Researchers at the University of Bristol, together with collaborators at London’s Global University Institute of Ophthalmology, and the University of Bristol spin-out Cirrus Therapeutics, have identified what they describe as a “revolutionary” treatment for age-related macular degeneration (AMD), which is the leading cause of vision loss among older adults.

The team’s studies on human samples and in mouse models demonstrated that boosting a protein called IRAK-M in retinal cells protects against retinal degeneration and could potentially represent a highly effective therapeutic approach for AMD. “This discovery represents the first pathway-agnostic approach toward AMD, offering a comprehensive treatment option for the millions of people who suffer from this debilitating condition,” said Andrew Dick, MD, head of the academic unit of ophthalmology at the University of Bristol, Director of the UCL Institute of Ophthalmology.

Dick and colleagues reported on their findings in Science Translational Medicine, in a paper titled “Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration,” in which they concluded, “Because IRAK-M is reduced with aging, oxidative stress, and AMD, the replenishment of IRAK-M may be a therapeutic strategy for treating patients with AMD.”

AMD is a progressive, multifactorial disease, and a leading cause of irreversible severe vision loss among the elderly, the authors explained. “Alongside aging, the interplay of oxidative stress and chronic inflammation, fueled by genotype-predisposed susceptibility and environmental stressors, contributes substantially to the pathogenesis of AMD.” For affected patients, AMD commonly starts with blurred vision or seeing a black dot in their central vision, and this can ultimately expand to the point where there is no useful central vision. Currently, AMD affects approximately 200 million people worldwide, a number projected to rise to 288 million by 2040 with as the population ages.

The exact cause of AMD is complex and thought to involve a combination of aging, environmental, and lifestyle factors. Several inflammatory pathways have been associated with AMD progression, and the team hypothesized that IRAK-M may play potentially regulatory role in retinal aging and degeneration. IRAK-M is involved in downregulating inflammatory activation, and is expressed in retinal pigment epithelial (RPE) cells in vitro, they pointed out. “The present study aimed to elucidate the role of IRAK-M in AMD by assessing genetic variants and their association with AMD risk.”

Through their study the team also evaluated IRAK-M expression in patient samples and in mouse models of retinal degeneration, alongside alterations in retinal function in Irak3-knockout (KO) mice. “Furthermore, we explored the therapeutic potential of IRAK-M augmentation in protecting RPE and outer retina against degenerative processes in murine models.”

Results from tests in human samples and in mouse models showed that IRAK-M abundance in the RPE declined with advancing age or exposure to oxidative stress and was further reduced in AMD. Their experiments also showed that augmenting IRAK-M levels in retinal cells could significantly protect against retinal degeneration. “Subretinal delivery of adeno-associated virus (AAV)–expressing human IRAK3 rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in Irak3-knockout mice,” they further reported. “Our data show that replenishment of IRAK-M in the RPE may redress dysregulated pro-inflammatory processes in AMD, suggesting a potential treatment for retinal degeneration.”

Jian Liu, PhD, the first author and senior research scientist at the academic unit of ophthalmology of the University of Bristol, added, “Since age stands as a primary risk factor for AMD, the gradual decrease of IRAK- M levels with age, which further declines in AMD, is a key way to identify the potential markers of early AMD progression and ultimately a new way of treatment.”

Noting limitations of their study, the team concluded, “… we have identified an age-related decline of IRAK-M abundance, largely restricted to the RPE, which is worsened in AMD. Our findings suggest that IRAK-M plays a crucial role in maintaining RPE cell homeostasis and function via co-targeting mitochondrial health, oxidative stress, autophagy, and inflammation. Gene augmentation of IRAK-M demonstrates translational benefit in counteracting side effects of aging or oxidative stress and reducing outer retinal degeneration in preclinical disease models, suggesting a therapeutic strategy via manipulating IRAK-M in the RPE in patients with AMD.

This discovery will build and improve upon current treatments for AMD, which are targeting single pathophysiology pathways. Dick is co-founder of and chief scientific advisor to Cirrus Therapeutics, which was recently spun out of the University of Bristol to develop therapies related to the discovery Commented Ying Kai Chan, PhD, Cirrus Therapeutics co-founder and chief executive officer, “Our novel approach not only addresses the multiple pathways involved in treating AMD but also offers the most compelling and evidence-based strategy available today.”

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