AMD is a complex disease with advancing age, a history of smoking, and genetics being major risk factors.
Researchers have determined that the complement system – part of the innate immune system which fights off bacteria and other pathogens – is overactive in people with AMD, leading to retinal degeneration.
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Virtually everyone who has AMD starts off with the dry form. The hallmark of dry AMD is the buildup of drusen deposits underneath or near the central region (macula) of the retina. These deposits are comprised of lipids (fats) and proteins. Many people develop drusen as they age. Certain types of drusen (the soft and large types) are more likely to lead to loss of retinal cells and vision loss.
In some cases, people with dry AMD develop wet AMD which is characterized by the growth of leaky, damaging blood vessels underneath the retina. People with wet AMD experience changes in vision relatively quickly – in a matter of weeks or even days. Retina doctors have injectable treatments that are FDA-approved for wet AMD and are most effective when administered at early stages of the condition.
Many people with dry AMD – the early and intermediate forms – never experience any significant vision loss. However, dry AMD can progress to an advanced condition known as geographic atrophy (GA) which often leads to significant central vision loss. Vision loss from GA is typically more gradual than it is from wet AMD. Approximately 5 million people around the world have GA with 1 million in the US affected.
GA is characterized by the loss of retinal pigment epithelial (RPE) cells which provide support for photoreceptors, the cells that make vision possible, as well as degeneration of the choriocapillaris, a layer of capillaries underneath the retina. Loss of the RPE cells and the choriocapillaris ultimately lead to loss of photoreceptors, and subsequently, central vision. People with GA develop what are known as scotomas, blind spots in or near their central field of vision. The scotomas grow in area over time causing more central vision loss.
In February 2023, SYFOVRETM became the first FDA-approved treatment for GA. Developed by Apellis, the therapy slows the growth rate of the lesions (regions of retinal cell degeneration) that lead to central vision loss. SYFOVRE is injected into the middle of the eye by a retinal specialist once every 25 to 60 days. The treatment works by inhibiting the C3 protein which is associated with an overactive and damaging innate immune system.
Iveric Bio is seeking FDA approval for its emerging GA treatment known as avacincaptad pegol, which slowed the growth rate of GA lesions in two Phase 3 clinical trials. The FDA’s decision on avacincaptad pegol is expected by the end of August 2023. Also injected into the middle of the eye, the treatment works by inhibiting the C5 protein which is associated with an overactive and damaging innate immune system.
]]>EL-PFDD meetings are unique among public meetings with the FDA and other stakeholders, with a format designed to engage patients and elicit their perspectives on two topic areas:
Below is a recording from the recent webinar.
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]]>Can Gene Therapy Address Your Inherited Retinal Disease?
When it comes to saving or restoring vision for people with inherited retinal diseases (IRDs) such as retinitis pigmentosa, Usher syndrome, or Stargardt disease, no approach has gained more attention than gene therapy. And rightfully so. The first gene therapy for the eye or any inherited disease was approved by the US Food & Drug Administration in late 2017 — that was LUXTURNATM for people with RPE65 mutations causing Leber congenital amaurosis or retinitis pigmentosa — and currently, there are about two dozen gene therapy clinical trials underway for IRDs. LUXTURNATM is bringing dramatic vision improvements to most who receive it, and many gene therapies in clinical trials are showing encouraging results.
One advantage of gene therapy is that it can be designed to address IRDs in different ways. Whom the gene therapy can help depends on which therapeutic gene is delivered to retinal cells. And the good news is that researchers are developing a range of gene therapies to address IRDs, even for those who don’t know the genetic profile of their disease. There are even gene therapies for those who have lost all of their photoreceptors, the retinal cells that make vision possible.
Here are summaries of four approaches that, together, can potentially address the needs of a majority of IRD patients:
For most people on the journey to managing and potentially treating their IRD, genetic testing is an important step in the process. “With no-cost genetic testing available to IRD patients in the US, it is a great time to get tested. Genetic testing often gives a clearer diagnosis, informs the family about who else may be at risk, and it can help patients understand which clinical trials and emerging therapies, including gene therapies, may be relevant to them,” says Benjamin Yerxa, PhD, chief executive officer at the Foundation Fighting Blindness. “Also, signing up in a patient registry can get people on the radar screen of therapy developers recruiting for clinical trials.”
The Foundation Fighting Blindness provides no-cost genetic testing and a patient registry through its My Retina Tracker Program.
What Exactly is Gene Therapy?
Virtually every cell in our bodies carries a complete set of an estimated 20,000 genes. Nearly 300 of these genes, when defective, have been associated with IRDs. Genes are like our body’s instruction manual. They instruct our cells which proteins to make. These proteins are essential to the development, health, and functioning of all cells, including those of the retina.
Most inherited retinal degenerative diseases are caused by variations in a single gene. These variations are like misspellings in our instruction manuals. Even having just one incorrect letter can cause the wrong, or not enough, protein to be made. That can lead to serious consequences, like degeneration of the retinal cells that enable us to see. When a variation causes disease, it is referred to as a mutation.
Scientists are developing gene therapies to deliver copies of new, corrective genes, without the misspellings, to the cells in our retina, enabling them to make the right proteins, and stay healthy and function properly. Specially designed viruses are commonly used to deliver the corrective gene copies to the cells. The viruses are said to “transfect” or penetrate the cells with their therapeutic genetic cargo.
Gene therapy is administered by injecting a tiny drop of liquid, also known as a bleb, underneath or near the retina. The solution is absorbed into the retina over a period of hours.
In today’s world of retinal gene therapy development, adeno-associated viruses (AAVs) are most often used to deliver therapeutic genes to cells in the retina. That’s because AAVs are safe and able to penetrate cells with their genetic cargo. They naturally occur in humans and don’t cause any known illness. For regulators like the US Food & Drug Administration, that excellent safety profile is highly desirable.
You can think of an AAV as being like a very large container delivery system. The containers, which scientists call capsids, hold copies of the therapeutic gene. A retinal dose of AAV could contain 300-500 billion capsids. Not all capsids will make it into the nucleus of the retinal cell — where they need to be to work — and some capsids don’t have cargo. That’s why so many capsids need to be in the bleb for enough therapeutic gene to get into the retinal cells.
But once the genes are delivered, they work for many years, perhaps the lifetime of the patient.
