Usher syndrome: first nonhuman primate model
US researchers evaluate an experimental gene therapy in the first ever nonhuman primate model for Usher Syndrome.
Usher Syndrome is the leading hereditary cause for simultaneous deafness and blindness, for which there is no treatment. Genetic mutations lead those with the disease to be born deaf, experience balance issues and gradually lose their sight. The syndrome affects an estimated 4 to 17 out of every 100,000 people, however it has been stymied by the lack of an animal model that closely mimics how the disease affects people.
OHSU scientists confirmed that their model – a rhesus macaque born a year ago – has symptoms that mirror the most severe form of Usher Syndrome: Type 1B. They reported these findings during a presentation at the Association for Research in Otolaryngology meeting. The researchers used the gene-editing technology CRISPR/Cas9 to create the model, and thereby make it possible to test experimental gene therapies for Usher syndrome.
“While children with Usher 1B are born deaf, cochlear implants can enable them to have good hearing, especially if they are implanted early enough,” said team lead, Dr Martha Neuringer, Professor of Neuroscience in OHSU’s Oregon National Primate Research Centre.
“However, there is no current treatment to stop the steadily increasing vision loss that occurs in children with Usher 1B,” Neuringer added. “That is why having an accurate Usher model is so important. It is our hope and goal that this model will enable us to one day preserve the sight of children with Usher syndrome.”
Scientists already use mice to study Usher hearing loss, but fundamental differences in eye anatomy mean mice are not suitable models for Usher vision loss. A pig model of a different form of the disease, Usher Type 1C, was recently created.
Eyes and vision of nonhuman primates and humans are nearly identical, nonhuman primates best help scientists understand human retinal diseases and evaluate potential treatments. However, Usher syndrome does not naturally occur in nonhuman primates. So, the researchers had to genetically engineer a nonhuman primate with a gene mutation that causes Usher.
They used the gene-editing technology CRISPR/Cas9 to insert a mutation into the MYO7A gene, which causes Usher Type 1B, in monkey embryos. The embryos were transferred to surrogate monkey mothers to create pregnancies.
As a result, the first infant with full MYO7A gene editing was born in late 2021. Testing quickly confirmed the new-born rhesus macaque had no functional hearing and its MYO7A gene was mutated. It also showed impaired balance, leading to a wobbly, uneven gait.
When the macaque was four months old, the scientists began to see signs that its retina was beginning to deteriorate, and these changes worsened over the first year.
Now that the team has confirmed their model has all three of the defining signs of Usher syndrome, they are turning their focus to developing an experimental gene therapy that is designed to deliver the normal MYO7A gene to the retina to counter retinal degeneration. Their gene therapy work is ongoing, and the team expects to have early results to share on that front later this year.