Nearly 40 million Americans say they have trouble hearing for one reason or another. There are no drug treatments, just hearing aids and cochlear implants, but biotech companies such as Frequency Therapeutics and Decibel Therapeutics believe they now have the means to make noise in this largely untapped market.
The race to drug the ears, so to speak, might soon include gene editing tools. In a paper published today in the journal Nature, scientific founders of Decibel and Editas Medicine (NASDAQ: EDIT), a leading CRISPR-Cas9 drug firm, and other authors show how they used the CRISPR-Cas9 gene editing system to deactivate a mutated gene that causes hearing loss.
It’s only a mouse study, but the authors say it’s the first to show the potential of CRISPR to treat hearing loss in animals. One of the researchers, Zheng-Yi Chen at the Massachusetts Eye and Ear Infirmary in Boston, tells Xconomy that he’s already working with collaborators in China to test the method in pigs. They are also tracking down patients with the same deafness mutation. The goal is to start a clinical trial in China in the next three years.
In their new paper, Chen and his colleagues write that nearly half of all deafness is linked to genetic factors. They showed that they could substantially reduce hearing loss in a strain of mice—the aptly named Beethoven mouse model, which has a mutation in the Tmc1 gene. Tmc1 mutations in humans have been linked to hearing loss that starts in childhood and results in deafness within 10 to 15 years.
CRISPR-Cas9 consists of two parts. The Cas9 enzyme is like a pair of DNA-cutting scissors. It reaches its target with the help of guides—strands of RNA whose code is programmed to match up with the section of DNA meant to be cut. Chen’s team injected the CRISPR machinery into the inner ear of the mice, which seems difficult enough. But their CRISPR engineering skills had to be even more precise. (David Liu of the Broad Institute and Harvard University, one of the other senior authors of the Nature paper and one of Editas’s founders, is a pioneer in developing new, precise CRISPR-based gene-editing tools.)
The Beethoven mice have a dominant form of hearing loss caused by a mutation in only one of the two copies of Tmc1. What’s more, the mutation itself is subtle: There is only one letter of difference in the sequence between the mutated and normal versions. So the CRISPR-Cas9 system the researchers designed had to cut and disable just that one copy to boost hearing. Knock out both, and hearing would have worsened, says Chen.
The researchers say they were able to thread the needle, disable the mutated version, and leave the healthy version alone for the most part to do its job.
This kind of precise targeting is one reason why this application of CRISPR genome editing “is certainly attractive from a therapeutic standpoint,” says John Brigande, who studies gene therapy for the inner ear at Oregon Health and Science University in Portland. He was not involved in the study.
Other CRISPR “knockout” programs are approaching human studies, such as the lead program of Intellia Therapeutics (NASDAQ: NTLA), which is working with Regeneron Pharmaceuticals (NASDAQ: REGN) to disable the gene responsible for the misfolded protein that leads to the rare disease transthyretin amyloidosis. (Using CRISPR to knock out aberrant genes is a more straightforward approach to creating a therapy; it will be a more complicated puzzle to replace an unwanted sequence with the correct version.)
Chen’s team has a long way to go. They kept the off-target cuts low, but only about 10 percent of the mouse ear cells were edited at all. “More widespread targeting of the mutant [copy of the gene] is a pressing need,” says Brigande. For comparison’s sake, Intellia has reported that it has achieved about 70 percent editing efficiency in the livers of mice in its amyloidosis program.
Repairing all targeted cells, however, might not be necessary for improvements in hearing, wrote Fyodor Urnov of the Altius Institute for Biomedical Sciences in Seattle, in a commentary published alongside the Nature paper. Urnov, who spent 16 years at gene-editing firm Sangamo Therapeutics (NASDAQ: SGMO), added that the study “provides an essential first step towards moving this type of approach nearer to the clinic.”
Other companies are attacking hearing loss from other angles. Novartis is running a phase 1/2 trial testing a gene therapy to deliver the gene for a protein (human atonal transcription factor) and spur the growth of sound-sensing hair cells in the inner ear. That trial began in 2014, has so far enrolled 14 patients with severe hearing loss, and should wrap up in 2019.
Frequency Therapeutics is using small molecule drugs to turn progenitor cells in the inner ear into hair cells, which don’t normally grow back after being damaged. Decibel is taking a variety of approaches, including the repair of connections, or synapses, between key neurons in the inner ear. A founder of Boston-based Decibel, Charles Liberman of the Massachusetts Eye and Ear Infirmary, is also a co-author of the Nature paper.
Jeffrey Holt, an inner-ear researcher at Boston Children’s Hospital and another co-author of the paper, is optimistic about the prospects of novel therapies, but he’s not betting on any one strategy, be it CRISPR, gene therapy or RNA interference (RNAi), which interrupts the cellular production of harmful proteins from messenger RNA. “They may all be useful to target some forms of hearing loss.”
Each strategy has its pros and cons, says Holt, who is a scientific advisor to Frequency, based in Woburn, MA. For example, RNAi may require multiple treatments to maintain the positive effect. And gene therapy’s success will depend on the new gene producing enough protein in the right type of cell. The efficiency of CRISPR needs improvement, and it may need to be tailored to each patient’s unique DNA sequence, he adds.
That might be the key to future hearing loss treatments of all kinds, says Holt. Hearing loss can stem from a variety of causes, from toxins and loud sounds to infection and inherited genetics. “I think we will need to invoke a precision medicine approach” to make sure the treatment is appropriate for the cause of the hearing loss, says Holt.