ANGPTL7 and Its Role in IOP and Glaucoma.
Brown Suzette Farber-Katz, Nguyen Hien, Mzyk Philip, De Ieso Michael L, Unser Andrea M, Brown Ian, Ramesh Pujhitha, Afzaal Hira, Ahmed Feryan, Torrejon Karen Y
AI Summary
This study found ANGPTL7 increases eye pressure by raising outflow resistance. Blocking ANGPTL7 lowered eye pressure in models, suggesting it's a promising target for new glaucoma therapies.
Abstract
Purpose
Loss-of-function variants in the ANGPTL7 gene are associated with protection from glaucoma and reduced intraocular pressure (IOP). We investigated the role of ANGPTL7 in IOP homeostasis and its potential as a target for glaucoma therapeutics.
Methods
IOP, outflow facility, and outflow tissue morphology of Angptl7 knockout (KO) mice were assessed with and without dexamethasone (Dex). ANGPTL7 was quantified in conditioned media from human trabecular meshwork cells in response to Dex, in effluent from perfused human donor eyes, and in aqueous humor from human patients treated with steroids. Antibodies to ANGPTL7 were generated and tested in three-dimensional (3D) culture of outflow cells and perfused human donor eyes. Rabbits were injected intravitreally with a neutralizing antibody targeting ANGPTL7, and IOP was measured.
Results
IOP was significantly elevated, but outflow facility and outflow tissue morphology were not different between Angptl7 KO mice and littermates. When challenged with Dex, IOP increased in wild-type but not Angptl7 KO mice. In human samples, increased ANGPTL7 was seen in the aqueous humor of patients treated with steroids, regardless of glaucoma status. Using 3D culture, recombinant ANGPTL7 decreased, and ANGPTL7-blocking antibodies increased hydraulic conductivity. Significantly, outflow facility increased in human eyes treated ex vivo with ANGPTL7-blocking antibodies, and IOP decreased for 21 days in rabbits after a single injection of blocking antibodies.
Conclusions
Using multiple models, we have demonstrated that excess ANGPTL7 increases outflow resistance and IOP and that neutralizing ANGPTL7 has beneficial effects in both naïve and steroid-induced hypertensive eyes, thus motivating the development of ANGPTL7-targeting therapeutics for the treatment of glaucoma.
MeSH Terms
Shields Classification
Key Concepts5
Intraocular pressure (IOP) was significantly elevated in Angptl7 knockout (KO) mice compared to littermates, but outflow facility and outflow tissue morphology were not different.
In human samples, increased ANGPTL7 was observed in the aqueous humor of patients treated with steroids, regardless of glaucoma status.
Outflow facility increased in human eyes treated ex vivo with ANGPTL7-blocking antibodies, and intraocular pressure (IOP) decreased for 21 days in rabbits after a single intravitreal injection of ANGPTL7-blocking antibodies.
Excess ANGPTL7 increases outflow resistance and intraocular pressure (IOP), and neutralizing ANGPTL7 has beneficial effects in both naive and steroid-induced hypertensive eyes.
Loss-of-function variants in the ANGPTL7 gene are associated with protection from glaucoma and reduced intraocular pressure (IOP).
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