1 shot of gene therapy and children with congenital blindness can now see

Born with a retinal disease that made him legally blind, and would eventually leave him totally sightless, the nine-year-old boy used to sit in the back of the classroom, relying on the large print on an electronic screen and assisted by teacher aides. Now, after a single injection of genes that produce light-sensitive pigments in the back of his eye, he sits in front with classmates and participates in class without extra help. In the playground, he joins his classmates in playing his first game of softball.

His treatment represents the next step toward medical science's goal of using gene therapy to cure disease. Extending a preliminary study published last year on three young adults, the full study reports successful, sustained results that showed notable improvement in children with congenital blindness.

The study, conducted by researchers from the University of Pennsylvania School of Medicine and the Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia, used gene therapy to safely improve vision in five children and seven adults with Leber's congenital amaurosis (LCA). The greatest improvements occurred in the children, all of whom are now able to navigate a low-light obstacle course—one result that the researchers call "spectacular."

"This result is an exciting one for the entire field of gene therapy," said Katherine A. High, M.D., co-first author of the study and the director of the Center for Cellular and Molecular Therapeutics, the facility that sponsored the clinical trial at The Children's Hospital of Philadelphia. High, an investigator of the Howard Hughes Medical Institute and a past president of the American Society of Gene Therapy, has been a pioneer in translational and clinical studies of gene therapy for genetic disease. "This study reports dramatic results in restoring vision to patients who previously had no options for treatment," said High. "These findings may expedite development of gene therapy for more common retinal diseases, such as age-related macular degeneration."

Although the patients did not attain normal eyesight, half of them (six of 12) improved enough that they may no longer be classified as legally blind. "The clinical benefits have persisted for nearly two years since the first subjects were treated with injections of therapeutic genes into their retinas," said senior author Jean Bennett, M.D., Ph.D., F.M. Kirby professor of Ophthalmology at the University of Pennsylvania School of Medicine. For Bennett, the results build on nearly 20 years of gene studies on hereditary blindness, starting with pioneering work in mice and dogs. "These remarkable results," she added, "have laid a foundation for applying gene therapy not only to other forms of childhood-onset retinal disease, but also to more common retinal degenerations."

The study team reported their findings today in an online article in The Lancet.

"Children who were treated with gene therapy are now able to walk and play just like any normally sighted child," said co-first author Albert M. Maguire, M.D., an associate professor of Ophthalmology at Penn and a physician at Children's Hospital. "They can also carry out classroom activities without visual aids."

Maguire and Bennett have been researching inherited retinal degenerations for nearly 20 years. Leber's congenital amaurosis, the target of this current study, is a group of inherited blinding diseases that damages light receptors in the retina. It usually begins stealing sight in early childhood and causes total blindness during a patient's twenties or thirties. Currently, there is no treatment for LCA.

Walking along a dimly lit, simulated street route, the children were able to negotiate barriers they bumped into before the surgery. Another child, who since birth, could only see light and shadows, stared into his father's face and said he could see the color of his eyes. Later they played soccer together.

For children and adults in the study, functional improvements in vision followed single injections of genes that produced proteins to make light receptors work in their retinas.

The 12 subjects ranged in age from 8 to 44 years old at the time of treatment. Four of the children, aged 8 to 11, are the world's youngest individuals to receive gene therapy for a non-lethal disease (A fifth subject was 17 years old). On the other end of the age scale, the 35-year-old man and 44-year-old woman are the oldest patients to ever receive gene therapy for retinal degeneration.

For the current human trial, the research team used a vector, a genetically engineered adeno-associated virus, to carry a normal version of the gene, called RPE65, that is mutated in one form of LCA, called LCA2, that accounts for 8 to 16 percent of all LCA cases. Jeannette Bennicelli, Ph.D., in Bennett's laboratory, cloned the gene. The clinical vector production facility at Children's Hospital's Center for Cellular and Molecular Therapeutics (CCMT), directed by Fraser Wright, Ph.D., manufactured the vector.

The clinical trial brought together subjects and scientists from two continents. Five patients enrolled in the study were identified at the Department of Ophthalmology at the Second University of Naples, an institution with a long-standing program in researching inherited retinal diseases, under the supervision of Francesca Simonelli, M.D. Two children from Belgium were recruited through Ghent University Hospital, under the supervision of Bart Leroy, M.D., Ph.D. Jennifer Wellman, of the CCMT, directed all local and federal regulatory interactions for the study.

Another co-author, Edwin Stone, M.D., Ph.D., Howard Hughes Medical Institute Investigator and director of the Carver Center, a genetic testing laboratory at the University of Iowa, identified and verified several of the disease-causing mutations in the study subjects.

