Journal Club: Proof of concept for gene therapy to restore hearing function in Usher's syndrome model mice
Today's journal article
Amariutei AE, Webb S, Carlton AJ, O'Connor A, Underhill A, Jeng JY, Hool SA, Zanella A, Hool M, Lecomte MJ, Johnson SL, Safieddine S, Marcotti W. Adeno-associated virus-based rescue of Myo7a expression restores hair-cell function and improves hearing thresholds in a USH1B mouse strain.
- J Physiol. 2025 Sep 27.
- doi: 10.1113/JP289526.
- Epub ahead of print. PMID: 41015536.
- Available online at: https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP289526
Why I picked this article
This research investigates the MYO7A gene replacement therapy in a murine model of Usher 1B (shaker-1, Myo7aSh1/Sh1).
In our hearing organ, the cochlea, auditory sensory hair cells have the tiny “antennae” that convert sound vibrations into electrical signals called the stereocilia. MYO7A is a protein essential for building and maintaining the stereocilia. Pathological variants to the MYO7A gene cause deafness and also sometimes have other impacts on the body, and cause Usher's syndrome (USHER1B).
A mouse model of Usher's syndrome is the "shaker-1" mouse, where pathological variants of the MYO7A gene exist in both copies of the gene in the body. In shaker-1 mice, stereocilia of hair cells degenerate, hair cells lose proper ion-channel profiles, and the animal becomes profoundly deaf. Much research in the past has investigated the role of the MYO7A protein in the cochlea to show its importance in hair cell and stereocilia development.
This research uses the animal model of Usher's syndrome to test adenovirus AAV-based gene therapy to restore the function of the Myo7a gene, and how this might rebuild the bundle and the electrical signature needed for hearing.
Some of the research findings
Animal Model:
- Myo7aSh1/Sh1 (shaker-1) mice: progressive stereocilia loss leading to sensory epithelium degeneration and profound deafness.
- Hearing of mice was assessed with auditory brainstem responses.
- Ex vivo (tissue extraction-based) experiments were also performed, with perfusion of artificial extracellular solution, to allow electrophysiological recording from the cell.
Intervention: - AAV viruses were designed for dual-AAV delivery: AAV8-Myo7a or AAV9-PhP.eB-Myo7a.
- Myo7a gene was split into two viral vectors.
- Part that encodes for amino acids 1–1036 and
- part of Myo7a that encodes for amino acids 1037–2215
- AAV injection into the mice was done at postnatal day 0 or postnatal day 1.
- 1-2 μL of the AAV was injected through the RWM and sealed with glue.
Rescue by the treatment: - In the mouse model of Usher's syndrome, a structural defect in the stereocilia and profound hearing loss were observed. This was accompanied by reduced ionic movement in hair cells as predicted.
- AAV predominantly transfected inner hair cells, with limited impact on the outer hair cells.
- With AAV treatment, inner hair cells regained some functionality, with what appeared to be structurally intact stereocilia.
- Treated IHCs reacquired a mature basolateral current profile (ion-channel complement typical of adult IHCs).
- OHCs did not achieve comparable rescue, as expected from the low level of transfection by AAV.
- Hearing thresholds improved by approximately 20–30 dB across most tested frequencies, driven by inner hair cell rescue. But it was not as good as the healthy mice due to a lack of recovery from outer hair cells.
Figure 8B. Hearing thresholds of non-Usher mice (black), Usher's model mice (red) and Usher's model mice treated with gene therapy (blue). Amariutei 2025.
Overall, this study provided a proof-of-concept for delivering exogenous Myo7a gene via AAV to neonatal cochleae and restored some functionality of hearing, by approximately 20–30 dB across most frequencies.
- AAV viruses were designed for dual-AAV delivery: AAV8-Myo7a or AAV9-PhP.eB-Myo7a.
- Myo7a gene was split into two viral vectors.
- Part that encodes for amino acids 1–1036 and
- part of Myo7a that encodes for amino acids 1037–2215
- AAV injection into the mice was done at postnatal day 0 or postnatal day 1.
- 1-2 μL of the AAV was injected through the RWM and sealed with glue.
- In the mouse model of Usher's syndrome, a structural defect in the stereocilia and profound hearing loss were observed. This was accompanied by reduced ionic movement in hair cells as predicted.
- AAV predominantly transfected inner hair cells, with limited impact on the outer hair cells.
- With AAV treatment, inner hair cells regained some functionality, with what appeared to be structurally intact stereocilia.
- Treated IHCs reacquired a mature basolateral current profile (ion-channel complement typical of adult IHCs).
- OHCs did not achieve comparable rescue, as expected from the low level of transfection by AAV.
- Hearing thresholds improved by approximately 20–30 dB across most tested frequencies, driven by inner hair cell rescue. But it was not as good as the healthy mice due to a lack of recovery from outer hair cells.
Figure 8B. Hearing thresholds of non-Usher mice (black), Usher's model mice (red) and Usher's model mice treated with gene therapy (blue). Amariutei 2025.
Haruna's takeaway
A proof-of-concept study like this is the step before the commercial development of gene therapy can go ahead, as was the case in OTOF-gene therapy. It is a big milestone, and gene therapy is probably being developed as we speak for USHER1B with clinical translation in sight. One major challenge may be the therapeutic window in this case, as the mouse pup used in this study is very young, and will correspond to a mid-late gestation foetus in humans. Whether or not introducing gene therapy targeting Myo7a will work with a later therapeutic window will still need to be investigated.
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This is Haruna's 49/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.