本文由小咖机器人翻译整理

期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-03023-5

摘要内容如下：

基因治疗是治疗遗传性耳聋的一种很有前途的方法。我们最近发现，用携带人OTOF转基因的双型腺相关病毒（AAV）血清型1进行单侧AAV1-HOTOF基因治疗是安全的，并且与常染色体隐性遗传性耳聋9（DFNB9）患者的功能改善相关。该方案随后被修订并批准为允许双侧基因治疗给药。在此，我们报告了一项单组试验的中期分析，该试验调查了5名DFNB9儿童患者双耳治疗的安全性和有效性。主要终点是6周时的剂量限制性毒性，次要终点包括安全性（不良事件）和有效性（听觉功能和言语感知）。未发生剂量限制性毒性或严重不良事件。共发生36例不良事件。最常见的不良事件是淋巴细胞计数增加（36例中有6例）和胆固醇水平升高（36例中有6例）。所有患者均恢复双侧听力。所有患者基线时右（左）耳平均听性脑干反应阈值均>95dB（>95dB），26周时患者1右（左）耳平均听性脑干反应阈值恢复至58dB（58dB），患者2恢复至75dB（85dB），患者3恢复至55dB（50dB）。13周时，4号患者为75dB（78dB），5号患者为63dB（63dB）。5例患者的言语感知和声源定位能力均得到恢复。这些结果为双耳AAV基因治疗遗传性耳聋的安全性和有效性提供了初步见解。该试验正在进行中，并进行了更长时间的随访，以证实其安全性和有效性。中国临床试验注册中心：CHICTR2200063181。

英文原文如下：

Abstracts

Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five pediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings. Chinese Clinical Trial Registry registration: ChiCTR2200063181 .

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