GENE REPLACEMENT SURGERY TRIAL AT UMASS MED

By Aaron Nicodemus

WORCESTER
David Schwarte has been legally blind since birth. His life is not completely enveloped in darkness, as he can see through “a little patch of light at the corner of my eye.” To him, colors are washed out, shapes are blurry. He walks with a long cane.

Born with a rare genetic disorder called Leber Congenital Amaurosis, Mr. Schwarte, of West Lafayette, Ind., had few options for treatment until recently.

Through a clinical trial being conducted at the University of Massachusetts Medical School, 12 people with LCA are undergoing surgery to have a malfunctioning gene in their eye replaced with a normal gene. It is the only clinical trial of its kind in New England, one of only a handful being conducted nationwide. While the procedure is not approved by the U.S. Food and Drug Administration, the first phase of trials established that the procedure is safe. The trial is sponsored by Applied Genetic Technologies Corp. of Gainesville, Fla.

It is hoped that the trial will lead to a treatment for the estimated 20,000 to 40,000 people worldwide who have LCA.

Mr. Schwarte has been coming to Worcester regularly since July, when he had the surgery. So far, he has seen a slight improvement in his peripheral vision, and that sight is slowly moving toward the center of his eye.

“I'm still in the healing stage,” he said recently.

Dr. Shalesh Kaushal, who joined the medical school in January as its chair of ophthalmology, described the vision of people with LCA as seeing shapes and shadows, as having most colors washed out. People with LCA typically lose their vision in the first months of their lives.

“A cloudy day for most people would be like sitting in a darkened movie theater for people with LCA,” he said. “And it's a progressive disease, meaning they will continue to lose their sight over time.”

He said that gene therapy, once it has been sufficiently tested, may one day be available to address any number of gene-related disorders and diseases.

“It's a type of transforming medicine that is made possible by a confluence of a set of events,” Dr. Kaushal said. “There is any number of applications possible.”

The reason researchers have focused on curing a rare disease such as LCA, he explained, is not because it is the most common but because it is the most treatable. LCA is caused by a mutation within a single gene. Because the gene can be isolated in the eye, it can be manipulated. The exact same type of disease can be found in mice and dogs, giving scientists nonhuman test subjects.

The final piece was the development of a human virus that does not cause a disease that can be injected — with the corrected gene inside — behind the retina. The virus causes a mild immune response in most patients, he said.

Interestingly, said Dr. Kaushal, the retina's lack of an immune response works in its favor.

“When a foreign substance is introduced into human tissues and cells, it triggers the body's immune system,” he said. “Stimulation of the body's immune system can inhibit the effectiveness of gene therapy treatments and, in some cases can have adverse effects on the body and other healthy tissues. However, the retina lacks an immune mechanism, which makes treating eye diseases with gene therapy possible.”

Once the virus with the normal gene is delivered behind the patient's retina, the patient's body activates the gene. The gene then begins producing the protein necessary for the rods and cones inside the eye to recognize light. With the malfunctioning gene, LCA patients do not produce enough of this protein, and therefore their eyes do not respond to light.

Dr. Kaushal joined the medical school in January, coming from the University of Florida where he was assistant professor of ophthalmology. He is one of the first researchers in the United States to use gene therapy to treat LCA. At Florida, he and Dr. Terence R. Flotte, now dean of the University of Massachusetts Medical School, had collaborated on earlier clinical trials for this disorder.

Dr. Kaushal is a member of the Gene Therapy Center, part of the Advanced Therapeutics Cluster at the medical school. Research at the center is being applied to diseases such as cystic fibrosis; a genetic lung and liver disorder called alpha-1 antitrypsin deficiency; inherited metabolic disorders such as lysosomal storage disease; a progressive nerve disease called Canavan disease; also eye disorders such as retinal and macular degeneration.

During initial clinical trials at the University of Florida, Dr. Kaushal said all of the LCA patients saw improvement in their vision. One patient was able to read the digital clock in her parents' minivan for the first time.

“I remember one patient taking me aside and saying to me, ‘Doctor, I never knew the sky was so blue,' ” he said. “That was confirmation to me that we're on the right path.”

For more information go to www.maculardegenerationassociation.org