Pharmacological chaperones for the treatment of Open-Angle Glaucoma

Open-angle glaucoma is the second leading cause of blindness worldwide, affecting nearly 70
million individuals. Nonsynonymous mutations in the myocilin gene lead to the most common
hereditary form of open-angle glaucoma and account for 3-4% of all cases. Disease-causing
mutations, localized to its olfactomedin domain (mOLF), destabilize the myocilin protein, leading
to its misfolding and accumulation in the endoplasmic reticulum of trabecular meshwork cells,
thereby activating a cellular stress response that ultimately results in cell death and disease
progression. Pharmacological chaperones are small molecules that bind to proteins and stabilize
their native conformation, preventing aggregation or aberrant behavior of the protein, and thereby
correcting disease. In this proposal, we outline a strategy to identify a pharmacological chaperone
that binds to myocilin protein, stabilizing it, preventing the death of trabecular meshwork cells,
and halting disease progression. In contrast to current therapies which target secondary
symptoms such as intraocular pressure, our approach represents the first treatment for open-
angle glaucoma that corrects the fundamental cause of disease.
Aim 1 – Execute a fragment-based NMR screen to identify small molecule mOLF binders
and characterize their binding modes using X-ray crystallography.
Aim 2 –Synthesize or purchase elaborated hit fragments to generate a focused library of
mOLF pharmacological chaperones.
Aim 3 – Screen and select the focused library using in vitro assays to define SAR of
elaborated hit fragments.
Our expected outcomes are 2-3 lead molecules that meet our defined potency targets and are
suitable starting points for a robust lead-optimization campaign to identify a clinical candidate for
development. Such a campaign would involve increased medicinal chemistry resources, in vitro
PK and ADME characterization, and pharmacology studies in a mouse model of myocilin-linked
glaucoma; this work would constitute a STTR Phase II program.RELEVANCE TO PUBLIC HEALTH. Open-angle glaucoma is the second leading cause of
blindness worldwide, affecting nearly 70 million people globally, including 3 million in the United
States. This proposal details our plan to develop the first therapeutic that corrects a causative
mechanism of open-angle glaucoma.