Back in 2001, scientists first treated inherited blindness in dogs using gene therapy. In that instance it was Congenital Stationary Night Blindness which manifests in Briards and is analogous to Leber congenital amaurosis in humans, both defects in the RPE65 gene.
Dogs blinded by an inherited retinal degenerative disease had their vision restored after treatment with genes from healthy dogs, marking the first successful gene therapy for blindness in a large animal. The treatment offers hope for humans with a similar condition.
“We have shown that gene therapy can restore vision in dogs with one of the most clinically severe retinal degenerations,” says Acland, a research veterinarian at Cornell’s James A. Baker Institute for Animal Health.
The RPE cell layer in the eyes of humans, dogs and other mammals supports the retina by providing nourishment and removing waste products while supplying vitamin A to the photoreceptors. Puppies and human infants with defective RPE65 genes produce a mutant form of the RPE65 protein, resulting in early vision loss, degeneration of the retinas and near-total blindness later in life.
The canine form of this retinal degenerative disease has been found only in the briard dog breed. In the gene therapy experiments, researchers used RPE65 genes that were cloned from dogs without the disease, together with a viral vector (recombinant adeno-associated virus, or AAV) to carry the normal dogs’ DNA. They injected the combination into the subretinal space of the eyes of 3-month-old briard-beagle mix dogs that were known to have the defective RPE65 gene and had been blind since birth. Within six weeks, the treated eyes were producing the correct form of RPE65 protein. By three months, a series of tests (electroretinography, pupillometry and obstacle-avoidance tests in a dimly lit room) demonstrated that vision was restored to the treated eyes.
In 2010, the same team successfully returned function to the cones of previously blind dogs affected by a form of blindness called Achromatopsia.
Now, scientists have again used gene therapy to prevent and reverse another form of blindness in dogs and humans called X-linked Retinitis Pigmentosa associated with a mutation in the RPGR gene.
The disease in humans and dogs is caused by defects in the RPGR gene and results in early, severe and progressive vision loss. It is one of the most common inherited forms of retinal degeneration in man.
“Every single abnormal feature that defines the disease in the dogs was corrected following treatment,” said lead author William Beltran, assistant professor of ophthalmology at Penn’s School of Veterinary Medicine.
“We were thrilled,” said senior author Gustavo Aguirre, professor of medical genetics and ophthalmology at Penn Vet. “The treated cells were completely normal, and this effect resulted from introducing the normal version of the human gene into the diseased photoreceptor cells.”
This is exciting for dog owners because there are numerous breeds that have epidemic levels of eye disease and the proliferation of these advancements could lead to routine treatments that would treat or cure the disease in individuals.
There’s still a barrier to a permanent cure for breeds that would extend to the offspring of treated individuals. Treated dogs only receive the working DNA in the somatic cells at the location of the viral vector. Somatic cells are all the cells in the body besides those directly involved in producing offspring. If there’s a mutation in a somatic “body” cell, it will not be passed on to future generations.
The cells that produce the sperm and egg are called germline cells and they are not necessarily amenable to the same gene therapy techniques that work on individual somatic cells. You can effectively cure the blindness by providing a working copy of the genes within the eye, but other cells in the body will not have the new gene and the germline cells will not produce sperm or eggs that benefit from the disease-free allele either.
This effect is called the Weismann barrier, which is the theory that genetic information moves only in one direction, from germline cells to somatic cells. This is why when you get an x-ray the tech is more concerned with lead shielding your private parts than the rest of your body because germline mutations have serious consequences for your offspring and germline cells are theoretically immortal (they can replicate for the entire life of the organism) whereas somatic cells only divide 30-50 times.
If the Weismann barrier can be broken, it’s theoretically possible for the treatment of eye cells to result in genetic change in somatic cells and thus in the offspring.
There’s also the potential to apply gene therapy techniques to germline cells (such as the sperm or egg) directly and this would enable genetic engineering that would last over generations. Scientists have already created lasting changes in organisms that do not differentiate somatic-germline cells (like plants: thus we have GMOs), but I’m not aware of any ongoing progress on germline gene therapy and there are currently institutional barriers against work in that area given the potential ethical implications of genetic engineering. Scientists have successfully inserted synthetic chromosomes into mice that were heritable but the current focus in treatment of human offspring disease is to perform IVF and genetically profile the blastocysts before implantation.
So this is good news for dogs, and possibly the beginning of an amazing new world of animal husbandry when genetic engineering will allow for some truly incredible health advancements and possibly some radical experimentation.
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