Why Blindness Will Be the First Disorder Cured by Futuristic Treatments
Stem cells and gene therapy were supposed to revolutionize biomedicine around the turn of the millennium and provide relief for desperate patients with incurable diseases. But for many, progress has been frustratingly slow. We still cannot, for example, regenerate damaged organs like a salamander regrows its tail, and genome engineering is more complicated than cutting and pasting letters in a word document.
"There are a number of things that make [the eye] ideal for new experimental therapies which are not true necessarily in other organs."
For blind people, however, the future of medicine is one step closer to reality. In December, the FDA approved the first gene therapy for an inherited disease—a mutation in the gene RPE65 that causes a rare form of blindness. Several clinical trials also show promise for treating various forms of retinal degeneration using stem cells.
"It's not surprising that the first gene therapy that was approved by the FDA was a therapy in the eye," says Bruce Conklin, a senior investigator at the San Francisco-based Gladstone Institutes, a nonprofit life science research organization, and a professor in the Medical Genetics and Molecular Pharmacology department at the University of California, San Francisco. "There are a number of things that make it ideal for new experimental therapies which are not true necessarily in other organs."
Physicians can easily see into the eye to check if a procedure worked or if it's causing problems. "The imaging technology within the eye is really unprecedented. You can't do this in someone's spinal cord or someone's brain cells or immune system," says Conklin, who is also deputy director of the Innovative Genomics Institute.
There's also a built-in control: researchers can test an intervention on one eye first. What's more, if something goes wrong, the risk of mortality is low, especially when compared to experimenting on the heart or brain. Most types of blindness are currently incurable, so the risk-to-reward ratio for patients is high. If a problem arises with the treatment their eyesight could get worse, but if they do nothing their vision will likely decline anyway. And if the treatment works, they may be able to see for the first time in years.
Gene Therapy
An additional appeal for testing gene therapy in the eye is the low risk for off-target effects, in which genome edits could result in unintended changes to other genes or in other cell types. There are a number of genes that are solely expressed in the eye and not in any other part of the body. Manipulating those genes will only affect cells in the eye, so concerns about the impact on other organs are minimal.
Ninety-three percent of patients who received the injection had improved vision just one month after treatment.
RPE65 is one such gene. It creates an enzyme that helps the eye convert light into an electrical signal that travels back to the brain. Patients with the mutation don't produce the enzyme, so visual signals are not processed. However, the retinal cells in the eye remain healthy for years; if you can restore the missing enzyme you can restore vision.
The newly approved therapy, developed by Spark Therapeutics, uses a modified virus to deliver RPE65 into the eye. A retinal surgeon injects the virus, which has been specially engineered to remove its disease-causing genes and instead carry the correct RPE65 gene, into the retina. There, it is sucked up by retinal pigment epithelial (RPE) cells. The RPE cells are a particularly good target for injection because their job is to eat up and recycle rogue particles. Once inside the cell, the virus slips into the nucleus and releases the DNA. The RPE65 gene then goes to work, using the cell's normal machinery to produce the needed enzyme.
In the most recent clinical trial, 93 percent of patients who received the injection—who range in age from 4 to 44—had improved vision just one month after treatment. So far, the benefits have lasted at least two years.
"It's an exciting time for this class of diseases, where these people have really not had treatments," says Spark president and co-founder, Katherine High. "[Gene therapy] affords the possibility of treatment for diseases that heretofore other classes of therapeutics really have not been able to help."
Stem Cells
Another benefit of the eye is its immune privilege. In order to let light in, the eye must remain transparent. As a result, its immune system is dampened so that it won't become inflamed if outside particles get in. This means the eye is much less likely to reject cell transplants, so patients do not need to take immunosuppressant drugs.
One study generating buzz is a clinical trial in Japan that is the first and, so far, only test of induced pluripotent stem cells in the eye.
Henry Klassen, an assistant professor at UC Irvine, is taking advantage of the eye's immune privilege to transplant retinal progenitor cells into the eye to treat retinitis pigmentosa, an inherited disease affecting about 1 in 4000 people that eventually causes the retina to degenerate. The disease can stem from dozens of different genetic mutations, but the result is the same: RPE cells die off over the course of a few decades, leaving the patient blind by middle age. It is currently incurable.
