June is Vision Research Month – a perfect time to highlight the innovative, cutting-edge research programs of the Foundation Fighting Blindness, headquartered in Columbia, Maryland. The urgent mission of the Foundation is to drive the research that will provide preventions, treatments, and cures for people affected by retinitis pigmentosa, macular degeneration, Usher syndrome, and the entire spectrum of retinal degenerative diseases.
Most recently, “Universal Appeal,” the lead story in the Spring 2014 edition of In Focus, the Foundation’s quarterly newsletter, explores the potential of optogenetics – a still-experimental treatment for a variety of blinding retinal disorders that uses gene therapy to empower retinal and brain cells to respond to light. It is reproduced here with the Foundation’s permission.
Genetic Research: Gaining Traction
In the late 1980s, as the death toll from AIDS skyrocketed, the public demanded a cure. So, over the next several years, researchers developed what became known as “the AIDS cocktail,” a mix of treatments enabling those infected by HIV, the virus the causes AIDS, to live unburdened by the full effects of the condition. But there’s still no cure for AIDS.
Today, those affected by inherited retinal diseases face a similar situation, albeit one that’s not life-threatening. There are no cures yet, and, for various reasons, most of those affected have not identified their disease-causing genes. But that’s changing, says John Flannery, Ph.D., a professor of neurobiology at the University of California, Berkeley. “The speed of identifying the mutated gene in a patient is increasing astronomically while the cost is going down.”
In the meantime, some researchers, Dr. Flannery included, are developing gene-neutral treatments, those designed to slow or halt vision loss due to retinal diseases even if a patient doesn’t know his or her genetic defect. “These are not cures; they’re not going to restore normal vision,” explains Dr. Flannery, who is a member of the Foundation’s Scientific Advisory Board.
“Some are designed to slow the loss of photoreceptors, the retinal cells that facilitate vision, without actually repairing the genetic defect. Others are for late-stage disease, where the photoreceptors have been lost and can’t be repaired. I expect some of these treatments will be in clinical trials within the next few years.”
Anyone who has lost vision completely knows how valuable even a small amount is. Gordon Gund, the Foundation’s chairman and co-founder, who lost his to retinitis pigmentosa (RP), once told Dr. Flannery that whenever he checks into a hotel, he has to memorize his room’s layout before navigating it. “If you could give Gordon enough function to show him a lighted bathroom door, that would be meaningful,” says Dr. Flannery.
Optogenetics: Enabling Retinal Cells to Sense Light
Not one to rest on laurels, Dr. Flannery is developing one of two Foundation-funded projects at UC-Berkeley that would provide those who have lost their photoreceptors with protein enabling remaining retinal cells to sense light. It’s a treatment known as optogenetics.
A bit of a tutorial here: There are two types of photoreceptors – rods and cones, the light-processing cells responsible for peripheral [rods] and central [cones] vision. With most RP and RP-like diseases, the rods are lost first, the cones second.
But, as Dr. Flannery points out, there are also bipolar and ganglion cells, which serve as links in the circuit relaying the photoreceptors’ signals from the retina to the brain. Providing those cells with light sensitivity could give people like Gordon the “function” they need.
More about Optogenetics
Stephen Rose, Ph.D., Chief Research Officer of the Foundation, provides a good explanation of optogenetics in Optogenetics: Seeing the Light in a Whole New Way, available on the Foundation website:
Conventional wisdom says that if there are no rods and cones left, as is the case in late-stage retinitis pigmentosa, you’ll have no vision. And without replacing those rods and cones with new ones or an artificial device, vision restoration is simply not possible.
Here’s where John [Flannery] comes in. He accomplished his vision-restoring feat by using gene therapy to enable the ganglion cells in highly degenerated retinas to respond to light. Normally, ganglion cells aren’t light-sensitive; rods and cones are what convert light into the electrical signals sent to the brain, where they’re interpreted as vision.
Ganglion cells play a different role, providing the finishing touches to the visual information produced by rods and cones — fine-tuning it, if you will — before it makes its way to the brain. But in many retinal degenerations, ganglion cells survive long after rods and cones are gone, which is what makes them a prime target for vision restoration.
This new approach John and other investigators in research fields are taking is called optogenetics – a process in which gene therapy is used to empower cells, including those in the retina and the brain, to respond to light. In addition to restoring vision, scientists are exploring ways to use optogenetics to treat a variety of conditions, including Parkinson’s disease and sleep disorders.
Optogenetic Gene Therapy: Better than the Argus II?
Dr. Flannery’s optogenetic treatment has worked in mice, but will need a large animal study before it can be tested in humans. Even so, he’s confident it could work better than what is currently the best-known prosthetic for blindness – the FDA-approved Argus II retinal prosthesis, or “bionic retina.”
“That device has a chip that sits on the retina with 60 evenly spaced electrodes. But in low vision or blind patients, there are hundreds of thousands of surviving retinal neurons that aren’t evenly spaced,” Dr. Flannery explains. “With an optogenetic gene therapy, you can transfer the light sensor to most of those cells, which is a big advantage.”
Additional Research in the Pipeline
Of course, not everyone affected by retinal diseases has lost most or all vision. So there are a variety of treatments being developed by researchers that bypass gene defects and focus on preserving rods and/or cones with the appropriate proteins. Also being developed are drug and stem cell treatments, including one Foundation-funded project which would, in essence, repair a damaged retina. While these projects have yet to enter into clinical trials, they’re attracted the attention of those best-suited to fund the trails and quickly move the therapies to the marketplace.
“Big-pharma companies ask about prevalence – how many people you’ll treat,” Dr. Flannery says. “The number of Leber congenital amaurosis (LCA) patients in North American is under 3,000, but I think $30 million has been spent developing a gene therapy for it.”
“Dividing patients into that, you get what they call a ‘cost per dose,’ which is more than your house. One of the appeals of therapies that are not targeted to a specific gene is that the patient base is not divided up – many people, many diseases.”
VisionAware will provide updates on Foundation Fighting Blindness research as they become available.
Advancing Laboratory Treatments into Human Studies by Dr. Stephen Rose, Foundation Fighting Blindness
Meet Aries Arditi, Ph.D., Founder and Principal Scientist of Visibility Metrics, LLC