Gene therapy restores vision in dogs with severe congenital Leber’s amaurosis

Gustavo Aguirre and William Beltran, veterinary ophthalmologists and vision specialists at the University of Pennsylvania School of Veterinary Medicine, have studied a wide range of retinal blindness disorders. But that caused by mutations in the NPHP5 gene, leading to a form of congenital Leber’s amaurosis (LCA), is one of the most severe.

Children with this disorder are not visual. They have a wandering and sought after look on their faces and are usually diagnosed at a young age. “

Gustavo Aguirre, veterinary ophthalmologist and vision researcher, University of Pennsylvania School of Veterinary Medicine

An almost identical disease occurs naturally in dogs. In a new newspaper article Molecular therapy, Aguirre, Beltran and colleagues at Penn and other institutions have demonstrated that canine gene therapy can restore both the normal structure and function of photoreceptor cells in the retinal cone, which in patients with ACV, do not develop normally. Delivery of a normal copy of the canine or human version of the NPHP5 gene restored vision in treated dogs.

“What’s amazing is that you can take this disease in which the cone cells weren’t fully formed, and the therapy restores their function – they had no function before – and recovers their structure,” Aguirre says. .

“This plasticity is incredible and gives us a lot of hope,” Beltran says.

Stroke encompasses a wide range of inherited vision disorders characterized by blindness that strike early childhood. The form of stroke associated with NPHP5 mutations is rare, affecting approximately 5,000 people worldwide. Known as ciliopathy, it affects the cilia of the cells of the retina. Hair cells are antennae structures on photoreceptor cells that translate the energy of light into visual signals.

In NPHP5 disease, the rod-shaped photoreceptor cells – responsible for low-light vision – degenerate and gradually die at the onset of the disease. Yet the conical photoreceptors, which enable color vision and, in the central retina, the perception of fine detail, although structurally abnormal, survive, without functioning.

Aguirre and Beltran, together with colleagues and co-authors on current work, Artur Cideciyan and Samuel Jacobson of Penn’s Perelman School of Medicine, have found success with gene therapy approaches to treat a variety of vision disorders. hereditary. Often, they have sought to treat early in retinal disease, before the photoreceptor cells are dead or fully degenerated. But the fact that cone cells persist in this form of ACV has led researchers to question whether therapy targeting the cones could not simply stop but reverse the course of the disease.

In testing this approach, the team administered retinal injections of adeno-associated viral vectors, a platform to transport the normal version of the NPHP5 gene, into one eye of each of the nine five-week-old dogs with the disorder. vision. Known as gene augmentation therapy, the injection is used to deliver a healthy gene in disorders where the causative mutation leads to a defective or absent protein.

To determine the effectiveness of the treatment, the researchers used a technique called electroretinography, which measures the electrical response of photoreceptor cells to a light stimulus, as well as optical coherence tomography, which allows non-invasive imaging of thin cross sections of the body. the retina. Both methods of evaluating experimental therapy have given encouraging results. In the treated eyes of dogs, the outer segment of the cones regressed.

Additionally, when the treated dogs were around six months old, their vision was tested using an obstacle avoidance course. When their treated eye was blindfolded, they found it difficult to navigate; however, when this eye was discovered, their ability to dodge obstacles improved dramatically.

“What is so attractive and so exciting here is that we are not just stopping a disease process, we are actually restoring an abnormal photoreceptor cell to become normal and functioning,” Beltran says. . “This disease in dogs resembles the disease in humans very closely, in fairly specific terms, so there is a lot of support for the idea that a similar treatment approach could help children as well.”

Ongoing studies suggest that the treatment may be effective even when given at later stages of the disease. With additional support, the researchers hope to push the research forward towards a clinical trial in humans.