People suffering from the more serious form of age-related macular degeneration known as wet AMD lose central vision when abnormal blood vessels sprout and leak fluid and blood into their retina, leading to further vision loss. Eye injections with medications such as bevacizumab or aflibercept can help control their growth; however, regular administration must occur for best results and to protect future vision loss.

A New Way to Deliver Sight-Saving Gene Therapy

Scientists are moving quickly from genetic research on blindness to groundbreaking clinical trials designed to bring back sight. Georgia Mills of the Genetics Unzipped podcast discusses researchers from Johns Hopkins and elsewhere working to help blind people see again.

The initial human gene therapy trial for LCA proved a tremendous success. Three patients are now able to navigate obstacles even in dim lighting and read large signs with ease; they also recognize faces and voices of people they meet. Their improved vision is due to an almost immediate change: areas of retina near where scientists injected functional genes for RPE65 began working more effectively again, helping restore some function lost through LCA.

Researchers must first refine this treatment before it can become widely utilized. To do this, they are currently testing new ways of administering viral vectors carrying functional genes into the eye – the aim being more precise delivery so that these vectors reach their destination in retina.

To put their approach through its paces, researchers created organoids from skin cells of two volunteers with autosomal dominant LCA as well as those from their unaffected relatives. Once exposed to both versions of RPE65 (faulty and normal), researchers measured whether adding healthy genes would restore production of light-sensing protein opsin production by retinal cells.

They compared various methods for administering gene-carrying viruses to retinal cells, including one which requires detaching it from its attachment at the back of the eye and injecting viral vectors directly. They have developed a computational platform described in an eLife paper which quickly and precisely evaluates which virus vector will provide its cargo best to retinal cells.

William Hauswirth of UF Health Ophthalmology developed an innovative system to quickly identify top performing AAV candidates through single cell RNA sequencing; this approach detects and measures whether genes reach cells that need them quickly compared with traditional AAV evaluation methods that take years and involve many experimental animals.

A Preliminary Study Finds That a Third of People with Wet AMD May Someday Stop Eye Injection Therapy

Skip Boyles witnessed his mother slowly become blind from age-related macular degeneration. When she visited her doctor with complaints of blurry vision, they informed her of a more serious wet form of the disease in which abnormal blood vessels grow beneath her retina – soft tissue located at the back of the eye that transmits light signals directly to the brain for interpretation – leading to permanent blindness without timely treatment.

Most physicians advise people with wet AMD to receive monthly injections of anti-VEGF drugs into their eyes to stop the formation of leaky new blood vessels and limit further vision loss. Unfortunately, however, these injections can be painful, necessitating visits to an eye specialist’s office or clinic every month, with missing even one session leading to further vision loss – further increasing costs with progressing disease.

Researchers led by Professor Akrit Sodhi of Johns Hopkins University School of Medicine and Wilmer Eye Institute examined medical records of 106 individuals with wet AMD who had been receiving anti-VEGF treatments for at least three years to conduct this analysis.

Investigators compared results between those receiving monthly injections vs those who discontinued therapy and found that approximately one third of those who discontinued did not experience further vision loss when discontinuing medication, according to Sodhi in a news release. Sodhi speculated that future research could provide accurate predictions of which patients could safely stop their medications without experiencing further vision loss, thus leading to an accurate test for safe discontinuance.

Though the findings from this study are intriguing, experts caution against drawing too many conclusions due to its small sample size and disparate timing of injections between those who did and did not continue treatment. Furthermore, results may not apply equally across forms of the drugs aflibercept and ranibizumab used in this research study.

A New Drug May Be Twice as Good at Fighting Vision Loss as Previously Thought

Doctors currently utilize anti-VEGF injections to help slow or stop further vision loss among those with wet macular degeneration. Leakage from blood vessels under the macula creates abnormal deposits called drusen which eventually cause retinal pigment layer degradation, leading to vision loss and resulting in geographic atrophy or the gradual disappearance of macula.

Over time, however, these medications may become ineffective and some patients must visit their physician more frequently to stay under control of the disease. A possible new solution may soon emerge; scientists have recently identified that bevacizumab-based drugs are twice as effective at preventing abnormal blood vessel formation; their successor drug works by blocking different proteins. Its clinical trials have begun.

Researchers tested AXT107’s effectiveness by injecting it into engineered mice with leaky blood vessels similar to those seen in wet macular degeneration. When they observed these animals’ eye fluids using fluorescent dye, AXT107 quickly sealed up these leaky vessels, preventing vision-blocking fluids from seeping into surrounding tissue and disrupting vision.

A randomized trial is necessary to ascertain whether AXT107 can help some people who require monthly injections for wet macular degeneration to reduce the frequency of their doctor visits and potentially even wean off these drugs altogether. Doctors can use photodynamic therapy, an advanced form of light-sensitive medicine administered intravenously and then activated by shining a laser beam into the eye, to target abnormal blood vessels with light. Once activated by exposure to light, blood clots form under the retina sealing off leaky vessels causing leakage from leaky vessels to be sealed off with blood clots created under retina, effectively sealing leaky vessels off.

Dr. Neil Bressler serves as chief of retinal division at Wilmer Eye Institute and holds an endowed chair as James P. Gills Professor of Ophthalmology at Johns Hopkins University School of Medicine. After earning an outstanding academic career from Smith College and earning his MD at Johns Hopkins School of Medicine respectively in 1982; followed by completion of an ophthalmology residency at Harvard Medical School’s Massachusetts Eye and Ear Infirmary residency from 1986.

A Study of Eye Fluid Finds That Levels of a Specific Protein May Help Accurately Predict Whether People with Wet AMD May Need Lifelong Injection Therapy

Anti-VEGF injections, designed to slow or stop leaky blood vessel growth that leads to vision loss, are the standard approach in treating wet age-related macular degeneration; Sodhi has long pondered whether proteins present in Aqueous Humor could provide insight into when patients might safely reduce or discontinue injections without further risking their vision loss.

His team collected AqH samples from 38 patients who started regular treatments for wet AMD at Wilmer Eye Institute between 2013 and 2020 at two Maryland locations. Researchers then analyzed this AqH for signs of protein expression in retina, which they knew could be affected by abnormal blood vessel growth. Their research team discovered that those requiring monthly injections had higher concentrations of angiopoietin-like 4 protein in their eye fluid.

Sodhi’s team found that measuring levels of angiopoietin-like four accurately predicted actual clinical outcomes with 91% accuracy among those receiving monthly injections, and helped identify 71% of them who may eventually need less frequent treatments, or possibly discontinuing altogether.

After these results were published, the team conducted further trials with small implantable devices designed to block angiopoietin-like 4 using nanoparticles developed in their lab to deliver genetically engineered versions of angiopoietin-like 4, specifically targeting eye cells where it would block release of vascular endothelial growth factor, or VEGF which is known to promote abnormal blood vessel growth resulting in wet AMD progression.

Researchers next turned their focus toward photodynamic therapy (PDT). With PDT, patients receive an intravenous infusion of medication that binds only under the retina; then using special lenses on both eyes, laser light is directed directly at the macula; when this light hits it binds to abnormal blood vessels and closes them off effectively preserving vision by stopping further growth and maintaining quality vision.