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MODELS ADVANCING THE FIGHT AGAINST DRY AGE-RELATED MACULAR DEGENERATION

Writer's picture: Hanagh WinterHanagh Winter

Last year marked a significant milestone for patients with dry AMD. After years of relying on antioxidant vitamins, new groundbreaking therapies emerged, offering renewed hope that dry AMD could not only be slowed but potentially halted or even reversed. Like the burgeoning alternatives to anti-VEGFs on the horizon for wet AMD, the floodgates have been opened for dry AMD treatments, promising varied new options for patients and their doctors both. The two new therapies target the complement system, but dozens of other pipeline candidates are under investigation for the treatment of a range of pathologies in dry AMD. So, what can we expect to see in the coming years? Here, we’ll explore some opportunities in the fight against dry AMD with a special mention of the models that will form the foundation of their development. After all, all good development builds from the best preclinical work, and the best preclinical models. Read on to find out more.


WHAT IS DRY AMD?

Expanding the toolkit for addressing dry AMD is crucial. Approximately 80% of AMD patients have the dry form, characterized by the accumulation of deposits called drusen on the macula (Johns Hopkins, 2024). As the central part of the retina is responsible for sharp vision, the macula's deterioration can severely impact a patient's central vision, limiting their independence. Dry AMD is a leading cause of vision loss among older adults, and so addressing dry AMD is key to improving the quality of life of millions worldwide. That’s 194 million people, to be exact, predicted to increase to 288 million by 2040 (Wong, 2014).


Figure 1: Some AMD facts and figures.

Dry AMD involves the build-up of drusen under the retina, leading to the degeneration of photoreceptors and the atrophy of the outer retina and retinal pigment epithelium (RPE). This process results in significant vision impairment over time. Contributing factors include age-related changes, chronic inflammation, oxidative stress, and impaired extracellular matrix maintenance. Drusen, deposits of materials including lipids, minerals, and proteins that are characteristic of AMD, grow in size as the disease progresses from early to intermediate stages. In the advanced stages two things can happen. The first is that the buildup of drusen and other changes cause the retinal pigment epithelium and photoreceptors to atrophy in patches on the retina, called geographic atrophy (GA). The second pathway that disease can take, which changes disease classification to wet AMD instead, is that new abnormal vessels begin to grow through the retina. These new vessels don’t work properly, allowing leakage in the retina that can cause damage like fibrosis to develop. There are many excellent reviews that cover the pathology of AMD in depth, find links to some of the latest below.


THE PATHOPHYSIOLOGY OF AMD


DIAGNOSIS


Unfortunately, the symptoms of AMD don’t manifest until later stages of the disease. Aging populations are often advised to look out for changes to their colour vision or distortions in straight lines. Many patients also report difficulties in performing tasks in lower light or during the night, as well as more general visual difficulties like blurred vision and difficulty in focusing (National Eye Institute, 2024). As with any progressive disease, gradual changes like these are often difficult to spot. These changes prompt the following clinical investigations.



AMD patient perspective - City centre street, Belfast, UK

Visual acuity tests, like line charts, are common in clinics. A comprehensive retinal examination using a range of imaging tools is essential. Optical coherence tomography (OCT) provides a 3D cross-sectional view of the retinal structures, revealing details of the drusen and retinal irregularities. OCT-angiography offers a detailed view of the microvasculature, such as alterations of the choriocapillaris. Fundus autofluorescence (FAF) provides detailed insight into the health of the retinal pigment epithelium, the drusen and the GA lesions. This combination of tools helps clinicians build a complete picture of the eye to classify the disease and determine the best treatment approach.

 

In the lab, however, lesions can be detected even earlier. Histology and electron microscopy reveal lesions in the RPE and basement membrane, rich in lipids and collagen fibres, or between the RPE basement membrane and the inner layer of the Bruch’s membrane, made up of phospholipid vesicles (Ebrahimi and Handa, 2011). The existence of these earlier manifestations of AMD pathology raises the question of why we don’t look for disease sooner and stop it before the signs start to show. In 2017, a risk score made up of four different easily measured biomarkers was proposed by Sadda and colleagues (Lei, 2017). These are the volume of drusen, the presence of intraretinal hyperreflective foci (HRF), hyporeflective foci within drusen and subretinal drusenoid deposits. Crucially, these were measured retrospectively in OCT scans from patients, demonstrating how clinically practical a tool like this would be spot early AMD and stratify patients based on risk to their vision. More, therapeutic developers are increasingly looking to these earlier disease stages as more and more early AMD interventions start to populate the wider AMD pipeline.

Fluid buildup is more common in wet AMD patients,  so I would here more focus on the drusen and RPE abnormalities.


WHAT ARE THE RISK FACTORS AND HOW CAN WE MODEL THEM?

The biggest risk factor for AMD is unsurprisingly age. Out of every 1000 people in European, Australian and US white populations, 0.3 from 55 to 59 will have late-stage AMD while 36.7 of those older than 90 will (Fleckenstein, 2024). There is also a significant genetic component, with an estimated 71% heritability (Seddon, 2005). The most consistently reported risk factor is cigarette smoke (Tomany, 2004). Most of the models that we use have developed from our appreciation of these risk factors and the pathology of human disease. As with any disease, no model can capture every intricacy of the pathology, but choosing a model that highlights an element relevant to your mechanism of action allows us to find the vision saving therapies of the future.


