Individuals born with Usher syndrome type 1F do not have a sense of balance, cannot hear, and lose their vision over time. But scientists have now developed a gene therapy that could enable patients with the disease to hear and see. In a mouse model of the condition, researchers were able to restore hearing and balance, and it seems possible that vision was be improved. The work has been reported in the Journal of Clinical Investigation.
In this effort, the researchers delivered the proper version of a gene called PCDH15 to cells; this gene is disrupted in patients with Usher syndrome type 1F. Previous work by this group has shown that hearing could be restored in a mouse model of the disease, but this new effort could be used as an alternative if there are problems with the first approach, which has not yet been tested in humans.
“Without a clinical trial in humans, we can’t know whether our first gene therapy restores normal function,” said senior study author David Corey, a Professor at Harvard Medical School (HMS). “This new strategy gives us a backup in case the first therapy doesn’t work. It might even turn out to be better than the first, once tested in patients.”
One major problem with PCDH15 gene therapy is that the gene itself is quite large, and it cannot fit into a delivery system that is usually used to send gene therapy cargo to cells where it has to do its job. This delivery system is typically an infectious virus, which can enter cells but is not supposed to cause any disease or problem. It is called adeno-associated virus vector (AAV), and it is meant to simply get the right material to the right places.
Since PCDH15 is so large, the researchers began by engineering a smaller version of the gene that can fit into an AAV.
In the latest effort, the investigators cut the complete PCDH15 in half, and sent each half separately in its own AAV, to the cells of the inner ear or retina. These two gene halves join up once they are inside the cells, and the protein they encode for is generated. The resulting protocadherin-15 protein functions as it should, and hopefully prevents disease.
The current mouse models of Usher syndrome type 1F do not recapitulate the vision loss seen in patients, so right now the researchers cannot know if this approach will also restore vision in patients.
But, they were able to detect normal protocadherin-15 protein in a human retina organoid model, as well as in nonhuman primate retinas. The protein that was generated went to the right location within cells, and may work as it should. More research will be needed to confirm that aspect of the study, however. The investigators will also have to perform tests to determine whether this approach will be successful and safe to apply in humans.
“These results are particularly exciting because, while cochlear implants can address hearing loss in human patients, there are currently no treatments for the vision dysfunction associated with Usher syndrome,” said first study author and ophthalmologist Maryna Ivanchenko, an HMS instructor.
Sources: Harvard Medical School, Journal of Clinical Investigation