“Gene therapy is a quickly evolving field. Researchers are enhancing AAV technology to be more effective and also address challenges such as delivering genes that are too big for current AAV capsids,” says Dr. Yerxa. “Dual vectors, delivering the therapeutic gene in two parts, and minigenes are two approaches that show promise for large gene delivery.”
How is a Gene Therapy Made?
Administering a gene therapy — injecting the bleb underneath the retina — may seem pretty simple. But what’s in that bleb is a highly complex human-engineered viral delivery system with genetic cargo. And, manufacturing the gene therapy on a large scale to be safe and effective in humans is no small feat.
“Gene therapy manufacturing differs from that of traditional small and large molecules because of the complexity of the systems,” says Dave Knop, PhD, executive director of process development at Applied Genetic Technologies Corporation (AGTC), which has gene therapy clinical trials underway for X-linked retinitis pigmentosa and achromatopsia.
AGTC produces AAV gene therapies in immortalized baby hamster kidney (BHK) cells — a cell line that has been safely and effectively used in the development of a variety of other therapies.
The process of producing AAV in the BHK cells is rather complex. There are a number of genetic components that need to be introduced into the BHK cells and they include:
All of the above genetic components are delivered into the BHK cells by two human-engineered (safe!) herpes simplex viruses (HSVs).
Then, the AAV production and expansion process occurs in a stirred single-use bioreactor, which holds 50 liters of material. The bioreactor has a plastic bag lining that is replaced after each use.
“You have this big mix of stuff in the cells that has all the right elements for replicating and producing the viral containers,” says Dr. Knop. “Once the AAV has matured, we break the cells open and pull out all of the AAV and put it into the purification operations.”
As part of the purification process, special plastic beads, called chromatography resin, are used to pull the AAV away from the rest of the unwanted material used in production.
The AAV is stored — for multiple years, if desired— in ultra-low temperature (-65 degrees Celsius) storage.
“That’s pretty cold. You don’t have that freezer hanging out in your kitchen,” says Knop. “We’re trying to come up with ways to store at higher temperatures, so it is a little less cumbersome.”
While the process to make AAV takes two to three weeks, the manufacturers need several months to make and test the biological reagents used in the process.
After the AAV is made, it goes through a long battery of tests for two to three months to ensure it is safe and has the desired profile.
Of course, it takes several years of lab studies to design and develop a vision-saving retinal disease gene therapy. Good manufacturing practices are an essential step in moving the treatment out of the lab and into human studies, where hopefully, it will deliver the magic of saving or restoring vision.
]]>The Foundation Fighting Blindness, in partnership with Blueprint Genetics and InformedDNA, offers no-cost genetic testing and counseling to people affected by the entire spectrum of inherited retinal diseases (IRDs) including retinitis pigmentosa (RP), Usher syndrome, and Stargardt disease. The test is available to those clinically diagnosed with an IRD living in the US or US territories (Puerto Rico, the commonwealth of the Northern Mariana Islands, Guam, American Samoa, and the US Virgin Islands: St. Thomas, St. Croix, St. John).
Why genetic testing for IRDs?
Eye care professionals make a clinical diagnosis of an IRD by examining a patient’s retinas. While a clinical examination provides critical information about the retinal condition, Identifying the IRD-causing gene mutations through genetic testing can provide more diagnostic information. In fact, studies have shown that clinical diagnoses change in about 15 percent of cases after genetic testing.
Identifying the disease-causing gene mutation(s) not only can provide more detail of a diagnosis, it can help a patient better understand the risk for other family members (siblings, children, etc.) for inheriting the IRD. Also, knowing one’s IRD gene mutation(s) can help them qualify for a clinical trial for an emerging therapy, many of which are now gene- or mutation-specific.
Why the Blueprint Genetics testing panel?
The Blueprint panel provides high-quality, broad, and deep testing for IRD genes. The panel screens 285 genes and includes the gene RPGR, a relatively common IRD gene, which when mutated causes X-linked RP. (Other panels may not test for the complete RPGR gene) The Blueprint panel also can identify hard-to-find mutations (i.e., intronic and copy-number variants), which other panels may not screen for.
Furthermore, Blueprint Genetics and its partners, the Foundation Fighting Blindness and InformedDNA, will never release a person’s personal information. A person’s privacy is always protected. With other IRD genetic tests, the patient’s personal information may be released.
The test ordering process
Tests can only be ordered by a clinician. The testing company, Blueprint Genetics, cannot take test orders directly from patients.
Any doctor in the US who is able to clinically diagnose a patient with an IRD can order the test online from Blueprint Genetics through the company’s Nucleus portal, which is available at www.BlueprintGenetics.com.
Patients with IRDs should contact their doctor and ask him or her to order the test. Doctors need to select the My Retina Tracker Program Panel to order the genetic test. Patients who have questions about testing or the program should contact their doctor. The test itself is simple; the clinician only needs to collect a saliva or blood sample from the patient. Patients should not contact Blueprint Genetics.
What to expect
Once a saliva sample is submitted to Blueprint Genetics, the test results are sent to the doctor in about four weeks. The results are conclusive in about 60-65 percent of cases. Whether the results are conclusive or not, the genetic counselor will help the patient understand what the results mean and potential next steps for the patient and family. Keep in mind that many emerging IRD therapies are designed to work independent of the mutated gene. So, while knowing one’s IRD gene is helpful in disease management, there are emerging treatment options for those who haven’t had their gene identified.
Why genetic counseling?
A genetic counselor helps patients and families understand what the genetic test results mean, what research (including clinical trials) may be relevant, the IRD inheritance pattern, and potential next steps. InformedDNA has extensive knowledge and experience in the IRD space and provides comprehensive, telephone-based genetic counseling to patients and families. The counseling session is typically 60-75 minutes.
The My Retina Tracker Registry
Any patient with an IRD can register in the Foundation’s global, secure My Retina Tracker Registry (www.MyRetinaTracker.org) to share their disease information with researchers and companies, many of which are recruiting for clinical trials for emerging therapies. Only de-identified information is shared. Personal information is never shared. A patient’s privacy is always protected. (The Foundation notifies the patient if he or she matches the researcher’s or company’s search criteria and then it is up to the patient to contact the researcher or company.) While a person’s genetic profile is valuable information to include in their registry record, they do not have to know their IRD gene mutation(s) to register.
Additional resources
Why genetic testing is important
Open Access Genetic Testing Program
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]]>Many of the benefits of eye research are obvious. Good eye health, and saving and restoring vision from disease and injury, are critical to helping us live independently and perform the many activities that are part of our daily lives such as seeing the faces of friends and family, reading, and driving.
