Clin Transl Med. 2023 Jun 14
Erkang Yi, Biting Lin, Yi Zhang, Xiaoyu Wang, Jiahuan Zhang, Yu Liu, Jing Jin, Wei Hong, Zhiwei Lin, Weitao Cao, Xinyue Mei, Ge Bai, Bing Bing Li, Yumin Zhou, and  Pixin Ran
Products used in the paper Details Operation
AAV vector packaging Adeno-associated virus encoding HSALR1 (AAVHSALR1) and AAV-empty vector (AAV-NC) were purchased from PackGene Biotech (Guangzhou, China).
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Research Field: lung

Keywords: Akt pathway, cell proliferation, chronic obstructive pulmonary disease, heat shock protein AB1, lncRNA HSALR1, Smad3

Dose: 10^11 genomic copies

Routes of Administration: intratracheal instillation

Targeted organ: lung

Animal or cell line strain: Twenty-eight C57/BL6 male mice, 5−6 weeks old, weighing 20–24 g


Mutations to the OTOF gene are among the most common reasons for auditory neuropathy. Although cochlear implants are often effective in restoring sound transduction, there are currently no biological treatments for individuals with variants of OTOF. Previous studies have reported the rescue of hearing in DFNB9 mice using OTOF gene replacement although the efficacy needs improvement. Here, we developed a novel dual-AAV-mediated gene therapy system based on the principles of protein trans-splicing, and we show that this system can reverse bilateral deafness in Otof –/– mice after a single unilateral injection. The system effectively expressed exogenous mouse or human otoferlin after injection on postnatal day 0–2. Human otoferlin restored hearing to near wild-type levels for at least 6 months and restored the release of synaptic vesicles in inner hair cells. Our study not only provides a preferential clinical strategy for the treatment of OTOF-related auditory neuropathies, but also describes a route of development for other large-gene therapies and protein engineering techniques.

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