Findings from a recent study published in Cell Reports Medicine evaluated the treatment outcomes in mouse and non-human primate (NHP) models of a therapy that may prevent the degenerative processes of wet age-related macular degeneration (AMD).
Give me some background first.
The current standard of care for wet AMD requires regularly scheduled chronic intravitreal anti-vascular endothelial growth factor (VEGF) injections.
Due to the invasive nature of this treatment, a research team from the University of Illinois, Chicago sought to develop an alternative topical therapy.
I’m listening …
Choroidal and retinal angiogenesis are mediated by environmental stresses such as VEGF-A, which is partially activated through intracellular calcium signaling in endothelial cells (ECs).
To note, a previous study by the same research group determined that inhibiting the protein end binding-3 (EB3) could potentially disrupt vascular inflammation by preventing pathological calcium signaling in ECs.
Now, talk about the study.
The novel treatment evaluated in this study, created via computational drug design methods, induced allosteric inhibition of the EB3 protein—called EBIN.
And what does EBIN do?
EBIN suppresses vascular leakage and choroidal neovascularization (CNV) by reducing the effects of environmental stresses on ECs via limiting pathological calcium signaling.
Findings?
Within 2 to 3 weeks, a twice-daily dose of EBIN reduced retinal tissue damage in mouse and NHP models of wet AMD.
Further, it reversed the epigenetic changes caused by environmental stresses, allowing for the activation of a regenerative process within ECs that make up CNV lesions.
So how does this therapy differ from anti-VEGF?
Anti-VEGF treatments like aflibercept and ranibizumab inhibit aberrant neovascular growth and hyperpermeability by removing VEGF in the eye.
Conversely, EBIN protects neovascular cells from the effects of environmental stresses and can promote wound healing in ocular tissues via epigenetic regulation of MEIS2 and PAX6 genes.
Anything else?
Environmental factors might alter genetic markers in patients with wet AMD, and interestingly, EBIN has demonstrated a unique ability to reverse these pathological epigenetic changes.
For example, EBIN preserved mitochondrial function in cells that experience both acute and chronic hypoxic stresses caused by wet AMD.
Take home.
The outcomes of EBIN in mouse and NHP models of wet AMD suggest the potential therapeutic value of this treatment in potentially reversing the degenerative processes linked with both neovascular and atrophic forms of AMD.
Next steps?
As blood vessel leakage and hypoxic stress impact many other medical conditions, the research group is also interested in testing models with EBIN in other disease states
- Acute lung injury
- Diabetic retinopathy
- Stroke
- Heart disease
- General effects of aging on the brain
Additional investigation is also being considered for whether an implantable sustained-release device could deliver EBIN more effectively than eye drop in AMD.