Retinal progenitor cells are baby retinal cells that develop naturally from stem cells and will turn into one of several types of adult retinal cells. When transplanted into a patient's eye, the progenitor cells don't replace the lost retinal cells, but they do secrete proteins and enzymes essential for eye health.
"At the stage we get the retinal tissue it's immature," says Klassen. "They still have some flexibility in terms of which mature cells they can turn into. It's that inherent flexibility that gives them a lot of power when they're put in the context of a diseased retina."
Klassen's spin-off company, jCyte, sponsored the clinical trial with support from the California Institute for Regenerative Medicine. The results from the initial study haven't been published yet, but Klassen says he considers it a success. JCyte is now embarking on a phase two trial to assess improvements in vision after the treatment, which will wrap up in 2021.
Another study generating buzz is a clinical trial in Japan that is the first and, so far, only test of induced pluripotent stem cells (iPSC) in the eye. iPSC are created by reprogramming a patient's own skin cells into stem cells, circumventing any controversy around embryonic stem cell sources. In the trial, led by Masayo Takahashi at RIKEN, the scientists transplant retinal pigment epithelial cells created from iPSC into the retinas of patients with age-related macular degeneration. The first woman to receive the treatment is doing well, and her vision is stable. However, the second patient suffered a swollen retina as a result of the surgery. Despite this recent setback, Takahashi said last week that the trial would continue.
Botched Jobs
Although recent studies have provided patients with renewed hope, the field has not been without mishap. Most notably, an article in the New England Journal of Medicine last March described three patients who experienced severe side effects after receiving stem cell injections from a Florida clinic to treat age-related macular degeneration. Following the initial article, other reports came out about similar botched treatments. Lawsuits have been filed against US Stem Cell, the clinic that conducted the procedure, and the FDA sent them a warning letter with a long list of infractions.
"One red flag is that the clinics charge patients to take part in the treatment—something extremely unusual for legitimate clinical trials."
Ajay Kuriyan, an ophthalmologist and retinal specialist at the University of Rochester who wrote the paper, says that because details about the Florida trial are scarce, it's hard to say why the treatment caused the adverse reaction. His guess is that the stem cells were poorly prepared and not up to clinical standards.
Klassen agrees that small clinics like US Stem Cell do not offer the same caliber of therapy as larger clinical trials. "It's not the same cells and it's not the same technique and it's not the same supervision and it's not under FDA auspices. It's just not the same thing," he says. "Unfortunately, to the patient it might sound the same, and that's the tragedy for me."
For patients who are interested in joining a trial, Kuriyan listed a few things to watch out for. "One red flag is that the clinics charge patients to take part in the treatment—something extremely unusual for legitimate clinical trials," he says. "Another big red flag is doing the procedure in both eyes" at the same time. Third, if the only treatment offered is cell therapy. "These clinics tend to be sort of stand-alone clinics, and that's not very common for an actual big research study of this scale."
Despite the recent scandal, Klassen hopes that the success of his trial and others will continue to push the field forward. "It just takes so many decades to move this stuff along, even when you're trying to simplify it as much as possible," he says. "With all the heavy lifting that's been done, I hope the world's got the patience to get this through."
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on new scientific theories and progress to give you a therapeutic dose of inspiration headed into the weekend.
This episode includes an interview with Dr. Helen Keyes, Head of the School of Psychology and Sports Science at Anglia Ruskin University.
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As a graduate student in observational astronomy at the University of Arizona during the 1970s, Diane Turnshek remembers the starry skies above the Kitt Peak National Observatory on the Tucson outskirts. Back then, she could observe faint objects like nebulae, galaxies, and star clusters on most nights.
When Turnshek moved to Pittsburgh in 1981, she found it almost impossible to see a clear night sky because the city’s countless lights created a bright dome of light called skyglow. Over the next two decades, Turnshek almost forgot what a dark sky looked like. She witnessed pristine dark skies in their full glory again during a visit to the Mars Desert Research Station in Utah in early 2000s.
“I was shocked at how beautiful the dark skies were in the West. That is when I realized that most parts of the world have lost access to starry skies because of light pollution,” says Turnshek, an astronomer and lecturer at Carnegie Mellon University. In 2015, she became a dark sky advocate.
Light pollution is defined as the excessive or wasteful use of artificial light.