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What’s good for the eye is good for the brain
However, research efforts for the eye, especially the development of therapies for the retina, are having a major impact on the advancement of treatments for the brain and neurological diseases and conditions. The retina is also an extension of the brain; its neurons are much like the neurons in the brain and nervous system. The retina, a thin piece of tissue which lines the back of the eye, is comprised of sensory neural cells that enable us to see.
That means that a treatment that might save or restore retinal neurons — some of these are referred to as neuroprotective therapies — might also help people with neurological conditions such as Alzheimer’s disease, Parkinson’s disease, or multiple sclerosis. In fact, the disease processes that occur in the retina are in some cases similar to those that affect the brain. For example, the harmful beta-amyloid proteins found in the brains of those with Alzheimer’s disease also accumulate in the retinas of people with age-related macular degeneration, a retinal disease that’s the leading cause of blindness in people 50 years of age and older.
What makes the retina special?
For scientists, the retina is a particularly attractive target to initiate studies of therapeutic drugs and molecules that might ultimately have broad application to the brain and nervous system. The reasons are numerous:
A success story
In December 2017, a treatment known as LUXTURNA ™ became the first FDA-approved gene therapy for the eye or any inherited condition. Developed by Spark Therapeutics with preclinical support from the Foundation Fighting Blindness, the treatment has restored vision for children and young adults who were virtually blind from a genetic retinal disease called Leber congenital amaurosis. Thanks in part to the clinical success of LUXTURNA and other emerging retinal gene therapies, the number of gene therapy programs for all diseases has grown dramatically — from about 200 programs in 2014 to more than 700 in 2018 (source Pharma Intelligence Informa).
]]>These misspellings are called mutations, and just like a mistake in a recipe, some mutations are more devastating than others. For example, when baking a cake, let’s say there is an error in the recipe. It incorrectly calls for a quarter cup of sugar, when the right amount is a half of a cup. The cake may not taste great, but it is still edible. But let’s say the instruction for adding flour is omitted entirely. Then the cake will be a complete failure and go uneaten.
Well, the same concept applies to genetic mutations in inherited retinal diseases. Some mutations can lead to devastating vision loss while others cause less severe, slower progressing impairment. So, a doctor or scientist is not only interested in which gene is defective in a patient, but how the defect affects vision. Identifying mutations cannot only help deliver a prognosis for a patient, it can direct them to clinical trials for therapies to save their vision.
Jason Comander, M.D., Ph.D., an FFB-funded clinical researcher from Massachusetts Eye and Ear Infirmary, presented the results of his work in cataloguing 190 mutations in the gene rhodopsin (RHO) at the RD2016 meeting, held September 19-24, 2016 in Kyoto, Japan. It’s the world’s largest semi-annual conference focused exclusively on retinal degenerative diseases, and supported in-part by FFB.
RHO is critical for vision, because it expresses a protein that enables rods — the photoreceptorsthat provide vision in dark settings — to absorb light. Mutations in RHO are also a leading cause of autosomal dominant retinitis pigmentosa (RP). About 100,000 people around the world have RP due to RHO defects.
Dr. Comander says that knowing the mutation can be very informative for patients and families by giving them a prognosis for vision loss.
“While there is a lot of variability among different people with the same mutation, rhodopsin mutations tend to be on the mild side,” says Dr. Comander. “Within the RHO severity spectrum, there are some mutations that can be relatively mild like E150K, moderate like P23H, or those that can be more severe like P347L.”
Dr. Comander and other investigators are studying the details of these mutations in the laboratory. He notes that knowing a mutation’s implications is critical to interpreting genetic test results.
“Certain changes in rhodopsin can be ‘red herrings.’ That is, they cause no problems at all and the real mutation, the mutation causing vision loss, could be in a different gene,” says Dr. Comander. “Because of this complexity, when you get genetic testing, it is better to use an institution that specializes in retinal disease and understands which DNA changes are truly important. You want an accurate diagnosis, especially when you rely on that information for seeking gene-based treatments.”
In the end, knowledge of a patient’s mutation may directly determine which potential future clinical trials of emerging therapies might be most relevant.
For example, the global biopharmaceutical company Shire is developing a drug known as SHP630 that addresses mis-folded RHO protein caused by a few mutations including P23H, T17M, and R135W. The drug is intended to stabilize the mis-folded RHO protein so that it can function properly in photoreceptors.
Don Zack, M.D., Ph.D., an FFB-funded scientist at Johns Hopkins University, is developing a CRISPR/Cas9 gene-editing tool to correct P23H and T4R mutations. CRISPR/Cas9 works like a “cut-and-paste” system to correct the mutations in the patients’ genes. Qin Liu, M.D., Ph.D., at MEEI, is also working on a CRISPR/Cas9 therapy for P23H mutations.
Spark Therapeutics and researchers from the University of Florida are each developing gene therapies that are designed to work by shutting down mutant copies of RHO and, at the same time, delivering healthy copies. These approaches are designed to work regardless of the RHO mutation.
“These strategies are targeted toward rescuing rods, which is usually most relevant for younger patients or those with milder disease. Those patients and families who can successfully identify their mutations can position themselves to take advantage of future clinical trials using these treatment strategies,” says Dr. Comander. “We are at a very exciting time in the development of potential therapies for people with RHO mutations.”
]]>Bradford Manning and his brother, Bryan, have a great sense of humor. You can see it in the video for their new clothing line, Two Blind Brothers — which donates its proceeds to retinal research — and hear it when you talk to Bradford over the phone.
His Spider-Man story is a great example. Late one night, a few years back, Bradford entered a New York City diner, where there was only one other customer. The Manning brothers have Stargardt disease, which impairs central vision, so Bradford couldn’t make out the details of the stranger’s face.
“But I just started talking to him,” Bradford, a member of the Foundation’s board of directors, recounts. “I asked, ‘You live around here?’ ‘Oh, yeah, a few blocks away.’ ‘Cool, what do you do?’”
The guy said he was an actor, and that he’d recently appeared in the movie The Amazing Spider-Man.
“’Wow,’ I said, ‘that’s awesome—a big studio film,’” Bradford continues. “Then I asked, ‘So, what was your role?’ And he kind of paused for a second, then said, ‘Uh, I was Spider-Man.’”
The stranger was Andrew Garfield.
