Using fMRI, new vision study uncovers promising model for restoring cone function

In the retina of human eyes, cones are photoreceptor cells responsible for color vision, daylight vision, and perception of small details. As scientists in the Division of Experimental Retinal Therapies at the University of Pennsylvania School of Veterinary Medicine, Gustavo D. Aguirre and William A. Beltran have worked for decades to identify the basis of inherited retinal diseases . They have already shown that they can recover the missing cone function by reintroducing a copy of the normal gene into photoreceptor cells.

Humans and dogs are both affected by retinal disease, and a new study of daylight vision using a canine model offers crucial insight into assessing “whether these cell replacements – by which we introduce cones in the retinas of these dogs – are an effective approach to restoring cone vision,” says Beltran, the Corinne R. and Henry Bower Professor of Ophthalmology.

Their findings were published in Translational Vision Science and Technology. Other co-authors are Huseyin O. Taskin, a former research specialist at Penn in the GKAguirre Lab and current graduate student at the University of Toronto, and Jacqueline Wivel, a veterinary technician.

Beltran and Gustavo Aguirre teamed up with researchers including cognitive neuroscientist Geoffrey K. Aguirre, professor of neurology at the Perelman School of Medicine, bringing together their knowledge of the retinal system and brain measurements. In dogs with three different types of naturally occurring retinal diseases and in dogs with normal vision, scientists used functional magnetic resonance imaging (fMRI) to assess brain responses to lights that stimulate only cone cells.

Researchers have found that fMRI can detect brain responses to daylight vision for black and white information as well as color information, and can identify the area of ​​the visual cortex that responds to visual stimulation. ‘a region of the dog’s retina rich in cones and similar to the human fovea. They also found that they could use fMRI to measure the relative degree of daytime vision loss.

Using this technique in animals with a retinal disease caused by a mutation in a gene called NPHP5, they demonstrated that gene augmentation therapy restored the cortex’s response to black-and-white stimulation. This makes this disease a promising disease for which to study photoreceptor cell replacement as a treatment in the future.

“Canine models are useful for studying retinal diseases because they present a variety of naturally occurring genetic disorders. The ultimate goal is to first demonstrate that these disorders can be treated in dogs before translating them to human patients” , explains Taskin, the first author. . Gustavo Aguirre says: “We hope that therapeutic approaches effective in humans will then be made available to veterinarians so that they can benefit man’s four-legged companion.”

Geoffrey Aguirre says: “The aim of the study was to see, in different versions of these retinal diseases, how much information about daytime vision reaches the visual system of these dogs. This knowledge is particularly useful, he says, because determining whether a treatment for a retinal disease has been effective requires knowing how much visual function was present before the treatment.

Beltran says this paper shows that gene therapy can recover cone function because it looks at an animal model without cone function and shows improvement. He explains that in the disease caused by the NPHP5 mutation, the cones are present but not functional. Animals with this condition are born blind, but initially have some night vision, although the rods (photoreceptors that allow night vision) die after several months, rendering dogs completely blind within a year.

Previous research has measured responses to stimuli using electroretinography and visual behavior tests, which Beltran said can require weeks or even months of dog training. Geoffrey Aguirre says the use of fMRI in this study is important because it is faster and easier than measuring behavior, and it is non-invasive. Taskin also notes that neither visual behavior tests nor electroretinography provide certainty about what is happening in the visual cortex.

A previous study showed that retinal gene therapy in a type of blindness disorder called Leber congenital amaurosis is associated with restoration of fMRI responses of the canine visual cortex, but the nature of this study meant that rod and cone responses would have may have contributed to cortical activity. . The new study furthers knowledge of retinal diseases by specifically stimulating cones.