Prenatal electroporation-mediated gene transfer restores Slc26a4 knock-out mouse hearing and vestibular function

The otocyst, an anlage of the inner ear, presents an attractive target to study treatment strategies for genetic hearing loss and inner ear development. We have previously reported that electroporation-mediated transuterine gene transfer of Connexin30 , utilizing a monophasic pulse into Connexin30 −...

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Bibliographic Details
Published in:Scientific reports 2019-11, Vol.9 (1), p.17979-12, Article 17979
Main Authors: Takeda, Hiroki, Miwa, Toru, Kim, Min Young, Choi, Byung Yoon, Orita, Yorihisa, Minoda, Ryosei
Format: Article
Language:English
Subjects:
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Animals
Cochlear implants
Electroporation
Electroporation - methods
Embryos
Female
Gene transfer
Gene Transfer Techniques
Genes
Genetic engineering
Genetic Predisposition to Disease
Genetic Therapy - methods
Hearing
Hearing aids
Hearing loss
Hearing Loss - genetics
Hearing Loss - physiopathology
Hearing Loss - prevention & control
Humanities and Social Sciences
Inner ear
Male
Mice
Mice, Knockout
Morphology
multidisciplinary
Otocysts
Otolaryngology
Pregnancy
Protein expression
Proteins
Science
Science (multidisciplinary)
Sulfate Transporters - genetics
Supplements
Surgery
Survival
Vestibular system
Vestibule, Labyrinth - physiopathology
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Summary:The otocyst, an anlage of the inner ear, presents an attractive target to study treatment strategies for genetic hearing loss and inner ear development. We have previously reported that electroporation-mediated transuterine gene transfer of Connexin30 , utilizing a monophasic pulse into Connexin30 −/− mouse otocysts at embryonic day 11.5, is able to prevent putative hearing deterioration. However, it is not clear whether supplementary gene transfer can rescue significant morphological changes, caused by genetic deficits. In addition, with the transuterine gene transfer technique utilized in our previous report, the survival rate of embryos and their mothers after treatment was low, which became a serious obstacle for effective in vivo experiments. Here, we set out to elucidate the feasibility of supplementation therapy in Slc26a4 deficient mice, utilizing biphasic pulses, optimized by modifying pulse conditions. Modification of the biphasic pulse conditions during electroporation increased the survival rate. In addition, supplementation of the target gene cDNA into the otocysts of homozygous Slc24a4 knockout mice significantly prevented enlargement of the endolymphatic space in the inner ear areas; moreover, it rescued hearing and vestibular function of mice in vivo .
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-54262-3