Posted inInteresting Papers

Shining a Light on Dry AMD: Photobiomodulation Therapy Offers Hope for Non-exudative Macular Degeneration

Summary:

Photobiomodulation (PBM) for Dry AMD

Innovative Light Therapy for Non-Exudative AMD

💡 Breakthrough Mechanism

Photobiomodulation uses specific wavelengths of red and near-infrared light (500–1000 nm) to stimulate Cytochrome C Oxidase in the mitochondria. This boosts ATP production, reduces oxidative stress, and stabilizes retinal metabolism.

Key Findings from LIGHTSITE III

Recent clinical trials, specifically LIGHTSITE III, have demonstrated the following benefits for patients with early to intermediate dry AMD:

Clinical Parameter Treatment Outcome
Visual Acuity Improvement +5.5 to +6.2 letters on eye chart
Disease Progression Lower risk of Geographic Atrophy
Anatomic Stability Significant reduction in drusen volume

Treatment Protocol & Expectations

  • Non-Invasive Procedure: Painless treatment requiring no needles, no dilation, and no surgical intervention.
  • Scheduling: Typically involves 9 brief sessions (approx. 5 minutes per eye) over 3–5 weeks, repeated every 4–6 months to maintain cellular health.
  • Patient Eligibility: Best suited for non-exudative AMD patients with BCVA between 20/32 and 20/70.
Source: farabiretina.com | FDA-Authorized Valeda® Light Delivery System

  • Overview of Age-related Macular Degeneration (AMD):

    • AMD: Leading cause of irreversible vision loss in elderly; affects 196 million globally, projected to reach 288 million by 2040.

    • Non-exudative (dry) AMD: Majority of cases; characterized by drusen accumulation and macular thinning.

    • Exudative (wet) AMD: Involves neovascularization, leakage, and scarring.

    • Beckman Classification (2013):

      • No aging changes: No drusen or pigmentary abnormalities.

      • Normal aging: Small drusen (≤63 μm), no pigmentary changes.

      • Early AMD: Drusen >63 μm and ≤125 μm.

      • Intermediate AMD: Drusen >125 μm.

      • Late AMD: Geographic atrophy (GA) or exudative AMD.

    • Pathogenesis: Multifactorial—genetic variants (e.g., CFH, ARMS2), aging, chronic inflammation, oxidative stress, and mitochondrial dysfunction.

  • Current Treatments for Non-exudative AMD:

    • Intermediate AMD: Limited to lifestyle modifications (e.g., smoking cessation, diet) and AREDS vitamin supplementation.

    • Geographic Atrophy: Recent FDA approvals for pegcetacoplan and avacincaptad pegol to slow progression.

    • No therapies reverse damage or improve vision in early/intermediate stages.

  • Photobiomodulation Therapy (PBT):

    • Definition: Noninvasive therapy using red/near-infrared light (600–1000 nm) via LED or laser to stimulate cellular processes.

    • Mechanism:

      • Targets mitochondria, enhancing cytochrome c oxidase activity, increasing ATP production, and reducing oxidative stress.

      • Increases nitric oxide bioavailability, promoting vasodilation and cellular function.

      • Modulates gene expression to enhance cell migration, proliferation, and antioxidant production; reduces apoptosis.

      • Protects Muller cells (retinal glial cells), preventing gliosis and inflammation, supporting photoreceptor survival.

    • Goal in AMD: Slow progression, preserve visual acuity, and improve retinal health by addressing mitochondrial dysfunction, inflammation, and oxidative stress.

  • Pathophysiology of Non-exudative AMD:

    • Affects macula lutea (highest cone density, central vision).

    • Retinal pigment epithelium (RPE) dysfunction: Key role in light absorption, phagocytosis, nutrient transport, and cytokine secretion.

    • Drusen: Extracellular deposits (lipids, vitronectin, apolipoproteins, inflammatory/amyloid proteins) beneath RPE; cause RPE detachment and photoreceptor loss.

    • Genetic factors: Variants in complement factor H (CFH) and ARMS2 linked to complement dysregulation and proinflammatory environment.

    • Aging: Increases reactive oxygen species (ROS), overwhelming autophagy, leading to retinal degeneration.

    • Mitochondrial dysfunction: Reduced mitochondrial proteins (e.g., heat shock proteins, electron transport chain); RPE relies on glycolysis, starving photoreceptors.

  • Animal Studies on PBT:

    • Rat models: 670 nm LED PBT slowed light-induced AMD progression; improved photoreceptor function (electroretinogram).

    • Reduced inflammation, complement factors (e.g., C3), and outer nuclear layer thinning.

    • CFH knockout mice: 670 nm PBT (6 min, twice daily, 14 days) decreased inflammatory markers and enhanced mitochondrial function.

    • Multiwavelength PBT (680, 780, 830 nm): Prevented RPE damage, retinal apoptosis, and rod bipolar cell depletion in sodium iodate-induced AMD rats.

