A challenge for research on Usher 1F is that the standard animal model for research, a mouse lacking the Usher 1F gene, has only mild impairment of vision. This may be because the structure of the photoreceptors in mice differs from that in humans, and PCDH15—the protein that is absent or dysfunctional in Usher 1F, just isn’t as important for vision in mice.
David Corey and his colleagues at Harvard Medical School are trying to develop gene therapy methods to treat the deafness and blindness of Usher 1F. They have focused thus far on preventing the deafness. The mice lacking PCDH15—being profoundly deaf—are a good model for those studies. But they recognize that reversing the congenital deafness in Usher 1F patients will be challenging, and that progress may come sooner in preventing the progressive blindness. So which animal model to choose?
Corey and his group were excited to discover that the photoreceptors of a small tropical fish, the zebrafish, were more like those in humans. These fish are a favorite laboratory animal because they are small and easy to maintain, and because they can see and hear within about a week of fertilization. Corey was additionally excited to learn that Monte Westerfield and Jen Phillips at the University of Oregon had already made a zebrafish model of Usher 1F. At the Usher 1F meeting in Vancouver last May, the two laboratories met to collaborate on using zebrafish to test strategies for delivering a functional PCDH15 gene to the retina. The fish were sent to Harvard, and Jen Phillips soon visited to contribute her experience. Maryna Ivanchenko in the Corey Laboratory and Artur Indzhykulian of Massachusetts Eye and Ear are assessing the retinal pathology in the fish with scanning electron microscopy and electroretinogram recording, and are designing new versions of the PCDH15 protein that can function in the eye but still be small enough to put in a conventional AAV gene therapy vector for human therapy. It’s just a start but they hope that the zebrafish will allow them to test strategies faster.