“These findings highlight the potential of self-complementary AAVs to reduce dose requirements, minimize toxicity, and broaden clinical use of inner-ear therapies,” said the head researcher.
An innovative method of gene therapy to treat hearing and balance disabilities caused by impaired function of the inner ear has been developed by researchers at Tel Aviv University (TAU). They said that this treatment, which was conducted on a mutant mouse model, offers a marked improvement over existing strategies, is more efficient, and could treat a wide range of mutations that cause hearing loss.
The study was led by Prof. Karen Avraham, dean of the Gray Faculty of Medical and Health Sciences, who is also a geneticist at the Department of Human Molecular Genetics and Biochemistry at the faculty and holds the Sarah and Felix Dumont Chair for Research of Hearing Disorders. She was assisted by doctoral student Roni Hahn, who worked in collaboration with Prof. Jeffrey Holt and Dr. Gwenaëlle Géléoc from Boston Children’s Hospital and Harvard Medical School.
Featured on the cover of the journal EMBO Molecular Medicine and titled “AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness,” it was supported by the US-Israel Binational Science Foundation (BSF), the National Institutes of Health/NIDCD, and the Israel Science Foundation Breakthrough Research Program. The team has worked with the Americans for four years, so there was no danger of losing the grant, a problem that has begun to crop up in the US and elsewhere due to cutbacks by the federal government and anti-Israel feeling in universities around the world, Avraham said.
As of 2023, the Central Bureau of Statistics reported that around 60,000 younger Israelis suffer from hearing loss; the number of those who develop deafness due to aging is probably much larger.
Therefore, hearing loss – the most common sensory disorder worldwide, more than blindness and other such disabilities – has long been explored as a condition amenable to gene therapy and involves over 220 different genes. In this study, the researchers investigated a mutation in the CLIC5 gene, which is vital for maintaining the stability and function of hair cells in the auditory and vestibular systems. Deficiency of this gene causes progressive deterioration of hair cells, at first leading to hearing loss and later causing balance problems.
A person cups their hand to their ear in an act of listening (illustrative) (credit: SHUTTERSTOCK)
“Injecting the gene in their inner ears in a surgical procedure, we corrected balance in almost 100% of the mice. We injected the congenitally deaf mice a day after birth, and at four weeks we tested them to see if they regained their hearing; we restored the hearing at a level of about 80%,” added Avraham, who believes that mice are a good model for this problem and that it will be relevant in humans.”
In the not-too-distant future, she continued, “we hope that gene therapy will become so mainstream that it won’t take years to try it on humans. We could obtain permission quickly for clinical trials. Although this genetic defect is rare, for biological reasons, there was a hint that it would be successful. Next, we hope to implement this approach on a more common form of deafness.”
Gene-specific strategy is necessary to ensure effective therapeutic development
WHILE GENE therapy using adeno-associated virus (AAV) is a powerful approach for treating inner ear diseases, a gene-specific strategy is necessary to ensure effective therapeutic development.
“We used a different type of AAV that previously was not used for treating deafness. As we succeeded in rescuing hearing and balance with this alternative form, we hope that this form will be used by other research groups. It might be more efficient for clinical work than what is used today,” Avraham noted.
So far, the team has not found Israelis suffering from this specific defect, but there may be, since not all those with hearing disabilities have been tested. “But we do know it is present in Cameroon and Turkey,” Avraham said.
“The inner ear consists of two highly coordinated systems – the auditory system, which detects, processes, and transmits sound signals to the brain, and the vestibular system, which enables spatial orientation and balance,” said the senior TAU geneticist, who was born in Canada and earned her doctoral degree from the Weizmann Institute of Science in Rehovot.
One of the treatment strategies includes the use of engineered viral vectors – carriers of an infectious agent between organisms of a different species – in which the native DNA is replaced with a functional sequence of the target gene. These vectors use the virus’s natural ability to enter cells to deliver the correct gene sequence, thereby restoring normal function. “Many gene therapies utilize AAVs to introduce therapeutic genetic material into target cells, and AAV-based gene therapy for hearing loss is currently in clinical trials, showing promising early results,” Avraham continued.
“Over half of congenital cases are caused by genetic factors. In this study, we aimed to investigate an effective gene therapy for these cases using an approach that has not been applied in this context before,” she said.
Hahn added, “Gene therapy has emerged as a powerful therapeutic approach in recent years and is now being applied to a range of genetic disorders, including spinal muscular atrophy (SMA) well as in cancer immunotherapy approaches such as CAR T-cell therapy.”
The researchers used an advanced, structurally optimized version of the AAV vector, the self-complementary AAV – a modified viral vector used in gene therapy that carries a double-stranded DNA genome.
They found that this vector achieved faster and more efficient transduction of hair cells – the process by which mechanical vibrations are converted into electrical signals in the inner ear –compared to traditional AAV methods, thus it requires a lower dose to achieve a similar therapeutic effect. In treated animal models, this approach prevented hair-cell degeneration and preserved normal hearing and balance.
“These findings highlight the potential of self-complementary AAVs to reduce dose requirements, minimize toxicity, and broaden clinical use of inner-ear therapies. We expect that these findings will pave the way for developing gene therapies to treat a wide range of genetically caused hearing disorders,” Avraham said.