NLY01 in OCULAR HYPERTENSION

 

Astrocytes are a type of glial cell which form the majority of cells in the human central nervous system (CNS). In the retina they occur exclusively in the ganglion cell layer, mixed with retinal ganglion cells (RGCs).

In response to local or systemic stimuli, the astrocytes (A1 and A2) adopt reactive forms.

The A1 astrocytes develop pro-inflammatory and neurotoxic functions. They lose their phagocytic capacity, and their ability for synapse formation and function.

A2 astrocytes upregulate neurotrophic factors, promoting a neuroprotective environment.

ASTROCYTES IN GLAUCOMA

Sterling and associates have shown that ocular hypertension can trigger microglia to produce and release pro-inflammatory cytokines C1q, interleukin-1α (IL-1α), and tumor necrosis factor-α (TNF-α). These three cytokines are necessary and sufficient to drive the formation of A1 astrocytes.

Studies have demonstrated a strong association between the above mentioned three cytokines and glaucoma. IL-1α and TNF polymorphisms are associated with primary open angle glaucoma. TNF-α protein levels are elevated in the vitreous, retina, and optic nerves of glaucomatous eyes. In the DBA/2J mouse model of hypertensive glaucoma, C1qa mRNA levels are associated with disease progression, and C1q inhibition is sufficient to prevent early RGC synapse loss and RGC death.

Glucagon-like peptide-1 is an incretin hormone that regulates blood glucose, weight, and satiety through its action at the glucagon-like peptide-1 receptor (GLP-1R) in both the systemic circulation and the central nervous system. NLY01 is a long-acting GLP-1R agonist with an extended half-life and favorable blood brain barrier penetration.

Sterling has shown NLY01 therapy reduces the production of C1q, TNF-a, and IL-1a by the CD11b+ CD11c and CD11b+ CD11c+ dendritic cells in a mouse model of glaucoma. It also reduces A1 astrocyte transformation and RGC loss.

Therefore, NLY01 has potential clinical use in the treatment of glaucoma and possibly other retinal diseases characterized by reactive astrogliosis.