improved ERG responses in I/R-injured eyes in HBI-002 treated mice.

Conclusions : Collectively, our proof-of-concept studies provide significant evidence for the therapeutic potential of HBI-002 in improving retinal I/R injury in mice. HBI-002 will enter Phase I testing in healthy subjects in early 2022, and rapid clinical evaluation in retinal disease could follow.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.