Vision is one of our primary ways of interacting with the world around us. Light enters the eye through the cornea and lens, the two components that create the clear, outermost layer of the eye. The cornea and lens then work together to focus the incoming light onto the retina, the light-receptive part of the eye. Disrupting any part of this process results in loss of visual perception, and even blindness.
Several research groups in the Johns Hopkins Institute for Basic Biomedical Sciences are devoted to understanding how our eyes capture light and turn it into a message the brain can comprehend. Figuring out the steps of this process will help reveal which steps have gone awry and caused blindness, and will eventually lead scientists to new treatments.
King Wai Yau, professor of neuroscience and ophthalmology, studies how the eye harnesses light and translates it into a language the brain recognizes.
During his career, Yau has revealed many of the individual steps of visual perception, which helped other scientists pinpoint many causes of blindness and develop targeted treatments. Yau also studies how certain biological clocks, such as our sleep/wake cycle, respond to light in their own ways.
His findings helped explain why, in many types of blindness, nonvisual light cues still make patients sleepy at night, and alert during the day, despite their inability to see images.
Seth Blackshaw, also a professor of neuroscience, identifies the combinations of genes in developing brain cells that form the retina.
Since the retina is an extension of the brain, Blackshaw views photoreceptor dystrophies, diseases in which the light-sensing cells of the retina degenerate, as neurodegenerative disorders.
However, in contrast to the many factors and cell types in the brain, only seven types of cells form the retina, making it easier to decode which factors influence a developing brain cell to become a retina cell.
By figuring out how this happens, Blackshaw and colleagues hope to identify steps in the process that could be targeted by therapies to delay or reverse disorders that lead to blindness. The eye’s physical isolation from other organs in the body makes it an ideal candidate for targeting such treatments in a contained manner.
Treating Blindness and Vision Loss – Restoring Eyesight
En español | If you had seen Lisa Kulik and her husband strolling the grounds of the University of Southern California's Eye Institute last summer, you would have thought nothing of it.
But for Kulik, that simple walk around the campus was “a miracle.
” Blind for more than two decades from an inherited eye disease called retinitis pigmentosa, Kulik was seeing again — clearly enough to make out the sidewalk and the grassy edge — thanks to a sophisticated microchip implanted in one of her eyes.
The device, called the Argus II, is just one of a growing number of bold new approaches to treating blindness, offering hope to the millions of mostly older Americans in danger of losing their sight from macular degeneration, glaucoma, diabetic retinopathy and other eye diseases.
In fact, progress in ophthalmology is so rapid that some researchers have already begun to envision an end to many forms of vision loss. “We still have a lot to learn,” admits Stephen Rose, chief research officer for the Foundation Fighting Blindness. “But it's not a question of if we'll end blindness.
It's really just a question of when.”
Joe Vellone, 76, received a telescope implant to improve his vision.
For years, Joe Vellone, 76, watched his sight gradually deteriorate from age-related macular degeneration (AMD), a condition in which the light-sensitive cells of the macula — the central part of the retina — are destroyed. “My vision was so bad I'd walk right by people I know because I didn't see them. I couldn't read at all,” says Vellone, who lives in Somers, N.Y., with his wife.
Researchers may have discovered a way to reverse blindness
Visual impairment is still rather rampant, according to the World Health Organization (WHO). Some 285 million people worldwide are considered visually impaired, and 39 million of them are blind. Thankfully, 80 percent of all visual impairment can now be treated or cured, except in cases of total loss of sight, particularly those due to severe retinal degeneration.
But what if it’s possible to restore visual function to blind patients? Laboratory tests in the University of Oxford demonstrate how this may be possible.
In a study published in the journal of the Proceedings of the National Academy of Sciences (PNAS), the Oxford researchers led by Samantha de Silva showed how it’s possible to restore the sight of people suffering from blindness previously considered untreatable.
“Inherited retinal degenerations may result in blindness due to a progressive loss of photoreceptor cells,” the researchers wrote. “We assess subretinal delivery of human melanopsin using an adeno-associated viral vector to remaining retinal cells in a model of end-stage retinal degeneration.”
Using gene therapy, the researchers introduced a viral vector in retinal cells found at the back of the eyes that weren’t originally sensitive to light.
The viral vector introduces a light-sensitive protein called melanopsin, which enables these residual retinal cells to respond to light and send visual signals to the brain.
