ANGPTL7: A PROMISING TARGET FOR GLAUCOMA THERAPEUTICS

Abstract

Purpose : ANGPTL7 is a secreted glycoprotein initially discovered in the cornea. There is evidence that ANGPTL7 levels are elevated in aqueous humor of glaucoma patients and it is highly upregulated upon steroid treatment of trabecular meshwork (TM) cells. We have also shown that in our scRNA-seq data, it is one of the most highly expressed genes in TM. We conducted whole exome sequencing of several large cohorts of individuals and demonstrated an association of the ANGPTL7 gene with both lowered IOP and a reduced risk of glaucoma. Both common and rare variants were identified. To further investigate the relationship of ANGPTL7 to IOP, a series of experiments were performed.

Methods : IOP measurements in wild-type and KO mice using a rebound tonometer (Tonolab). Intravitreal and intracameral injections of several agents.

Results : First, we injected ANGPTL7 protein into the eyes of mice and monitored IOP. Either intravitreal or intracameral injection led to elevated IOP that persisted for more than a 4 days. Next, we made an ANGPTL7 knockout (KO) mouse. There was a gene-dose dependent decrease in IOP, with Het mice exhibiting IOP significantly lower than wt and in homozygous KOs the pressure was further decreased (about 2-3 mm difference between wt and full KO). Ocular anatomy was normal. These results suggest, but do not prove, that ANGPTL7 is involved in the normal physiological maintenance of IOP. To further test this notion, we used an RNAi based approach to test whether a distinct means of acute gene silencing, in an adult animal, will lower IOP. We identified several siRNA duplexes that decreased ANGPTL7 expression, and those that showed >50% mRNA KD also lowered IOP (comparably to the KO). We have also shown that siRNA against ANGPTL7 normalizes IOP in several rodent models of ocular hypertension.

Conclusions : These data strongly indicate that ANGPTL7 contributes to the normal physiological regulation of IOP and that pathological over-expression could lead to potentially damaging elevations in IOP. ANGPTL7 thus is a promising new glaucoma therapeutic target.

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