Scientists have developed a gene therapy for an extremely rare genetic disorder, known as USH3. The gene therapy constrains hearing loss in a new USH3 mouse model.
USH3, a subtype of Usher syndrome (USH), is an autosomal recessive disorder characterized by deafness and blindness. Patients with USH3 experience a progressive hearing loss as well as loss of vision. In some patients, the symptoms appear as early as in infancy, while in others, the symptoms may occur years after birth and even in adulthood. Treating the disease before the symptoms become detectable is thought to be a reasonable strategy. However, there are no suitable animal models to mimic progressive hearing loss seen in USH3, hindering research on disease progression.
USH3 is caused by mutations in the CLRN1 gene. The protein encoded by CLRN1, namely clarin-1
, is a four-transmembrane protein and is critical for the normal development of the inner ear and retina. The precise functions of clarin-1 have not been fully characterized and how mutated clarin-1 contributes to hearing and vision loss remains unclear.
Previous studies showed that within several days after birth, clarin-1 mutant mice already have defects in hair cells (sensory receptors in the inner ear critical for hearing). These mice are not suitable models for investigating postnatal therapeutic intervention, because treatment should be given before the deterioration of hair cells.
In this work, a team consisting of scientists from Case Western Reserve University, University of California San Francisco, University of Florida, Keele University, and Vitreoretinal Associates of Washington successfully created a new USH3 mouse model that showed a delayed-onset progressive hearing loss. Working with the new mouse model, the team discovered that hair cell-specific expression of Clrn1 is sufficient for hearing development, and that viral-mediated CLRN1 gene therapy could significantly preserve the hair bundle structure and hearing.
Furthermore, the team found that both the translated and untranslated regions of CLRN1 are important for the efficacy of CLRN1 gene therapy. Based on the findings, the scientists hypothesized that CLRN1 untranslated regions may promote stability of the transcript and efficiency of translation. More investigation is needed to test this hyperthesis.
In conclusion, the study indicates that CLRN1 gene therapy might be a way to protect against hearing loss in patients with USH3. At present, it is possible to identify which individuals are at risk of developing USH3 before symptoms appear through genetic analysis and family history investigation. We may be able to constrain and prevent deafness in this population of people, if further research confirms the efficacy of the new gene therapy.
The study is a progress in this field in terms of several aspects, according to senior author Dr. Kumar Alagramam from Case Western Reserve University. Dr. Alagramam and other scientists participating in the study have already published their findings online in the 18 Oct. 2017 issue of the journal Scientific Reports.