Bradford, who’s 31, was diagnosed with Stargardt disease at age 6, a year after he failed the eye-chart test in kindergarten. Bryan, who’s five years younger, was diagnosed “as soon as they noticed he had eye problems,” Bradford recalls. Ever since then, with encouragement from their parents, the brothers have taken on every challenge not only with a sense of humor, but with grit and intelligence.
Both started learning Braille in middle school. Bradford swam competitively in high school and played water polo at the University of Virginia, where he majored in finance. Today he’s a founder and principal at Tiger Lily Capital, an investment-management company. Bryan played lacrosse and football, majored in statistics at UVA and now works for S&P Global Market Intelligence.
“Our parents allowed Bryan and me to participate in whatever we wanted,” Bradford says. “They encouraged us to find our own limitations.”
There don’t seem to be many. When it came time to think of a way to benefit retinal research while tackling yet another challenge, the brothers teamed up together. “That’s when we came up with the name Two Blind Brothers,” Bradford recalls. “It’s us. It’s authentic. It’s what our brand stands for.”
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The same strategy dictated design — upscale, short- and long-sleeve henley shirts. “We’ve relied on our sense of touch throughout life, and we’ve leveraged that sense to source incomparable fabrics,” Bradford explains. “The clothing is designed for people who care a lot about the way clothes feel on the skin. We are serving a wide audience, particularly our friends in New York. The clothing is casual, but it’s also able to be dressed up with a sport coat.”
The company’s logo includes the word “look” written in Braille. “That word alludes to our mission,” Bradford explains. “Esthetically, we thought it looked interesting—it almost looks like an arrow going to the right. But it’s also a pun on ‘looking good.’”
One other detail is significant—a raised-Braille metal tag on one sleeve of each shirt. “It says ‘brother,’ but we will change the word in future collections,” Bradford says. “It’s another way in which we bring our experience with visual disability to the clothing. If you don’t know Braille, that tag feels like breadcrumbs. But to someone who’s not sighted, it’s like reading poetry.”
All production is done in New York, with top-line tailoring and fabrics. But the shirts are less pricey than major luxury brands — $100 for the short-sleeve shirts, $125 for the long-sleeves. In the future, the Mannings plan to expand the line, to include women’s wear and accessories. And in mid-July, the company’s headquarters, in Soho, will open a showroom.
Bradford will share some of these plans, and offer Two Blind Brothers’ shirts for sale, in the Exhibit Hall at VISIONS 2016, FFB’s national conference, which kicks off June 30 in Baltimore. He’ll also emphasize that he and Bryan won’t be profiting from the sales; with help from an advisory board, they’ll review various research projects, then distribute the funding.
As an FFB board member focused on cutting-edge research, Bradford has no doubt the Foundation will be on the receiving end of the proceeds. “And the message we want to get across,” he says, “is much like the Foundation’s — it’s not so much a question about revolutionary science at this point; it’s about getting these projects through clinical trials and into commercialization.”
]]>But the reality is, such a procedure can be mind-blowingly complex, and there is no one-size-fits-all therapy for people with conditions such as age-related macular degeneration (AMD) or retinitis pigmentosa. There are innumerable considerations for researchers developing therapies. Here are just a few:
These issues constitute just the tip of the proverbial iceberg; there’s so much more to consider, including clinical-trial design, therapy manufacturing and regulatory compliance.
Before the start of the 2016 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO), the Foundation Fighting Blindness Clinical Research Institute (FFB-CRI) and Casey Eye Institute at Oregon Health & Science University hosted “Innovation Summit: Retinal Cell and Gene Therapy.” It convened many of the world’s best retinal surgeons and stem-cell and gene-therapy developers to share their insights and lessons learned in taking on these important questions and challenges.
While there were seven outstanding stem-cell presentations during the summit, I want to highlight two that were particularly intriguing.
Jeffrey Stern, M.D., Ph.D., co-founder of the Neural Stem Cell Institute (NSCI), discussed how the human retina has its own resident stem cells, which his group is working to harness as a therapy for diseases like AMD. In AMD, the disease causes degeneration of supportive cells known as retinal pigment epithelium, or RPE. When RPE are lost, the photoreceptors, the cells that make vision possible, die off as well, and central vision is lost.
Along with his wife and NSCI co-founder, Sally Temple, Ph.D., Stern is leading an effort to coax dormant stem cells in the patient’s retina to become new RPE. While it isn’t as far along as other RPE-replacement therapies, some of which are in early clinical trials, the NSCI “grow your own” approach would avoid many of the issues—including immune-system reactions, manufacturing and transplantation—associated with other stem-cell therapies.
I’d also like to applaud the opening stem-cell presentation delivered by consultant Jane Lebkowski, Ph.D. She has been involved with the California Project to Cure Blindness, which launched a clinical trial of an RPE-replacement therapy derived from blastocysts. She gave a nice summary of the many considerations one must make in launching a human stem-cell study. I have no doubt that the many summit attendees working toward clinical trials found her discussion to be invaluable. There’s nothing like experiential knowledge from someone who has successfully met the challenge you are trying to conquer.
The two-day summit included 25 presentations and 150 attendees. It was the third ARVO-associated summit hosted by FFB-CRI and Casey.
]]>As everyone knows, there is never just one side to a story. That’s certainly true in the case of Dr. Shannon Boye, whose Foundation-funded research is the subject of not just one but two new Foundation videos.
In “Harnessing Nature to Save Vision,” Dr. Boye, an assistant professor in the University of Florida’s ophthalmology department, does a bang-up job of describing one project in particular. Noting that her lab’s research team is focused on developing vision-saving gene therapies, she compares a new delivery system it’s working on to “newer, stronger taxi cabs” delivering cargo designed to simplify treatments and combat multiple diseases.
And this work, she makes clear, has been facilitated by funding and support from the Foundation Fighting Blindness.
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“Driving Research, Saving Vision” takes her story a step further, by intertwining it with the challenges faced by Brendon Cavainolo, a Florida teenager who’s lost a good deal of his eyesight to a disease known as X-linked retinoschisis. In the video, Brendan and his mother, Lisa, visit Dr. Boye’s lab, where they learn about the promising work she’s doing—and how, one day, it may very well benefit Brendon directly.
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In tandem, these videos demonstrate the Foundation’s commitment to two groups of people—those affected by vision-robbing retinal diseases, of which there are tens of millions worldwide, and the hundreds of investigators it has funded for 45 years to help bring an end to blindness caused by these diseases.
