A New Era in AMD Research
For decades, there was no treatment for dry AMD—the most common form of the disease, affecting millions of Americans. That changed in 2023, when the FDA approved the first-ever medications for geographic atrophy, the advanced stage of dry AMD.[1] These approvals represent the culmination of years of NEI-sponsored research and a launching point for future innovation.
Today, the research landscape for AMD prevention spans six major frontiers: complement inhibition, cholesterol metabolism, small molecule prevention, stem cell therapy, gene therapy, and AI-powered early detection. Each builds on foundational discoveries funded by the National Eye Institute.
NEI Research Milestones
The National Eye Institute has played a central role in the key scientific discoveries that are shaping AMD prevention:
Complement Factor H Discovery
An NEI-funded research team discovered strong associations between complement factor H (CFH) and AMD as part of the first genome-wide association study (GWAS) for the disease. This established that immune system dysfunction contributes to AMD.[1]
Rare C3 Gene Variant Identified
Researchers, including NEI’s Anand Swaroop, Ph.D., discovered a rare C3 gene variant that significantly elevates AMD risk, suggesting that complement suppression could address the condition therapeutically.[1]
First Dry AMD Drugs Approved
The FDA approved Syfovre (pegcetacoplan) and Izervay (avacincaptad pegol)—the first medications for geographic atrophy. Both target the complement cascade and were built on years of NEI-funded research.[1]
ApoM Prevention Pathway
A new NEI-supported study identified apolipoprotein M (ApoM) as a potential way to slow or block AMD progression, linking cholesterol metabolism to macular degeneration.[2]
1. Complement Pathway Inhibitors
Both FDA-approved dry AMD drugs target the complement cascade—the immune system’s protein chain reaction. In AMD, overactive complement proteins damage retinal cells. CFH and CFI act as regulatory “brakes,” while C1–C9 provide activation “gas.” Imbalances in these proteins contribute to disease progression.[1]
Syfovre (Pegcetacoplan)
Inhibits C3, a protein central to all three complement activation pathways. In clinical trials, Syfovre slowed geographic atrophy growth rates by 18–22% over two years.[1]
Izervay (Avacincaptad Pegol)
Blocks C5, operating downstream where the complement pathways converge. Izervay decreased geographic atrophy progression by 14% over one year.[1]
While both drugs slow GA progression, patients receiving either are at increased risk of developing wet AMD. Follow-up research is needed to understand which patients benefit most relative to the risks.[1]
Next-generation complement therapies in development include gene therapy vectors that deliver complement inhibitors (CFI and CD59) for sustained expression after a single injection, potentially eliminating the need for repeated intravitreal injections.[6]
2. Cholesterol Metabolism & ApoM Pathway
A 2025 NEI-supported study identified a new approach to AMD prevention by targeting cholesterol metabolism. The research found that patients with macular degeneration have reduced levels of apolipoprotein M (ApoM) circulating in their blood compared with healthy controls.[2]
ApoM levels decline naturally with age, and the study showed that this decline contributes to dysfunctional cholesterol processing that leads to cellular damage in both the eyes and other organs—potentially explaining the known links between AMD and cardiovascular disease.[2]
“Various methods of dialing up ApoM could serve as new treatment strategies for AMD and perhaps some forms of heart failure triggered by similar dysfunctional cholesterol processing.”
— National Eye Institute, 2025 [2]This finding is significant because ApoM is measurable through a standard blood test, making it a promising candidate for non-invasive risk screening—a key component of the proactive health care approach to AMD prevention.
3. Small Molecule Prevention (GSK3 Pathway)
University of Minnesota researchers, funded by NEI, discovered that small molecules blocking the GSK3 cellular pathway can prevent AMD-like pathology in preclinical models. Using unbiased drug screening, they identified inhibitors that successfully prevented the characteristic features of AMD in living organisms.[3]
“To our knowledge, this is the first demonstration of a small molecule preventing AMD-like pathology in our preclinical model. AMD may indeed be preventable, or at least modifiable by administration of a single drug.”
