Genetic factors account for approximately half of all cases of deafness, but few treatments exist for genetic hearing loss. Recently, a study led by scientists at Harvard and MIT demonstrated a genome-editing approach to target an inherited form of deafness using CRISPR-Cas9.
The work targeted the dominant deafness-associated allele in the Tmc1 gene. TMC1 is an essential component of mechanotransduction channels in mammalian hair cells, and sensory hair cells are critical components in transducing acoustic vibrations into electrical nerve cells. These delicate hairs within the ear vibrate in response to sound. Nerve cells then sense the motion and transmit the signal to the brain, where the signal gets translated into sound. As a result, a Tmc1 mutation in these hair cells leads to hearing loss in humans. For this study, researchers turned to the heterozygous Beethoven mouse model (named for the renowned composer and pianist who famously continued to write music despite suffering from hearing loss), which harbors one healthy Tmc1 allele and one mutant Tmc1 allele.
CRISPR-Cas9 ribonucleoprotein complexes were designed to target the deafness-associated Tmc1 allele. CRISPR-Cas9 acts as precise molecular scissors, honing in on a defined sequence of DNA that is selected by the user and coded into the guide RNA. These complexes were encapsulated in liposomes and injected into the inner ears of neonatal mice. Eight weeks after injection, mice that received treatment maintained their stereocilia, the mechanosensing organelles of hair cells, while the control mice showed severe degeneration at certain frequency detection locations. Furthermore, mice that received the CRISPR-Cas9 treatment outperformed untreated control mice in a suite of hearing tests.
These results are even more impressive when one considers that the Tmc1 allele in the heterozygous Beethoven mouse model differs from the healthy allele by a single base pair. To check the specificity of the CRISPR-Cas9 ribonucleoprotein complex, the treated mice were sequenced. On average, samples contained 15-fold higher modification of the mutant allele than healthy allele, demonstrating the high selectivity of this method.
The article, titled “Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents,” was published in Nature.