GENETIC TREATMENT FOR GLAUCOMA

 

In primary congenital glaucoma (PCG), there are developmental defects in the conventional aqueous outflow pathway, comprising of the trabecular meshwork (TM) and Schlemm’s canal (SC).

Studies have shown the central role played by ANGPT1-TEK signaling and TM-SC crosstalk in IOP homeostasis.

Further information about these pathways can provide new candidates for SC-targeted glaucoma therapy.

The angiopoietin (ANGPT)-TEK (tunica interna endothelial cell kinase, also known as TIE2) system is an endothelial growth factor pathway comprised of the receptor tyrosine kinase TEK, which is highly expressed by SC endothelial cells and its ligands, the angiopoietins.

Heterozygous loss of function variants in TEK or its primary ligand ANGPT1 have been linked to PCG in children, and ANGPT1 and ANGPT2 have been associated with primary open-angle glaucoma (POAG) in adults.

ANGPT1-TEK signaling is required for SC development in mice, suggesting a potential mechanism for IOP elevation. In addition, the pathway is an essential regulator of IOP homeostasis in adult mice and nonhuman primates, which rapidly develop ocular hypertension and glaucoma after inhibition of ANGPT-TEK signaling.

In parallel with ANGPT-TEK signaling, SC and the TM are regulated by numerous pathways, many of which are likely to regulate outflow and provide IOP-lowering therapeutic targets.

SVEP1 (Sushi, von Willebrand factor type A, EGF, and pentraxin domain containing protein 1), a gene encoding a large extracellular matrix protein also known as Polydom is expressed in the TM. It has been reported to bind ANGPT1 in vitro.

SVEP1 is essential for lymphatic development and was linked to PCG via a large family containing five generations of affected individuals also harboring a heterozygous loss of function variant in TEK22 and has been associated with POAG in a large multi-ethnic cohort.

Using mouse models, it was shown that deletion of Angpt1 or Svep1 from the neural crest tissues leads to major defects in the adjacent SC, ocular hypertension and phenotypes similar to PCG. These studies demonstrate the importance of TM-SC crosstalk and confirm that TM-expressed molecules are essential drivers of SC development and function.

A study from USA has shown that treatment of Angpt1ΔNC mice with intra-peritoneal Hepta-ANGPT1 from birth to P14 partially compensated for the loss of endogenous ANGPT1 and allowed the development of a functional SC.

Despite the discontinuation of treatment at P14, adult Hepta-ANGPT1 treated mice had reduced IOP compared to vehicle-treated Angpt1ΔNC controls, increased SC size and blunted loss of RGCs, indicating lasting effect of this developmental rescue.

In WT mice, developmental Hepta-ANGPT1 boosted SC development, leading to an enlarged SC with elevated PROX1 expression. Retention or increase in PROX1 expression in treated eyes was important confirmation that the enlarged canal retained its differentiated phenotype and was conducting outflow as PROX1 is an important marker of the differentiated SC phenotype and reduced aqueous humor outflow leads to decreased PROX1 expression.

Several other signaling molecules identified in the single-cell transcriptomics dataset have been implicated in glaucoma and offer exciting opportunities for future studies and drug development directly targeting the conventional outflow pathway.