Human eye with dna, human vision concept, optic nerve health, 3d illustration
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Scientists at the University of Bristol have demonstrated that restoring a protein that declines with age can prevent age-related and immune-mediated retinal degeneration. The researchers identified rare genetic mutations in the IRAK3 gene, which produces the IRAK-M protein and has been associated with age-related macular degeneration (AMD), a leading cause of irreversible, severe vision loss in the elderly. Using adeno-associated virus (AAV) to deliver the human IRAK3 gene into the retina protects the retinas of mice from damage caused by light and stops the retina from naturally degenerating in a mouse model of AMD. This article in Science Translational Medicine suggests a gene therapy approach for treating patients with AMD by replenishing IRAK-M levels in the retinal pigment epithelium (RPE).

Toll-like receptors and the Myddosome

The development of AMD is greatly impacted by the interplay of oxidative stress and chronic inflammation, which are further intensified by genetic predisposition and environmental factors. AMD progression involves various inflammatory pathways, such as the activation of the complement cascade, inflammasome, production of cytokines and chemokines, infiltration of immune cells, and immune activation of retinal microglia and RPE.

When activated, toll-like receptors (TLRs), which are implicated in AMD development, facilitate the assembly of large intracellular oligomeric signaling complexes that initiate key signal transduction pathways to elicit critical inflammatory immune responses. These complexes are known as Myddosomes and consist of myeloid differentiation primary response 88 (MyD88) protein and interleukin-1 (IL-1) receptor (IL-1R)–associated kinase (IRAK) family proteins. While it has been noticed that aberrant Myddosome activity in the RPE of patients with geographic atrophy, which is a late-stage form of atrophic AMD, there are still uncertainties about how it contributes to the progression of AMD and which specific components of Myddosome are responsible for the dysregulation of pro-inflammatory signaling through the TLR–IL-1R axis.

A potential therapeutic strategy for AMD

Given the documented expression of IRAK3 in RPE cells in vitro and the known role of Myddosomes in AMD, lead author Jian Liu, PhD, and colleagues hypothesized that IRAK3 may have regulatory significance in retinal aging and degeneration. Rare genetic variants of IRAK3 were associated with an increased likelihood of developing AMD. Furthermore, in both human samples and mouse models, the abundance of IRAK-M in the RPE decreased as individuals aged or were exposed to oxidative stress, and this reduction was even more pronounced in individuals with AMD.

Irak3-knockout mice displayed a higher occurrence of outer retinal degeneration at younger ages, worsened by oxidative stressors. The lack of IRAK-M resulted in a disturbance in the balance of RPE cells, marked by impaired functioning of mitochondria, cellular aging, and abnormal production of cytokines. The researchers concluded that a feed-forward loop involving aging, oxidative stress, and a decrease in IRAK-M may lead to the development of a pro-inflammatory microenvironment that causes retinal degeneration. 

Overexpression of IRAK-M protected retinal pigment epithelial (RPE) cells against oxidative or immune stressors. Administering an adeno-associated virus (AAV) that expresses human IRAK3 directly into the subretinal space successfully reversed light-induced damage to the outer retina in normal mice and reduced age-related degeneration of the retina in mice lacking the Irak3 gene. Liu and his team have demonstrated that restoring IRAK-M can preserve mitochondrial function, suppress senescence, and enhance cell viability, safeguarding the retina against degeneration in a mouse model of light-induced retinal degeneration (LIRD) and in Irak3−/− mice. This suggests that manipulating IRAK-M in the RPE could be a potential therapeutic strategy for patients with AMD.

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