Dr. Boye, in particular, is a recent recipient of the Foundation’s Board of Directors Award. She’s also a member of a new generation of retinal researchers whose work coincides with a pivotal moment, when a wave of clinical trials are underway, some of which are rendering sight-saving results.
But the researchers’ work is far from over, which is why the Foundation will be using these new videos to promote and raise funds for its work over the next year. As Brendon’s mom, Lisa, makes clear, “There’s so much research out there that’s actually meaningful.”
We couldn’t agree more.
]]>Collecting retinal-disease data, and making it available to scientists, is one of the major driving forces behind the development of My Retina Tracker, the Foundation’s free, secure and confidential registry for people with inherited retinal diseases. One thing I do want to make clear—the data collected is protected and only shared, with each patient’s consent, for legitimate research purposes. Only disease-related data can be accessed by researchers; no personal information is shared. FFB staff will notify registrants if they match a researcher’s clinical-trial criteria.
When the Foundation launched My Retina Tracker in 2014, we knew investigators and companies would want the data provided by patients and families. And even though we’re still in a growth phase in terms of registration, it’s remarkable how many companies and investigators are already asking for disease information.
In our first year of operation alone, we’ve had data inquiries from more than eight companies and applications for data access from 10 individual researchers. Many of the companies are interested in identifying people who may be eligible for participation in clinical studies launching soon. They’re also looking at patient and disease numbers to determine if future therapy development efforts and clinical trials are warranted.
For example, Applied Genetic Technologies Corporation, a developer of retinal-disease gene therapies asked us to query My Retina Tracker to identify potential candidates for its gene-therapy clinical trial for X-linked retinoschisis. The company also intends to initiate studies for achromatopsia (day blindness) and X-linked retinitis pigmentosa in the not-too-distant future.
Looking forward, both retinal-disease patients and FFB still have a lot of work ahead to populate My Retina Tracker; we need thousands of more registrants. FFB’s job is to get the word out.
But, ultimately, it is up to the affected individuals and families to register and provide as much current disease information as possible. While genetic and vision test results are valuable, any information from patients and their blood-related family members (both affected and unaffected) is helpful. Registrants can always sign up and add more information later, as it becomes available.
Please send an e-mail to coordinator@myretinatracker.org if you have any questions or need registration assistance.
Thanks for helping drive sight-saving research.
]]>[[image-left 111]]However, women can have vision loss from XLRP as well, and an FFB-funded study of 242 XLRP carriers led by Jason Comander, M.D., Ph.D., at the Massachusetts Eye and Ear Infirmary, indicates that it may happen more than previously thought. Results of the study were published in the journal Ophthalmology.
“I thought that most XLRP carriers would be normal. That is the traditional clinical teaching,” says Dr. Comander.“However, when you put carriers ‘under the microscope,’ you find retinal abnormalities in most. Usually the abnormalities are mild and don’t change quality of life. Only 2.5 percent of XLRP carriers are legally blind.”
Dr. Comander and his team found that 40 percent of genetically tested XLRP carriers showed a definitive abnormality in at least one of three visions tests: visual acuity, visual field or dark adaptation.
What XLRP Carriers Can Do
“I recommend that an XLRP carrier try to figure out how much she is affected,” says Dr. Comander.“Imaging technologies are widely available at retinal-specialist offices that can evaluate the central retina, an area known as the macula, which is where the most severe problems tend to show up.But, again, these are rare in carriers.” He suggests a complete work-up for affected women.
For the moderately or severely affected XLRP carrier, Dr. Comander suggests that she consider a supplementation regimen of Vitamin A palmitate, docosahexaenoic acid (DHA) and lutein. He notes, however, that this regimen hasn’t been studied in XLRP carrier women. An FFB information packet provides details for the supplementation regimen, which should only be taken under a doctor’s supervision.
Why Women May be Affected
In XLRP and other X-linked diseases, the mutated gene is on an X chromosome. Women aren’t expected to have vision loss from XLRP because they have two X chromosomes—a healthy X in addition to the X with the mutation. Because men have one X and one Y, they experience severe vision loss if they inherit the X with the mutation from their mothers.
However, some copies of a woman’s healthy X chromosome are inactivated as a result of a process aptly called “random X inactivation.” That means women can experience vision loss from XLRP because some copies of healthy X chromosomes in the retina are turned off. Because X inactivation is random, there’s variability from woman to woman in how much of the retina is affected.
The Calico in Calico Cats Result from X Inactivation
If you’ve made it this far in the blog post, you may be wondering why I included a photo of a calico cat (above). Well, just about all calico cats are female and, therefore, have two X chromosomes. One X codes for brown coloring and the other for black. The random inactivation of the “brown” X and “black” X is what gives calicos their distinctive splotchy coloring.
]]>However, if a child is born with severe vision loss from a retinal disease like Leber congenital amaurosis (LCA), these pathways don’t develop normally due to lack of retinal input. They also further deteriorate as the retina degenerates.
Since we see with our eyes and the brain, researchers have wondered what happens to the brain when the eye can’t see. More interestingly, what happens to the brain when the eye is enabled to see through gene therapy? Would the brain and eye restart their partnership? Would this handshaking happen for humans of all ages? Would the brain be able to harness the visual-processing pathways later in life?
Thanks to Manzar Ashtari, Ph.D., who is leading groundbreaking, brain-imaging studies at the University of Pennsylvania and The Children’s Hospital of Philadelphia (CHOP), we now know the answer is yes. Published in the journal Science Translational Medicine, and funded in part by the Foundation Fighting Blindness, her research shows that retina-brain pathways can be established in LCA patients not only after decades of near blindness, but that they are strengthened with use after the retina has been treated.
This is exciting news, because researchers were concerned that the brain’s plasticity—its ability to develop and respond to the new input from the retina—would be lost. The study shows that the brain has the capacity to adapt to retinas with improved function thanks to gene therapy. This not only bodes well for people with LCA; it is good news for others who might receive gene therapy later in life for an early-onset retinal disease.
Dr. Ashtari used advanced magnetic resonance imaging techniques that examine the deeper brain layers to observe that eyes treated with gene therapy had a stronger connection to the brain than untreated eyes. She is continuing her comprehensive imaging studies to better understand the brain structure and function of the LCA patients before and after treatment.