In April 2008, the current study team published encouraging preliminary results in the New England Journal of Medicine regarding three young adults, the first to receive gene therapy in this current clinical trial. Those subjects showed improvements in their visual function in both objective vision tests and subjective reports by the patients themselves. Patients who could only detect hand movements gained the ability to read lines on an eye chart.

After the first group of three young adults was treated safely, the study team extended gene therapy to five children from the United States, Italy and Belgium, in addition to four other adults. Because animal studies conducted by Bennett and colleagues had shown that visual improvement was age-dependent, the researchers tested the hypothesis that younger human subjects would receive greater benefits from the treatment. "LCA is a progressive disease, so if a treatment was possible, it was plausible to intervene before damage to the retina was severe," said Bennett.

In all, 12 patients received the gene therapy via a surgical procedure performed by Maguire starting in October 2007 at The Children's Hospital of Philadelphia. For each subject, Maguire injected the therapeutic genes into the eye with poorer function. There were three patient cohorts, receiving low, middle and high doses. No serious adverse events occurred in any of the test subjects.

Starting two weeks after the injections, all 12 subjects reported improved vision in dimly lit environments in the injected eye. An objective measurement, which measures how the eye's pupil constricts, showed that all the subjects were able to detect significantly more light after treatment and also showed greater light sensitivity in each patient's treated eye compared to the untreated eye. In addition, before treatment, nine patients had nystagmus, an involuntary movement of the eyes that is common in LCA. After treatment, seven of them had significant improvements in nystagmus.

Some of the most dramatic results, captured on video by the researchers, are apparent as subjects traverse a standardized obstacle course. Before the treatment, the patients had great difficulty avoiding barriers, especially in dim light. After treatment, the children navigated the course more quickly, with fewer errors than before, even at the lowest light levels. Not all the adults performed better on the mobility course, and for those who did, the improvements were more modest compared to the children's.

"In follow-up studies, we will continue to monitor these patients to determine whether this treatment stops the progression of this retinal degeneration," said Maguire. "In the future, we hope to investigate whether other
retinal disease will be amenable to this gene therapy approach."

Thanks to University of Pennsylvania School of Medicine for this article.

For more information go to www.maculardegenerationassociation.org

Fish intake can help prevent macular degeneration

The addition of omega-3 fatty acids to the diet, particularly in the form of fish, can help prevent the development of age-related macular degeneration vision loss by more than 30 per cent, according to a new study.

Macular degeneration is the leading cause of blindness in people older than 50, and is an eye disease that attacks the central part of the retina called the macula, which controls fine, detailed vision. The condition results in progressive loss of central vision, leaving only peripheral sight, making it difficult to drive a car, read a book or recognize faces.

With an aging population in Canada, the incidence of age-related macular degeneration (AMD) expected to increase by 50 per cent over the next two decades.

Previous research has shown that a high intake of omega-3 fatty acids and fish may slow the progression of macular degeneration in those in the advanced stages of the disease.

The current study, published online in the American Journal of Clinical Nutrition, looked at 1,837 people in the Age-Related Eye Disease Study (AREDS) who had a moderate to high risk of developing advanced macular degeneration.

They found that those with the highest omega-3 fat intake - mainly from fish and seafood - were 30 per cent less likely to progress to advanced AMD over 12 years than their peers who consumed the least.

Those with the highest intake ate the equivalent of about 3 ounces of Atlantic salmon or 5 ounces of rainbow trout per week.

It's thought that an omega-3 fatty acid found in fish called DHA (docosahexaenoic acid) may work to prevent damage to the retina through its anti-inflammatory and antioxidant properties.

Since omega-3 fatty acids cannot be manufactured by the body, it is essential that people get them through their diet., says Canada AM nutrition expert Leslie Beck.

"I would recommend eating oily fish like salmon, trout or sardines twice per week," she says. "If you don't like fish, consider taking a fish oil capsule once or twice daily. If you're a vegetarian, DHA supplements made from algae are available."

Other sources of omega-3 fatty acids include nuts, which also have anti-inflammatory and antioxidant effects and may also reduce the risk of heart disease and type 2 diabetes -- diseases that are linked to AMD.

More studies are underway to investigate the role of the diet and AMD. AREDS2, a five-year randomized trial involving 4,000 people will test the effectiveness of supplementing with certain antioxidants and/or omega-3 fatty acids on the progression to advanced AMD.

