TAU team restores hearing and balance in mice using self‑complementary AAV

Researchers at Tel Aviv University (TAU) have developed a promising gene therapy that rescued both hearing and balance in a mouse model with a mutation in the CLIC5 gene. The study, led by Prof. Karen Avraham with doctoral student Roni Hahn and collaborators Prof. Jeffrey Holt and Dr. Gwenaëlle Géléoc (Boston Children’s Hospital and Harvard Medical School), was published on the cover of EMBO Molecular Medicine.

Background

CLIC5 is essential for the structural integrity and function of hair cells in the inner ear. Loss of CLIC5 causes progressive degeneration of these sensory cells, producing congenital hearing loss followed by vestibular (balance) dysfunction. Hearing loss is the world’s most common sensory disorder and involves mutations in more than 220 genes, making gene‑replacement approaches an attractive therapeutic route.

Method

The team used a structurally optimized vector known as a self‑complementary adeno‑associated virus (scAAV) to deliver a functional copy of CLIC5 directly into the inner ears of newborn mutant mice via surgical injection. Unlike traditional single‑stranded AAVs, scAAVs carry a double‑stranded genome that accelerates and improves gene expression, allowing effective transduction at lower doses.

Results

The treated mice showed near‑complete recovery of vestibular function (balance) and about an 80% restoration of auditory function when tested four weeks after birth. In addition, treated animals were protected from progressive hair‑cell degeneration. The researchers report that the scAAV vector achieved faster and more efficient transduction of hair cells compared with conventional AAVs, reducing required dose and potentially lowering toxicity risks.

“These findings highlight the potential of self‑complementary AAVs to reduce dose requirements, minimize toxicity, and broaden clinical use of inner‑ear therapies,” said Prof. Karen Avraham.

Significance and next steps

The strong rescue of both hearing and balance in this CLIC5 model suggests that scAAV vectors could be adopted by other groups for preclinical and ultimately clinical inner‑ear gene therapies. The authors say that while the specific CLIC5 mutation is uncommon, it has been identified in populations in Cameroon and Turkey and may be underdiagnosed elsewhere. The team hopes to adapt the approach to more common genetic forms of deafness and to accelerate translation toward human trials.

Funding and collaboration

The work was supported by the US‑Israel Binational Science Foundation (BSF), the US National Institutes of Health/NIDCD, and the Israel Science Foundation Breakthrough Research Program. The international collaboration between TAU and US partners was central to the project’s progress.

Context

Israel’s Central Bureau of Statistics reported roughly 60,000 younger Israelis with hearing loss as of 2023; the number of people who develop hearing loss with age is substantially higher. Over half of congenital hearing‑loss cases are genetic, underscoring the potential impact of gene‑replacement strategies for a meaningful fraction of patients.