Peptide Therapies for Macular Degeneration
Ocular Peptides
Eye drops replacing injections
Peptide-bound aflibercept eye drops achieved therapeutic retinal concentrations and reduced choroidal neovascularization in nonhuman primates, potentially eliminating the need for intravitreal injections.
Fan et al., Advanced Science, 2025
Fan et al., Advanced Science, 2025
View as imageAge-related macular degeneration (AMD) is the leading cause of irreversible central vision loss in adults over 50, affecting over 200 million people worldwide. Current treatment for the wet (neovascular) form relies on monthly or bimonthly intravitreal injections of anti-VEGF antibodies (ranibizumab, aflibercept, bevacizumab), which are effective but burdensome. For the dry (atrophic) form, which represents 85-90% of AMD cases, no approved pharmacological treatment existed until recently. Peptide-based approaches are being developed across both forms, with strategies ranging from anti-VEGF peptide eye drops to neuroprotective peptides, integrin inhibitors, and the unexpected finding that GLP-1 agonists may reduce AMD risk. For background on the first anti-VEGF peptide approved for ocular use, see our pillar article on pegaptanib.
Key Takeaways
- Peptide-bound aflibercept eye drops reached therapeutic concentrations in the choroid and retina within 30 minutes and reduced neovascularization in nonhuman primates (Fan et al., 2025)
- Cell-penetrating peptide-modified anti-VEGF drugs applied topically alleviated choroidal neovascularization in mouse models, avoiding intravitreal injection (Hu et al., 2024)
- Risuteganib, an integrin-inhibiting peptide, improved visual function in dry AMD patients in a phase II trial, a disease with no other approved treatments (Shaw et al., 2020)
- H105A peptide eye drops promoted photoreceptor survival in both mouse and human retinal organoid models of retinal degeneration (Bernardo-Colon et al., 2025)
- GLP-1 receptor agonist use was associated with reduced risk of neovascular AMD in a large retrospective cohort study (Allan et al., 2025)
- A nanoparticle-hydrogel system achieved sustained release of anti-VEGF peptides for up to 30 days, potentially reducing injection frequency (Durak et al., 2026)
The Problem: Intravitreal Injections Every Month
The central limitation of current AMD treatment is delivery. Anti-VEGF antibodies like ranibizumab (Lucentis) and aflibercept (Eylea) must be injected directly into the vitreous cavity of the eye because they are too large to penetrate the ocular barriers when applied topically. These injections are performed every 4-8 weeks for years or decades.
The injection burden is substantial: each injection carries risks of endophthalmitis (eye infection), retinal detachment, and intraocular pressure elevation. More practically, elderly patients with AMD often have difficulty attending monthly ophthalmology appointments, and non-adherence to injection schedules is a major cause of vision loss even in patients who initially respond well to treatment.
Peptides offer a potential solution because their smaller size (typically 1-5 kDa versus 48-115 kDa for antibodies) allows them to penetrate ocular barriers that antibodies cannot cross. This opens the possibility of topical (eye drop) delivery, which would transform AMD treatment from an invasive procedure to a self-administered medication.
Peptide-Bound Eye Drops: The Most Exciting Development
Fan et al. (2025) published what may be the most important advance in AMD drug delivery in years: peptide-bound aflibercept eye drops that work in nonhuman primates.[1]
The approach uses a cell-penetrating peptide called bxyPenetratin that binds to aflibercept through hydrophobic interactions, forming a stable non-covalent complex. When applied as eye drops, this complex penetrates through the cornea, conjunctiva, and sclera to reach the choroid and retina. Key findings:
- Therapeutic concentrations were achieved in the choroid and retina within 30 minutes of topical application
- The peptide-drug complex was stable in tear fluids
- Treatment reduced choroidal neovascularization in a laser-induced CNV model in nonhuman primates
- No ocular toxicity was observed
This represents a paradigm shift: delivering a large anti-VEGF protein to the retina via eye drops, enabled entirely by the peptide carrier. If this translates to human clinical trials, it could eliminate the need for intravitreal injections for millions of AMD patients.
