New Gene Therapy Restores Hearing, Balance

Scientists from the Gray Faculty of Medical & Health Sciences at Tel Aviv University introduced an innovative gene therapy method to treat impairments in hearing and balance caused by inner ear dysfunction. According to the researchers, "This treatment constitutes an improvement over existing strategies, demonstrating enhanced efficiency and holds promise for treating a wide range of mutations that cause hearing loss."

The study was led by Prof. Karen Avraham, Dean of the Gray Faculty of Medical & Health Sciences, and Roni Hahn, a Ph.D. student from the Department of Human Molecular Genetics and Biochemistry. The study was conducted in collaboration with Prof. Jeffrey Holt and Dr. Gwenaëlle Géléoc from Boston Children's Hospital and Harvard Medical School. The research paper was featured on the cover of the journal EMBO Molecular Medicine.

Prof. Avraham explains, "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.

"A wide range of genetic variants in DNA can affect the function of these systems, leading to sensorineural hearing loss and balance problems. Indeed, hearing loss is the most common sensory impairment worldwide, with over half of congenital cases 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."

Targeting the CLIC5 gene

Hahn states, "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) and Leber congenital amaurosis (LCA), as well as in cancer immunotherapy approaches such as CAR T-cell therapy.

"One of the treatment strategies includes the use of engineered viral vectors, in which the native DNA is replaced with a functional sequence of the target gene. These vectors utilize the virus's natural ability to enter cells to deliver the correct gene sequence, thereby restoring normal function.

"Many gene therapies utilize adeno-associated viruses (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."

In this study, the researchers investigated a mutation in the CLIC5 gene, which is essential for maintaining the stability and function of hair cells in the auditory and vestibular systems. Deficiency of this gene causes progressive degeneration of hair cells, initially leading to hearing loss and later resulting in balance problems.

A new generation of viral vectors

The researchers utilized an advanced, structurally optimized version of the AAV vector, the self-complementary AAV (scAAV). They found that this vector achieved faster and more efficient transduction of hair cells compared to traditional AAV methods, requiring 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.

Prof. Avraham states, "In this study, we applied an innovative treatment approach for genetic hearing loss and found that it improves therapeutic effectiveness while also addressing combined impairments in hearing and balance. We anticipate that these findings will pave the way for developing gene therapies to treat a wide range of genetically caused hearing disorders."