Starting with the cell

A widely used first step in the screening of therapeutic candidates for dry AMD in the in vitro sodium iodate model. Simply put, sodium iodate is used to induce oxidative stress and injury on RPE cells in culture. The cells used are typically ARPE-19 cells, a human RPE cell line that can regain a classic RPE phenotype including key gene expression and morphology (Samuel, 2017). ARPE-19 cells are well-characterised and perform many important RPE functions including the assimilation of photoreceptor outer segments by phagocytosis (Finnemann, 1997) and EMT when properly polarised (Samuel, 2017).

 

Sodium iodate

The evolution of the sodium iodate model involves the same treatment but this time in the in vivo setting, typically the rodent eye. Like in culture, sodium iodate induces RPE death, this time followed by photoreceptor degeneration. With the effect of sodium iodate on the retina discovered over 80 years ago (Sorsby, 1941), the use of the sodium iodate model is now widespread. At the concentrations used, sodium iodate damages the RPE and retina through oxidative stress while remaining below the threshold that can damage other organs. This history and popularity bring the benefit of well characterised outcomes and knowledge of sex and age differences (Anderson, 2023). More, sodium iodate dosing can be finetuned to produce marked and measurable AMD phenotypes, but over a longer time period to extend the therapeutic window for interventions.

 

Light induced neurodegeneration

Excessive light exposure aggravates AMD and other retinal disorders by inducing photoreceptor apoptosis and other pathological changes (Wenzel, 2005). The ability of light to induce retinal degeneration, starting with the photoreceptors, is well documented. This is leveraged in light induced models of retinal degenerations, for example by exposing the retina to intense blue or bright light. Visible light can change the photochemical reactions in the photoreceptors and RPE, which in turn causes the accumulation of ROS and oxidation of lipids and proteins (Baksheeva, 2018), all of which are representative of AMD. By using light-induced retinal degeneration models, researchers can investigate the efficacy of novel treatments in preventing or mitigating retinal damage, thereby accelerating the development of new therapeutic strategies for AMD.


Cigarette smoke models

With evidence including a markedly higher incidence of AMD in those who smoke versus those who never have (Seddon, 1996; Christen, 1996), a preclinical model is essential. This comes in the form of the HQ-model, which uses the administration of hydroquinone (HQ), an important toxicant in tobacco tar, to mimic the effects of cigarette smoke including in the retina. Specifically, the administration of HQ induces both acute and chronic mitochondrial changes that are consistent with those found in the early stages of dry AMD. The delivery route can be adjusted to suit the study, with end-points ranging from 7 months for water feeding (Zheng, 2023) down to 14 days if given by subconjunctival injection (Cousins, 2016).

 

MNU model

Like some of the other articles mentioned, the N-methyl-N-nitrosourea (MNU) model uses administration of a substance, in this case MNU, to elicit relatively fast retinal changes. The MNU model has the advantage of stimulating inflammatory pathways as well as oxidative stress (Harkin, 2022). MNU is a DNA alkylating agent that damages the molecular integrity of DNA, and so is also implicated in some cancers in addition to retinal degeneration. MNU induces cell death in a pathway that relies on Aim2/Casp11/Il18 inflammasome activation and so therapies that are able to modulate the inflammasome activation have shown promise in this model (Harkin, 2022). Likewise, this is an ideal test for therapies that aim to reduce oxidative stress.

 

Genetic models

Perhaps more than any other disease, the models used in the elucidation of AMD pathology are wide ranging and diverse. A range of knockouts have been used to explore all caveats of a multifaceted and nuanced disease, ranging from inflammatory models like the superoxide dismutase 1 and 2 (Sod1/2) knockdowns (Biswal, 2016), to those that specifically examine lipid metabolism, like the ApoE knockdown mouse in which a ApoE deficiency develops in the retina that leads to reduced retinal function and Bruch’s membrane thickening (Vessey, 2022). These models are continuously being improved, for example by combining knockdowns to create more complex AMD phenotypes, like the Sod1, DJ-1 (Park-7), and Parkin (Prkn) triple knockout (Zhu, 2019). Complement pathway dysregulation is heavily implicated in dry AMD progression, and models like the Cfh-/- mouse, in which C3 activation is uncontrolled and which leads to disorganisation of the photoreceptor outer segment (Coffey, 2007), have allowed this to be dissected.

 

CONCLUSION


The development of innovative treatments for dry AMD is rapidly advancing, driven by a deeper understanding of the disease and sophisticated preclinical models. These models, ranging from light-induced degeneration to genetic knockouts, play a crucial role in evaluating new therapies' efficacy and safety. As research progresses, the future holds promise for more effective treatments that can significantly improve the lives of millions affected by dry AMD.



Figure 2: Considering the changes that occur in the AMD eye, there are numerous opportunities for developing new therapeutics. Some changes have already been targeted by recently approved therapies, such as pegcetacoplan and avacincaptad pegol, both of which address aberrant complement activation in AMD. Other potential treatments are at various stages of development, aiming to correct these changes as well as other pathological features identified in AMD.


WITH ALL THE MODELS TO CHOOSE FROM, WHICH DO YOU PREFER?

  • Starting with the cell

  • Sodium iodate

  • Light induced neurodegeneration


REFERENCES


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