Combined AAV-mediated gene replacement therapy improves auditory function in a mouse model of human DFNB42 deafness

被引:4
作者
Isgrig, Kevin [1 ]
Cartagena-Rivera, Alexander X. [2 ]
Wang, Hong Jun [1 ]
Grati, Mhamed [1 ]
Fernandez, Katharine A. [3 ]
Friedman, Thomas B. [4 ]
Belyantseva, Inna A. [4 ]
Chien, Wade [1 ,5 ,6 ]
机构
[1] Natl Inst Deafness & Other Commun Disorders, Inner Ear Gene Therapy Program, NIH, Bethesda, MD USA
[2] Natl Inst Biomed Imaging & Bioengn, Sect Mechanobiol, NIH, Bethesda, MD USA
[3] Natl Inst Deafness & Other Commun Disorders, Sect Sensory Cell Biol, NIH, Bethesda, MD USA
[4] Natl Inst Deafness & Other Commun Disorders, Lab Mol Genet, NIH, Bethesda, MD USA
[5] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA
[6] 35A 1F220,35A Covent Dr, Bethesda, MD 20892 USA
关键词
TRICELLULAR TIGHT JUNCTIONS; BARRIER; HEARING; ILDR1; DEGENERATION; ARCHITECTURE; DELIVERY; CELLS; ORGAN; CORTI;
D O I
10.1016/j.ymthe.2023.07.014
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Hearing loss is a common disorder affecting nearly 20% of the world's population. Recently, studies have shown that inner ear gene therapy can improve auditory function in several mouse models of hereditary hearing loss. In most of these studies, the underlying mutations affect only a small number of cell types of the inner ear (e.g., sensory hair cells). Here, we applied inner ear gene therapy to the Ildr1Gt(D178D03)Wrst (Ildr1w-/-) mouse, a model of human DFNB42, non-syndromic autosomal recessive hereditary hearing loss associated with ILDR1 variants. ILDR1 is an integral protein of the tricellular tight junction complex and is expressed by diverse inner ear cell types in the organ of Corti and the cochlear lateral wall. We simultaneously applied two synthetic adeno-associated viruses (AAVs) with different tropism to deliver Ildr1 cDNA to the Ildr1w-/- mouse inner ear: one targeting the organ of Corti (AAV2.7m8) and the other targeting the cochlear lateral wall (AAV8BP2). We showed that combined AAV2.7m8/AAV8BP2 gene therapy improves cochlear structural integrity and auditory function in Ildr1w-/- mice.
引用
收藏
页码:2783 / 2795
页数:13
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