Photobiomodulation (PBM) is a non-invasive light therapy that irradiates tissue with red to near-infrared light of 590–850 nm. It does not aim for thermal or photochemical tissue destruction but rather for cytoprotection and functional recovery through activation of mitochondrial metabolism. It is also called low-level light therapy (LLLT). 6)
In ophthalmology, atrophic age-related macular degeneration (non-exudative AMD) is the most studied indication. In November 2024, the U.S. Food and Drug Administration (FDA) approved LumiThera’s Valedea system as a treatment device for atrophic age-related macular degeneration. 5) It became the first non-invasive treatment device to receive FDA approval for atrophic age-related macular degeneration.
In addition to atrophic age-related macular degeneration, applications for diabetic retinopathy (DR), retinitis pigmentosa (RP), and axial myopia are also being investigated. 10)
The three representative wavelengths are 590 nm (yellow), 660 nm (red), and 850 nm (near-infrared). The Valedea system combines these using LEDs to deliver non-coherent, non-thermal light energy to the retina. 6)
In atrophic age-related macular degeneration and related conditions targeted by PBM, the following symptoms occur.
The main objective indicators used to evaluate the therapeutic effect of PBM are as follows.
In the LIGHTSITE II trial (Burton B et al., 2023), the PBM group showed a +4-letter improvement in best-corrected visual acuity (BCVA) (p=0.02). 2) Drusen volume stabilized, and GA progression was suppressed by approximately 20%. 2)
In the LIGHTSITE III trial (Boyer D et al., 2024), the PBM group showed significant suppression of new GA onset (p=0.024) and an improvement of +2.4 letters in best-corrected visual acuity (p=0.02). 4)
Atrophic Age-Related Macular Degeneration
Best-corrected visual acuity: Improved by +4 letters in LIGHTSITE II (p=0.02). 2)
New GA onset: Significantly suppressed in LIGHTSITE III (p=0.024). 4)
Drusen volume: Showed a trend toward stabilization in the PBM treatment group. 2)
Retinitis Pigmentosa
Mitochondrial redox: 810 nm irradiation protected mitochondrial function in an RP animal model. 11)
Photoreceptor protection: Suppression of degeneration and improvement in electroretinogram responses have been confirmed. 11)
Axial myopia
Axial length: In an RCT of 188 children, axial elongation in the PBM group was suppressed by −0.06 mm compared to the control group.
Diabetic retinopathy
Oxidative stress reduction: Protective effects via reduction of oxidative damage caused by hyperglycemia are being investigated.
Anti-inflammatory: Effects on the NF-κB pathway are under research.
The 36-month extension study of LIGHTSITE III (GALE study) continues to evaluate the sustained effect of maintenance irradiation (every 3–6 months). 4) However, long-term data are still being accumulated, and the frequency and duration of maintenance irradiation will be established in future research.
The pathogenesis of the major retinal diseases targeted by PBM is as follows.
Multiple tests are combined to determine the indication for PBM and to evaluate treatment efficacy. The main evaluation indicators and their roles are shown below.
| Test | Purpose | Evaluation Indicator |
|---|---|---|
| Best-corrected visual acuity | Visual function assessment | ETDRS letter score |
| OCT | Retinal structure evaluation | GA area, drusen volume |
| Electroretinogram | Retinal electrical function | Amplitude, latency |
The FDA-approved Valedea system delivers irradiation using a combination of three wavelengths: 590 nm, 660 nm, and 850 nm. 5) No dilation or anesthesia is required, and the procedure can be performed on an outpatient basis.
The standard irradiation schedule is shown below.
| Item | Standard Protocol |
|---|---|
| Frequency | 2–3 times per week |
| Induction period | 3–5 weeks/cycle |
| Maintenance irradiation | Every 3–6 months |
LIGHTSITE I to III are a series of multicenter RCTs of PBM for atrophic age-related macular degeneration.
LIGHTSITE I (Markowitz SN et al., 2020) was a single-center pilot RCT that confirmed safety. 1)
LIGHTSITE II (Burton B et al., 2023) was a multicenter randomized double-masked controlled trial. The PBM group showed a +4-letter improvement in best-corrected visual acuity (p=0.02) and a 20% reduction in GA progression. 2) Among completers, 35.3% showed an improvement of 5 or more letters. 2)
LIGHTSITE III (Boyer D et al., 2024) was conducted in 100 patients (148 eyes) with a 4-month cycle, showing suppression of new GA onset (p=0.024) and a +2.4-letter improvement in best-corrected visual acuity (p=0.02) at 13 months. 4) These results provided the basis for FDA approval.