In lab tests with mice suffering from retinitis pigmentosa, the most common cause of blindness in young people, the researchers were able to maintain sight in the mice for over a year. The mice demonstrated high levels of visual perception, recognizing objects in their environment.
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It’s worth noting that de Silva and her colleagues have also been successfully trialing an electronic retina. However, they observed that gene therapy may be simpler and easier to administer. Similar work has been done by others involving age-related blindness, while an FDA-approved gene therapy seeks to cure hereditary retinal blindness.
The results are quite promising, and de Silva noted how much hope this treatment gives to patients suffering from blindness. “There are many blind patients in our clinics and the ability to give them some sight back with a relatively simple genetic procedure is very exciting,” she said in a press release. “Our next step will be to start a clinical trial to assess this in patients.”
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With single gene insertion, blind mice regain sight
Adeno-associated viruses (AAV) engineered to target specific cells in the retina can be injected directly into the vitreous of the eye to deliver genes more precisely than can be done with wild type AAVs, which have to be injected directly under the retina. UC Berkeley neuroscientists have taken AAVs targeted to ganglion cells, loaded them with a gene for green opsin, and made the normally blind ganglion cells sensitive to light. Credit: John Flannery, UC Berkeley
It was surprisingly simple. University of California, Berkeley, scientists inserted a gene for a green-light receptor into the eyes of blind mice and, a month later, they were navigating around obstacles as easily as mice with no vision problems. They were able to see motion, brightness changes over a thousandfold range and fine detail on an iPad sufficient to distinguish letters.
The researchers say that, within as little as three years, the gene therapy—delivered via an inactivated virus—could be tried in humans who've lost sight because of retinal degeneration, ideally giving them enough vision to move around and potentially restoring their ability to read or watch video.
“You would inject this virus into a person's eye and, a couple months later, they'd be seeing something,” said Ehud Isacoff, a UC Berkeley professor of molecular and cell biology and director of the Helen Wills Neuroscience Institute. “With neurodegenerative diseases of the retina, often all people try to do is halt or slow further degeneration. But something that restores an image in a few months—it is an amazing thing to think about.”
About 170 million people worldwide live with age-related macular degeneration, which strikes one in 10 people over the age of 55, while 1.7 million people worldwide have the most common form of inherited blindness, retinitis pigmentosa, which typically leaves people blind by the age of 40.
OHSU doctors edit a person’s genes inside the eye to try to reverse blindness
By MARILYNN MARCHIONE, AP Chief Medical Writer
Scientists at Oregon Health & Science University say they have used the gene editing tool CRISPR inside someone’s body for the first time, a new frontier for efforts to operate on DNA to treat diseases.
A patient recently had it done at OHSU’s Casey Eye Institute in Portland for an inherited form of blindness, the companies that make the treatment announced Wednesday. They would not give details on the patient or when the surgery occurred.
It may take up to a month to see if it worked to restore vision. If the first few attempts seem safe, doctors plan to test it on 18 children and adults.
“We literally have the potential to take people who are essentially blind and make them see,” said Charles Albright, chief scientific officer at Editas Medicine, the Cambridge, Massachusetts-based company developing the treatment with Dublin-based Allergan. “We think it could open up a whole new set of medicines to go in and change your DNA.”
Dr. Jason Comander, an eye surgeon at Massachusetts Eye and Ear in Boston, another hospital that plans to enroll patients in the study, said it marks “a new era in medicine” using a technology that “makes editing DNA much easier and much more effective.”
Doctors first tried in-the-body gene editing in 2017 for a different inherited disease using a tool called zinc fingers. Many scientists believe CRISPR is a much easier tool for locating and cutting DNA at a specific spot, so interest in the new research is very high.
The people in this study have Leber congenital amaurosis, caused by a gene mutation that keeps the body from making a protein needed to convert light into signals to the brain, which enables sight. They're often born with little vision and can lose even that within a few years.
Scientists can't treat it with standard gene therapy — supplying a replacement gene — because the one needed is too big to fit inside the disabled viruses that are used to ferry it into cells.
So they're aiming to edit, or delete the mutation by making two cuts on either side of it. The hope is that the ends of DNA will reconnect and allow the gene to work as it should.
