Gene Therapy Restores Balance and Auditory Functions in a Mouse Model of Usher Syndrome

Isgrig, Kevin; Shteamer, Jack W; Belyantseva, Inna A.; Drummond, Meghan C.; Fitzgerald, Tracy S.; Vijayakumar, Sarath; Jones, Sherri M.; Griffith, Andrew J.; Friedman, Thomas B.; Cunningham, Lisa L.; Chien, Wade W.

doi:10.1016/j.ymthe.2017.01.007

Cited by 134 publications

(114 citation statements)

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“…Various viral vectors containing GFP as a reporter gene have been shown to transduce inner ear hair cells (11)(12)(13)(14)(15), and several studies have investigated the use of gene therapy to restore hearing and balance in animal models, with different degrees of success. However, to date, partial hearing improvement was only obtained for mouse models without severe dysmorphogenesis of the inner ear hair cells (16)(17)(18)(19)(20)(21)(22). Here, we focused on the genetic form of USH1 caused by mutations of USH1G, encoding the submembrane scaffold protein sans (23,24).…”

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confidence: 99%

Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G

Emptoz

Michel

Lelli

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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Our understanding of the mechanisms underlying inherited forms of inner ear deficits has considerably improved during the past 20 y, but we are still far from curative treatments. We investigated gene replacement as a strategy for restoring inner ear functions in a mouse model of Usher syndrome type 1G, characterized by congenital profound deafness and balance disorders. These mice lack the scaffold protein sans, which is involved both in the morphogenesis of the stereociliary bundle, the sensory antenna of inner ear hair cells, and in the mechanoelectrical transduction process. We show that a single delivery of the sans cDNA by the adenoassociated virus 8 to the inner ear of newborn mutant mice reestablishes the expression and targeting of the protein to the tips of stereocilia. The therapeutic gene restores the architecture and mechanosensitivity of stereociliary bundles, improves hearing thresholds, and durably rescues these mice from the balance defects. Our results open up new perspectives for efficient gene therapy of cochlear and vestibular disorders by showing that even severe dysmorphogenesis of stereociliary bundles can be corrected.gene | therapy | balance | mouse | Usher

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mentioning

confidence: 99%

Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G

Emptoz

Michel

Lelli

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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“…However, two of the nine treated mice exhibited a remarkably lower threshold at 32 kHz, suggesting that the treatment improved their sensitivity to higher frequency sounds (Figure S6A). Although functional rescue was not statistically significant due to the inherent variability of the treatment to P2 mice (Isgrig et al, 2017; Suzuki et al, 2017), immunofluorescence analysis revealed more inner hair cells in treated cochlea than those of untreated cochlea (Figures S6B–S6D). The hair cells at the cochlear base are tonotopically tuned for high-frequency sounds (Davis and Silverman, 1970).…”

Section: Resultsmentioning

confidence: 98%

“…To test whether the myo-tail vector could complement the mutation in cochlear hair cells, which are responsible for auditory sensation, the vector was injected into the posterior semicircular canal at P2 (Isgrig et al, 2017; Suzuki et al, 2017), and the mice were examined for auditory brainstem response (ABR) at 3 months of age. The mice displayed more severe auditory deficits when responding to higher frequency sound, because a significantly elevated ABR threshold was detected in all untreated mice when a 32-kHz stimulus was given (Figure S6A).…”

Section: Resultsmentioning

confidence: 99%

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A CEP290 C-Terminal Domain Complements the Mutant CEP290 of Rd16 Mice In Trans and Rescues Retinal Degeneration

et al. 2018

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SUMMARY Mutations in CEP290 cause ciliogenesis defects, leading to diverse clinical phenotypes, including Leber congenital amaurosis (LCA). Gene therapy for CEP290-associated diseases is hindered by the 7.4 kb CEP290 coding sequence, which is difficult to deliver in vivo. The multi-domain structure of the CEP290 protein suggests that a specific CEP290 domain may complement disease phenotypes. Thus, we constructed AAV vectors with overlapping CEP290 regions and evaluated their impact on photoreceptor degeneration in Cep290rd16/rd16 and Cep290rd16/rd16;Nrl—/— mice, two models of CEP290- LCA. One CEP290 fragment (the C-terminal 989 residues, including the domain deleted in mutant mice) reconstituted CEP290 function and resulted in cone preservation and delayed rod death. The CEP290 C-terminal domain also improved cilia phenotypes in mouse embryonic fibroblasts and iPSC-derived retinal organoids carrying the Cep290rd16 mutation. Our study strongly argues for in trans complementation of CEP290 mutations by a cognate fragment and suggests therapeutic avenues.

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“…First, some enhancements will simply be serendipitous side effects of legitimate treatments for serious disease, like genetic analogues of the prosthetic blade legs that rendered Walter Pistorius too fast to compete with normal runners. Such cases might be rare, but then again, there is the recent report of a murine model of gene therapy for Usher's disease that not only restored its subject's hearing and balance but improved them as well . The report does not discuss this prospect, but such improvements could presumably be tolerated under its recommendations through some version of the principle of double effect, using therapeutic intentions to shield the beneficiaries and providers from prosecution.…”

Section: Public Square or Free Market?mentioning

confidence: 99%

Crowdsourcing the Moral Limits of Human Gene Editing?

Juengst¹

2017

Hastings Center Report

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In 2015, a flourish of "alarums and excursions" by the scientific community propelled CRISPR/Cas9 and other new gene-editing techniques into public attention. At issue were two kinds of potential gene-editing experiments in humans: those making inheritable germ-line modifications and those designed to enhance human traits beyond what is necessary for health and healing. The scientific consensus seemed to be that while research to develop safe and effective human gene editing should continue, society's moral uncertainties about these two kinds of experiments needed to be better resolved before clinical trials of either type should be attempted. In the United States, the National Academies of Science, Engineering and Medicine (NASEM) convened the Committee on Human Gene Editing: Scientific, Medical and Ethical Considerations to pursue that resolution. The committee's 2017 consensus report has been widely interpreted as "opening the door" to inheritable human genetic modification and holding a line against enhancement interventions. But on a close reading it does neither. There are two reasons for this eccentric conclusion, both of which depend upon the strength of the committee's commitment to engaging diverse public voices in the gene-editing policy-making process.

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Gene Therapy Restores Balance and Auditory Functions in a Mouse Model of Usher Syndrome

Cited by 134 publications

References 44 publications

Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G

Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G

A CEP290 C-Terminal Domain Complements the Mutant CEP290 of Rd16 Mice In Trans and Rescues Retinal Degeneration

Crowdsourcing the Moral Limits of Human Gene Editing?

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