Laser Photobiomodulation as a Potential Multi-Hallmark Therapy for Age-Related Macular Degeneration

A s a result of population aging, the prevalence of age-related macular degeneration (AMD), the leading cause of irreversible blindness among the elderly in industrialized countries, is expected to rise substantially by 2050. ¹ No treatments currently exist for early and intermediate AMD other than lifestyle changes, a heart-healthy diet, and oral supplementation with antioxidant vitamins and minerals. Reports from the Age-Related Eye Disease Study 2 (AREDS2) will indicate if lutein, zeaxanthin, and omega-3 fatty acids may be effective, safe, and protective against the onset and progression of AMD. ²

There are two forms of advanced AMD: neovascular AMD (NV-AMD) and geographic atrophy (GA-AMD). These account for 90% and 10%, respectively, of severe visual loss cases. ³ Anti-vascular endothelial growth factor (VEGF) agents are the “gold standard” for treating NV-AMD. However, they only improve visual acuity temporarily, requiring recurring and costly intravitreal injections. Inherent treatment risks include infection, detachment, and retinal tears. ³ For GA-AMD, there is no effective treatment, ^3,4

As the pathogenesis of AMD is unraveled, there is a growing perception that therapeutic approaches that address underlying mechanisms are more likely to succeed. Genomic and genetic studies have improved our understanding of AMD's pathogenesis, in some cases identifying new pathways, and in others confirming factors identified by other means. ⁴ The aim of this Editorial is to encourage discussion on the potential application of laser photobiomodulation (PBM) in NV-AMD and other complex diseases (CDs) of the eye.

Pathways that modulate cytokines in NV-AMD and other growth factors (GFs) are being studied to identify markers affecting clinical response and to optimize anti-VEGF therapy. ⁵ One proposed approach is multitarget pharmacotherapy, a combination of therapeutic agents with different action modes designed to treat NV-AMD. ³ Multitarget pharmacotherapy research seeks to remedy the effect of decreased bioefficacy of current anti-VEGF agents caused by tachyphylaxis, relieve discomfort from intravitreal drug delivery, and identify new therapeutic targets. ³

However, we believe that light-based therapies that act on multiple targets may prove safer, more effective, and easier to monitor. PBM has already shown potential for AMD and other eye CDs, ⁶ in accord with data on light-emitting diode (LED) PBM and its neuroprotective effects, ⁷ as well as our own studies with laser PBM (LPBM). ^8,9 Recently, we proposed LPBM as a multitarget (multi-hallmark) therapy for cancer and other CDs, ¹⁰ based on an approach that aims to substitute and/or complement metabolic energy pathways through oxygen-dependent (cytochrome c oxidase) and/or oxygen-independent (light-water interactions [F0-F1 motors]) mechanisms with critical signaling pathways. ¹¹

Pathological angiogenesis is the hallmark of NV-AMD, in which injury, chronic inflammation, and genetic susceptibility determine progression. ⁴ LPBM may block retinal NV, resulting in elevated levels of hypoxia-inducible factor-1 (HIF-1), ¹² and reduce oxidative stress (OS). ¹³ OS in the outer retina and retinal pigmented epithelium (RPE) elevates HIF-1, which upregulates vasoactive gene product promoters of subretinal NV. ¹⁴ LPBM modulates gene expression, GF, and cytokine release. ¹⁵ It enhances matrix reinforcement and modifies inflammatory response at sites of transmural injury. ¹⁶ LPBM may also counteract chronic inflammation in AMD, as suggested by our results ¹⁷ on immune system activation and modulation in cancer patients, in accord with Coussens et al. ¹⁸ and others.

Whereas signal and receptor characteristics determine biological outcome, which is optimal for only one set of conditions, ^11,19 properly tailored LPBM can trigger a cascade of biochemical/metabolic, biomechanical, and hydrodynamic mechanisms that control cell fuel (adenosine triphosphate [ATP], guanosine triphosphate [GTP], and other high-energy molecules) and receptors (purine and adenine). These are needed to power and modulate, in a specific and selective manner, cellular work at the cell and tissue level, ¹¹ and are required in extensive cell signaling networks that span the energy-dependent path from the genotype to the phenotype. Thus, homeostasis/homeokinesis of tissue microenvironments and peripheral systems may be restored. ^11,19 Remarkably, LPBM can be effective even when faulty genes or other factors block metabolic pathways. ²⁰ Targeted energy interactions underlie the structure and function of metabolic control levels and are based on the laws of electromagnetism and Onsager's non-equilibrium theory. ²¹

Finally, and in accord with Abrahamse, ²² LPBM may trigger regenerative responses, alone or associated with stem cell therapy. Epigenetics modulate chromatin structure, which affects gene transcription. ²³ LPBM has been shown to reduce the frequency of chromosome aberrations. ²⁴ Clinical results also suggest that it can induce phenotypic changes ^8,11 consistent with theoretical data from a nonlinear DNA model, in which chaotic behaviors generated by damping, external fields and torque in solitone dynamics may induce open states of the DNA that regulate transcription and replication. ²⁵

In view of the abovementioned, and given that the eye can be described as an electrochemical aqueous organ and that water is a key photoacceptor, LPBM may represent a potentially powerful multi-hallmark monotherapy ^8,9,11 for AMD ⁸ and other eye CDs. ^{9 –11} LPBM may further optimize treatment costs, and improve quality of life and functional status. ¹¹ Hence, although LPBM is not a panacea, new research is needed to ascertain whether it may improve the lives of millions of people who currently have or will develop AMD.