Experimental Gene Therapy to Reverse Common Hearing Loss Has Early Success

An experimental gene therapy developed at Boston Children’s Hospital was able to reverse a common type of inherited hearing loss in a mouse model.

This is a new type of gene therapy, as the gene causing the hearing loss, stereocilin (STRC), is too big to be incorporated into normal adeno-associated virus (AAV) vectors, which have become gold standard vectors for gene therapies.

“The challenge we faced was that the gene for stereocilin is too big to fit into the gene therapy vector,” said Jeffrey Holt, a scientist at Boston Children’s Hospital, who led the research, in a press statement. “The gene is about 6,200 DNA base pairs long, but the AAV only has a capacity of 4,700 base pairs.”

Although many genes are involved in hearing loss, genetic variants causing a loss of function of the STRC gene are a common cause of recessive, inherited hearing loss, also known as DFNB16.

“Some reports suggest that up to 16% of genetic hearing loss may be due to mutations in STRC, making DFNB16 the second most common form of genetic hearing loss and the most common form to affect sensory hair cells,” write the authors in the journal Science Advances.

The stereocilin protein acts as a protective base for sensory hair cells in the inner ear, also allowing them to stand up in an organised bundle and touch the ear’s tectorial membrane. “If stereocilin is mutated, you don’t have that contact, so the hair cells are not stimulated properly,” says Holt.

To solve the size issue with the STRC gene, Holt and colleagues first created a mouse model with a dysfunctional version of this gene and then created an experimental gene therapy by splitting the gene sequence in two and creating two AAV vectors each containing half the protein sequence. They used a technique called intein-mediated protein recombination to recreate the functional protein in the body once injected.

Initially the protein recombination did not appear to work, but the team realized that they needed to attach a special, short locator sequence to both sections of the gene sequence so the protein could combine properly.

“When we split the protein in half, we realized that one half had the signal, but the other half did not, so the halves might not end up in the same location,” said Olga Shubina-Oleinik, a researcher also based at Boston Children’s Hospital and the study’s first author.

The end result from the gene therapy was very promising. Levels of the STRC protein increased significantly, hair bundles in the inner ear recovered their structure and cochlear amplification and auditory sensitivity were much improved in the mice.

As the hair cells are not dead in this kind of hearing loss, simply disordered, the team hopes that this kind of therapy could have the potential to treat a wide range of patients.

“Importantly, the hair cells still remain functional, so they are receptive to the gene therapy.  We think this will provide a broad window of opportunity for treatment – from babies to adults with hearing loss,” says Holt.

The team now wants to progress their therapy to the clinical trial stage.  Research suggests that up to 2.3 million people around the world have hearing loss caused by STRC mutations and therefore the patient population that could benefit from this kind of therapy is large.

“The results were remarkable and are the first example of hearing restoration using dual-vector gene therapy to target sensory outer hair cells,” says Shubina-Oleinik.