Eye Researchers Take on the Retina

Allowing the blind to see again: it sounds improbable, maybe even miraculous. “If looked at through the lens of 100 years ago, this would be pure science fiction,” says Russell Van Gelder, M.D., Ph.D., director of the UW Medicine Eye Institute and holder of the Boyd K. Bucey Memorial Endowed Chair in Ophthalmology.

In 2014, thanks to a collaboration spanning UW Medicine, UC Berkeley and the University of Munich, science fiction has turned into a distinct possibility.

The mystery, the revelation

The retina — the light-sensitive tissue at the back of the inner eye that translates images to the brain — is something of a mystery.

“No one fully understands the code that the retina uses to communicate with the brain,” Van Gelder says. What is known is that the millions of cells in the retina are grouped into families that sense and encode different types of information: motion, direction, contrast and radiance, for example.

And for two of the diseases that cause retina damage and lead to blindness — age-related macular degeneration
and retinitis pigmentosa — there is no cure. At least, not yet. Enter AAQ, a compound that blocks potassium channels, the connectors between cells that, as potassium flows back and forth, allow neurons to communicate.

A few years ago, organic chemist Dirk Trauner, Ph.D., modified AAQ to become light-sensitive. He and his colleagues at UC Berkeley — Richard Kramer, Ph.D., John Flannery, Ph.D., and Ehud Isacoff, Ph.D. — then conducted an experiment. They put brain tissue in a petri dish, added AAQ and inserted an electrode. The result? They found that AAQ rendered the tissue light-sensitive. They then began experimenting with retinas from blind mice, thinking that AAQ might be able to restore vision.

In the meantime, Van Gelder and his colleagues had developed an efficient tool to study and record the activity of many photo receptors at once: multi-array electrodes. When Van Gelder saw Kramer present AAQ findings at a conference, he had a revelation.

“The little light bulb that went off in my head,” he says, “was that our technique would be a very rapid way to demonstrate if AAQ had the potential to restore vision.”

If looked at through the lens of 100 years ago, this would be pure science fiction.
— Russell Van Gelder, M.D., Ph.D.

Blind mice begin to see

“I was excited about this project because it was something so new and novel,” says Jack Sychev, M.D. Now in his fourth year of residency, Sychev had taken off a year from medical school at Washington University in St. Louis to do research in Van Gelder’s lab.

The UC Berkeley group had already proven that — in the dish, at least — a retina from a blind mouse would become light-sensitive if exposed to AAQ. Sychev would be part of the next step: ascertaining if a blind mouse dosed with AAQ would react to light.

It worked. Sychev watched and recorded as mouse pupils constricted in response to certain wavelengths of light, an indication that the retina was back online, at least partially.

“The science behind it was sound,” says Sychev. Still, experimentation can be hit and miss; a plan can look good on paper, but then fail in the lab. Not this time.

“The first time it works, that’s kind of marvelous,” he says.

Van Gelder holds an amplifier for a multielectrode array chip, used to measure the light-related responses of the mammalian retina in the laboratory.

The light switch and the five-year plan

What’s the science behind the work? “It’s as though Dirk put an on/off switch on AAQ,” says Van Gelder. Unless it’s bathed in the right light, AAQ is inactive; the switch is off.

In its first stage of development, green wavelengths put AAQ in the off position; it had no effect on the potassium channels it would normally affect. “But when we put blue light on it, the drug is active. It will find the channel and block it,” Van Gelder says. And once the channel is blocked, the retina starts “seeing” light.

As promising as AAQ was, however, it had drawbacks. “It didn’t turn off by itself,” says Van Gelder, and it needed two types of light to act as triggers. Blue: on; green: off. “That’s not going to be very useful in people.”

So the collaboration continues, now expanding to the University of Munich, where Dirk Trauner works. With the support of a Nanotechnology Roadmap Grant from the National Institutes of Health, Trauner developed second-generation versions of AAQ: DENAQ and PhENAQ.

UW Medicine and Berkeley began testing the drugs, and the results are positive. DENAQ is an improvement over AAQ in several ways: it activates at lower light levels and with both blue and green light; it also responds well to white light. Kramer, Van Gelder, Trauner and collaborators published their results with AAQ and DENAQ in two major papers in the journal Neuron last year.

Russell Van Gelder, M.D., Ph.D., takes patient Mark Bathum — who is enthused about Van Gelder’s progress in vision restoration — on a tour of the lab.

The Paralympian’s perspective

Mark Bathum is a 55-year-old businessman, a University of Washington alumnus and an award-winning Paralympic skier. He is also one of Van Gelder’s patients. Bathum has retinitis pigmentosa.

In classic disease progression, Bathum had trouble seeing in the dark as a child; he remembers trick-ortreating forays that left him tripping and stumbling. In later years, vision problems likely cost him a place on the U.S. Ski Team. He can now see only straight in front of him.

Bathum has noticed a major shift — fueled by research — in how his physicians approached his prospects. In the 1980s and 90s, their diagnoses offered little hope beyond disease progression. Things, happily, have changed. “Since five or 10 years ago,” Bathum says, “all the doctors are more optimistic about retina treatments.”

He shares that optimism, and he hopes that Van Gelder’s work could arrest or cure his condition. “It’s not that I expect a solution in five years,” Bathum says. “But maybe 15.”

The possibilities

Using the small-molecule approach — developing AAQ and its successors — is only one of a number of promising projects at the UW Medicine Eye Institute.

In the effort to defeat blindness, researchers also are pursuing stem cell solutions: growing new, working eye cells, then transplanting them into the eye to replace non-working tissue. Another group is developing minimally invasive techniques to introduce gene therapy vectors into the eye, with the aim to fix faulty photoreceptors.

That said, Van Gelder and his colleagues are invested in DENAQ and the compounds that are likely to follow. A chemical solution has decided benefits over, say, a prosthetic eye implant (even with current technology, the resolution is low) or a genetic modification (which offers only one opportunity to fix the problem). In contrast, drugs can be modified and improved, so that patients can start a treatment, then upgrade as the medication is upgraded.

Even now, DENAQ and PhENAQ are being refined. The compounds need to be made more soluble, so that they are easier to deliver to the eye, and they need to be tested for toxicity. The end goal, of course, is to help the millions of people affected by macular degeneration and retinitis pigmentosa worldwide.

Van Gelder cautions that this work may not come to fruition. But he’s still optimistic, and he even gives an estimate for how long it will take until a compound is ready to test in humans.

“As a scientist, I’m naturally skeptical,” says Van Gelder. “But barring the unforeseen…I’d say that a five-year time window is reasonable.”

By Delia Ward
Photos: Karen Orders