Meanwhile, the Phase III LCA gene-therapy clinical trial at CHOP and the University of Iowa is moving full steam ahead with children as young as 3 receiving the treatment. Also, all patients in the trial are having both eyes treated. If all continues to go well, the trial’s sponsor, Spark Therapeutics, could seek approval for the gene therapy from the U.S. Food and Drug Administration in less than two years.
]]>With about 15 clinical trials underway for inherited retinal diseases, and several more poised to begin in a few years, patients are eager to sign up for access to potential vision-saving therapies.
However, a clinical trial isn’t a promised land. It’s an experiment with risks, and a person’s motivation for participating in the study should be to help advance the research. Though investigators take extensive precautions to protect the patients, they continue to learn about a therapy’s safety and effect on vision and the body, especially during early stages of the study.
Also, participants often make a big commitment to visiting research centers, perhaps several times a year, for many hours of grueling tests. Sometimes, they travel long distances to get to the center. Some drop out of studies, because the commitment is too much. Unfortunately, losing patients can jeopardize the study and the future of the treatment.
It’s also important to understand that, in some trials, participants might not actually be treated. In masked, randomized studies, some will get a placebo, and won’t know whether they received the placebo or the therapy until the study concludes. Those who get the placebo are still helping to advance the trial. Hopefully, the emerging therapy performs better than the placebo.
Phase I
A participant’s experience also depends on what phase of the study he or she has enrolled in. For example, in a Phase I study, investigators are focused on safety, ensuring that the potential treatment does no harm. In some cases, they may recruit healthy volunteers to evaluate the systemic effects of a treatment.
For a therapy that’s applied directly to the eye — for example, a gene or stem-cell therapy — they may enroll patients with very little remaining vision; so there’s little vision to lose if something goes wrong. Phase I studies are usually of short duration, from a few months to a year, and involve about a dozen patients.
Investigators may also evaluate increasing doses of a treatment in different patient groups, often referred to as dose escalation, to identify the maximum tolerable level.
Phase II
In a Phase II study for an inherited retinal disease, researchers are still monitoring safety, but also begin evaluating efficacy. Is the treatment saving or restoring vision? Depending on the therapy and the prevalence of the diseases included in the trial, the number of participants could range from two dozen to a few dozen. A Phase II is likely to last from two to four years.
Phase III
A Phase III study is the final, or “pivotal,” stage before seeking marketing approval from the U.S. Food and Drug Administration or the European Medicines Agency. In this phase, investigators are looking for strong evidence of efficacy. The therapy may be studied at multiple clinical sites to determine if investigators can achieve the same results independently.
For a blockbuster drug, for example, a new therapy for high blood pressure, thousands of patients may be enrolled in a Phase III. But in the world of rare, inherited retinal conditions, researchers may only be able to enroll a few dozen participants. A Phase III usually lasts from two to four years.
Combined Phases
For many emerging therapies for rare conditions, clinical phases are combined. For example, Phase I and II can be combined as a Phase I/II, or Phase II and III as a Phase II/III. This is done to save time and money and accommodate the limited number of participants available for the clinical trial.
For instance, the gene therapy clinical trial for Leber congenital amaurosis (RPE65 mutations)at the Children’s Hospital of Philadelphia was organized in two phases: a 12-patient Phase I/II and a 24-patient Phase III. The University of Iowa was added as a site for the Phase III. This study began in late 2007 and is scheduled to conclude later this year.
Qualifying for a Study
Finally, it’s important to understand that clinical trials have several inclusion and exclusion criteria for participants. One’s age, genetic profile, level of vision and medical history are all factors in determining eligibility for a study.
Help Drive the Research
I hope my cautionary comments do not dissuade anyone from considering a clinical trial. We need participants, because without them we would have no trials or treatments. But at the same time, it’s important for anyone considering participating to have realistic expectations.
To learn more about clinical trials underway for inherited retinal diseases, visit www.clinicaltrials.gov.
]]>What exactly is CME?
It’s the buildup of fluid, usually in the central region of the retina called the macula, which gives us the ability to read, perceive colors and see in lighted conditions. CME is analogous to having a sponge that’s wet all the time. It eventually deteriorates. If the retina sustains and leaks fluid for a long period of time, it can lead to permanent breakdown of the retinal structure.
A supportive layer of cells called the retinal pigment epithelium (RPE) normally pumps the fluid out. But with CME, the RPE can’t keep up.
How is CME diagnosed?
CME often causes reduced or blurry vision, but there isn’t always a correlation early on between the fluid buildup in the macula and vision loss. This can be surprising. Regardless, patients should always see their doctors with a significant change in vision to address any potential problems, CME or otherwise.
Ultimately, only a doctor can make the diagnosis of CME. If there’s enough fluid in the macula, we’ll often see a honeycomb or four-leaf clover when looking at the back of the eye with an ophthalmoscope during an exam. But we can be fooled; the fluid is there, but we may not see these signs.
To make a definitive diagnosis of CME, we capture an image of the retina’s layers using optical coherence tomography (OCT), a technique employing infrared light. If the fluid’s there, the OCT will detect it.
Even if I don’t see evidence of fluid when looking at the back of the eye, I like to do a baseline OCT for all my RP patients to see if they have CME. OCT will also tell us something about the anatomy in and around the macula.
What retinal diseases can lead to CME?
CME most often occurs in people with night-blinding retinal diseases such as RP, Usher syndrome, choroideremia, gyrate atrophy and enhanced S-cone syndrome. Also, people with X-linked retinoschisis can develop cystic lesions, which are somewhat different from CME; they’re accumulations of fluid, which are treatable, but they don’t leak. We don’t see CME in juvenile macular dystrophies, such as Stargardt disease. It’s also rarely observed in cone-rod dystrophy.
What are the treatments?
My first line of therapy is a topical carbonic anhydrase inhibitor (CAI), such as dorzolamide, which helps the RPE pump the fluid out faster. Some physicians prefer oral CAIs first, because they’re stronger. But those can have unpleasant side effects, such as fatigue and tingling in the fingers and toes.
Other treatment options include steroids and non-steroidal anti-inflammatory drugs. Also, the age-related macular degeneration therapies — Lucentis, Avastin and Eylea — may be considered, because they reduce fluid accumulation.
Not every patient responds to treatment for CME, but this is true for many other drugs and conditions. In some cases, people may not show improvement for as long as four months. I like to see some movement by two months to justify continuing treatment.