The AAO AMD PPP (2024 edition) evaluates LIGHTSITE I/II as having unproven benefit, and while recognizing GA suppression in LIGHTSITE III, it classifies the evidence as level I- (limited evidence). 12) The EMA has not approved the PBM device. 12)
The FDA-approved indication is for intermediate to advanced atrophic age-related macular degeneration (non-exudative type). 5) Efficacy has not been established for exudative age-related macular degeneration with active choroidal neovascularization or for advanced GA. Application requires individual assessment by a specialist.
The primary target of PBM is cytochrome c oxidase (CcO), an oxidative phosphorylation enzyme in the inner mitochondrial membrane. 6)When red to near-infrared light is absorbed by CcO, the electron transport chain is activated, increasing ATP production and enhancing cellular metabolic activity. 6)
In aging and hypoxic conditions, nitric oxide (NO) binds to the active site of CcO, suppressing ATP production. PBM photodissociates the NO-CcO bond, relieving this inhibition and restoring ATP synthesis. 7, 8)
Poyton RO et al. (2011) argued that NO dissociation by red to near-infrared light is a key mechanism protecting mitochondrial function. 7)
Kashiwagi S et al. (2023) showed that modulation of the NO pathway by PBM contributes to tissue protection. 8)
Low-dose PBM transiently increases ROS and activates cellular redox-sensitive signaling pathways (NF-κB, AP-1). 9)This induces antioxidant enzyme expression and anti-inflammatory effects. High doses conversely cause oxidative damage, so optimizing irradiation dose is important. 9)
Karu TI (2008) showed that ROS production acts as a secondary messenger in PBM, inducing cytoprotection at the gene transcription level. 9)
Gopalakrishnan S et al. (2020) reported that 810 nm irradiation in a hereditary RP animal model suppressed photoreceptor degeneration and improved mitochondrial redox state. 11) Maintenance of mitochondrial function was shown to be key to photoreceptor protection.
Increased ATP Production
CcO activation: Red to near-infrared light is absorbed by CcO, activating the electron transport chain. 6)
NO dissociation: Photodissociates NO that inhibits CcO, restoring ATP synthesis. 7, 8)
Reduction of Oxidative Stress
ROS regulation: Low-dose ROS induces transcription of antioxidant genes. 9)
Anti-inflammatory pathway: Inflammatory cytokines are suppressed through regulation of NF-κB and AP-1. 9)
Retinal Protection
RPE function maintenance: Expected to suppress drusen accumulation and prolong RPE survival. 2)
Photoreceptor protection: Degeneration suppression was confirmed in RP animal models. 11)
2024年11月、FDAはValedeaシステムを萎縮型加齢黄斑変性治療デバイスとして承認した。5)非侵襲的な光学的デバイスとして萎縮型加齢黄斑変性に初めてFDA承認が与えられた歴史的な出来事である。
Boyer Dら（2024）によるLIGHTSITE IIIでは、GA新規発症抑制（p=0.024）と最高矯正視力+2.4文字改善（p=0.02）が示された。4)この結果がFDA承認の直接根拠となった。
LIGHTSITE IIIの36か月延長試験（GALE試験）では、長期的な維持照射による持続効果の検証が進行中である。4)
The Cochrane review by Henein C et al. (2021) concluded that the evidence at that time was insufficient to determine the effectiveness of PBM. 3) The results of LIGHTSITE III were obtained after this evaluation, and future review updates may change the evidence assessment.
An exploratory clinical trial of PBM for RP (NCT06224114) is ongoing, and photoreceptor protective effects regardless of genotype are expected. The translation of findings demonstrated in animal models 11) to clinical practice is of interest.
The EMA has not approved PBM devices, so they cannot be used as a formal treatment in Europe. 12) The regulatory decisions of the FDA and EMA are divergent, and integrating international evidence remains a challenge.
Currently, the Valedea system is not approved in Japan. Its use is limited to research and clinical trial frameworks. Facilities that can provide it as standard treatment are extremely limited, so consultation with the attending physician is necessary.
FDA-approved indications are limited to dry age-related macular degeneration (non-exudative type). The efficacy of PBM for wet age-related macular degeneration with active choroidal neovascularization has not been established; in such cases, anti-VEGF therapy is the standard treatment.
