Genetically destined for deafness, “Beethoven” lab mice had their hearing rescued by a gene editing technique that holds promise for humans with the same hereditary fate, “excited” scientists said Wednesday.
By injecting a gene “editor” directly into the sound-sensing ear cells of newborn rodents bred with deafness-causing DNA, scientists “disabled” the mutant gene that would have robbed them of hearing over time.
At the age of four weeks, uninjected mice were unable to hear sound at 80 decibels on the loudness scale — about the level of city traffic.
Treated mice, however, reacted to sound at a much lower 65 decibels — the level of normal human conversation — a team of scientists in the United States and China wrote in the science journal Nature.
Some of the lab rodents, dubbed “Beethoven” mice after the German composer who became deaf mid-career, had one ear treated and the other not.
In the injected ears, the researchers noticed much healthier “hair cells”. These are the cells responsible for sensing sound in humans and mice, but are killed off by a mutated version of the TMC1 gene.
“We were really excited when we observed hearing preservation in the injected ears but not the uninjected ears” of individual mice, study co-author David Liu of Harvard University told AFP.
As they grew older, by the age of eight weeks, untreated mice did not respond at all to sudden, loud sounds, while treated ones were startled.
“We observed a substantial benefit to hearing function and hair cell health,” Liu said by email.
– More precise tools –
Almost half of cases of hearing loss in humans have an underlying genetic cause, according to the research team.
Humans with the TMC1 mutation generally start losing their hearing between the ages of five and 30, and most are deaf by the age of 50-60, said Liu.
Mice typically live to about the age of two.
The team employed the CRISPR-Cas9 gene editing technique, in which the Cas9 protein acts as “scissors” cutting through the disease-causing mutated gene in a cell, to be replaced or repaired.
Typically, researchers use a deactivated virus to deliver coded instructions for the cell itself to manufacture the Cas9 “scissors”.
But Liu and colleagues injected the already-formed Cas9 protein, packaged in a fatty envelope, directly into the inner ear cells.
Delivered this way, the protein was shorter-lived and less likely to cause coding mistakes by moving on to make cuts at other, non-targeted DNA zones before disintegrating.
The work was “an excellent illustration of how the toolkit available to the field of genetic medicine is expanding while the tools become ever more precise,” commented Simon Waddington, a gene transfer expert at University College London.
“Hitherto incurable and often even untreatable diseases are now within the scope of gene therapy.”
Liu said drug delivery, and potential side effects “are still important challenges”.
The results must be repeated in other animals more closely related to our species before human trials can be considered.
Fyodor Urnov of the Altius Institute for Biomedical Sciences in Seattle, said more than 5,000 diseases have been linked to gene mutations but scientists have battled to translate this knowledge into effective treatment.
“The progress being made with genome editing is changing this,” he wrote in a comment carried by Nature.
“Although Beethoven never heard his famous ‘Ode to Joy’, it could be that — thanks in no small part to his murine namesakes’ fateful encounter with Cas9 — we are getting closer to the day when individuals with deafness-causing mutations can be treated by gene editing to prevent hearing loss.”