Table 1.
A summary of representative pre-clinical studies of cochlear gene therapy using mutant mouse models.
| Animal model | Viral vector | Injection method and time | Ave. ABR improvement (@best freq.) & treatment efficacy duration | Targeted cells & major morphological improvement | References |
|---|---|---|---|---|---|
| Vglut3−/− mice | AAV1-VGLUT3 | Time: P1-3 & P10. Route: RWM injection & Cochleostomy Delivery. |
~30 dB by tone burst, ~60 by click ABR. Lasted for 3–6 months depending on injection time. |
IHC. Morphological improvement observed at the ultracellular level. | Akil et al., 2012 |
| Kcnq1−/− mice | AAV1-kcnq1 | Time: P0-P2 Route: injection into the scala media |
~60 dB (control (ctrl) used was 90 dB), lasted for 4–6 months | SV marginal cells. Correction of the collapse of the Reissner's membrane and degeneration of HCs and cells in the spiral ganglia |
Chang et al., 2015b |
| MsrB3−/− mice | rAAV2/1-MsrB3-GFP | Time: E12.5 Route: Injection into the otocyst using the transuterine approach |
~70 dB (ctrl used was 100 dB). | IHCs and OHCs. Restoration of stereociliary bundles |
Kim et al., 2016 |
| Lhfpl5/Tmhs− | exo-AAV1-HA-Lhfpl5 | Time: P1-P2 Route: RWM injection and by cochleostomy at the basal turn. |
~30 dB (ctrl used was 100 dB). | Improved IHC and OHC survival. In vitro FM1-43 loading assay showed increased HC function. | Gyorgy et al., 2017 |
| Usher1c (c.216G>A) | AAV2/Anc80L65. CMV.harmonin and others |
Time: P0–P1 and P10–P12. Route: RWM |
~50–60 dB (ctrl used was 110 dB) for mice injected at P0-P1. Efficacy lasted for 6 months, which is longest time point tested. | Improved IHC and OHC survival. In vitro FM1-43 loading assay showed increased HC function. | Pan et al., 2017 |
| TMC−/− | AAV2/1-Cba-Tmc | Time: P0–P2. Route: RWM |
~20-30 dB (ctrl used was 110 dB). | Transduction current at the single-cell level was preserved in hair cells of injected Tmc-deficient mice. | Askew et al., 2015 |
| conditional Gjb2 knockout mice | AAV-CB7-Gjb2-GFP | Time: P0-P1 Route: scala media injection |
0 dB | Cx26 expression was restored and ectopically expressed in several cell types. Cochlear gap junctions (GJs) were re-established. Both cell death in the organ of Corti and degeneration of SGNs were substantially reduced. |
Yu et al., 2014 |
| Gjb2 conditional KO mice Cx26fl/flP0-Cre | AAV5-Cx26 | Time: P0 and P42 Route: RWM |
0 dB when injection was made at P42. ~30 dB when treated on P0, unclear how long the treatment effects lasted. |
No morphological improvement when treated on P42. Proper formation of the tunnel of Corti and preservation of IHCs and OHCs, as well as SCs and SGs were observed when treated at P0. |
Iizuka et al., 2015 |
| Whrnwi/wi mice | AAV2/8-whirlin | Time: P1~P5 Route: injection into the posterior semicircular canal. |
~20 dB at 8 kHz. Significant vestibular function preservation observed. Treatment effects last for about 4 months. | IHC expression of whirlin and its transportation to stereocilia tips were restored. The length of stereocilia was fully or partially restored. The stereocilia architecture was also improved. IHCs survival was increased, but only temporarily. | Isgrig et al., 2017 |
Those in shaded rows are studies in which only morphological and no significant hearing improvements are observed. More complete and detailed information obtained from genetic mouse models, as well as pharmacologically-induced and noise-induced mouse models, is given in Supplemental Table 1. RWM, round window membrane.