It's done in an hour-long surgery under general anesthesia. Through a tube the width of a hair, doctors drip three drops of fluid containing the gene editing machinery just beneath the retina, the lining at the back of the eye that contains the light-sensing cells.
“Once the cell is edited, it's permanent and that cell will persist hopefully for the life of the patient,” because these cells don't divide, said one study leader not involved in this first case, Dr. Eric Pierce at Massachusetts Eye and Ear.
Doctors think they need to fix one tenth to one third of the cells to restore vision. In animal tests, scientists were able to correct half of the cells with the treatment, Albright said.
The eye surgery itself poses little risk, doctors say. Infections and bleeding are relatively rare complications.
One of the biggest potential risks from gene editing is that CRISPR could make unintended changes in other genes, but the companies have done a lot to minimize that and to ensure that the treatment cuts only where it's intended to, Pierce said. He has consulted for Editas and helped test a gene therapy, Luxturna, that's sold for a different type of inherited blindness.
Some independent experts were optimistic about the new study.
Mission and History
Passion and Focus
The Foundation Fighting Blindness was established in 1971 by a passionate group of individuals driven to find treatments and cures for blinding retinal diseases that were affecting themselves or loved ones. At the time, very little was known about these devastating retinal degenerative diseases that lead to blindness.
The Foundation’s goal was clear: To drive the research that would lead to preventions, treatments and vision restoration for the degenerative retinal diseases – including macular degeneration, retinitis pigmentosa, and Usher syndrome – that together affect more than 10 million Americans and millions more throughout the world.
Today, the Foundation is the world’s leading private source for inherited retinal disease research funding. The Foundation is committed to driving research until the entire spectrum of retinal degenerative diseases is eradicated.
Key Facts about the Foundation
During its now 47 year history, the Foundation has raised over $760 million in support of its effort to reverse blindness and restore vision.
The Foundation has over 40 volunteer-led chapters across the U.S. These dedicated volunteers raise funds, increase public awareness, and provide support to families affected by retinal diseases in their communities.
In 2014, the Foundation kicked off Envision 20/20, a campaign to end blindness and raise the funds necessary to advance current and future research. To accelerate funding, then FFB Chairman, Gordon Gund and his wife, Llura, created The Gordon and Llura Gund Family Challenge. The Gund Family Challenge closed in June of 2016 having raised over $111 million for retinal disease research.
Over the past four decades, the Foundation has raised over $760 million to support and advance the research that will reverse blindness and restore vision.
Gene Therapy Restores Vision
Gene therapy shows promise for reversing blindness
In a laboratory study in Oxford, researchers have shown how it might be possible to reverse blindness using gene therapy to reprogram cells at the back of the eye to become light sensitive. Most causes of untreatable blindness occur due to loss of the millions of light sensitive photoreceptor cells that line the retina, similar to the pixels in a digital camera.
The remaining retinal nerve cells which are not light sensitive however remain in the eye. Samantha de Silva and colleagues used a viral vector to express a light sensitive protein, melanopsin, in the residual retinal cells in mice which were blind from retinitis pigmentosa, the most common cause of blindness in young people.
The mice were monitored for over a year and they maintained vision during this time, being able to recognise objects in their environment which indicated a high level of visual perception.
The cells expressing melanopsin were able to respond to light and send visual signals to the brain.
The Oxford team has also been trialling an electronic retina successfully in blind patients, but the genetic approach may have advantages in being simpler to administer.
The research was led by Professors Robert MacLaren and Mark Hankins at the Nuffield Laboratory of Ophthalmology in Oxford.
Samantha de Silva, the lead author of the study said: 'There are many blind patients in our clinics and the ability to give them some sight back with a relatively simple genetic procedure is very exciting.
Our next step will be to start a clinical trial to assess this in patients.'
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Materials provided by University of Oxford. Note: Content may be edited for style and length.
- Samantha R. De Silva, Alun R. Barnard, Steven Hughes, Shu K. E. Tam, Chris Martin, Mandeep S. Singh, Alona O. Barnea-Cramer, Michelle E. McClements, Matthew J. During, Stuart N. Peirson, Mark W. Hankins, Robert E. MacLaren. Long-term restoration of visual function in end-stage retinal degeneration using subretinal human melanopsin gene therapy. Proceedings of the National Academy of Sciences, 2017; 201701589 DOI: 10.1073/pnas.1701589114
Curing blindness with stem cells – here’s the latest science
In 2006, Nature published a paper describing how stem cells could be used to restore sight in blind mice. This study, and similar subsequent studies, created a lot of excitement about the potential of stem cells to cure blindness in humans.