Light-emitting diodes (LEDs) -- which became commercially available in 2002 and rapidly gained popularity in offices, schools, and hospitals when their price dropped six years later — inadvertently fueled the surge in light pollution. As traditional light sources like halogen, fluorescent, mercury, and sodium vapor lamps have been phased out or banned, LEDs became the main source of lighting globally in 2019. Switching to LEDs has been lauded as a win-win decision. Not only are they cheap but they also consume a fraction of electricity compared to their traditional counterparts.
But as cheap LED installations became omnipresent, they increased light pollution. “People have been installing LEDs thinking they are making a positive change for the environment. But LEDs are a lot brighter than traditional light sources,” explains Ashley Wilson, director of conservation at the International Dark-Sky Association (IDA). “Despite being energy-efficient, they are increasing our energy consumption. No one expected this kind of backlash from switching to LEDs.”
Light pollution impacts the circadian rhythms of all living beings — the natural internal process that regulates the sleep–wake cycle.
Currently, more than 80 percent of the world lives under light-polluted skies. In the U.S. and Europe, that figure is above 99 percent.
According to the IDA, $3 billion worth of electricity is lost to skyglow every year in the U.S. alone — thanks to unnecessary and poorly designed outdoor lighting installations. Worse, the resulting light pollution has insidious impacts on humans and wildlife — in more ways than one.
Disrupting the brain’s clock
Light pollution impacts the circadian rhythms of all living beings—the natural internal process that regulates the sleep–wake cycle. Humans and other mammals have neurons in their retina called intrinsically photosensitive retinal ganglion cells (ipRGCs). These cells collect information about the visual world and directly influence the brain’s biological clock in the hypothalamus.
The ipRGCs are particularly sensitive to the blue light that LEDs emit at high levels, resulting in suppression of melatonin, a hormone that helps us sleep. A 2020 JAMA Psychiatry study detailed how teenagers who lived in areas with bright outdoor lighting at night went to bed late and slept less, which made them more prone to mood disorders and anxiety.
“Many people are skeptical when they are told something as ubiquitous as lights could have such profound impacts on public health,” says Gena Glickman, director of the Chronobiology, Light and Sleep Lab at Uniformed Services University. “But when the clock in our brains gets exposed to blue light at nighttime, it could result in a lot of negative consequences like impaired cognitive function and neuro-endocrine disturbances.”
In the last 12 years, several studies indicated that light pollution exposure is associated with obesity and diabetes in humans and animals alike. While researchers are still trying to understand the exact underlying mechanisms, they found that even one night of too much light exposure could negatively affect the metabolic system. Studies have linked light pollution to a higher risk of hormone-sensitive cancers like breast and prostate cancer. A 2017 study found that female nurses exposed to light pollution have a 14 percent higher risk of breast cancer. The World Health Organization (WHO) identified long-term night shiftwork as a probable cause of cancer.
“We ignore our biological need for a natural light and dark cycle. Our patterns of light exposure have consequently become different from what nature intended,” explains Glickman.
Circadian lighting systems, designed to match individuals’ circadian rhythms, might help. The Lighting Research Center at Rensselaer Polytechnic Institute developed LED light systems that mimic natural lighting fluxes, required for better sleep. In the morning the lights shine brightly as does the sun. After sunset, the system dims, once again mimicking nature, which boosts melatonin production. It can even be programmed to increase blue light indoors when clouds block sunlight’s path through windows. Studies have shown that such systems might help reduce sleep fragmentation and cognitive decline. People who spend most of their day indoors can benefit from such circadian mimics.
When Diane Turnshek moved to Pittsburgh, she found it almost impossible to see a clear night sky because the city’s countless lights created a bright dome of light called skyglow.
Diane Turnshek
Leading to better LEDs
Light pollution disrupts the travels of millions of migratory birds that begin their long-distance journeys after sunset but end up entrapped within the sky glow of cities, becoming disoriented. A 2017 study in Nature found that nocturnal pollinators like bees, moths, fireflies and bats visit 62 percent fewer plants in areas with artificial lights compared to dark areas.
“On an evolutionary timescale, LEDs have triggered huge changes in the Earth’s environment within a relative blink of an eye,” says Wilson, the director of IDA. “Plants and animals cannot adapt so fast. They have to fight to survive with their existing traits and abilities.”