Hu et al. (2024) took a similar approach using a different cell-penetrating peptide modification.[2] They modified anti-VEGF drugs with cell-penetrating peptides and demonstrated that topical application alleviated choroidal neovascularization in mouse models. The study confirmed that peptide modification can enable large biologics to cross ocular barriers topically, and the effect was comparable to intravitreal injection in preclinical models.
For more on the anti-VEGF peptide approach to wet AMD, see our article on anti-VEGF peptide treatments.
Risuteganib: A Peptide for Dry AMD
While wet AMD has effective (if burdensome) treatments, dry AMD has been a therapeutic desert. Risuteganib (Luminate) is an integrin-inhibiting peptide that targets a different mechanism entirely.
Shaw et al. (2020) reviewed risuteganib's mechanism and clinical data for dry AMD.[3] Rather than blocking blood vessel growth (like anti-VEGF agents), risuteganib modulates integrin signaling to protect retinal cells from oxidative stress, mitochondrial dysfunction, and inflammation, the upstream processes that drive the slow degeneration of photoreceptors and retinal pigment epithelium in dry AMD.
In a phase II clinical trial, intravitreal risuteganib improved best-corrected visual acuity (BCVA) in patients with intermediate dry AMD. The peptide was administered as a single intravitreal injection, with visual improvements observed at 28 weeks. The response rate (proportion of patients gaining 8 or more letters on a standard eye chart) exceeded that of the sham control group.
Risuteganib represents a different therapeutic paradigm from anti-VEGF approaches. Instead of blocking a single growth factor, it modulates cellular stress responses at the integrin level, potentially protecting multiple cell types simultaneously. This broader mechanism may explain its activity in dry AMD, where cell death is driven by accumulated oxidative damage rather than new blood vessel growth.
Neuroprotective Peptide Eye Drops
Bernardo-Colon et al. (2025) tested H105A, a small peptide derived from pigment epithelium-derived factor (PEDF), as eye drops for retinal degeneration.[4]
PEDF is a naturally occurring neuroprotective protein produced by retinal pigment epithelial cells. It promotes photoreceptor survival and inhibits pathological angiogenesis. The full PEDF protein is too large for topical delivery, but H105A captures its neuroprotective activity in a small peptide fragment that can penetrate ocular barriers.
In both mouse models of retinitis pigmentosa and human retinal organoids (miniature lab-grown retinas), H105A eye drops promoted photoreceptor survival. The study demonstrated efficacy in both murine and human tissue models, increasing confidence that the results will translate across species. While the primary target was retinitis pigmentosa rather than AMD, the neuroprotective mechanism is directly relevant to dry AMD, where photoreceptor death is the ultimate cause of vision loss.
GLP-1 Agonists: An Unexpected Retinal Connection
Three studies published in 2025 revealed that patients taking GLP-1 receptor agonists for diabetes or obesity had reduced rates of AMD progression and neovascularization.
Allan et al. (2025) conducted a retrospective cohort study using the TriNetX electronic health records network, finding that GLP-1 receptor agonist use was associated with reduced risk of neovascular AMD.[5]
Machida et al. (2025) provided the mechanistic basis: GLP-1 receptor stimulation directly inhibited laser-induced choroidal neovascularization in mice.[6] The GLP-1 receptor is expressed on retinal cells, and its activation suppressed the inflammatory and angiogenic signaling that drives wet AMD. This suggests the retinal protection is a direct effect of GLP-1R activation, not just an indirect consequence of improved metabolic health.
Myers et al. (2025) compared AMD rates in nondiabetic patients prescribed GLP-1 agonists for weight loss versus other weight loss medications, finding lower AMD rates in the GLP-1 group.[7] By studying nondiabetic patients, this study partially controlled for the confounding effect of diabetes on AMD risk, strengthening the case that GLP-1 agonists have direct retinal protective effects.
These findings raise the possibility that GLP-1 agonists prescribed for metabolic conditions may be providing unrecognized retinal protection as a secondary benefit. Whether GLP-1 agonists could be specifically developed or repurposed for AMD prevention remains to be tested in prospective trials.
