SLC26A5

编辑丨王多鱼排版丨水成文遗传性听力损失约占先天性耳聋的 60%。尽管腺相关病毒（AAV）介导的基因疗法在治疗遗传性听力损失方面显示出巨大潜力，但人们对 AAV 载体的特异性和安全性仍存在重大担忧。此外，耳蜗的复杂结构进一步加大了精准靶向基因递送的难度。2025 年 4 月 21 日，上海科技大学 iHuman 研究所钟桂生课题组在 Cell 子刊 Neuron 上发表了题为：Deciphering enhancers of hearing loss genes for efficient and targeted gene therapy of hereditary deafness 的研究论文。该研究提出并验证了一种创新的体内转录增强子重构技术——ARBITER（AAV reporter-based in vivo transcriptional enhancer reconstruction）。该研究不仅在耳蜗基础科研领域开辟了新路径，还在基因表达调控的底层机制研究和遗传性耳聋精准基因治疗中展现了巨大潜力。听力损失是最常见的感觉障碍，全球有超过 4 亿人受其影响，其中有 3400 万是儿童。遗传突变约占所有先天性耳聋的 60%，迄今为止已发现 100 多个非综合征型听力损失基因。腺相关病毒（AAV）介导的基因疗法已成为治疗遗传性和基因性疾病的一种有前景的策略，包括遗传性听力损失。近期的临床试验表明，通过采用双 AAV 载体策略递送 OTOF 基因，成功恢复了患有 DFNB9 型隐性耳聋儿童的听力功能。尽管 AAV 载体由于其高效性和低免疫原性而颇具前景，但人们对高剂量 AAV 给药的安全性仍存担忧。例如肝细胞因脱靶转染而出现肝毒性、血栓性微血管病（TMA）以及 AAV 的基因组整合可能引发肝细胞癌风险等问题，都是其面临的显著挑战。为了降低这些风险，提高 AAV 的效率和特异性，同时尽量减少脱靶效应并降低所需剂量至关重要。Myo15 启动子可靶向内耳的毛细胞（HC），是研究最为透彻的内耳细胞特异性启动子，在遗传性听力损失的基因治疗的临床前和临床研究中得到了广泛应用。然而，耳蜗的复杂结构极大地挑战了基因递送的精准定位。作为一个高度极化且结构有序的器官，耳蜗内存在多种细胞类型，例如毛细胞（HC），可细分为外毛细胞（OHC）和内毛细胞（IHC），此外还有支持细胞（SC）和螺旋神经节神经元（SGN）。每种细胞类型都含有独特的细胞特异性基因，这些基因对于听觉至关重要。耳蜗的复杂结构体现了器官发育过程中精细的调控机制；然而，这极大地增加了基因传递精准定位的难度。在这项研究中，研究团队介绍了一种基于 AAV 报告基因的体内转录增强子重构（AAV-reporter-based in vivo transcriptional enhancer reconstruction，ARBITER）工作流程，能够高效且可靠地解析增强子。通过 ARBITER 技术，研究团队成功证明了基因位点内的保守非编码元件（CNE）协同调控 Slc26a5 基因的表达，这一结论进一步通过基因敲除小鼠模型得到了验证。研究团队还通过在 Slc26a5 突变小鼠中进行基因治疗，评估了所鉴定增强子治疗遗传性听力损失的潜力。基于效率有限的原始 Slc26a5 增强子，研究团队设计出了一种高效且具有外毛细胞特异性的增强子——B8，它成功地恢复了 Slc26a5 基因敲除小鼠的听力。ARBITER 系统的建立不仅标志着耳蜗基础研究的一项重要突破，也为遗传性耳聋患者带来了切实的治疗希望。其在创新性、严谨性及临床潜力方面均展现出卓越优势，为遗传性耳聋的基因治疗开辟了全新的路径。为未来拓展到支持细胞、不同遗传背景与更复杂疾病模型的基因治疗提供了可行方案。此外，ARBITER 方法还有助于深入理解非编码序列与转录因子的调控关系，为人类发育与疾病研究打开了新窗口。论文链接：https://www.cell.com/neuron/abstract/S0896-6273(25)00223-5设置星标，不错过精彩推文开放转载欢迎转发到朋友圈和微信群 微信加群 为促进前沿研究的传播和交流，我们组建了多个专业交流群，长按下方二维码，即可添加小编微信进群，由于申请人数较多，添加微信时请备注：学校/专业/姓名，如果是PI/教授，还请注明。点在看，传递你的品味

MONTPELLIER, France, Sept. 06, 2018 (GLOBE NEWSWIRE) -- Sensorion (FR0012596468 – ALSEN), a biotech company specializing in the treatment of inner ear diseases, today presented three posters at the 55th Inner Ear Biology Workshop (IEB 2018) at the Charité Campus Mitte in Berlin, Germany. “We are pleased to share new research at the Inner Ear Biology Workshop. Our findings will benefit the development of our clinical candidates for the treatment of inner ear disorders,” said Nawal Ouzren, Sensorion’s Chief Executive Officer. “Presenting at this meeting is a great opportunity to introduce to the field new methods that may further advance the discovery and development of inner ear therapies.” The data presented at IEB 2018 include results from preclinical ototoxicity, or ear toxicity, and inner ear neuronal activity studies. Research methods and findings from these studies have the potential to help advance drug development for ototoxicity prevention and inner ear activity modulation. Highlights from data presented include: Two posters presented data demonstrating the feasibility and applicability of using a high content screening time-lapse live-cell imaging assay for the development of ototoxicity prevention therapies   In one study, this method showed advantages over current methods used to quantify damaging effects, like gentamicin-induced ototoxicity, in cochlear explant culturesIn a second study, this method was used to assess cisplatin-induced ototoxicity in vestibular and cochlear neuron primary cultures and showed its ability to discriminate between injury susceptibility of different cell types  One poster presented data demonstrating the potential application of high content screening assay with multi-electrode array recordings to facilitate screening of drug candidates for inner ear activity modulating therapies   Dysfunctional neuronal activity plays a key role in inner ear disorders such as hearing loss, tinnitus and vertigoActivity of vestibular and cochlear primary neuron cultures were measured by this novel electrophysiological assayFurther analytical developments