Bertarelli Foundation-funded scientists at Harvard Medical School and Boston Children’s Hospital have published research that describes how they have used a novel gene-editing approach to salvage the hearing of mice with genetic hearing loss. They have succeeded in doing so without any apparent off-target effects as a result of the treatment.
The animals—known as Beethoven mice—were treated for the same genetic mutation that causes progressive hearing loss in humans, culminating in profound deafness by their mid-20s.
The new approach, described online July 3 in Nature Medicine, involves an optimized, more precise version of the classic CRISPR-Cas9 gene-editing system that is better at recognizing the disease-causing mutation seen in Beethoven mice. The refined tool allowed scientists to selectively disable the defective copy of a hearing gene called Tmc1, while sparing the healthy copy.
Notably, the researchers report, their system managed to recognize a single incorrect DNA letter in the defective copy among 3 billion letters in the mouse genome.
Much more work remains to be done before even a highly precise gene-editing therapy like this one could be used in humans, the researchers cautioned. However, they said, the work represents a milestone because it greatly improves the efficacy and safety of standard gene-editing techniques.
“Our results demonstrate that this more refined, better targeted version of the now-classic CRISPR/Cas9 editing tool achieves an unprecedented level of identification and accuracy,” said study co-senior investigator David Corey, the Bertarelli Professor of Translational Medical Science in the Blavatnik Institute at Harvard Medical School.
Furthermore, the team said, the results set the stage for using the same precision approach to treat other dominantly inherited genetic diseases that arise from a single defective copy of a gene.
Everyone inherits two copies of the same gene—one from each parent. In many cases, one normal gene is sufficient to ensure normal function that spares the individual from disease. By contrast, in so-called dominantly inherited genetic disorders, a single defective copy can cause illness.
“We believe our work opens the door toward a hyper-targeted way to treat an array of genetic disorders that arise from one defective copy of a gene,” said study co-senior investigator Jeffrey Holt, Harvard Medical School professor of otolaryngology and neurology at Boston Children’s Hospital. This truly is precision medicine.”
The mice carrying the faulty Tmc1 gene are known as Beethoven mice because the course of their disease mimics the progressive hearing loss experienced by the composer.
The full news story announcing the research is here.