How Gene Editing is Changing Otolaryngology

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Many factors come into play to cause hearing loss. In childhood, almost 50% of cases can be traced to the patient’s genes. Genetic testing promises to help identify such hearing loss before it has progressed, or potentially even before birth, while also helping to steer treatment—most notably, by identifying candidates for a new groundbreaking gene-editing strategy that selectively removes defective genes and eliminates the risk of inheriting the trait for future generations.

To explore the current status of gene editing in the field of otolaryngology, ENTtoday spoke with a number of leading researchers in the field.

Genes Involved in Hearing Loss

Researchers have identified 46 known genes involved in non-syndromic hearing loss, and expect to discover more. The most frequent genes implicated in recessive non-syndromic hearing loss are GJB2 (connexin 26 gene), which is responsible for more than half of cases, followed by SLC26A4, MYO15A, OTOF, CDH23 and TMC1 (Mutat Res. 2009;681[2-3]:189-196).

Although the majority of hereditary hearing loss is non-syndromic, many genetic syndromes also cause deafness, including neurofibromatosis type 2 and Usher syndrome. In addition, age-related hearing loss is thought to have a genetic component (SNPs rs4932196 and rs58389158), although the exact genetic cause(s) of the disease is still being elucidated (PLoS Genet. 2016;12:e1006371).

The discovery of genetic mutations has come with a whole host of potential genetic therapies; however, “the dominant deafness genes cannot be corrected with gene replacement strategies, so researchers are turning to gene-editing approaches to correct those types of hearing losses: either silencing RNA (siRNA) or CRISPR strategies,” said Hinrich Staecker, MD, PhD, the David and Mary Zamierowsky Professor of otolaryngology at the University of Kansas School of Medicine in Kansas City.

CRISPR, which stands for clustered regularly interspaced short palindromic repeats, uses the Cas9 enzyme to cut a specific target sequence on a mutant gene—cutting both strands of the DNA. Repair enzymes can then be inserted to repair and seal the cut with new genetic information, permanently changing the underlying genetic code. A landmark study in Nature reported the results of using CRISPR-Cas9 to correct a mutation in a gene that causes hypertrophic cardiomyopathy in human embryos (Nature. 2017;548:13–14). Researchers have questioned the findings of that study, however (see “Landmark Gene-Editing Study Called into Question,”).

The Promise of Gene Editing

“Gene editing is now much simpler and better than it has ever been. Even though we have tried to edit genes for a long time, the relatively recent discovery of the CRISPR-Cas technology, in which we can discreetly edit parts of the gene, is very exciting,” said D. Bradley Welling, MD, PhD, the Walter Augustus LeCompte Professor and chair of the department of otolaryngology at Harvard Medical School in Boston, and editor of ENTtoday’s sister publication Laryngoscope Investigative Otolaryngology.