Tag: vision loss

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Tests on Animals Demonstrate that New Eye Drops can Slow Vision Loss

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Model of PEDF protein alongside the 17-mer and H105A peptides. Amino acid 105, which is changed from histidine in PEDF and the 17-mer peptide to alanine in the H105A peptide, is shown in green.

Researchers at the National Institutes of Health (NIH) have developed eye drops that extend vision in animal models of a group of inherited diseases that lead to progressive vision loss in humans, known as retinitis pigmentosa. The eye drops contain a small fragment derived from a protein made by the body and found in the eye, known as pigment epithelium-derived factor (PEDF). PEDF helps preserve cells in the eye’s retina. A report on the study is published in Communications Medicine.

“While not a cure, this study shows that PEDF-based eye drops can slow progression of a variety of degenerative retinal diseases in animals, including various types of retinitis pigmentosa and dry age-related macular degeneration (AMD),” said Patricia Becerra, PhD, chief of NIH’s Section on Protein Structure and Function at the National Eye Institute and senior author of the study. “Given these results, we’re excited to begin trials of these eye drops in people.”

All degenerative retinal diseases have cellular stress in common. While the source of the stress may vary—dozens of mutations and gene variants have been linked to retinitis pigmentosa, AMD, and other disorders—high levels of cellular stress cause retinal cells to gradually lose function and die. Progressive loss of photoreceptor cells leads to vision loss and eventually blindness.

Previous research from Becerra’s lab revealed that, in a mouse model, the natural protein PEDF can help retinal cells stave off the effects of cellular stress. However, the full PEDF protein is too large to pass through the outer eye tissues to reach the retina, and the complete protein has multiple functions in retinal tissue, making it impractical as a treatment. To optimize the molecule’s ability to preserve retinal cells and to help the molecule reach the back of the eye, Becerra developed a series of short peptides derived from a region of PEDF that supports cell viability. These small peptides can move through eye tissues to bind with PEDF receptor proteins on the surface of the retina.

Model of PEDF protein alongside the 17-mer and H105A peptides. Amino acid 105, which is changed from histidine in PEDF and the 17-mer peptide to alanine in the H105A peptide, is shown in green.

In this new study, led by first author Alexandra Bernardo-Colón, Becerra’s team created two eye drop formulations, each containing a short peptide. The first peptide candidate, called “17-mer,” contains 17 amino acids found in the active region of PEDF. A second peptide, H105A, is similar but binds more strongly to the PEDF receptor. Peptides applied to mice as drops on the eye’s surface were found in high concentration in the retina within 60 minutes, slowly decreasing over the next 24 to 48 hours. Neither peptide caused toxicity or other side effects.

When administered once daily to young mice with retinitis pigmentosa-like disease, H105A slowed photoreceptor degeneration and vision loss. To test the drops, the investigators used specially bred mice that lose their photoreceptors shortly after birth. Once cell loss begins, the majority of photoreceptors die in a week. When given peptide eye drops through that one-week period, mice retained up to 75% of photoreceptors and continued to have strong retinal responses to light, while those given a placebo had few remaining photoreceptors and little functional vision at the end of the week.

“For the first time, we show that eye drops containing these short peptides can pass into the eye and have a therapeutic effect on the retina,” said Bernardo-Colón. “Animals given the H105A peptide have dramatically healthier-looking retinas, with no negative side effects.”

A variety of gene-specific therapies are under development for many types of retinitis pigmentosa, which generally start in childhood and progress over many years. These PEDF-derived peptide eye drops could play a crucial role in preserving cells while waiting for these gene therapies to become clinically available.

To test whether photoreceptors preserved through the eye drop treatment are healthy enough for gene therapy to work, collaborators Valeria Marigo, PhD and Andrea Bighinati, PhD, University of Modena, Italy, treated mice with gene therapy at the end of the week-long eye drop regimen. The gene therapy successfully preserved vision for at least an additional six months.  