  • Human Studies and Clinical Trials:

    • Ivandic et al. (2008): 348 eyes, 780 nm PBT (transconjunctival); improved visual acuity (sustained up to 36 months), reduced metamorphopsia, scotoma, and dyschromatopsia.

    • TORPA Study:

      • Used Warp10 and Gentlewaves devices; 18 treatments over 6 weeks.

      • Significant improvements in visual acuity (P<0.0001) and contrast sensitivity (P<0.0032) at 6 weeks and 1 year.

    • TORPA II Study:

      • 590/790 nm wavelengths, 3-week treatment.

      • Visual acuity improved by 5.14 letters (P<0.001); contrast sensitivity improved by 0.11–0.16 log units (P=0.02).

      • Drusen volume decreased by 0.024 mm³ (P<0.001); central drusen thickness reduced by 3.78 μm (P<0.001).

    • LIGHTSITE I Study (Valeda Light Delivery System, 590/660/850 nm, 3x/week, 3–4 weeks):

      • Improved contrast sensitivity (+0.35 log units, month 12), drusen volume (P=0.05), drusen thickness (P=0.03), and quality of life (P=0.003–0.015).

      • BCVA gains in high responders (≥5 letters) at early AMD stages; less benefit in advanced disease.

    • LIGHTSITE II Study (53 eyes, intermediate AMD, 9 sessions over 3–5 weeks at months 0, 4, 8, 9):

      • BCVA gain of 3.94 letters (P=0.02) in PBT group vs. 0.5 letters (P=0.10) in sham at 9 months; 35.3% achieved >5-letter gain.

      • Drusen volume stable in PBT group (+0.0003 mm³) vs. increase in sham (+0.032 mm³, P>0.05).

      • GA growth reduced in PBT group (0.73 mm² vs. 1.29 mm² in sham, P=0.46, confounded by baseline lesion size).

    • LIGHTSITE III Study (148 eyes, 9 sessions every 4 months, 24 months):

      • BCVA gain: 5.4 letters (P<0.0001) in PBT vs. 3.0 letters (P=0.0094) in sham at 13 months; significant between-group difference (P=0.0204).

      • Over 58% achieved >5-letter gain.

      • New-onset GA: 1.1% (PBT) vs. 10% (sham) at 13 months (P=0.024).

      • Drusen volume: Non-significant difference (0.947 mm³ PBT vs. 1.02 mm³ sham, P=0.36).

    • ELECTROLIGHT Study (23 eyes, Valeda, 3x/week, 3 weeks):

      • BCVA improved by 12.6 letters at 1 month, 12.8 letters at 6 months.

      • Contrast sensitivity improved at multiple distances (P<0.05).

      • Electroretinography: 14.4% increase in multifocal ERG magnitude (P=0.001).

    • DRUSEN Study (152 eyes, EYE-LIGHT, 590/630 nm, 2x/week, 4 weeks):

      • High tolerability, minimal adverse effects.

      • BCVA stable in PBT group (+0.48 letters, P=0.184); significant vs. sham (P=0.026).

      • Drusen volume reduction significant vs. sham (P=0.013).

  • Ongoing Trials:

    • LIGHTSITE IIIB (NCT06229665): Phase 2/3, 75 subjects, Valeda system, 9 treatments over 3–5 weeks, re-treated at 4, 8, 12 months; primary outcome: BCVA.

    • EUROLIGHT (NCT06351605): Multicenter, 500 subjects, Valeda system, 9 treatments over 3–4 weeks, up to 5 rounds every 4–6 months; primary outcome: BCVA; secondary: retinal thickness, drusen volume, GA.

  • Limitations and Future Directions:

    • Challenges: Small sample sizes, variable treatment protocols (wavelengths, frequency), and limited long-term follow-up.

    • Unanswered questions: Optimal treatment algorithms, durability, and ideal patient populations (e.g., early vs. intermediate AMD).

    • Future trials aim to address larger cohorts, global populations, and long-term outcomes.

Citation

Rodriguez DA, Song A, Bhatnagar A, Weng CY. Photobiomodulation Therapy for Non-exudative Age-related Macular Degeneration. Int Ophthalmol Clin. 2025;65(1):47-52. doi:10.1097/IIO.0000000000000543

Efficacy and safety evaluation of multiwavelength photobiomodulation in nonexudative age-related macular degeneration using the Lumithera Valeda Light Delivery System: 13-month results from the LIGHTSITE III trial

References

  1. Boyer D, Hu A, Warrow D, Xavier S, Gonzalez V, Lad E. LIGHTSITE III: 13-month efficacy and safety evaluation of multiwavelength photobiomodulation in nonexudative (dry) age-related macular degeneration using the Lumithera Valeda Light Delivery System. Retina. 2024;44:487–97. https://doi.org/10.1097/IAE.0000000000003980.