University Times

A cure for glaucoma. A device that allows blind persons to experience the visual realm via other senses. Eye transplants. Regenerating the optic nerve. Creating biosynthetic corneas. Treating previously untreatable age-related macular degeneration.

These may sound like science fiction, but some actually have been accomplished while others are on the near horizon, thanks to cutting-edge research being performed at the Louis J. Fox Center for Vision Restoration.

A joint program of UPMC Eye Center and Pitt’s McGowan Institute for Regenerative Medicine, the Fox Center is the first national, comprehensive, multi-disciplinary research and clinical program dedicated to the new field of ocular regenerative medicine.

Initially called the Center for Ocular Regeneration, the center was renamed in June 2009, following a $3 million gift — matched by UPMC — from Louis Fox, a philanthropist and Pitt alumnus with central retinal vein occlusion, an incurable condition caused by blood vessel obstruction.

The Fox Center is headed by Joel S. Schuman, Eye and Ear Foundation Professor and director of UPMC Eye Center, and Alan Russell, director of the McGowan Institute.

“About four or five years ago, Alan and I were chatting and we talked about the possibility of leveraging the expertise of the McGowan Institute for Regenerative Medicine toward the eye, because there are not a lot of people working in that area and regenerative ophthalmology really didn’t exist at that time,” Schuman said. “Our vision — no pun intended — was for a comprehensive center that would be able to create new discoveries and inventions, but, importantly, to translate them into clinical practice.”

Schuman said, “Typically, scientists will be able to work on their ideas in any way that they choose, as long as they can convince peers who control funding that they should be funded. This center is a little different, because it’s very specific to regenerative medicine and ophthalmology, with a target of taking the basic science into clinical practice. It’s more like a mission than regular, normal science.”

The Fox Center now specializes in the most common disease areas associated with vision loss, including macular disease, glaucoma, diabetic retinopathy, optic nerve disorders, corneal scarring and ocular trauma.

Schuman and Russell initially inventoried the research interests in the ophthalmology department and at the McGowan Institute in order to pair up people who were working in similar areas.

“We found that there are a lot of pretty good resources right here at the University,” Schuman said. “We’ve also encouraged some people who are here to look at their work in a different way and marry this different approach to the goals they have.”

In addition, the Fox Center recruited researchers in novel areas, such as scientists who were working in stem cell therapy in the retina and the optic nerve.

Biosynthetic corneas

Among the current Fox Center initiatives, one project grew out of a previous discovery by James Funderburgh, professor of ophthalmology and of cell biology and physiology.

Funderburgh was studying the materials in the cornea that allow it to remain clear so that light can pass through to the retina, Schuman explained. About a decade ago those studies led to Funderburgh’s discovery of corneal stromal stem cells.

“This particular type of stem cell is responsible for most of the tissue that makes up the cornea, sitting in the middle part of the ‘sandwich’ that is the cornea,” Schuman said. “It’s a very important cell. His thought was that you could create a biosynthetic cornea using these stem cells.”

The Fox Center recruited Yiqin Du, a stem cell expert and ophthalmologist from China, to partner with Funderburgh on the project.

The two scientists demonstrated in the lab that creating a biosynthetic cornea is possible. In addition, they injected human corneal stromal stem cells into the corneas of a special strain of mice that normally get cloudy corneas and discovered that the human stem cells essentially rebuilt and cleared the corneas in the mice.

“This is very dramatic. It’s truly regenerative medicine,” Schuman said.

The next step is testing the project in a clinical trial. Funderburgh and Du are working with researchers in India to design and conduct such a trial.

“The work is advancing in the lab. They haven’t started trials yet, but the pieces are coming into place in order for those trials to begin. That’s very exciting,” Schuman said.

Curing glaucoma

In another research project, Funderburgh and Du partnered with Schuman to develop a potential cure for glaucoma, which is Schuman’s specialty.

“In glaucoma, there is damage to the optic nerve, the nerve in the back of the eye,” Schuman explained. The optic nerve damage and vision loss usually occurs so gradually and painlessly that a person is unaware of a problem until the optic nerve is badly damaged.

“That nerve damage is permanent once it occurs. Most often it occurs when the pressure in the eye is too high,” because the drain in the eye stops functioning properly and can become blocked, causing the loss of cells that form the draining mechanism, Schuman noted.

Du has identified stem cells in human eyes specific to the drainage meshwork. Currently, Du is trying to determine whether those cells can be placed into an eye where they can grow and provide the factors necessary to rejuvenate the drain of the eye and thus restore trabecular meshwork  function, Schuman said.

“These are human stem cells being tested in animals,” he said. While there are no guarantees of success, Schuman said, “Everything is looking very promising in that area, and it really does have the potential to cure glaucoma.”

Regenerating the retina

Another project stems from the condition of the center’s benefactor, Louis Fox, who has retinal vein occlusion in both eyes.

“One of the reasons he has provided funds to the Fox Center is to try to find answers to that problem. So another focus of our work is the regeneration of the retina,” Schuman said.

Fox Center scientists are working with Stephen Badylak, deputy director of the McGowan Institute, on the project. To regenerate tissue in various parts of the body, Badylak has worked with the extracellular matrix, the connective tissue in animals produced by cells and secreted into the environment where the cells are embedded, which can influence the behavior of the cells.

“In this case, he’s doing experiments to stimulate optic nerve regeneration with these techniques. This also is very promising,” Schuman said.

Translating visual images for other senses

Another project, sensory substitution, is nearing the marketplace, based on promising preliminary data.

