dry AMRD

New Gene Therapy Shows Promise for Treating Age Related Macular Degeneration

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Summary: A new study reports that a new gene therapy shows promise in treating dry age-related macular degeneration. The gene therapy, ophNdi1, directly targets mitochondrial function that is malfunctioning in AMD.

Source: TCD

Researchers from Trinity College Dublin have developed a new gene therapy approach that shows promise for treating the dry form of age related macular degeneration (AMD)—a progressive eye disease that affects up to 10% of adults over 65 years of age and is a leading cause of severe vision impairment and blindness in this age group.

Dry AMD cases represent about 85–90% of all AMD cases and there are no treatments available to treat or prevent disease progression, underlining the need for developing treatment options for this debilitating disease. In adults, many diseases of aging have been found to have defects of mitochondrial function, including AMD.

The team, in Trinity’s School of Genetics and Microbiology, have developed a new gene therapy (ophNdi1) that is the first of its kind to directly target mitochondrial function in cells that are malfunctioning in AMD.

Mitochondria are known as the “powerhouses” of the cell because they manage the production of energy but their performance dips greatly in dry AMD and this is linked to a deterioration in sight.

The new gene therapy cleverly uses a virus to access the cells that are suffering and deliver the code needed to give the failing mitochondria a lifeline, enabling them to generate extra energy and continue to function in supporting vision.

The therapy has shown benefit in multiple models of dry AMD, offering hope that it could one day progress to a treatment that could help millions across the globe.

This shows a man's eye
The therapy has shown benefit in multiple models of dry AMD, offering hope that it could one day progress to a treatment that could help millions across the globe.

Professor Jane Farrar, senior author, said, “Critically, this study provides the first evidence in models that directly modulating bioenergetics in eye cells can provide benefit and improve visual function in dry AMD. In doing so, the study highlights the energy powerhouses of the cell, mitochondria, as key targets for dry AMD.”

Dr. Sophia Millington-Ward, first author and research fellow in Trinity’s School of Genetics and Microbiology, said, “The novel gene therapy targeting cellular energy, or mitochondrial function, that we explored for dry AMD consistently provided benefit in the model systems tested.

“Many retinal cells, essential for vision, require particularly high levels of energy compared to most other cells, which makes them particularly vulnerable to mitochondrial dysfunction.

“The therapy we are developing directly targets mitochondrial function and increases energy production levels in the retina, which leads to better visual function in disease models of dry AMD.

“Although there is further work to be done before this could be made available as a treatment for patients, the results give us hope that we are getting closer to a solution to this challenging, debilitating condition.”

Abstract

AAV‐mediated gene therapy improving mitochondrial function provides benefit in age‐related macular degeneration models

With an estimated 196 million people suffering from age-related macular degeneration (AMD) in 2020 and predicted to increase to 288 million by 2040, dry AMD, representing 70%–90% of AMD cases, represents an enormous clinical need with no current therapies.

We have demonstrated that NDI1 and an optimised version of NDI1 (ophNdi1), a mitochondrial complex 1 equivalent from Saccharomyces cerevisiae, provide functional and histological benefit in two murine models of dry AMD as well as benefit in two cellular models of dry AMD. There are no drugs on the market for dry AMD.

However, there are currently a small number of candidate gene therapies in clinical trial (clinicaltrials.gov).

To our knowledge, this is the first demonstration that a gene therapy directly targeting mitochondrial dysfunction provides functional benefit in in vivo models of dry AMD, making this a novel approach to treating this devastating condition.

Geography lesson in dry AMD

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American researchers have identified an RNA-based mechanism in the retina that could be responsible for triggering the blindness associated with advanced dry age-related macular degeneration.1 The team is developing inhibitors and ultimately hopes to submit an IND.

Unlike wet AMD, which results from scarring caused by leaky blood vessels and thus can be treated with a variety of angiogenesis inhibitors, dry AMD is initially characterized by the buildup of extracellular debris beneath the retina. Over time, those deposits cause significant atrophy of the retinal pigment epithelial (RPE) layer—a condition known as geographic atrophy—and can ultimately advance to permanent blindness.