Sustained-Release Peptide Delivery Systems
Even if peptide drugs prove effective against AMD, the challenge of maintaining therapeutic concentrations in the eye over weeks or months remains. Durak et al. (2026) developed a nanoparticle-hydrogel drug delivery system for sustained release of anti-VEGF peptides.[8]
Their system encapsulated anti-VEGF peptides in nanoparticles embedded within an injectable hydrogel. The combination achieved sustained peptide release for up to 30 days, compared to the hours-to-days half-life of free peptides in the vitreous. This could reduce the frequency of intravitreal injections from monthly to quarterly or less, even for drugs that still require injection rather than topical application.
The development of sustained-release formulations is critical because even the most effective anti-AMD peptide will fail clinically if patients cannot maintain adequate drug levels between treatments. The combination of peptide therapeutics with advanced delivery systems represents a convergent engineering challenge that spans drug design, biomaterials science, and ophthalmology.
The Complement System: Another Peptide Target
AMD pathogenesis involves chronic activation of the complement system, the immune cascade that tags cells for destruction. Genetic variants in complement factor H (CFH), complement factor I (CFI), and complement component 3 (C3) are among the strongest genetic risk factors for AMD. This has led to the development of complement-inhibiting peptides and peptidomimetics.
Pegcetacoplan (Syfovre), a complement C3 inhibitor derived from the cyclic peptide compstatin, became the first FDA-approved treatment for geographic atrophy (advanced dry AMD) in 2023. While pegcetacoplan is technically a PEGylated peptide-based molecule, its approval validated the concept that peptide-derived complement inhibitors can address dry AMD. The drug slows the growth of geographic atrophy lesions by approximately 20-25% over 12 months, administered via monthly or every-other-month intravitreal injection.
The complement pathway represents a particularly attractive target for peptide-based approaches because the protein-protein interactions involved can be disrupted by relatively small cyclic peptides. Compstatin and its derivatives demonstrated that a 13-amino-acid cyclic peptide can effectively block a critical complement interaction, providing a template for future peptide drug development in AMD and other complement-mediated diseases. Next-generation complement peptide inhibitors are being designed with improved potency and pharmacokinetics for sustained retinal delivery.
What Is Available Now and What Is Coming
Currently available: No peptide-specific AMD therapy is in widespread clinical use. Pegaptanib (Macugen), the first anti-VEGF agent approved for wet AMD, is an RNA aptamer rather than a traditional peptide. It has been largely superseded by antibody-based anti-VEGF agents that show greater efficacy.
In clinical trials: Risuteganib completed phase II for dry AMD. Peptide-bound aflibercept eye drops are in preclinical development with nonhuman primate data. H105A peptide eye drops have preclinical validation in human organoids.
Emerging evidence: GLP-1 agonists show epidemiological associations with reduced AMD risk and mechanistic evidence of direct retinal protection. Sustained-release peptide delivery systems are in preclinical development.
The trajectory is clear: peptides are being developed not to replace the anti-VEGF mechanism that works, but to deliver it better (eye drops instead of injections, sustained release instead of monthly dosing) and to address the dry AMD population that current treatments cannot help. The convergence of cell-penetrating peptide technology, neuroprotective peptide fragments, complement-inhibiting cyclic peptides, and the retinal protective effects of GLP-1 agonists means that multiple peptide-based approaches could reach clinical practice within the next decade, each targeting a different aspect of this complex disease.
The Bottom Line
Peptide approaches to AMD span anti-VEGF eye drops enabled by cell-penetrating peptides, integrin-inhibiting peptides for dry AMD, neuroprotective peptide eye drops, GLP-1 agonist retinal protection, and sustained-release delivery systems. The most transformative near-term development is peptide-bound aflibercept eye drops that achieved therapeutic retinal concentrations in nonhuman primates, potentially replacing intravitreal injections. Risuteganib addresses the unmet need in dry AMD. GLP-1 agonists may provide retinal protection as an unrecognized secondary benefit.