But not all types of LEDs are inherently bad -- it all comes down to how much blue light they emit. During the day, the sun emits blue light waves. By sunset, red and orange light waves become predominant, stimulating melatonin production. LED’s artificial blue light, when shining at night, disrupts that. For some unknown reason, there are more bluer color LEDs made and sold.
“Communities install blue color temperature LEDs rather than redder color temperature LEDs because more of the blue ones are made; they are the status quo on the market,” says Michelle Wooten, an assistant professor of astronomy at the University of Alabama at Birmingham.
Most artificial outdoor light produced is wasted as human eyes do not use them to navigate their surroundings.
While astronomers and the IDA have been educating LED manufacturers about these nuances, policymakers struggle to keep up with the growing industry. But there are things they can do—such as requiring LEDs to include dimmers. “Most LED installations can be dimmed down. We need to make the dimmable drivers a mandatory requirement while selling LED lighting,” says Nancy Clanton, a lighting engineer, designer, and dark sky advocate.
Some lighting companies have been developing more sophisticated LED lights that help support melatonin production. Lighting engineers at Crossroads LLC and Nichia Corporation have been working on creating LEDs that produce more light in the red range. “We live in a wonderful age of technology that has given us these new LED designs which cut out blue wavelengths entirely for dark-sky friendly lighting purposes,” says Wooten.
Dimming the lights to see better
The IDA and advocates like Turnshek propose that communities turn off unnecessary outdoor lights. According to the Department of Energy, 99 percent of artificial outdoor light produced is wasted as human eyes do not use them to navigate their surroundings.
In recent years, major cities like Chicago, Austin, and Philadelphia adopted the “Lights Out” initiative encouraging communities to turn off unnecessary lights during birds’ peak migration seasons for 10 days at a time. “This poses an important question: if people can live without some lights for 10 days, why can’t they keep them turned off all year round,” says Wilson.
Most communities globally believe that keeping bright outdoor lights on all night increases security and prevents crime. But in her studies of street lights’ brightness levels in different parts of the US — from Alaska to California to Washington — Clanton found that people felt safe and could see clearly even at low or dim lighting levels.
Clanton and colleagues installed LEDs in a Seattle suburb that provided only 25 percent of lighting levels compared to what they used previously. The residents reported far better visibility because the new LEDs did not produce glare. “Visual contrast matters a lot more than lighting levels,” Clanton says. Additionally, motion sensor LEDs for outdoor lighting can go a long way in reducing light pollution.
Flipping a switch to preserve starry nights
Clanton has helped draft laws to reduce light pollution in at least 17 U.S. states. However, poor awareness of light pollution led to inadequate enforcement of these laws. Also, getting thousands of counties and municipalities within any state to comply with these regulations is a Herculean task, Turnshek points out.
Fountain Hills, a small town near Phoenix, Arizona, has rid itself of light pollution since 2018, thanks to the community's efforts to preserve dark skies.
Until LEDs became mainstream, Fountain Hills enjoyed starry skies despite its proximity to Phoenix. A mountain surrounding the town blocks most of the skyglow from the city.
“Light pollution became an issue in Fountain Hills over the years because we were not taking new LED technologies into account. Our town’s lighting code was antiquated and out-of-date,” says Vicky Derksen, a resident who is also a part of the Fountain Hills Dark Sky Association founded in 2017. “To preserve dark skies, we had to work with the entire town to update the local lighting code and convince residents to follow responsible outdoor lighting practices.”
Derksen and her team first tackled light pollution in the town center which has a faux fountain in the middle of a lake. “The iconic centerpiece, from which Fountain Hills got its name, had the wrong types of lighting fixtures, which created a lot of glare,” adds Derksen. They then replaced several other municipal lighting fixtures with dark-sky-friendly LEDs.
The results were awe-inspiring. After a long time, residents could see the Milky Way with crystal clear clarity. Star-gazing activities made a strong comeback across the town. But keeping light pollution low requires constant work.
Derksen and other residents regularly measure artificial light levels in
Fountain Hills. Currently, the only major source of light pollution is from extremely bright, illuminated signs which local businesses had installed in different parts of the town. While Derksen says it is an uphill battle to educate local businesses about light pollution, Fountain Hills residents are determined to protect their dark skies.
“When a river gets polluted, it can take several years before clean-up efforts see any tangible results,” says Derksen. “But the effects are immediate when you work toward reducing light pollution. All it requires is flipping a switch.”