In some cases, a patient responds for a while, but the CME recurs. So I’ll pull them off the drug for a few months and then re-start it. Sometimes, they show a positive response again.
Treating CME is an art, and with each case, I try to get better at practicing it.
One other important point: I always make sure the patient is getting the eye drops in their eyes. So I teach them how to do it. If the patient is a youngster, I instruct the parents.
]]>Enter a two-minute animated video which does a nice job of simply explaining what stem cells are, where they come from and how they can be used to treat disease. It was put together by the National Center for Research Resources at the National Institutes of Health. There are times when the language can get a little technical—the use of the word “pluripotent,” for example—but I suspect many kids will get most of it. [[youtube tPulEAryPO0]]
The Foundation Fighting Blindness currently funds several stem-cell projects, because of their potential for replacing and saving photoreceptors, the cells that make vision possible, lost to disease. Listed below are a few Foundation posts highlighting the great stem-cell work underway for the retina.
Encouraging Vision Improvements Reported in ReNeuron’s Cell-Therapy Clinical Trial
Stem-Cell Therapy for Retinitis Pigmentosa Safe Thus Far in Early Human Study
UCI Stem-Cell Pioneer Poised to Launch Clinical Trial for RP Patients
]]>One good example is valproic acid, or VPA, which was approved by the U.S. Food and Drug Administration (FDA) for treating epilepsy and bipolar disorders. Thanks to FFB-supported scientists, it is now being tested in clinical trials, or human studies, to evaluate its efficacy in treating a form of retinitis pigmentosa (RP). Because repurposing relies on prior research and clinical data, it reduces the cost and time needed to establish a new therapeutic application for the drug.
Dr. Nawajes Mandal, an assistant professor at the Dean McGee Eye Institute at the University of Oklahoma College of Medicine, thinks it might be possible to slow retinal degeneration with another FDA-approved drug. It’s known as Gilenya® and is used to treat multiple sclerosis(MS).
Dr. Mandal received his Ph.D. in lipid biochemistry in India, then worked in two FFB-funded facilities in the United States, one at the University of Michigan, the other at the University of Oklahoma. Aside from researching Gilenya®, he’s studying the role of fatty acids in retinal diseases and looking at other compounds that may serve as treatments.
Recently, I asked him a few questions about the Gilyena® project, which is funded by FFB.
Can you explain what Gilenya ® is and what it is used for?
It’s a drug that inhibits immune activation in lymphoid tissue. People with MS are thought to have an “overactive” immune system, and Gilyena® has been shown to be effective at reducing immune system flare-ups.
We know that some retinal diseases, such as RP, may involve a secondary immune response, and so the direct immunosuppressant effects of Gilenya® may help in this respect. However, it has another interesting property. It is effective at inhibiting the production of a waxy lipid molecule known as “ceramide.”
So, what does ceramide have to do with retinal diseases?
In reviewing the scientific literature 10 years back, I found a paper that showed that ceramide levels increase in the mutant retina of fruit flies. I, therefore, decided to evaluate lipid profiles in the retina of normal and RP rodent models.
I was amazed when I found that, as in the fruit fly, ceramide levels increased in mammalian retinal cells that were undergoing programmed cell death, or apoptosis, which is caused by retinal diseases. So now, with FFB funding, I am trying to see if photoreceptor cells in various RP rodent models will survive longer if ceramide levels can be decreased using Gilenya®.
What have you found so far?
After evaluating the effects of Gilenya® in three different rodent models of RP, I found that, in each model, systemic administration was effective in decreasing retinal ceramide levels. As a consequence, the photoreceptor cells were protected.
What are your next steps?
Because of the systemic side effects of the drug, some of which can be harmful, I’m developing a topical formulation, or an eye drop. This way, the drug won’t enter the body. If Gilenya® eye drops are able to produce the same level of efficacy as the oral medication, I am hoping to apply to the Foundation Fighting Blindness’ Clinical Research Institute and the National Eye Institute for funding to support a clinical trial to evaluate the drops in humans with retinitis pigmentosa.
Long before the advent of genetic testing, or even knowledge of DNA and RNA, astute observers noticed that many traits were passed from one generation to another. But it still can be difficult to understand why some people inherit a genetic disease and others do not. Also, it’s often not clear which family members are at risk of inheriting a condition.
To understand heredity, you have to know a little about genetics. Below is a review of the three major genetic-disease inheritance patterns. But, first, a little background:
Genes and Mutations
Genetic conditions, including many retinal diseases, are caused by genetic variations, or mutations, passed down from one or both parents. Everyone has about 25,000 pairs of genes, which play a major role in determining who we are—our height, hair color, etc. We all have many variations and mutations in our genes, and most do not affect health or well-being. However, some cause problems and lead to diseases, including those of the retina.
Genes are wrapped in structures called chromosomes, of which humans normally have 23 pairs. We inherit one of each chromosome from our mother and father. Chromosomal pairs 1 through 22 are known as autosomal (non-sex) chromosomes. The X and Y chromosomes on pair 23 are known as the sex chromosomes, because one of their functions is to determine our sex.
Autosomal Dominant
To get an autosomal dominant disease, a child receives one copy of a mutated gene from an affected parent. It’s likely the affected parent knows he or she has the disease, or at least has related symptoms. The other parent is usually neither affected nor a carrier.
With dominant diseases, there’s a 50 percent chance that a child will receive the mutated gene and be affected by the disease. Dominant diseases frequently appear in several generations of a family, with many family members being affected.
Autosomal Recessive
To get a recessive disease, a child must inherit a mutated copy of the gene from both parents. With recessive conditions, each parent has one mutated copy and one normal copy of the relevant gene. Because each parent has only one mutated copy of the gene, they’re unaffected carriers of the condition. They usually have no idea that they’re carriers because they have no related vision problems.
If their child inherits only one mutated gene from one parent, then the child will only be a carrier of the disease and usually won’t experience any vision problems. If their child inherits a mutated copy from each parent, then the child will develop the disease and associated vision loss.
With recessive disease, there’s a 25 percent chance that the child will be affected and a 50 percent chance he or she will be an unaffected carrier. Recessive diseases are more likely to surprise a family because parents of an affected child usually don’t know they’re carriers.
X-Linked
Inheritance patterns for X-linked diseases are more complex than the others, because the gender of both parents and their children often determine if the disease will be passed down.
