An international research project led by the Research Institute of the McGill University Health Centre in Montreal reports that a new oral medication is showing significant progress in restoring vision to patients with Leber’s congenital amaurosis. Until now, this inherited retinal disease that causes visual impairment ranging from reduced vision to complete blindness, has remained untreatable. The study was published The Lancet.

“This is the first time that an oral drug has improved the visual function of blind patients with LCA,” says the study’s lead author, Robert Koenekoop, MD, PhD, who is director of the McGill Ocular Genetics Laboratory at the Montreal Children’s Hospital of the MUHC, and a professor of human genetics, pediatric surgery and ophthalmology at McGill University. “It is giving hope to many patients who suffer from this devastating retinal degeneration.”

The study involved 14 participants from around the world with LCA ranging in age from 6 to 38 years old. Their blindness was caused by either mutations in the genes RPE65 or LRAT, leading to a serious defect in the retinoid cycle. The retinoid cycle is one of the most important cycles in the human retina because it produces a molecule called 11-cis retinal which has the special capacity to capture light and initiate vision. Patients with RPE65 or LRAT mutations cannot produce this crucial molecule thus the retinal cells cannot create vision, and slowly die.

“By giving patients with RPE65 or LRAT mutations an oral retinoid intermediate (QLT091001) most patients’ vision improved rapidly. We discovered that a certain portion of the retinal cells that were not working because of the lack of 11-cis retinal could be woken up,” explains Dr. Koenekoop. “Contrary to what was previously thought, children with LCA and defects in RPE65 or LRAT are not born with dead retinal cells; the cells can simply go dormant, and they can remain dormant for years before they eventually die. The oral drug we tested awakened these cells and allowed patients to see.”

Ten out of the 14 patients expanded their visual fields; others improved their visual acuity. The research team performed special brain scans of the visual cortex, which showed marked improvements in brain activities in patients who also improved in field size and acuity. More research will now be conducted to learn more about the retinal function in blind people in relation to dosage and methodology.


Targeting AMD-related Depression
Depression is a common risk for people who have lost their vision from age-related macular degeneration, but a new study shows that a type of rehabilitation therapy can cut this risk in half.

“Our results emphasize the high risk of depression from AMD, and the benefits of multi-disciplinary treatment that bridges primary eye care, psychiatry, psychology and rehabilitation,” said Barry Rovner, MD, a professor of psychiatry and neurology at Thomas Jefferson University in Philadelphia. Dr. Rovner and his colleagues published their findings in Ophthalmology.

U Iowa Researchers Map Proteins that Trigger Vision Loss University of Iowa researchers have created the most detailed map to date of a region of the human eye long associated with blinding diseases, such as age-related macular degeneration. The high-resolution molecular map catalogs thousands of proteins in the choroid. By seeing differences in the abundance of proteins in different areas of the choroid, the researchers can begin to figure out which proteins may be the critical actors in vision loss and eye disease. “This molecular map now gives us clues why certain areas of the choroid are more sensitive to certain diseases, as well as where to target therapies and why,” says Vinit Mahajan, MD, PhD, assistant professor in ophthalmology at the UI and corresponding author on the paper, published in JAMA Ophthalmology. “Before this, we just didn’t know what was where.” The researchers set out to determine why some areas of the choroid-RPE are more susceptible to disease than others, and what is happening at the molecular level. Dr. Mahajan and Jessica Skeie, PhD, a post-doctoral researcher in ophthalmology at the UI, created a map that catalogs more than 4,000 unique proteins in each of the three areas of the choroid-RPE: the fovea, macula and the periphery. They found that a CFH, a protein that helps prevent a molecular cascade that can lead to AMD, is most abundant in the fovea. That helps, because now they know to monitor CFH abundance there.“Now you can see all those differences that you couldn’t see before,” explains Dr. Mahajan. Previous studies have compared the abundance of single proteins in the fovea, macula and periphery. The UI choroid-RPE map corroborates findings from these studies, while also opening a whole new avenue of research into thousands of proteins that may be involved in vision loss. “We were able to identify thousands of proteins simultaneously and develop a map that shows what are the patterns of proteins that make these regions unique. This has helped explain why certain genes are associated with macular degeneration, and helps point us to new treatment targets,” says Dr. Skeie, the study’s first author.

