How fMRI Brain Scans and Gene Therapy Help Restore Vision in Dogs

University of Pennsylvania vision study reveals fMRI as a helpful tool in treating inherited retinal diseases in dogs.

Dogs, like people, may suffer from inherited eye diseases. Studying inherited eye disorders in man’s best friend also may help researchers in developing treatments for people with genetic eye diseases. A new University of Pennsylvania (UPenn) study that shows how functional magnetic resonance imaging (fMRI) is an effective non-invasive tool as part of gene augmentation therapy to restore vision in dogs affected by genetic eye diseases.

“Cone-directed stimulation during fMRI can be used to measure the integrity of luminance and chrominance responses in the dog visual system,” the UPenn researchers wrote.

In eye anatomy, there are two types of photoreceptors. Cylindrical-shaped rods provide vision in low light and are found mostly in the outer areas of the eye’s retina, and cone cells provide color vision, and are mostly in the center of the retina in the macula, according to the American Academy of Ophthalmology.

“The dog is an important model for studies of retinal cone disease and its treatment, owing to the availability of diverse, naturally occurring genetic disorders and to the presence of a fovea-like, cone-rich zone in the canine area centralis,” wrote the UPenn researchers.

Functional magnetic resonance imaging is a special form of magnetic resonance imaging (MRI) that is a painless, non-invasive way to measure changes in blood flow that happen over time due as a way to measure brain activity. This new fMRI and gene therapy treatment canine vision study was performed by UPenn professors Geoffrey Aguirre, MD, PhD, professor of neurology, William Beltran, DVM, PhD, professor of ophthalmology, and Gustavo Aguirre, VMD, PhD, professor of medical genetics and ophthalmology, along with researchers Jacqueline Wivel, and Huseyin Taskin.

Professors Gustavo Aguirre and Beltran demonstrated the efficacy of gene therapy for treating dogs with hereditary retinal blindness in a prior study published in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) in 2012. This research paves the way for discovering a potential gene therapy for treating X-linked form of retinitis pigmentosa in people.

Two years prior in 2010, Professor Gustavo Aguirre and other UPenn researchers published different research that demonstrated gene replacement therapy to treat canine day blindness (achromatopsia). Canine day blindness has an autosomal recessive pattern of inheritance, which means both parents must carry the trait in order to pass it to their children.

Labrador Retrievers, German Shepherds, German Shorthaired Pointers, Alaskan Malamutes, Siberian Huskies, and Miniature American Shepherds are examples of dog breeds affected by canine day blindness; a genetic eye disease caused by a mutation in the specific gene that impacts a dog’s ability to see in bright light conditions such as daytime conditions according to the Consortium for Research of Inherited Eye Diseases in Dogs (CRIEDD). Mutations in the CNGA3 gene causes canine day blindness in Labrador Retrievers and German Shepherds, and CNGB3 gene mutations cause Achromatopsia in German Shorthaired Pointers, Alaskan Malamutes, Siberian Huskies, and Miniature American Shepherds per CRIEDD.

Canine day blindness is just one of many identified gene mutations for inherited retinal degenerations. Certain dog breeds are at more risk than others for inherited eye diseases. Progressive retinal atrophies (PRAs) are caused by gene mutations in mixed breed dogs, as well as Irish Setters, Collies, Cardigan Welsh Corgis, Miniature Schnauzers, English Mastiffs, Siberian Huskies, Gordon Setters, Tibetan Terriers, Norwegian Elkhounds, Papillons, Schapendoes, Sloughis, and Samoyeds according to a paper by Cathryn Mellersh of the UK Animal Health Trust published in the Canine Genetics and Epidemiology. Cone-Rod Degenerations (CRDs) impact Standard Wirehaired Dachshunds, Miniature Longhaired Dachshunds, and Glen of Imaal Terriers per Mellersh.

In genetics, “autosomal” refers to non-sex chromosomes, and “recessive” refers to the requirement of an inherited copy of the mutated gene from each parent in order to cause the inherited disease according to the National Human Genome Research Institute. For example, a Labrador Retriever puppy has roughly a 25% chance of having achromatopsia in cases where both the mother and father do not have canine day blindness but do carry copies of the mutated gene.

A form of inherited early-onset retinal degeneration called Rod-Cone Dysplasia 1 affects Irish Setters. Cone-Rod Dystrophy 2 causes early onset retinal degeneration that can lead to blindness in American Pit Bull Terriers. In dogs, X-linked progressive retinal atrophy 2 (XLPRA2) is an inherited eye disease that occurs in mixed breed dogs.

For this newly published research, UPenn scientists focused on brain responses recorded by fMRI in response to cone-directed light stimulation in wild-type dogs with late-stage retinal degeneration due to inherited genetic mutations. Specifically, for progressive retinal atrophy, the subjects had mutations in the PDE6B gene for Rod-Cone Dysplasia 1 (RCD1), for X-linked progressive retinal atrophy 2 (XLPRA2) subjects had mutations in the RPGR (Retinitis Pigmentosa GTPase Regulator) gene, and for Cone-Rod Dystrophy 2 (CRD2), subjects had mutations in the nephrocystin-5 (NPHP5) gene.

According to the UPenn researchers, fMRI was effective in validating the effectiveness of gene augmentation therapy in recovering cone function in dogs. fMRI offers a non-invasive method that is quicker and easier than measuring behavior.

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