Intermittent Systemic Hypoxia as Therapy for Vision Loss in Usher Syndrome

Abstract

Purpose : Usher Syndrome is a genetic disorder characterized by congenital deafness, vestibular dysfunction, and eventual blindness from photoreceptor degeneration. Currently there are no treatments for the blindness. We previously found that intermittent hypoxia protected against the progressive demise of retinal ganglion cell somas and axons in a mouse model of glaucoma. Herein, we tested the hypothesis that a similar, epigenetics-based therapy would show efficacy in protecting against photoreceptor degeneration in Usher.

Methods : Cohorts of Usher mice (expressing the human Ush1c²¹⁶ mutation) that exhibit progressive reductions in photoreceptor function starting at 1 month of age, and matched wildtype controls, were subjected to one hour of 11% O₂ systemic hypoxia between the ages of 2 weeks and 3 months, either 3 or 5 times per week. Hypoxia exposures involved placing mice in their home cages into a chamber in which O₂ tension was regulated. Additional cohorts of Usher and wildtype mice not exposed to hypoxia were included as controls. Photoreceptor function and structure was assessed serially at 1 and 3 months of age by scotopic electroretinograms and OCT, respectively. Data was analyzed by ANOVA.

Results : Our findings suggest both doses of intermittent hypoxia show benefit in improving photoreceptor viability based on improved a-wave amplitudes at each age relative to untreated mutants. OCT analyses are underway. No gender-dependent differences were noted in any cohort.

Conclusions : Our preliminary results suggest that specific frequencies of intermittent, systemic hypoxia may be a viable therapeutic option for preventing or reducing the rate of photoreceptor degeneration in humans with Usher. In addition, the ease of administration and low cost of such a treatment would obviate the need for often poorly-tolerated intravitreal and intraretinal injections of agents that otherwise cannot cross the blood-retinal barrier. Planned measurements at 6 and 12 months of age in these mice will ultimately reveal whether this short-term intermittent hypoxia treatment provides lasting benefit.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.