Trends may shift AMD treatment paradigm

(Image Credit: AdobeStock/Andrii Yalanskyi)

There once were no treatment options for age-related macular degeneration (AMD), the leading cause of irreversible blindness in the elderly, but there now are multiple therapies available for wet AMD with research focusing on dry AMD.

It is expected that 288 million people will be affected by 2040,1 which creates a significant financial burden. As people live longer, the societal burden will increase, and could become unsustainable in the future.2

Kaustabh Ghosh, PhD, principal investigator and associate professor of Ophthalmology, David Geffen School of Medicine, UCLADoheny Eye Institute, discussed current trends in AMD treatment during a conversation with Ophthalmology Times.

“The most important thing that we have to recognize is that the current clinically approved treatments, the most effective ones, at least, only target the end stage of the disease,” Ghosh said. “When the blood vessels from the back end of the retina, they start proliferating, and they invade the retina. and then you get a whole, basically literally a bloody mess in the retina, you blood pours over into the retina, and you start losing vision.”

Ghosh pointed out this is the stage during which the most effective current clinical therapies are being used, however only 10 to 15% of all AMD patients actually experience the end stage.

“Even though the clinically approved drugs do work, it is targeting a very small fraction of fall end patients,” Ghosh said. “And so then the question is, what happens to the remaining 80 to 85% of the patients who don't get to the end stage. Now, it turns out that even among those 80 to 85%, there is a significant portion who get the advanced, dry stage of the end.”

The wet form of AMD is marked by blood flowing into retina, and another advanced form is dry AMD.

“For dry AMD, we recently had a drug approved, and it's a complement inhibitor,” Ghosh pointed out. “But only yesterday, I was speaking with a clinician here and I learned that it is yet not showing significant improvement in the vision of these patients who are receiving this drug, which means there's still an awful lot we need to learn and then addressed in the clinic for these 80 to 85% of the patients.”

This, according to Ghosh, is where the real unmet need exists. He has been involved in research targeting the early stages of AMD, common to both the advanced wet stage and the advanced dry stage.

“The early AMD can be seen as a risk factor for the late stage that causes vision loss,” he explained. “Now, at this early stage, what we see is the blood vessels that feed the photoreceptors, these are the cells that sense light and give us the vision these blood vessels start to die in the early stages.”

It is at this early stage of vascular degeneration that researchers are trying to understand mechanistically.

“In other words, how do these blood vessels die, and once they die, why don't the normal vessels that are in the neighborhood proliferate to make up for the last ones because in normally you do see some kind of a turnover?” Ghosh explained. “Some vessels die, they may bring healthy vessels they proliferate and then the base quickly make up for the last ones. But in this case of early AMD, that does not happen.”

This, according to Ghosh, leaves two questions for researchers to unravel. First, how do these blood vessels degenerate? Second, why is it that the normal healthy ones from the neighborhood don't proliferate to take their spot?

“This is a very important question because blood vessels, they provide vital nutrition to the overlying photoreceptor cells,” he said. “You can imagine you are starving these photoreceptor cells by cutting off the blood vessels supply, and so the idea is that if we understand how these blood vessels die in the early stages. We prevent that from happening, by intervening with some kind of molecular therapy based on our mechanistic studies, then we can slow down.”

The key, according to Ghosh, is to slow down progression of AMD, and develop treatment options for earlier stages of the disease. He added that the disease progresses slowly, so ophthalmologists can see it coming.

“The early stages that we are trying to understand and allowed can be diagnosed in the clinic by ophthalmologists who can see these fatty deposits on the back end of the eye. and so you know that the early stage has already begun,” he said. “Now, if you understand what is causing these blood vessels to die in those early stages, then we can probably slow down the progression.”

By doing this, the patient may never encounter the loss of vision that is a frequent complaint when patients are treated in the clinic, Ghosh said, and by slowing progression of the disease can preserve vision, because once it is lost, can be impossible to restore.

To investigate this disease, Ghosh relies upon a multidisciplinary approach, stemming from his engineering background, which includes an undergraduate degree in chemical engineering. He also has a PhD in biomedical engineering, and over the years has ventured further into medicine and vision research.

“We are looking at the vascular stiffness in early AMD,” he said. “By that what I mean is a normal blood vessel that feels like a plastic straw becomes hard and feels like a plumbing pipe, and that is what we recently discovered happens with these blood vessels in early AMD, compared to the normal aging eyes.”

Ghosh explained the vessels from the AMD eyes become significantly stiffer, and once this happens, those vessels become more susceptible to the loss of induced pluripotent stem (iPS) cells that is known to occur.

The next step, Ghosh said, is to determine how to prevent the stiffening from happening, and he said he believes the cells can be rescued.

“That's the paper we published last year, saying that if we understood the mechanisms that contribute to the stiffening of these blood vessels in the eye in early AMD, and when we could use drugs that can prevent this from happening,” he said. “You can also prevent the degeneration to these different iPS cells that AMD patients experience. and so that's what I mean by multidisciplinary because the conventional approach to understanding AMD has been it is a disease that results from on genetic, or biochemical abnormalities, what we are showing is that it also results from physical abnormalities that manifest in the form of the stiffness of the blood vessels. and that's where we bring the multidisciplinarity to this approach.”

Moving forward, Ghosh said researchers will continue to examine the role that stiffness plays in AMD progression and the biological changes that occur as a result. This can include detecting stiffness genes and examining the biology of the cells and how they respond according to risk factors.

“We are now suggesting that stiffness is one of the major risk factor, and that's what we want to continue to investigate to determine at what level the endothelial biology contributes to the disease,” he said.

Moreover, Ghosh said he hopes to eventually work with imaging experts who can help researchers diagnose the changes in the stiffness of the vessels in patients diagnosed with AMD.

“If stiffness is a real phenomenon, it would be great to know when stiffness is changing, and if so to what extent it is changing in different patients with early AMD,” he said.

In order to develop treatments for the disease in the large number of patients not benefitting from current treatment options, Ghosh said researchers will have to identify molecular targets to go after, that that is where the future lies.

“The push, in my perspective, should still be in basic science,” he said. “But when you talk to clinicians, they're also pushing for new ways of delivering the drug, not just relying on the intraretinal or intravitreal injections. That is the common route right now.”

Ghosh noted that if the same drugs could be administered orally to travel through the body and affect both eyes simultaneously, it would be a major achievement.

“We don't work on that aspect,” he concluded. “I know that there's a huge push in the AMD research field that is trying to achieve smarter ways of delivering drugs that can reduce the need for intraocular injections.”

References:

1. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2:e106-e116.

2. Cabral de Guimaraes TA, Daich Varela M, Georgiou M, Michaelides M. Treatments for dry age-related macular degeneration: therapeutic avenues, clinical trials and future directions. Br J Ophthalmol. 2022;106:297-304.