ANTIBODY-MEDIATED TREATMENT OF GLAUCOMA

 

Early-onset familial glaucoma is attributed to nonsynonymous mutations in the gene encoding myocilin. The protein myocilin is secreted at relatively high levels in the trabecular meshwork (TM) extracellular matrix. Mutant myocilin aggregates intracellularly in the endoplasmic reticulum (ER). Subsequent ER stress causes cytotoxicity that hastens dysregulation of intraocular pressure, the primary risk factor for most forms of glaucoma.

Recombinant antibodies represent an emerging class of versatile and powerful therapeutics to treat protein conformational and misfolding associated with neurodegenerative diseases. Glaucoma management has entered a new phase with the development of antibodies targeting the aggregation-prone β-propeller olfactomedin (OLF) domain of myocilin, variants of which comprise the strongest genetic link to glaucoma.

These new antibodies target the domain of myocilin that misfolds in the ER and causes pathogenic cytotoxicity. These antibodies degrade aggregating mutant myocilin in situ by rerouting mutant myocilin for lysosomal degradation.

Clearance of OLF-resident myocilin mutants is hindered by aberrant interactions with molecular chaperones such as glucose-regulated protein 94 (Grp94), leading to the accumulation of misfolded proteins, ER stress, and subsequent TM cell death.

Multi-centric research by Ma and colleagues has discovered two recombinant antibodies: anti-OLF1 recognizes a linear epitope, while anti-OLF2 is selective for natively folded OLF and inhibits aggregation in vitro. By binding OLF, these antibodies engage autophagy/lysosomal degradation to promote degradation of two pathogenic mutant myocilins.

The interaction between Grp94 and mutant myocilin can be abrogated with selective small molecules targeting Grp94 or by downregulation of Grp94 with siRNA.

Treatment with Grp94-targeted small molecules or siRNA leads to the clearance of mutant myocilin by autophagy, similar to what is observed with anti-OLF1 and anti-OLF2.

This research shows the promise of antibodies in the treatment of familial open-angle glaucoma associated with myocilin.

REFERENCE:

Ma MT, Qerqez AN, Hill KR, Azouz LR, Youngblood HA, Hill SE, Ku Y, Peters DM, Maynard JA, Lieberman RL. Antibody-mediated clearance of an ER-resident aggregate that causes glaucoma. PNAS Nexus. 2024 Dec 10;4(1):pgae556. doi: 10.1093/pnasnexus/pgae556. PMID: 39726989; PMCID: PMC11670252.