Vision cells light up in blind mice
| Date: May 22, 2007 | 
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Bar Harbor, Maine — Gene therapy has been used to restore sight in mice with achromatopsia, a form of hereditary blindness also seen in human patients, researchers at the University of Florida (UF) and The Jackson Laboratory report.
In a paper published online May 21 in the journal Nature Medicine, the UF scientists, in collaboration with the laboratory of Jackson research scientist Bo Chang, M.D., the scientists described their use of a harmless virus to deliver corrective genes to mice with a genetic impairment that robs them of vision. The discovery shows that it is possible to target and rescue cone cells — the most important cells for visual sharpness and color vision in people.
Dr. Chang's laboratory is part of The Jackson Laboratory's Genetic Resource Sciences division. GRS DirectoræLeah Rae Donahue, Ph.D.,æsaid, "This successful translational collaboration between Genetic Resource scientists and clinical researchers underscores the importance of spontaneous mutations in mice that mimic clinical phenotypes in humans. Without the mouse model, this important step toward restoring sight in humans could not have been made."
“Cone vision defines whether someone is blind or not,” said William W. Hauswirth, Ph.D., the Rybaczki-Bullard professor of ophthalmic molecular genetics and a member of the UF Genetics Institute. “If you can usefully deliver a gene specifically to cone cells, there are implications for all blinding diseases, not just inherited ones. Even in two very common types of blindness, age-related macular degeneration and diabetic retinopathy, if you can target cones you might be able to rescue that vision.”
The mice had a hereditary form of blindness called achromatopsia, which affects about 1 in 30,000 Americans by silencing cone photoreceptors in the retina. The disease results in nearly complete color blindness and extremely poor central vision.
According to Dr. Chang, “We discovered the achromatopsia mouse about three years ago in the course of screening many strains of mice for vision problems,” as part of The Jackson Laboratory’s program to develop new mouse models for human eye conditions. He and Jackson colleagues then identified the genetic mutation that caused achromatopsia; meanwhile, scientists at other institutions were zeroing in on the analogous human mutation.
Within two months of the gene therapy injection into the subretinal space of the mouse eyes, scientists measured the electrical activity in the retinas, finding that 19 of the 21 treated eyes positively responded to therapy, and 17 of those 19 had electrical readings from their retinas on par with those taken in normal mice.
When the mice were between 6 and 7 months old, tests showed 18 of the 21 treated eyes continued to respond normally.
In addition, a separate, smaller group of treated mice were evaluated using an exam akin to an eye test at the doctor’s office.
In experiments overseen by Robert B. Barlow, Ph.D., a professor of ophthalmology at State University of New York Upstate Medical University, the mice were surrounded by four computer monitors that simulated the appearance of being inside a moving drum that had vertical stripes on the walls.
Scientists knew the mice could see the stripes because sighted animals naturally move their heads in the same direction as the moving stripes. By making the stripes ever-narrower — similar to how the letters get smaller toward the bottom of on an eye chart — researchers could assess the mice’s visual abilities.
As a group, all of the mice displayed normal visual acuity in their treated eyes.
“People can talk and tell us what they see,” said lead researcher John J. Alexander, Ph.D., a postdoctoral fellow in the department of ophthalmology at UF. “Animals are much more difficult. What makes this test so fantastic is that it involves an animal’s natural response, and the results tell us that the animals’ brains are involved in the process; that they are actually seeing something.”
In addition to cones, which number about 6 million in the retina, the eye’s rod cells are important for low-light and peripheral vision and exist in much greater amounts, with populations of more 100 million.
But treating cones could play a role in diseases that begin with the destruction of rods, such as retinitis pigmentosa, which affects about 1 in 3,000 Americans
“This is the first to my knowledge of a cone-targeted gene therapy that restores function in an animal model where cones are the primary defect,” said Richard Weleber, Ph.D., a professor of molecular and medical genetics at Oregon Health & Science University who was not involved in the research. “This validates the concept that it is possible to deliver a gene therapy targeting the cone system, and that is incredibly important for a number of degenerative diseases.”
The research was supported by grants from the National Institutes for Health, the Foundation for Fighting Blindness, the Juvenile Diabetes Research Foundation, the Macula Vision Research Foundation, the Lions of Central New York, Research to Prevent Blindness, Fight for Sight and NASA.
Contact(s): Joyce Peterson, joyce.peterson@jax.org, 207-288-6058
John Pastor, University of Florida, 352-273-5815, jdpastor@ufl.edu
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