To see whether the eye drops could work in humans – without actually testing in humans directly – the researchers worked with Natalia Vergara, PhD, University of Colorado Anschutz, Aurora, to test the peptides in a human retinal tissue model of retinal degeneration. Grown in a dish from human cells, the retina-like tissues were exposed to chemicals that induced high levels of cellular stress. Without the peptides, the cells of the tissue model died quickly, but with the peptides, the retinal tissues remained viable. These human tissue data provide a key first step supporting human trials of the eye drops.

Source: NIH/National Eye Institute

Categories : Genetics OphthalmologyTags :

Gene Therapy for Inherited Blindness Results in 100-fold Vision Improvement

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Photo by Victor Freitas on Pexels

People with a rare genetic mutation that causes significant vision loss early in childhood experienced a 100-fold improvement in vision after receiving a corrective gene therapy. Some patients even experienced a 10 000-fold improvement in their vision after receiving the highest dose of the therapy, according to researchers from the Perelman School of Medicine at the University of Pennsylvania who co-led the clinical trial published in The Lancet.

“That 10 000-fold improvement is the same as a patient being able to see their surroundings on a moonlit night outdoors as opposed to requiring bright indoor lighting before treatment,” said the study’s lead author, Artur Cideciyan, PhD, a research professor of Ophthalmology and co-director of the Center for Hereditary Retinal Degenerations. “One patient reported for the first time being able to navigate at midnight outdoors only with the light of a bonfire.”

A total of 15 people participated in the Phase 1/2 trial, including three paediatric patients. Each patient had Leber congenital amaurosis as the result of mutations in the GUCY2D gene, which is essential to producing proteins critical for vision. This specific condition, which affects less than 100 000 people worldwide and is abbreviated as LCA1, causes significant amount of vision loss as early as infancy.

All subjects had severe vision loss with their best measure of vision being equal or worse than 20/80 – meaning if a typically-sighted person could see an object clearly at 80 feet (24m), these patients would have to move up to at least 20 feet (6m) to see it. Glasses provide limited benefit to these patients because they correct abnormalities in the optical focusing ability of the eye, and are unable to address medical causes of vision loss, such as genetic retinal diseases like LCA1.

The trial tested different dosage levels of the gene therapy, ATSN-101, which was adapted from the AAV5 microorganism and was surgically injected under the retina. For the first part of the study, cohorts of three adults each received either a low, mid, ore high dose. Evaluations were held between each level of dosage to ensure that they were safe before upping the dosage for the next cohort. A second phase of the study involved only administering the high dosage levels to both an adult cohort of three and a paediatric cohort of three, again after safety reviews of the previous cohorts.

Improvements were noticed quickly, often within the first month, after the therapy was applied and lasted for at least 12 months. Observations of participating patients are also ongoing. Three of six high-dosage patients who were tested to navigate a mobility course in varying levels of light achieved the maximum-possible score. Other tests used eye charts or measured the dimmest flashes of light patients perceived in a dark environment.

Of the nine patients who received the maximum dosage, two had the 10 000-fold improvement in vision.

“Even though we previously predicted a large vision improvement potential in LCA1, we did not know how receptive patients’ photoreceptors would be to treatment after decades of blindness,” said Cideciyan. “It is very satisfying to see a successful multi-center trial that shows gene therapy can be dramatically efficacious.”

Primarily, the study sought to determine the safety of the gene therapy and its varying dosage levels. Researchers did find some patients had side effects, but the overwhelming majority were related to the surgical procedure itself. The most common side effect was conjunctival haemorrhage, the breakage of small blood vessels underneath the clear surface of the eye, which healed. Two patients had eye inflammation that was reversed with a course of steroids. No serious side effects were related to the study drug.

This work comes on the heels of another successful ophthalmological trial at Penn restoring sight in patients with a different form of LCA. Earlier in 2024, CRISPR-Cas9 gene editing was used to improve the sight of many patients with a form of LCA tied to mutations in the CEP290 gene. Co-led by one of the new paper’s co-authors, Tomas S. Aleman, MD, professor in ophthalmology and co-director with Cideciyan of the Center for Hereditary Retinal Degenerations, the study used similar tests and was the first time children were involved in any gene editing work.

