Preclinical and clinical studies of photobiomodulation therapy for macular oedema

Abstract

Aims/hypothesis Diabetic macular oedema (DME) is the leading cause of visual impairment in people with diabetes. Intravitreal injections of vascular endothelial growth factor inhibitors or corticosteroids prevent loss of vision by reducing DME, but the injections must be given frequently and usually for years. Here we report laboratory and clinical studies on the safety and efficacy of 670 nm photobiomodulation (PBM) for treatment of centre-involving DME. Methods The therapeutic effect of PBM delivered via a light-emitting diode (LED) device was tested in transgenic mice in which induced Müller cell disruption led to photoreceptor degeneration and retinal vascular leakage. We also developed a purpose-built 670 nm retinal laser for PBM to treat DME in humans. The effect of laser-delivered PBM on improving mitochondrial function and protecting against oxidative stress was studied in cultured rat Müller cells and its safety was studied in pigmented and non-pigmented rat eyes. We then used the retinal laser to perform PBM in an openlabel, dose-escalation Phase IIa clinical trial involving 21 patients with centre-involving DME. Patients received 12 sessions of PBM over 5 weeks for 90 s per treatment at a setting of 25, 100 or 200 mW/cm 2 for the three sequential cohorts of 6-8 patients each. Patients were recruited from the Sydney Eye Hospital, over the age of 18 and had centreinvolving DME with central macular thickness (CMT) of >300 μm with visual acuity of 75-35 Log minimum angle of resolution (logMAR) letters (Snellen visual acuity equivalent of 20/30-20/200). The objective of this trial was to assess the safety and efficacy of laser-delivered PBM at 2 and 6 months. The primary efficacy outcome was change in CMT at 2 and 6 months. Results LED-delivered PBM enhanced photoreceptor mitochondrial membrane potential, protected Müller cells and photoreceptors from damage and reduced retinal vascular leakage resulting from induced Müller cell disruption in transgenic mice. PBM delivered via the retinal laser enhanced mitochondrial function and protected against oxidative stress in cultured Müller cells. Laser-delivered PBM did not damage the retina in pigmented rat eyes at 100 mW/cm 2 . The completed clinical trial found a significant reduction in CMT at 2 months by 59 ± 46 μm (p = 0.03 at 200 mW/cm 2 ) and significant reduction at all three settings at 6 months (25 mW/cm 2 : 53 ± 24 μm, p = 0.04; 100 mW/cm 2 : 129 ± 51 μm, p < 0.01; 200 mW/cm 2 : 114 ± 60 μm, p < 0.01). Laser-delivered PBM was well tolerated in humans at settings up to 200 mW/cm 2 with no significant side effects.

Photobiomodulation Therapy for Age-Related Macular Degeneration and Diabetic Retinopathy: A Review

“…A maximal reduction of −129±51 μm in central macular thickness (CMT) for patients dosed 100 mW/cm 2 was observed. 22 Although CMT reductions were noted across all dosages, no significant VA gains were noted.…”

“…Preservation of visual function. C-Kit cells and Cyp24a1 are not significant - mechanism might not be mediated by stem cells or VDR signaling Shen 22 (NIRD, NCT02181400) 2020 Preclinical Transgenic Müller cell mice 30 670 WARP10 LED Device (Barneveld,WI) 40 mW/cm 2 for 180 sec daily for 9 days Enhanced photoreceptor mitochondrial membrane, protected Müller cells, protected photoreceptors, reduced retinal vascular leakage Sprague Dawley and Dark Agouti Rats 670 Ellex Integre NIR (Minneapolis, MN) 100 or 500 mW/cm 2 for ? sec every two days for 1 week One week after last treatment, safety assessed.…”

“…In addition to the aforementioned mechanisms, separate experimenters demonstrated a significant reduction in retinal microvascular leakage observed in the inner plexiform layer, inner nuclear layer and outer plexiform layer. 22 , 31 These would suggest a unique application for PBT in diabetic retinopathy.…”

“…Müller cells show a decrease in Vimentin and GFAP, which are cell-specific markers for stress and inflammation, and possibly a prolonged lifetime. 22 , 24 , 27 Tang et al demonstrated rescue of retinal ganglion cells, while Fuma et al demonstrated PBT increased phagocytic activity of RPE cell lines. 25 , 28 Supporting cells are crucial for a healthy retina and evidence of their rescue appears positive.…”

“…35 , 36 Trials such as Shen et al and Protocol AE show a focus on patients with VA ≥ 20/25 and Central Subfield Thickness (CST) ≥ 300 μm as inclusion criteria, which limits generalizability of available results and conclusions. 22 , 34…”