Fast forward 12 years and we still don’t seem to be quite there – one notable human clinical trial in Japan was stopped in 2015 due to a risk of tumour development in a patient’s eye.
So are we any closer to using stem cell therapies to treat blindness, or will we always be “ten years away”?
The retina is an important tissue at the back of the eye that senses light and sends visual information to the brain. Eye diseases such as glaucoma and macular degeneration are characterised by damage to retina cells, which can eventually lead to vision loss and blindness. Scientists hope to find a way to replace or preserve damaged retina cells in order to treat these eye diseases.
Stem cells might be useful for this because they can be triggered to turn into any type of cell. In 2010 scientists successfully guided stem cells into becoming retina cells in a laboratory. It is hoped that these cells could later be delivered into the diseased eye to replace or preserve damaged retina cells.
Although scientists have previously had success isolating and maintaining retina stem cells in the laboratory, there is still more work to do before these cells can be routinely delivered to patients for treatment.
The first big challenge is figuring out how treatments can safely be delivered into the patient’s eye in the right location.
The eye is such a small and fragile organ that injection needles and surgery may cause even greater damage to the eye.
Once a delivery method has been established, the next challenge is deciding how to get the stem cells to communicate with existing retina cells and function properly inside the eye. Getting this to happen is not easy and there are risks that the stem cells may not function correctly and could cause problems, such as inflammation and tumour development, inside the eye.
Stem cells created with new reprogramming method could help blindness
A team of researchers from John Hopkins Medicine (MD, USA) have reprogrammed fibroblast cells to a state more primitive than human pluripotent stem cells, which may be more similar to the state of embryonic cells six days after fertilization. The findings from this study, published in Nature Communications, may enhance the regenerative medicine techniques and help reverse the progression of diabetic retinopathy.
The team bathed fibroblast cells in a chemical mixture called 3i. The mixture included two chemicals previously used by scientists to reprogram stem cells: GSK3Î² inhibitor CHIR99021, which works by blocking carbohydrate storage in cells, and MEK inhibitor PD0325901, which works by blocking cancer cell growth. The new component in the mixture was a PARP inhibitor.
“Our study results bring us a step closer to using stem cells more widely in regenerative medicine, without the historical problems our field has encountered in getting such cells to differentiate and avoid becoming cancerous,” explained Elias Zambidis (Johns Hopkins Kimmel Cancer Center; MD, USA).
The researchers tracked the reprogrammed stem cells’ molecular profile and measured the protein level of NANOG, NR5A2, DPPA3 and E-cadherin. The team found the molecular profile to be similar to naÃ¯ve epiblast cells.
Lab-made stem cells are often affected by epigenetic alterations and genetic aberations, however, the stem cells in this study that had been reprogrammed with the 3i chemical mixture had no abnormal changes to the DNA.
Vascular progenitors were created from the fibroblast cells of type I diabetic patients, passing through the naÃ¯ve stem cell state recreated by the 3i cocktail.
These vascular cells where then injected into the eyes of mice bred specifically to have a form of diabetic blindness. The vascular progenitors migrated into the retina’s innermost tissue layer that encircles the eye.
The naive vascular cells remained in the retina and most survived the duration of the four-week study.
The researchers also reprogrammed diabetic fibroblasts into non-naÃ¯ve stem cells using a more conventional method, in order to compare their result. They found that the vascular progenitor cells created this way failed to migrate as deeply or survive the four-week study.
“Interestingly, the 3i ‘naÃ¯ve reprogramming’ cocktail appeared to erase disease-associated epigenetics in the donor cells, and brought them back to a healthy, pristine non-diabetic stem cell state,” concluded Zambidis.
Further experiments are required in order to refine the 3i mixture and study the regenerative capacity of the stem cells grown from the mixture.
Source: Park T, Zimmerlin L, Evans-Moses R, et al. Vascular progenitors generated from tankyrase inhibitor-regulated naÃ¯ve diabetic human iPSC potentiate efficient revascularization of ischemic retina. Nat. Comm. 1195(11), (2020).