“The treatment success in our most recent clinical trials together with our earlier experience brings hope for a viable treatment for about 20 percent of infantile blindness caused by inherited retinal degenerations,” Aleman said. “The focus now is on perfecting the treatments and treating earlier manifestations of these conditions once safety is confirmed. We hope similar approaches will lead to equally positive outcomes in other forms of congenital retinal blindness.”

Moving forward, approval of this experimental medicine for clinical use requires a randomised controlled trial.

Source: University of Pennsylvania School of Medicine

Categories : Metabolic Disorders OphthalmologyTags :

Study Reveals Association Between Semaglutide Use and Optic Neuropathy

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Photoreceptor cells in the retina. Credit: Scientific Animations

Researchers from Mass Eye and Ear have discovered an association between semaglutide use and an increased risk of nonarteritic anterior ischaemic optic neuropathy (NAION) in patients with type 2 diabetes, overweight or obesity. The findings, which appear in JAMA Ophthalmology, only show an association and cannot establish causation.

Though NAION is relatively rare, occurring in in about 10 in 100 000, it is the second most common cause of optic nerve blindness, behind glaucoma, and it is the most common cause of sudden optic nerve blindness. Caused by decreased blood flow to the optic disc, it usually affects only one eye but in 15% of cases both eyes are involved. There are no treatments for this disease and little prospect for improvement, although it is painless.

The study was led by Joseph Rizzo, MD, director of the Neuro-Ophthalmology Service at Mass Eye and Ear and the Simmons Lessell Professor of Ophthalmology at Harvard Medical School.

In mid-2023 Rizzo, a resident (study co-author Seyedeh Maryam Zekavat, MD, PhD) and other Mass Eye and Ear neuro-ophthalmologists noticed a disturbing trend – three patients in their practice had been diagnosed with vision loss from this relatively uncommon optic nerve disease in just one week. They did notice however that all three were taking semaglutide.

“The use of these drugs has exploded throughout industrialised countries and they have provided very significant benefits in many ways, but future discussions between a patient and their physician should include NAION as a potential risk,” said Rizzo, corresponding author of the study. “It is important to appreciate, however, that the increased risk relates to a disorder that is relatively uncommon.” 

This prompted the Mass Eye and Ear research team to run a retrospective analysis of their patient population to see if they could identify a link between this disease and these drugs.

They performed matched cohort study of 16 827 patients revealed higher risk of NAION in patients prescribed semaglutide compared with patients prescribed non–GLP-1 receptor agonist medications for diabetes or obesity.

The researchers found that patients with diabetes who were prescribed and took semaglutide were four times (hazard ratio [HR], 4.28) more likely to be receive a NAION diagnosis. The odds increased to more than seven times (HR, 7.64) when the prescription was for weight control in obesity.

The researchers analysed the records of more than 17 000 Mass Eye and Ear patients treated over the six years since Ozempic was released and divided the patients in those who were diagnosed with either diabetes or overweight/ obesity. The researchers compared patients who had received prescriptions for semaglutide compared to those taking other diabetes or weight loss drugs. Then, they analysed the rate of NAION diagnoses in the groups, which revealed the significant risk increases.

Study limitations include the fact that Mass Eye and Ear sees an unusually high number of people with rare eye diseases, and the number of NAION cases seen over the six-year study period is relatively small. With small case numbers, statistics can change quickly, Rizzo noted. Medication adherence could also not be assessed.

Only correlation can be shown by the study, not causality. How or why this association exists remains unknown. Likewise, the reason for the reported difference between diabetic and overweight groups – but this does not appear to result from a difference in baseline characteristics. The optic nerve is known to host GLP-1 receptors, but the study did not adequately address all the confounding factors. They also caution against generalising the results (from a majority white population) since Black individuals have a lower risk of NAION.

“Our findings should be viewed as being significant but tentative, as future studies are needed to examine these questions in a much larger and more diverse population,” Rizzo said. “This is information we did not have before and it should be included in discussions between patients and their doctors, especially if patients have other known optic nerve problems like glaucoma or if there is pre-existing significant visual loss from other causes.”