“The depression is a response to disability, so we reasoned an effective treatment would be to reduce the disability through rehabilitation,” Dr. Rovner said. In the Low Vision Depression Prevention Trial (VITAL), he led a team of psychologists, ophthalmologists, optometrists and occupational therapists to test an approach called behavior activation.

“Behavior activation involves helping people to focus on activities they enjoy, to recognize that loss of those activities can lead to depression and to re-engage in those activities,” said Robin Casten, PhD, a co-author and an associate professor of psychiatry and human behavior at Jefferson. Helping people maintain an active social life is an important part of the approach, she said.

The trial recruited 188 participants with bilateral AMD from an ophthalmology practice affiliated with Wills Eye Hospital in Philadelphia. “We felt that this trial addressed an important need. Ophthalmologists have many tools at the ready for treating AMD, and we are continuing to forge links with other health-care providers to effectively treat the whole patient,” said Allen C. Ho, MD, director of the Clinical Retina Research Unit at Wills Eye Hospital and professor of ophthalmology at Jefferson.

The participants averaged 84 years of age, 70 percent were women and 50 percent lived alone. All had a best-corrected vision of less than 20/70. Each participant had mild depressive symptoms and was at risk for developing clinical depression, based on a subtest of the Patient Health Questionnaire.

During the trial, the participants had two visits with an optometrist, during which they were prescribed low-vision devices such as handheld magnifiers. After those initial visits, the participants were randomized to two groups.

One group received behavior activation from an occupational therapist specially trained in the approach. The occupational therapist worked with participants to guide them on using the low-vision devices, to make changes around the home (using brighter lights and high-contrast tape), to increase their social activities and to help them set personal goals and break these down into manageable steps.

“Blending the behavior activation with low-vision rehabilitation was straightforward and natural,” said Mark Hegel, PhD, a co-author and professor of psychiatry at Dartmouth’s School of Medicine in Hanover, N.H. “Occupational therapy helps people regain valued activities in their daily lives, and behavior activation capitalizes on this through formal goal setting and reinforcement of progress.”

The second group of participants served as controls. They talked about their difficulties to a therapist, but did not receive behavior activation or low-vision occupational therapy. Both groups had six one-hour therapy sessions in their homes over a two-month period. All participants were allowed to take antidepressants, but less than 10 percent did so. All received medical management of AMD as prescribed by their primary eye care providers.

By four months, 12 participants in the control group and seven participants in the behavior activation group had withdrawn from the trial or passed away. Of the remaining 169 participants, 18 in the control group and 11 in the behavior activation group developed clinical depression, based on retesting with the PHQ-9. Behavior activation had the most benefit for participants with the worst vision (less than 20/100), reducing the risk of depression by about 60 percent compared to controls. When the data were adjusted for vision status, physical health and baseline PHQ-9 score, behavior activation reduced the risk of depression by 50 percent compared to the control treatment.

“AMD is typically diagnosed and treated in primary eye-care settings, where there is no defined standard of care for depression. This study was a unique and compelling effort to address that issue by strengthening teamwork between eye-care professionals and mental health professionals,” said Eleanor Schron, PhD, of the National Eye Institute.

Dr. Rovner hopes the study will serve as a model for similar approaches to preventing and treating depression in AMD. “Stronger links between primary eye-care and mental health care workers would be needed to make behavior activation more widely available for AMD patients,” Dr. Rovner said. Specialized instruction would also be needed for occupational therapists, who are not typically trained in behavior activation.

The study is continuing to follow participants to see if the benefits of treatment are maintained out to one year.  REVIEW