Gene therapy delivered by virus restores hearing and balance in mice with genetic disorder

Genetic hearing disorders are estimated to affect 125 million people worldwide.

Mice suffering from a rare genetic hearing disorder, Usher syndrome, have had their hearing and balance restored after researchers used a virus to safely deliver a mutated gene to their inner ear. The accomplishment is presented in two new studies—one detailing the viral delivery method and the other its successful application. The virus was a synthetic variant of the adeno-associated virus, a small virus that infects humans without causing disease. It was used to deliver the gene therapy just after the mouse was born, giving the once profoundly deaf mice the ability to hear sounds at the level of whispers.

We spoke to Gwenaëlle Géléoc of Harvard Medical School, who authored the paper focusing on gene therapy.

ResearchGate: What motivated this study?

Gwenaëlle Géléoc: We have been using viral vectors as a research tool for many years in dishes. So we wondered if such a vector could be used in live animals to restore auditory and vestibular function.

RG: Can you tell us briefly about your results?

Géléoc: In this study, we used a viral vector to target the sensory cells of the inner ear in a mouse model of Usher syndrome type 1C. The mouse is profoundly deaf, dizzy, and suffering from progressive retinal degeneration. Reintroduction of the normal copy of the gene in the ear of newborn mice lead to a recovery of balance and hearing function. The recovery was beyond what anyone has seen before, with sensitivity down to 25 decibels or a whisper.

Unaffected mice, at left, have sensory hair bundles organized in 'V' formations with three rows of cilia (bottom left). This orderly structure falls apart in the mutant mice (middle column), but is dramatically restored after gene therapy treatment. Credit: Gwenaelle Géléoc and Artur Indzkykulian.

RG: How did you achieve this?

Géléoc: We injected the viral vector into newborn mice through the round window – a small structure that can be accessed through the middle ear – and let the mice recover. At six weeks of age, adult mice were observed in open chambers and tested on a rotating rod to assess their balance function. Hearing was assessed by looking at startle responses and auditory brainstem responses. Recovery was still observed by six month of age.

RG: How long is the delivery window? Does it have to be directly after the mice are born?

Géléoc: Injections at later stages failed to rescue auditory function. But this may be partly due to a decrease in penetrance of the vector at later stages, or it may be that the time window for treatment is restricted to a short time window after birth.

RG: What was your initial reaction when you realized this approach had worked?

Géléoc: I joined Boston Children’s Hospital a little over five years ago with a specific goal: to develop novel therapies for Usher syndrome. The results of this work have been beyond what I could have hoped for. I am grateful to have had an excellent team to work with and an institution that has supported my work. This work is a proof of principal that such therapy could be used as a treatment for hearing loss. At the same time, much more work is needed before such therapy can be translated to patients.

RG: Are you planning to look at other genetic diseases?

Géléoc: My goal is to expand this work to other genes that cause sensory hearing loss, including many of the Usher genes. The challenge for some of the most common forms of Usher syndrome is that they affect genes that are much larger than the Ush1c gene in this study. The vectors that we used have a limited cargo capacity and cannot fit large genes such as Ush1b or Ush2A. So more work is needed to find ways to circumvent this limitation.

Featured image courtesy of wikimedia.