— John Hulleman, Ph.D., University of Minnesota, Larson Endowed Chair for Macular Degeneration Research [3]Future research will focus on determining whether blocking GSK3 can also reverse existing AMD damage—not just prevent it. This could represent a major shift from slowing progression to actually restoring retinal function.[3]
4. Stem Cell Transplant Therapy
The NEI is conducting a Phase I/IIa clinical trial testing whether a patient’s own stem cells can be used to replace damaged retinal cells—a personalized medicine approach to treating advanced dry AMD.[4]
How It Works
- Blood draw — Adult blood cells are collected from the patient
- Reprogramming — Blood cells are reprogrammed into induced pluripotent stem cells (iPSCs)
- Differentiation — iPSCs are differentiated into retinal pigment epithelium (RPE) cells
- Scaffold creation — RPE cells are grown on a biodegradable PLGA scaffold (~2 x 4 mm oval sheet)
- Transplantation — The iRPE patch is surgically placed under the retina alongside geographic atrophy
- Support — New RPE cells support surviving photoreceptors to prevent further vision loss
Because the cells are derived from the patient’s own blood, this autologous approach may reduce immune rejection risks compared to donor cells. The iRPE patch takes approximately 6 months to manufacture, followed by 5 years of post-surgery monitoring.[4]
This first-in-human trial prioritizes safety assessment. Up to 12 participants aged 55+ with advanced dry AMD will be enrolled. While vision improvement for reading is not expected at this stage, the trial advances understanding of stem cell therapy’s potential for retinal disease.[4]
5. Gene Therapy: Toward “One-and-Done” Treatment
Gene therapy aims to deliver a single injection that transforms retinal cells into continuous producers of therapeutic proteins, potentially eliminating the need for repeated anti-VEGF injections that current wet AMD treatment requires.[5][6]
ADVM-022 (Ixo-vec)
An intravitreal gene therapy using AAV.7m8 vector to transform retinal cells into continuous producers of aflibercept (a VEGF antagonist) after a single injection.[5]
Phase I results: 83% of patients (10 of 12) did not require rescue anti-VEGF treatment for approximately 11 months after a single injection.[5]
RGX-314
A subretinal gene therapy for sustained VEGF-A suppression. Phase 1/2a results published in The Lancet (April 2024).[6]
73% of subjects remained injection-free for 6 months. At 1.5 years, 50% remained free of anti-VEGF drugs. Regulatory submission expected 2025–2026.[6]
4D-150 (Dual-Action)
A single intravitreal gene therapy that delivers two therapeutic payloads simultaneously: aflibercept expression and a VEGF-C inhibitory RNA interference molecule.[5]
Currently in Phase 2 (SPECTRA trial)—multicenter, randomized, double-masked evaluation.[5]
CRISPR Gene Editing
A Cas9-based system delivered via AAV9 to knock out the VEGFA gene achieved a 45% reduction in abnormal vessel area in preclinical models (vs. 39% for aflibercept)—with long-lasting effect from a single injection.[5]
The SIGHT-I clinical trial (NCT06031727) is underway for CRISPR-based wet AMD treatment in humans.[5]
“The implementation of gene therapy methods to achieve sustained delivery of various therapeutic proteins holds the promise of a single treatment that could ameliorate the treatment challenges associated with chronic intravitreal therapy, and potentially improve visual outcomes.”
— National Institutes of Health, PMC [5]6. AI Screening & Blood-Based Early Detection
The sixth frontier in AMD prevention combines artificial intelligence with blood-based biomarkers to detect risk before any structural damage or symptoms occur.
AI-Powered Retinal Screening
NEI-funded AI systems like iPredict enable non-eye-care specialists to screen patients for AMD and predict which individuals with early AMD are at risk for accelerated vision loss. Deep learning networks analyze retinal images combined with patient data (age, smoking status, genetic profile) to detect patterns invisible to the human eye.[7]
Blood-Based Biomarker Panels
NIH research has identified multiple blood biomarkers associated with AMD—including ApoM, CRP, HDL cholesterol, homocysteine, and inflammatory interleukins.[2][8] Multi-marker panels measuring these from a simple blood draw could enable population-level screening for AMD risk, analogous to cholesterol panels for heart disease.
Currently, no blood-based AMD screening test is available to the public. Developing such a test is a significant unmet medical need that could shift AMD care from reactive treatment to proactive prevention.
Key Takeaways
- The first dry AMD drugs (Syfovre, Izervay) were approved in 2023, built on NEI’s 2005 complement pathway discovery[1]
- ApoM blood levels may predict AMD risk and offer a new prevention target[2]
- GSK3 inhibitors represent the first small molecule shown to prevent AMD in preclinical models[3]
- NEI is testing personalized stem cell transplants (iPSC-derived RPE) for advanced dry AMD[4]
- Gene therapy could replace monthly injections with a single “one-and-done” treatment[5][6]
- CRISPR gene editing achieved 45% vessel reduction from a single injection in preclinical models[5]
- AI screening can identify patients at highest risk of rapid vision loss[7]
- Blood-based biomarker panels could enable population-level AMD risk screening[8]
Explore More
Learn about how proactive health care and early risk assessment can help protect your vision today.
References
- Story of Discovery: NEI-Funded Research Paves Way for New Dry AMD Drugs. NEI News & Events. nei.nih.gov
- Strategy to Prevent Age-Related Macular Degeneration Identified. NEI Research News, 2025. nei.nih.gov
- U. Minnesota Researchers Discover Potential New Pathway to Prevent Age-Related Macular Degeneration. NEI News & Events. nei.nih.gov
- Clinical Trial Highlight: Stem Cell Transplants for Dry AMD. NEI Eye Health Information. nei.nih.gov
- A New Generation of Gene Therapies as the Future of Wet AMD Treatment. Int J Mol Sci. 2024; 25(4):2386. PMC10888617. pmc.ncbi.nlm.nih.gov
- Recent Developments in Gene Therapy for Neovascular Age-Related Macular Degeneration: A Review. Clin Ophthalmol. 2023; 17:3567–3584. PMC10740940. pmc.ncbi.nlm.nih.gov
- AI-Based Systems Can Help Identify Rapidly Advancing Age-Related Macular Degeneration. NEI News & Events. nei.nih.gov
- Biomarkers for the Progression of Intermediate Age-Related Macular Degeneration. Surv Ophthalmol. 2024; 69(1):1–16. PMC10640447. pmc.ncbi.nlm.nih.gov
- Risk Factors for Progression of Age-Related Macular Degeneration. Ophthalmic Epidemiol. 2020; 27(3):191–197. PMC7155063. pmc.ncbi.nlm.nih.gov
- Genetic Markers and Biomarkers for Age-Related Macular Degeneration. Expert Rev Mol Diagn. 2007; 7(5):585–604. PMC2000850. pmc.ncbi.nlm.nih.gov
- Age-Related Eye Disease Studies (AREDS/AREDS2). NEI Clinical Trials. nei.nih.gov