Led by Amy Nau, director of optometric and low-vision services at UPMC Eye Center and a faculty member in the Department of Ophthalmology, the project is studying different types of sensory substitution devices, notably the BrainPort vision device, a non-surgical assistive visual prosthetic that translates information from a digital video camera to the tongue, through gentle electrical stimulation.

BrainPort consists of a postage-stamp-size electrode array for the top surface of the tongue, a base unit, a digital video camera and a hand-held controller for zoom and contrast inversion. Visual information is collected from a head-mounted camera and sent to the BrainPort base unit. The unit stimulates nerves in the tongue, which the brain can interpret as visual images.

“The device takes a visual image and translates it into an electrical simulation on the tongue,” Schuman explained. “So people are able to experience the visual environment through their tongue. You might call it ‘taste-a-vision.’”

Blind volunteer study participants have described the sensation as low-resolution pictures and shapes that are painted on the tongue with bubbles. Based on conversations with users, Nau has described the sensation as similar to Pop Rocks, the carbonated candy that creates a fizzy reaction as it dissolves in the mouth.

Nau’s study has shown that, with practice, users can identify and reach for nearby objects, and point to and estimate the distance of objects out of reach. Some people were able to identify letters and numbers, and recognize landmarks.

“It’s not vision exactly. But it is the information that they need to perceive the world so they can ambulate,” Schuman said.

Nau currently is trying to fill a cohort of 24 blind people and six sighted controls for a clinical trial of the device set to begin in June.

Nau also is studying the rewiring of the brain that occurs in adults who use this device. In people who are completely blind, there is no activity in the part of the brain where visual messages go. But through the use of this device, over time the brain rewires and the signals from this device get processed in the part of the brain that’s usually responsible for vision, Schuman explained.

Eye transplantation

The most futuristic project being explored at the Fox Center is eye transplantation, Schuman said, a project headed by Vijay Gorantla, a Pitt faculty member in the Department of Surgery and administrative medical director of the Pittsburgh reconstructive transplant program at UPMC.

Schuman said, “We’re pretty sure that we can do the eye transplant technically and prevent rejection. But the hardest part, actually, is going to be getting the optic nerve to reconnect to the brain. That will take a lot of effort, time and money in order for us to be able to do it.” But Schuman is confident eye transplants eventually will be a reality.

Initially, he believes, the transplants will be performed using cadaveric eyes, as opposed to biosynthetic eyes, which are years away from development.

“But one of the tricky parts is that the eye needs to be implanted within four hours of death. The window is very narrow for maintaining the health of the tissue in the eye,” Schuman said.

Fox Center OTERO projects

Several other Fox Center projects are being developed through the ocular tissue engineering and regenerative ophthalmology (OTERO) postdoctoral fellowship program, begun in 2009-10.

“These OTERO fellows are specifically people who are working with a scientist at the McGowan Institute and either a scientist or clinician in ophthalmology,” Schuman said. “The concept is to create scientists who have expertise in regenerative ophthalmology.”

One OTERO project is investigating ways of using ultrasound to break up clots that are blocking blood vessels in the retina or the optic nerve.

Other OTERO projects are looking at extended-release drug delivery for age-related macular degeneration patients and at extended-release drug delivery for glaucoma patients.

The future

The new field of regenerative ophthalmology has not yet filtered down into medical school or ophthalmology training, Schuman noted, but he believes it will eventually.

“I don’t think we’re ready yet, because all of this stuff is cutting-edge right now, and until we make the discoveries and implement them in terms of clinical trials, it’s hard to argue that it’s a good idea teaching this stuff to students who are learning the basic skills of how to be a doctor,” Schuman said.

One of the first applications for stem cell therapy, he said, may be for Lasik, laser refractive surgery than corrects people’s vision so they can avoid wearing glasses or contacts, he said. Sometimes, during Lasik surgery, a haze develops in a portion of the two flaps of the cornea, the clear parts in the front of the eye.

“Stem cells placed in that interface, we believe, would inhibit what is essentially scar formation that caused the haze — stem cells that would reverse the scarring,” Schuman explained. “But, for now, that’s a theoretical application.”

With so many irons in the Fox Center fire and so much potential for dramatic developments in eye disease treatments, Schuman is  cautiously optimistic.

“Imagine that instead of having a scar that you can have restoration of normal tissue again. That analogy works throughout the body,” he said. “So the expectations would become you’re not going to do just regular healing of scars, you’re going to do ‘constructive healing.’ It’s actually being able to get the tissue to repair itself to where it was before it was injured,” Schuman said.

“It’s my job to be skeptical and I am. But it’s also my job to dream. We’ve got a lot of dreamers in the department, in a good way, a lot of creative people. And it really does take that type of creativity to see beyond the ordinary and be able to come up with new insights and new ideas for ways to cure or prevent diseases.”

He also is encouraged by the support the Fox Center gets from Pitt and UPMC, as well as from foundations such as the Western Pennsylvania Medical Eye Bank.

“In fact, UPMC is matching one for one every dollar we get from philanthropy or industry and they haven’t placed any limit on that,” Schuman said. “I’m really excited about all of this. The Fox Center was a concept and now it’s a reality.”

The Fox Center is organizing the first annual Regenerative Medicine in Ophthalmology conference, to be held on May 26 and 27 at the University Club. For more information on the conference or on the Fox Center, visit www.foxcenter.pitt.edu, or contact Larisa Munsch at 412/624-5247; munschl@upmc.edu.

—Peter Hart