ANGPTL7 and its role in IOP and glaucoma

Abstract

Purpose : Vision loss in glaucoma patients can be prevented by lowering intraocular pressure (IOP); however, despite both medical and surgical treatment options to reduce IOP, many patients progress to advanced disease with significant loss of vision. To address this shortcoming, new therapies are needed, particularly those with a strong genetic rationale. Previous studies have shown that loss-of-function variants in the ANGPTL7 gene are associated with protection from glaucoma and reduced IOP. We investigated the role of ANGPTL7 to further understand its role in IOP homeostasis and its potential as a target for the development of therapeutics.

Methods : Bioengineered scaffolds with a co-culture of human trabecular meshwork (TM) and human Schlemm’s Canal (SC) cells were subjected to various treatments, and hydraulic conductivity was measured. Angptl7^-/- mice were treated with dexamethasone or PBS control, and IOP was measured. Mouse eyes of Angptl7^-/- mice were enucleated, and outflow facility was measured. Mouse eyes were also examined for effects of genetic deletion on morphology of the outflow tract. Lastly, rabbits were injected intravitreally with neutralizing antibodies targeting ANGPTL7, and IOP was measured over the course of 21 days.

Results : Using a bioengineered scaffold with co-cultures of TM and SC, we found that addition of recombinant ANGPTL7 protein decreased outflow facility by 45% (n = 9, p<0.001), while blocking antibodies neutralized this effect (n = 3, p<0.05). IOP, outflow facility and morphology of outflow tissues were not significantly different between Angptl7^-/- mice and WT littermates. However, when challenged with dexamethasone, the IOP increased 2-4 mm Hg in WT but not Angptl7^-/- mice (n = 5-15 animals/group, similar results seen in 3 experiments). Lastly, Intravitreal injection of ANGPTL7 neutralizing antibodies into rabbit eyes resulted in decreased IOP at several timepoints over 21 days (n = 3/group, p <0.05).

Conclusions : Angptl7^-/- mice have normal IOP and outflow function, but absence of Angptl7 protected mice from an ocular hypertensive response to dexamethasone. This effect was recapitulated in the human organoid and rabbit IOP models, as ANGPTL7 neutralizing antibodies increased outflow facility and lowered rabbit IOP. These data provide a strong rationale for the development of ANGPTL7 targeting therapeutics for treatment of glaucoma.

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