of this approach suggests potential advantages over traditional methods used to screen neuromodulatory drugs candidates About IEB 2018This Workshop has over half a century tradition of gathering researchers and clinicians interested in the inner ear issues. Over the years they have learned a lot and based on this knowledge, an enormous technical progress has been made in the hearing aid technology. Inner ear-specific proteins such as prestin, pendrin or otoferlin have been discovered and characterized, but researchers and clinicians still do not know enough about them. The workshop will focus on the physiology, pathology and therapies of the inner ear. Excellent keynote speakers will give stimulating talks which will lay a ground for discussions and contribute to further translational research and innovative treatment. Hands-on workshops can be used for people who want to deepen their practical skills. Researchers and clinicians will have an opportunity to present their newest findings during numerous oral and poster sessions. About Sensorion Sensorion is a biotech company pioneering novel treatments of inner ear diseases such as severe vertigo, tinnitus or hearing loss. Two products are currently in the clinical development stage: SENS-111, in phase 2 in acute unilateral vestibulopathy (vestibular neuritis), and SENS-401, which will enter in Phase 2 in sudden sensory hearing loss. The company was founded by Inserm (the French Institute of Health and Medical Research) and is utilizing its pharmaceutical R&D experience and comprehensive technology platform to develop first-in-class easy-to administer, notably orally active, drugs for treating and preventing hearing loss and the symptoms of bouts of vertigo and tinnitus. Based in Montpellier, Southern France, Sensorion has received financial support from Bpifrance, through the InnoBio fund, and Inserm Transfert Initiative. Sensorion has been listed on the Euronext Growth Paris exchange since April 2015. www.sensorion-pharma.com Contacts Sensorion  Nawal OuzrenCEO contact@sensorion-pharma.com   Tél : +33(0)4 67 20 77 30Investor Relations – InternationalLifeSci Advisors LLC Chris Maggos - Managing Director, Europechris@lifesciadvisors.comTél. : +41 79 367 6254  European PresseAlize RP Caroline Carmagnol & Wendy Rigal sensorion@alizerp.com Label : SENSORIONISIN : FR0012596468Mnemonic : ALSEN US Media – LifeSci Public RelationsMike Tattorymtattory@lifescipublicrelations.comTel: (646) 751-4362   DisclaimerThis press release contains certain forward-looking statements concerning Sensorion and its business. Such forward-looking statements are based on assumptions that Sensorion considers to be reasonable. However, there can be no assurance that such forward-looking statements will be verified, which statements are subject to numerous risks, including the risks set forth in the Document de référence registration document filed with the Autorité des marchés financiers (AMF- French Financial Market Authority) on September 6, 2017 under n°R.17-062 and to the development of economic conditions, financial markets and the markets in which Sensorion operates. The forward-looking statements contained in this press release are also subject to risks not yet known to Sensorion or not currently considered material by Sensorion. The occurrence of all or part of such risks could cause actual results, financial conditions, performance or achievements of Sensorion to be materially different from such forward-looking statements. This press release and the information that it contains do not constitute an offer to sell or subscribe for, or a solicitation of an offer to purchase or subscribe for, Sensorion shares in any country. The communication of this press release in certain countries may constitute a violation of local laws and regulations. Any recipient of this press release must inform oneself of any such local restrictions and comply therewith.