Gene Therapy in Mouse Models of Deafness and Balance Dysfunction

Abstract

Therapeutic strategies to restore hearing and balance in mouse models of inner ear disease aim to rescue sensory function by gene replacement, augmentation, knock down or knock out. Modalities to achieve therapeutic effects have utilized virus-mediated transfer of wild type genes and small interfering ribonucleic acids; systemic and focal administration of antisense oligonucleotides (ASO) and designer small molecules; and lipid-mediated transfer of Cas 9 ribonucleoprotein (RNP) complexes. This work has established that gene or drug administration to the structurally and functionally immature, early neonatal mouse inner ear prior to hearing onset is a prerequisite for the most robust therapeutic responses. These observations may have significant implications for translating mouse inner ear gene therapies to patients. The human fetus hears by gestational week 19, suggesting that a corollary window of therapeutic efficacy closes early in the second trimester of pregnancy. We hypothesize that fetal therapeutics deployed prior to hearing onset may be the most effective approach to preemptively manage genetic mutations that cause deafness and vestibular dysfunction. We assert that gene therapy studies in higher vertebrate model systems with fetal hearing onset and a comparable acoustic range and sensitivity to that of humans are an essential step to safely and effectively translate murine gene therapies to the clinic.

Keywords: congenital deafness; fetal gene transfer; gene therapy; transuterine microinjection; window of therapeutic efficacy.

Figure 1

Morphogenesis of the mouse and human inner ears from otic vesicle to the mature membranous labyrinth. The mouse inner ear is structurally and functionally immature at birth with hearing emerging by postnatal day 12 (P12; Shnerson and Willott, 1980). The gene and pharmacotherapeutic strategies identified in Table 1 with the cross symbol compared efficacy at different ages of delivery and suggest that the most effective age to intervene is at P0-P5 prior to the onset of hearing (Early Neonatal Window of Efficacy). The human inner ear is capable of auditory function as early as 19 weeks gestational age (19 GA) when a startle response to low frequency stimuli is present (Hepper and Shahidullah, ; Shahidullah and Hepper, 1994). A corollary window of therapeutic efficacy in humans is predicted to close by about GA 18 prior to the onset of hearing (Prenatal Window of Efficacy). There is no human fetal data to set the early boundary of the Prenatal Window of Efficacy and this is represented by the timeline fading to white by GA8. Abbreviations: ac, anterior crista; asc, anterior semicircular canal; g, ganglion; GA, weeks gestational age; E, embryonic day; es, endolymphatic sac; lc, lateral crista; lsc, lateral semicircular canal; P, postnatal day; pc, posterior crista; psc, posterior semicircular canal; s, saccule; u, utricle. Credits: the mouse artwork was modeled after paint fills from Doris K. Wu (Morsli et al., 1998). The human artwork was modeled after George L. Streeter’s drawings (Streeter, 1906).