Purchase this article with an account.
Vahitha Shameem Nizamudheen, Anat Yanai, Kevin Gregory-Evans, Cheryl Y Gregory-Evans; Nonsense suppression therapy in an animal model of Usher 1D syndrome. Invest. Ophthalmol. Vis. Sci. 2021;62(8):3074.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Usher syndrome 1D (USH1D) is an autosomal recessive condition characterized by severe deafness, vestibular dysfunction and progressive vision loss. Cadherin 23(CDH23) is a structural protein present in stereo cilia of mechanosensory hair cells of the cochlea. In photoreceptors CDH23 is thought to mediate membrane–membrane adhesion between the inner segment membranes of neighboring photoreceptor cells and at synapses, to keep the synaptic cleft in close proximity. We have obtained a mouse model Y2209X line (Cdh23) which has a nonsense mutation in Cdh23. Homozygous Cdh23 mice exhibited head shaking, circling behavior and a reduction in the ERG response. In this study, we hypothesized that manipulation of Cdh23 dosage by a nonsense suppression strategy could rescue the disease phenotype in this animal model.
Two drug treatment protocols was performed (i) Prenatal: time-mated pregnant mice received daily subcutaneous injections of 30 μg/g Ataluren® and then the offspring received the same daily injections from P4 to P90. (ii) Postnatal: mice from P4-P90 received daily injections of 30 μg/g Ataluren®. ERGs were measured at P45 and P90 and P120. After treatment, IHC was performed to confirm Cdh23 protein expression and the trafficking of photoreceptors proteins. Structural benefits in photoreceptors were studied by immunohistochemistry and by transmission electronmicroscopy.
We characterised this mouse model of USH1D (Cdh23) that had a nonsense mutation in Cdh23. The Cdh23 mouse was significantly smaller than wildtype mice and did not survive past 60 days of age. As with other models of USH1D, we did not find any structural abnormalities in the Cdh23 retinal structure. However, we found abnormalities in light-induced trafficking of proteins including rhodopsin, arrestin, α-transducin and recoverin. When Cdh23 mice were treated with Ataluren®, Cdh23 protein was expressed in the connecting cilium, the trafficking defects were rescued and electrical response to light were improved. The mice survival rate was increased to P120 and the circling behaviour was reduced.
These data show for the first time that nonsense suppression in a mouse model of USH1D was able to rescue the major phenotypic features observed in the homozygous mutant mice. We conclude that translational readthrough by the small molecule Ataluren® improved the disease phenotype in this mouse model.
This is a 2021 ARVO Annual Meeting abstract.
This PDF is available to Subscribers Only