Although difficult to predict, dry AMD can turn into wet AMD at any time during disease progression. There are no medical or surgical treatments for dry AMD.

To find potential targets for geographic atrophy, Jayakrishna Ambati and colleagues at the University of Kentucky College of Medicine initially looked at levels of proteins and nucleic acids in eye samples from dry AMD patients. Ambati is vice chair of ophthalmology and visual sciences at the college.

The researchers found that levels of the microRNA-processing enzyme dicer 1 ribonuclease type III (DICER1) were significantly lower in patient eyes than in non-AMD control eyes (p=0.0036). DICER1 levels were unchanged in the RPE layer of human eyes with other retinal diseases, suggesting that low DICER1 could be a specific marker of geographic atrophy.

The team next generated Dicer1 knockout mice to recapitulate the geographic atrophy phenotype in animals. All the Dicer1 knockouts showed degeneration of the RPE layer compared with wild-type littermate controls.

Subsequent studies in human RPE cells and mice revealed the specific mechanism by which low DICER1 levels led to degeneration of the RPE cells or layer, respectively. The decrease in DICER1 caused the accumulation of cytotoxic Alu RNA molecules in the RPE layer, where they caused degeneration of tissues making up the retina and macula. Alu RNAs are retrotransposon sequences that exist throughout the human genome but do not code for proteins.

In cultured human RPE cells with low DICER1 levels, antisense oligonucleotides targeting Alu RNA significantly blocked RPE cellular degeneration compared with control oligonucleotides (p<0.05).

The findings were published in Nature.

Ambati told SciBX that he now plans to explore “molecular platforms for Alu inhibition, including the Alu antisense therapy described in the paper. Once we settle on a lead candidate, we plan to proceed to GMP manufacture and FDA IND filing.”

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Targeting Alu

Although the University of Kentucky researchers initially plan to test Alu inhibitors as monotherapy for dry AMD, the heterogeneous nature of the disease makes it unlikely that targeting only Alu RNA would be sufficient to stave off blindness.

“A cocktail or combination therapy will likely result in the ideal therapeutic strategy.”

Samir Patel
Ophthotech Corp.

“Chronic diseases such as dry AMD are very heterogeneous and progress through a series of early and late stages. The advanced stage of dry AMD is characterized as either geographic atrophy or conversion to neovascular disease,” said Samir Patel, cofounder, president and CEO of Ophthotech Corp. “As a result, different molecular mechanisms may predominate at different times, and a single therapeutic target may not be useful for all stages. A cocktail or combination therapy will likely result in the ideal therapeutic strategy.”

He added: “It is important to use preclinical animal models, together with human histopathology and genetic studies, if possible, to better understand the role of Alu RNA in the overall pathogenesis and progression of dry AMD and geographic atrophy,” he continued. “This information should give us a better idea of how best to pair an Alu RNA–targeting strategy with other complementary mechanisms in dry AMD.”

Ophthotech’s ARC1905, a selective inhibitor of complement component 5, is in Phase IIa testing to treat advanced dry AMD with geographic atrophy. The company is targeting the complement system “because there is strong evidence that excessive inflammation is important in AMD and that local inflammation and activation of the complement cascade drives formation of crystalline deposits beneath the retina that are the hallmark of dry AMD,” said Patel.

Ryo Kubota, president and CEO of Acucela Inc., noted that it’s still unclear what causes the initial decreases of DICER1 levels that lead to high amounts of Alu RNA. “Our research suggests that the underlying pathology of AMD can be traced to oxidative stress caused by toxic byproducts of the visual cycle, which negatively impact human RPE cells,” said Kubota.

Acucela’s ACU-4429, a small molecule that targets the retinal pigment epithelium–specific protein 65 kDa (RPE65) to modulate the visual cycle, is in Phase II testing to treat dry AMD.

Ambati thinks targeting Alu RNA might have advantages over the other strategies. “Compared with complement inhibitors, which modulate the immune system, targeting Alu RNA could have less potential to increase the patient’s risk of infection. And compared with visual cycle inhibitors, an anti–Alu RNA approach might have lower rates of nontolerance by avoiding the negative effects visual cycle inhibitors can have on night vision,” he said.

source: sciBX