Kellogg's Retinal Dystrophy Clinic—a Destination for Patients with Inherited Eye Disease

Coming next, a gene therapy center to move treatment to patients

The Retinal Dystrophy group in the Kellogg Eye Center garden
From left: Kari Branham, M.S. CGC,
K. Thiran Jayasundera, M.D., Naheed Khan, Ph.D., Debra Thompson, Ph.D., David Zacks, M.D., Ph.D.; seated: John Heckenlively, M.D.

For years, John R. Heckenlively, M.D., a world expert in inherited eye disease, has collected genetic profiles of his patients so that he can notify them when treatments for these blinding diseases become available. Now, as breakthroughs in gene therapy begin to emerge, Dr. Heckenlively and his research colleagues believe the time is right to form a molecular treatment center at the U-M Kellogg Eye Center.

The Center for Gene and Molecular Therapy will build on the success of Kellogg's Retinal Dystrophy Clinic—which today is a destination for patients with rare genetic eye diseases—and the Eye Center's years of experience in the genetics of eye disease.

Such a center could not exist without the decades of work conducted by Dr. Heckenlively and his predecessors in identifying gene mutations in patients with retinitis pigmentosa (RP), a group of diseases that cause slow but progressive vision loss. Dr. Heckenlively is one of a handful of physicians skilled at making a precise diagnosis for a disease with many variations, each appearing nearly identical to the other.

Dr. John Heckenlively pointing at an image of a retinal dystrophy that has been projected on a whiteboard.
Dr. Heckenlively illustrates the features of retinitis pigmentosa as seen
in an image of the back surface of the eye.

"Twenty-five years ago, clinicians would tell you there are three types of retinitis pigmentosa," says Dr. Heckenlively, the Paul R. Lichter Professor of Ophthalmic Genetics. "Now we can identify gene mutations in well over 100 forms of the disease—150 if you include syndromes—and we need to find a cure for every one of them."

In Kellogg's Retinal Dystrophy Clinic, patients undergo eye examinations, extensive testing, and genetic counseling—all essential pieces leading to an eventual diagnosis of the disease. "Data generated in the clinic— genetic history and electrophysiological testing—are integral to both current and future treatment," says K. Thiran Jayasundera, M.D., who completed a fellowship in retinal dystrophies with Dr. Heckenlively and another in vitreoretinal surgery at McGill University before joining the Eye Center.

"Our patients know that gene therapy is evolving," says Dr. Jayasundera. "For now, they appreciate having comprehensive care; the opportunity to participate in research studies; and, ultimately, knowing what genetic mutation they have."

Building a center for gene and molecular therapy— gene by gene

In the most basic terms, gene replacement therapy involves identifying a defective gene and replacing it with a "normal" copy of the gene. This therapy won't work for every retinal dystrophy, and it's not likely to be effective for people who have experienced a degenerative disease over a long period of time. Thus, some of the early promise lies with diseases that affect children and young adults.

One of the driving forces behind the Center for Gene and Molecular Therapy is Debra A. Thompson, Ph.D., a senior scientist at Kellogg who investigates the molecular mechanisms of retinal degenerations and has contributed to the discovery of a number of disease causing genes. Among them is RPE65, a gene that has come to play a pivotal role in gene therapy.

"Individuals with a mutation in RPE65 have lost their light sensitivity," explains Dr. Thompson. "So adding back the correct gene gives an immediate measurable response." She points to recent pioneering Phase I clinical trials in which gene therapy with RPE65 produced stunning results, restoring vision in more than a dozen children and young adults.

The team is perhaps most optimistic about the knowledge and data they have amassed through years of study on a form of RP known as X-linked RP (XLRP), with research support from the Foundation Fighting Blindness. Among rare diseases, this form of RP affects a relatively large number of people, accounting for 20 percent of retinitis pigmentosa cases.

"We know which gene causes the most prevalent form of X-linked RP, and we have identified hundreds of patients who could be treated with gene therapy once the technology has been sufficiently tested," says Dr. Thompson. Current research for XLRP involves analyzing treatment outcomes in animals with the disease.

Many view Kellogg's new gene therapy center as a continuation of the Department of Ophthalmology's rich history in ophthalmic genetics. Professor Harold F. Falls, M.D., helped to establish the first Heredity Clinic in the nation in 1941. "Dr. Falls studied genetic diseases long before the structure of DNA was discovered," says Kellogg clinician-scientist David N. Zacks, M.D., Ph.D.

Dr. Zacks' research points to yet another strategy the Center will adopt in treating retinal disease—intervening in the disease process rather than targeting a specific gene. He studies the mechanisms that lead to cell death and thus the deterioration of the retina. The concept is neuroprotection, finding ways to keep these vital cells alive and working despite the presence of a genetic disease. And, he adds, "We have drugs in the pipeline for that purpose."

The Center for Gene and Molecular Therapy will develop over time. Some clinical studies could begin within one to two years; other therapies for age-related diseases that have multiple genetic and environmental causes will take longer.

And, there is always the challenge of support for cutting-edge research. "We have talented scientists and the newest facilities, but research at this level requires significant funding," says Dr. Heckenlively.

"Nearly every one of my patients wants to hear about the latest research," observes Dr. Heckenlively. "More specifically they ask, 'When will there be a cure for me?' We are closer than ever to giving our patients an answer."


Last Modified: Wednesday, 08-Feb-2012 10:23:26 EST