期刊
MOLECULAR THERAPY
卷 14, 期 3, 页码 328-335出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2006.04.003
关键词
adeno-associated virus; hearing loss; cochlea; mouse model; gene transfer; in utero therapy; hair cells
资金
- NEI NIH HHS [R01 EY010820-09, R01 EY010820-07, R01 EY010820-08, R01 EY010820-11, R01 EY010820, R01 EY010820-10] Funding Source: Medline
- NIDCD NIH HHS [R01 DC008595, R01 DC006442 02, R01 DC006442-02, R01 DC008595-01, R01 DC006442, T32 DC005363] Funding Source: Medline
- NIDDK NIH HHS [P30 DK047757, 5-P30-DK-47747-10, P30 DK047757-10] Funding Source: Medline
Congenital hearing deficits can be caused by a variety of genetic and acquired conditions. Complete reversal of deficits in the peripheral auditory system may require delivery of corrective genes to cochlear progenitor cells. We tested delivery of lentivirus and an array of recombinant adeno-associated viral (AAV) serotypes for efficiency and cellular specificity of transgene expression after in utero delivery to the developing mouse otocyst. Stability of expression and safety with respect to auditory function were then tested in those vectors that had the most favorable in utero cochlear transduction characteristics (AAV2/1, AAV2/8, and lentivirus). AAV2/1 was found to be the optimal vector for in utero cochlear gene transfer. It efficiently transduced progenitors giving rise to both inner and outer hair cells and supporting cells and had no adverse effect on cochlear cell differentiation. Further, it had no pathological effect on differentiated hair cells or the integrity of the auditory nerve or brain-stem nuclei as measured by auditory brain-stem response testing. AAV2/1 promises to be useful in further studies evaluating differentiation pathways of cochlear cells in health and disease and for developing gene-based therapies for congenital and acquired forms of peripheral hearing loss.
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