Neurodegeneration in glaucoma: Disease progresses despite pharmaceutical and surgical intervention

Glaucoma is a leading cause of blindness, and commonly associated with an elevation in intraocular pressure (IOP).1 One quarter to one third of patients have moderate to rapidly progressive disease despite treatment with IOP lowering medication.2 The current standard of care does not address neuroinflammation or provide neuroprotection — patients still lose sight and suffer blindness.

Normotensive glaucoma is a form of disease not associated with changes in IOP, with the highest prevalence in Asian populations (up to 80%).3 For these patients, there are limited treatment options.
Recent insights by our Scientific Founder Dong Feng Chen show that dysfunctional microglia foster an inflammatory environment that is toxic to retinal ganglion cells, the neurons that connect the retina to the brain.

Retinal Ganglion Cell Death and Optic Nerve Degeneration

Beyond Glaucoma

FireCyte’s novel proteins provide optionality to pursue other neurodegenerative back of the eye indications and have the potential to pivot to broader neuroscience applications outside of ophthalmology.

Transformative therapeutic approach based on a unique protein: IGFBPL1

To halt glaucoma progression, therapeutics must mitigate toxic neuroinflammation and promote retinal ganglion cell survival. These two processes cannot be effectively modulated by a single target.

IGFBPL1: The first multi-targeting, multifunctional therapeutic protein for glaucoma and other ophthalmologic diseases.

We discovered that a natural protein produced in the human CNS interacts with two distinct targets, creating a novel combination of pharmacology uniquely beneficial for neurodegenerative diseases.

Sortilin 1 (SORT1)

  • Identified due to its link with Alzheimer’s disease.
  • Modulates processes integral to inflammation and stress response.
  • Expressed by both microglia and neurons.
  • IGFBPL1 inhibits SORT1.
Netrin 1 Receptor (DCC)
  • A growth-factor like receptor in neurons.
  • Promotes neuronal survival, regulates axon guidance and promotes neurite outgrowth (especially during development).
  • Expressed by neurons.
  • IGFBPL1 modulates DCC.

SOURCE  Images courtesy of the Nation Library of Medicine (NLM): ncbi.nlm.nih.gov/Structure/pdb/3F6K, ncbi.nlm.nih.gov/Structure/pdb/4URT

Loss of IGFBPL1 leads to development of normotensive glaucoma and tauopathies

FireCyte has engineered native IGFBPL1 into a therapeutic protein that can be delivered directly to the back of the eye. This first-in-class therapeutic fosters an anti-inflammatory state in microglia and exhibits a direct neuroprotective effect in neurons.

In animal studies, IGFBPL1 preserves visual function in models of glaucomatous retinal degeneration and accelerates wound healing in models of retinal damage.

Pipeline

Transformative therapeutics for neurodegenerative disease