Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model

被引：190

作者：

Akil, Omar ^{[1
]}

Dyka, Frank ^{[2
]}

Calvet, Charlotte ^{[3
,4
,5
]}

Emptoz, Alice ^{[3
,4
,5
]}

Lahlou, Ghizlene ^{[3
,4
,5
]}

Nouaille, Sylvie ^{[3
,4
,5
]}

de Monvel, Jacques Boutet ^{[3
,4
,5
]}

Hardelin, Jean-Pierre ^{[3
,4
,5
]}

Hauswirth, William W. ^{[2
]}

Avan, Paul ^{[6
]}

Petit, Christine ^{[3
,4
,5
,7
]}

Safieddine, Saaid ^{[3
,4
,5
,8
]}

Lustig, Lawrence R. ^{[9
,10
]}

机构：

[1] Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, San Francisco, CA USA

[2] Univ Florida, Coll Med, Dept Ophthalmol, Gainesville, FL 32610 USA

[3] Inst Pasteur, Genet & Physiol Hearing Lab, F-75015 Paris, France

[4] INSERM, Unite Mixte Rech Sante 1120, F-75015 Paris, France

[5] Sorbonne Univ, Complexite Vivant, F-75005 Paris, France

[6] Univ Auvergne, Ctr Jean Perrin, Fac Med, Lab Biophys Sensorielle, F-63000 Clermont Ferrand, France

[7] Coll France, F-7505 Paris, France

[8] CNRS, F-75794 Paris, France

[9] Columbia Univ, Med Ctr, Dept Otolaryngol Head & Neck Surg, New York, NY 10032 USA

[10] New York Presbyterian Hosp, New York, NY 10032 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2019年 / 116卷 / 10期

关键词：

dual AAV; gene therapy; otoferlin; deafness; DFNB9; VESTIBULAR FUNCTION; DEAFNESS; OTOFERLIN; EXPRESSION; VECTOR; OTOF; MUTATIONS; PROGRESS; FORM;

D O I：

10.1073/pnas.1817537116

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Autosomal recessive genetic forms (DFNB) account for most cases of profound congenital deafness. Adeno-associated virus (AAV)-based gene therapy is a promising therapeutic option, but is limited by a potentially short therapeutic window and the constrained packaging capacity of the vector. We focus here on the otoferlin gene underlying DFNB9, one of the most frequent genetic forms of congenital deafness. We adopted a dual AAV approach using two different recombinant vectors, one containing the 5' and the other the 3' portions of otoferlin cDNA, which exceed the packaging capacity of the AAV when combined. A single delivery of the vector pair into the mature cochlea of Otof(-/-) mutant mice reconstituted the otoferlin cDNA coding sequence through recombination of the 5' and 3' cDNAs, leading to the durable restoration of otoferlin expression in transduced cells and a reversal of the deafness phenotype, raising hopes for future gene therapy trials in DFNB9 patients.

引用

页码：4496 / 4501

页数：6

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