As mentioned previously, men have an X and Y chromosome and women have two Xs. In most cases, mothers pass X-linked diseases down to their sons. Daughters usually don’t get the disease, because they also have a healthy X chromosome from their fathers. However, researchers have found that women can sometimes have mild vision loss or, in rarer cases, severe vision loss from X-linked retinal diseases.
If an X-linked carrier mother has a son, there’s a 50 percent chance he will be affected. If an X-linked carrier mother has a daughter, there’s a 50 percent chance the daughter will be a carrier.
A Word on Age-Related Macular Degeneration (AMD)
AMD is the leading cause of blindness in people over 55 living in developed countries. It’s different from inherited retinal diseases, because risk of the condition is caused by a complex combination of genetic and lifestyle factors, including advancing age and smoking. The best way to determine risk of vision loss from AMD is through an examination of the retina by an eye doctor.
For more information, check out FFB’s Inheritance of Retinal Degenerations and About Genetic Testing booklets.
]]>Your eyes are not just windows to your soul, but to your health as well. People rarely pay attention to their eyes, until something goes wrong. The eye is a delicate organ, and vision is a complex process involving various components.
Photoreceptors, in particular, get a lot of attention from researchers because they’re the main cells in the retina that make vision possible. They convert light into electrical signals, which are sent to the brain and used to construct the images we see. Also, many retinal diseases begin with loss of photoreceptors.
However, the retina is like a multi-layer cake, with each layer comprised of different types of cells, all playing important roles in retinal health and vision. While preserving and restoring photoreceptors is often job number one for scientists, they also explore ways to protect other retinal cells from deterioration and even harness them to restore vision.
Here’s a summary of the major retinal cell types, their functions and their potential roles in future treatments of diseases:
Choroid — The choroid is a layer of blood vessels that supplies oxygen and nourishment to the retina. Defects in the CHM gene cause choroideremia, a disease characterized by deterioration of the choroid, retinal pigment epithelium and photoreceptors. In the wet form of age-related macular degeneration, leaky blood vessels expand from the choroid into the retina—a process called choroidal neovascularization—which causes loss of photoreceptors and central vision.
Retinal pigment epithelium — Also known as the RPE, this is a single layer of cells above the photoreceptors that provides them with essential nutrition and waste removal. In age-related macular degeneration and Stargardt disease, toxic waste products accumulate in the RPE or between the RPE and photoreceptors. Subsequently, the RPE deteriorates, leading to loss of photoreceptors.
Photoreceptors —These are the retinal cells, known as rods and cones, that initiate the vision process by converting light into electrical signals. Rods provide low-light and peripheral vision. Cones are concentrated in the macula, the central region of the retina, and provide central and color vision. The outer segments of rods and cones are antenna-like projections that absorb light and convert it into electrical signals. Inner segments are the cell bodies where other supportive functions are performed. The adult human retina has approximately 125 million photoreceptors.
Bipolar cells — Their job is to receive electrical information on lighting intensity from photoreceptors and pass it along to other retinal cells. Bipolar cells often survive after photoreceptors are lost to disease. This makes them an attractive target for emerging optogenetic treatments, which are designed to provide light sensitivity and restore vision.
Ganglion cells — Ganglion cells receive input from many different cells in the inner retinal layers and process visual information, including detection of edges, contrast and colors. Ganglion cells extend to form an optic nerve, a million-fiber cable that conveys visual information from the eye to the brain. In people with advanced retinal disease, ganglion cells often survive longer than bipolar cells, making them a potential target for optogenetic therapies. Currently, scientists believe that bipolar cells may provide a more detailed visual experience than ganglion cells when treated with a light-sensing therapy, because they reside in layers of the retina closer to photoreceptors.
Muller glia — Muller cells extend through the retina, like spokes of a wheel, providing structural support and guiding light through the inner retina. They also transport molecules critical to retinal health and vision. Researchers believe Muller cells may even have the capacity to become new photoreceptors, which could lead to restoring vision. The research is still new, but success might someday have a big impact on the vision of people with advanced diseases.
A final note
The processing of visual information in the retina—beginning with 125 million photoreceptors and converging on a one-million-fiber optic nerve—remains a subject of intense research. There’s still much that scientists don’t know about the retinal cells and their roles. For example, little is known about the processing activities of amacrine and horizontal cells, which reside between bipolar and ganglion cells. However, advancing imaging technologies, including adaptive optics and optical coherence tomography, are helping complete the picture.
For additional information about retinal anatomy and function, please see the Eye on the Cure post “Appreciating the Beauty of the Retina.” The University of Utah’s Webvision is one of the best online sources for detailed information about the retina. I also want to thank John Flannery, Ph.D., at the University of California, Berkeley, for his editorial input.
]]>n the early 2000s, Harvard researcher Ted Kaptchuk collaborated with gastroenterologists on a placebo study of 262 people with irritable bowel syndrome (IBS). The participants were put into one of three groups.
The first cohort was told they were in a waiting line for an up-and-coming treatment and given little verbal support or additional information from the clinical practitioner.
The second group received a procedure they thought was an active treatment, but was actually a sham (placebo) therapy. They, too, received little support from the practitioner.
The third cohort received the sham treatment and was also given an extraordinary amount of attention and support — including a report that the treatment had worked well previously.
As you might have guessed, the third group, the patients who received the “therapy” and the most support, had the best results. The first group, which got virtually nothing, had the worst.
That study highlights the placebo effect in all its glory.
The following three-minute video also does a nice job of illustrating the surprising power of the placebo in its many forms.
[[youtube yfRVCaA5o18]]
The placebo effect is a concern when potential treatments have not been studied in randomized, double-blind clinical trials. In those studies, neither patient nor researcher knows who is receiving the actual therapy or a placebo, and the decision of who gets what is completely arbitrary.
But even in a well-designed clinical trial, the placebo effect can rear its head. Suggesting to a patient that he or she might receive a treatment could lead to that patient experiencing a placebo effect. Hopefully, in these cases, the actual treatment outperforms the placebo.
In our world, where we are developing treatments to save and restore vision, we have a number of tools to objectively measure changes in vision. While they are not perfect, they go a long way in helping researchers determine if a therapy is really working.
If you are interested in learning more about the resources used to measure treatment effects and vision changes, I recommend the following Foundation posts:
New Imaging Technique May Be Game-Changer for RP Clinical Trials
Proving a Vision-Saving Treatment Works
Vision Testing and Retinal Imaging in Clinical Trials: What Patients Can Expect
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