For more information go to www.maculardegenerationassociation.org

MIT’s Retinal Implant is Moving Forward, But Hasn’t Caught Up with Argus II

By Aaron Saenz

Way back at the beginning of the year we told you about the Argus II, an artificial retina that was helping some blind people to see. MIT researchers from the Retinal Implant Research Group led by John Wyatt are developing their own retinal implant that works along much the same principles. As reported in IEEE’s Transactions on Biodmedical Engineering, Wyatt and his team are currently testing the implants for viability in the eyes of pigs. He hopes in the next three years to move to a new prototype and human testing. However, the Argus II is already there with 20 human patients currently testing those devices.

Diseases like macular degeneration and retinitis pigmentosa are responsible for around 25 million cases of blindness worldwide. Retinal implants have the unique ability to bypass the damaged retinal tissue and stimulate the optical nerves that still function. In this way, the blindness is replaced with a very simplified vision that many users define as hazy and limited. Still, tests for the Argus II have allowed some patients to cook, make out shapes at sporting events, and move more easily through their homes. Current artificial retinas are clearly in their infancy, but as these devices are improved in the next few decades, they may serve as a means to restore near-perfect vision.

Distinguishing between the MIT artificial retina and the Argus II isn’t easy. They both use cameras or sensors embedded on glasses to record visual information that is sent to a processing pack. That pack then wirelessly relays the information to an electrode array implanted directly on the eye. As the electrodes stimulate the optic nerve, patients should see a limited series of light and dark spots that correspond to the original visual information from the glasses. The MIT artificial retina may have a superior casing structure, made of titanium.

The biggest difference between the two implants is where the electrodes attach. While the Argus array is placed on the retina, the MIT implant will be connected subretinally. This will reduce the risk of tearing during implantation. This difference may have important implications as complications during operation could affect long term viability (the MIT team wants the implant to last more than 10 years). In most other ways, the two devices are remarkably similar.

Except of course that Argus II seems to be years ahead in terms of producing a marketable product. Besides the fact that the MIT implant is still being tested for safety while the Argus II is in human trials, there’s also the issue of image resolution. The next version of the device, Argus III, is slated to have many more electrodes in the array (1000 vs. the current 60) which will greatly increase the level of detail available to users. The MIT implant, with 15 channels, has a ways to go to catch up.

Yet, even if the MIT device seems to be lagging behind the Argus, it’s good that there is more than one team in the race. Teams, which we should emphasize, are both making good progress even if they are at different stages. The Argus II, as we’ve said before is being tested in 20 patients with remarkable results. The MIT implant has been proven to be safe in pig eyes for at least 10 months, and the programming algorithms have been thoroughly tested. Both teams are well funded and have the potential to create a viable product at some point in the future. For the millions of blind people who suffer from retinal problems, who makes a retinal implant isn’t so important as long as it gets done.

For more information go to www.maculardegenerationassociation.org

Scientists Develop Antidote For New Class Of Drugs

A new antidote has been developed by scientists which appears to work against a whole new class of drugs called aptamers.The new compound can quickly counteract the action of the drugs, offering a way to reverse the drugs' actions if a patient develops serious side effects.

The compound was designed to work with a new blood-thinner being developed for heart patients undergoing angioplasty to clear out blocked arteries. Such patients need to take blood thinners to prevent blood clots during surgery, but bleeding is a common side effect.

Bruce Sullenger of Duke University Medical Center said that having an antidote on hand would make the treatments safer. His study was published in the journal Nature Medicine.

The antidote agent appears to work against a whole new class of drugs called aptamers.

Sullenger said,"Most drugs target proteins. The type of drugs we're talking about are ribonucleic acids (RNAs) that target proteins.”


"Normally in our body we don't have these types of molecules outside of cells," Sullenger said.

"What we are doing is using agents that will sop up any nucleic acid. It's basically acting like a sponge. We put the sponge in the one compartment where the drug is," he said.

These antidote molecules controlled the activity of eight different aptamer compounds that was tested by the team.

They also tried it in a pig that had been given an aptamer blood thinner compound. "We showed you could rapidly reverse that blood-thinning effect," he said.

Pfizer's Macugen, a treatment for age-related macular degeneration, is the only aptamer drug that has been currently approved for sale by the U.S. Food and Drug Administration. Sullenger confirmed that several others were undergoing test.

Regado Biosciences in Durham, North Carolina is the company that is testing his blood thinner, called REG1.

Sullenger thinks that an antidote to this emerging class of drugs will make them safe."We predict that this advance will significantly expand the number of diseases that can be more safely treated using antidote-controllable agents," he said.

For more information go to www.maculardegenerationassociation.org