Crosstalk Between Trabecular Meshwork, Schlemm Canal Could be Drug Target in Primary Congenital Glaucoma

Experimental evidence suggests the importance of trabecular meshwork-Schlemm canal crosstalk in intraocular pressure (IOP) homeostasis, which may provide a potential drug target for patients with primary congenital glaucoma (PCG), according to research published in Nature Communications.

Researchers from Northwestern University used angiopoietin 1 (Angpt1) and sushi, von willebrand factor type A, EGF and pentraxin domain containing 1 (Svep1) knockout mouse models for this study. Mice were assessed for IOP, retinal vasculature, Schlemm canal features, and mesenteric lymphatic vessels. Expression was assessed using quantitative real-time PCR and RNA was assessed using single-cell RNA sequencing. A drug targeting an identified gene was assessed for effects on IOP.

A knockout of Angpt1 in the neural crest was sufficient to recapitulate a glaucoma model, as IOP was elevated by 7 weeks of age (P ≤.001) and remained elevated thought life with an increased axial length by 15 weeks of age (P =.0013) and decreased Schlemm canal area (P =.0008). These observations indicated that ANGPT1 secretion by trabecular meshwork cells may be essential for IOP homeostasis.

A knockout of Svep1 in the neural crest caused severely hypomorphic Schlemm canal without prospero homeobox 1 (PROX1) expression and disorganized limbal vasculature. By 4 weeks of age, IOP was elevated (P ≤.01), confirming that SVEP1 is likely involved with IOP homeostasis.

Cells from control and Angpt1 knockout mice expressed distinct clusters of proteins. The cells from Schlemm’s canal had significantly different expression of 9 genes, 5 of which have functional links with glaucoma, including TEK receptor tyrosine kinase (Tek). Similarly, trabecular meshwork cells had increased expression of 18 genes, 3 of which are functionally related with glaucoma. The 2 cell types shared altered expression of 12 genes and the glaucoma-specific genes forkhead box C1 (Foxc1), cytochrome P450 family 1 subfamily B member 1 (Cyp1b1), and vascular endothelial growth factor A (Vegfa).

These observations led the study investigators to hypothesize that the ANGPT-TEK signaling pathway could be crucial for Schlemm’s canal development and may be a viable therapeutic target for glaucoma. To test this, wild-type mice were treated with 1 mg/kg daily Hepta-ANGPT1 administered via intraperitoneal injections from birth until 14 weeks. They found that the Schlemm’s canal area was significantly increased compared with untreated controls (P =.0014).

The same treatment among the Angpt1 knockout mice also significantly increased Schlemm’s canal area (P =.0008) as well as lowering IOP pressure at 5 (P <.001), 6 (P <.001), and 7 (P <.01) weeks of age.

These data indicated that ANGPT1 and SVEP1 were molecules derived in the trabecular meshwork of the neural crest which were essential regulators of Schlemm canal development and function. These signaling molecules may be effective treatment targets for glaucoma. Additional study is needed in humans to confirm these findings.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.

Reference

Thomson BR, Liu P, Onay T, et al. Cellular crosstalk regulates the aqueous humor outflow pathway and provides new targets for glaucoma therapies. Nat Commun. 2021;12(1):6072. doi:10.1038/s41467-021-26346-0