Dec 20, 2017

Hearing loss treated successfully in mice with gene editing

Illustration: Rebecca Zisser / Axios

Scientists are able to disrupt progressive hearing loss in mice via gene editing, according to a study published in Nature Wednesday. The team used CRISPR-Cas9 to cut the mutated gene and substantially improve the chance of hearing.

Why this matters: The technique would have to be proven safe and effective for humans but is a step closer to the goal of being able to offer one-time treatment for certain genetic hearing-loss disorders, according to Altius Institute for Biomedical Sciences' Fyodor Urnov, who was not part of the study. The experiment was done directly in the organ in the animal rather than taking out the cell, manipulating it and reintroducing it back — and may expand the limited scope of editable organs to the ears, he tells Axios.

What they did: The team treated more than 100 mice that had both a single mutated and a single normal copy of the TMC1 gene associated with progressive hearing loss. Since the mutated gene is dominant, it leads to profound deafness both in mice and humans, study author David Liu says. "If left unmodified, this particular mutant form of TMC1 results in hair cell death, even if the animal or patient has one normal copy of the TMC1 gene," he says.

The team designed a CRISPR system to target only the mutated version of the gene. They injected the complex into one ear and left the other ear untouched.

"We were really excited when we observed hearing preservation in the injected ears but not the un-injected ears of the same mouse," Liu, a chemical biologist at Broad Institute, tells Axios.

The ear that received the edited gene showed much better hair-cell health and preservation of hearing and also preserved their ability to respond to loud noises. They also found it was not necessary to edit all of the hair cells — neighboring unedited cells didn't not degenerate despite still having the mutant gene, Urnov says.

Side effects: One of the concerns in the scientific community on gene editing is the possible side effects, in particular the creation of undesirable, unintended changes in the DNA. In this study, Liu says, "[w]e did not observe any off-target editing in the animal, and in cultured cells, where our sensitivity to detect off-target modification is much higher, we detected only one off-target modification, which was not known to play any role in hearing function."

Yes, but: Stephen Tsang, a clinical geneticist at Columbia University who was not part of the study, says while the off-target change may not be associated with hearing function, the concern is if it would be oncogenic, or cause the development of a tumor. He says while this study is "good for basic research," particularly in showing gene editing can be done even when there is only a single mutant gene to target, there are many more steps needed to prove it's safe and effective for humans.

What's next: In an article accompanying the study, Urnov wrote that researchers would need to find an effective and specific enzyme for cutting DNA in human cells and a way to safely inject it in the human inner ear before testing the technique in primates.

He points to a recent study demonstrating a gene therapy that can be injected into the eye. It received approval from the FDA on Tuesday and will provide "a road map for the scientific, medical and commercial considerations that need to be taken into account when moving to the clinic," says Urnov.

This story has been updated to reflect the FDA's approval of Luxturna, a gene therapy to treat an inherited form of blindness.

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