Preclinical Efficacy And Safety Evaluation of AAV-OTOF in DFNB9 Mouse Model And Nonhuman Primate.
Jieyu QiLiyan ZhangFangzhi TanYang ZhangYinyi ZhouZiyu ZhangHongyang WangChaorong YuLulu JiangJiancheng LiuTian ChenLianqiu WuShanzhong ZhangSijie SunShan SunLing LuQiuju WangRen-Jie ChaiPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2023)
OTOF mutations are the principal causes of auditory neuropathy. There are reports on Otof-related gene therapy in mice, but there is no preclinical research on the drug evaluations. Here, Anc80L65 and the mouse hair cell-specific Myo15 promoter (mMyo15) are used to selectively and effectively deliver human OTOF to hair cells in mice and nonhuman primates to evaluate the efficacy and safety of OTOF gene therapy drugs. A new dual-AAV-OTOF-hybrid strategy to transfer full-length OTOF is generated, which can stably restore hearing in adult OTOF p.Q939*/Q939* mice with profound deafness, with the longest duration being at least 150 days, and the best therapeutic effect without difference in hearing from wild-type mice. An AAV microinjection method into the cochlea of cynomolgus monkeys without hearing impairment is further established and found the OTOF can be safely and effectively driven by the mMyo15 promoter in hair cells. In addition, the therapeutic dose of AAV drugs has no impact on normal hearing and does not cause significant systemic toxicity both in mouse and nonhuman primates. In summary, this study develops a potential gene therapy strategy for DFNB9 patients in the clinic and provides complete, standardized, and systematic research data for clinical research and application.
Keyphrases
- gene therapy
- wild type
- high fat diet induced
- induced apoptosis
- hearing loss
- mouse model
- cell therapy
- end stage renal disease
- gene expression
- dna methylation
- cell cycle arrest
- newly diagnosed
- primary care
- endothelial cells
- ejection fraction
- single cell
- insulin resistance
- chronic kidney disease
- stem cells
- oxidative stress
- machine learning
- cell death
- risk assessment
- metabolic syndrome
- prognostic factors
- endoplasmic reticulum stress
- drug induced
- intellectual disability
- bone marrow
- cell proliferation
- big data
- young adults
- signaling pathway
- peritoneal dialysis
- induced pluripotent stem cells