Kv7.4

听力损失即听觉系统异常引起的听功能障碍，是最常见的感觉障碍性疾病。然而，遗传性耳聋临床尚无有效治疗药物，探究新的疗法是耳聋治疗领域的研究重点，基因治疗为遗传性耳聋提供了根治的可能。近期，由中国细胞生物学学会细胞与基因治疗分会主办的第四届中国细胞与基因治疗大会在天津隆重举行。本次大会上，梅斯医学特邀来自复旦大学附属眼耳鼻喉科医院王天奇博士分享耳聋基因治疗现状及取得大重磅成果。 梅斯医学：近年来，基因疗法的快速发展给耳聋儿童带来了重获听力的希望。临床上关于耳聋基因治疗研究现状如何？目前已知导致遗传性耳聋的主要基因有哪些？ 王天奇博士：基因治疗是指将正常功能的基因或有治疗作用的基因通过一定方式导入靶细胞内，以纠正、替代基因缺陷或者异常，实现治疗疾病的方法。近年来，随着基因疗法的快速发展，耳聋基因治疗为耳聋患者带来了新希望。据世界卫生组织(WHO) 统计，全球患有致残性听力损失的人数约为 4.66 亿人，占世界总人口的 5%，其中成年人 4.32 亿人、儿童 3400 万人。全球约 1/500 的新生儿患有听力损失，约 2600 万先天性耳聋患者；我国每年新增约 3 万例新生聋儿，其中约 60% 与遗传因素有关。耳聋可以由多种原因引起，但大致上可以归结为两大类：环境因素和遗传因素。值得注意的是，在所有先天性耳聋案例中，遗传因素导致的病例占据了相当大的比例。由于遗传性耳聋的原因相对清晰，因此在基因治疗领域有着广阔的前景。 耳聋基因治疗正是我们团队目前关注的重点之一，也是有望实现耳聋治疗重大突破的关键方向。至今为止，科学家已经识别出超过200种与听力损失相关的基因。在临床前动物模型中，针对 VGLUT3、GJB2、GJB6、KCNQ1、PJVK、TMC1、OTOF、STRC、SYNE4、MYO6、KCNQ4、PCDH15、ATP2B2 等致聋基因，研发了有效的基因治疗策略。 梅斯医学：从开始研究耳聋基因治疗到现在，您的团队是否取得了阶段性成果？在研究过程中，经历了哪些关键的突破点？ 王天奇博士：针对OTOF基因突变导致的耳聋患者，基因治疗提供了一种潜在的革命性治疗方法。2022年，我们的研究小组成功开发出一种针对OTOF基因缺陷的创新基因疗法。同年12月，该疗法首次应用于人体，并于次年的10月份发布了初步临床试验结果，耐受性和安全性好，且成功纠正患儿听力。这一成就标志着世界上首例遗传性耳聋基因治疗取得了实质性的进展。自那时起，全球范围内的多个研究机构纷纷加入到了耳聋基因治疗的研究行列当中。当前阶段，中国、欧洲以及美国共有四家企业正在开展相关临床试验。这些研究均显示出积极的疗效反馈，并且到目前为止没有观察到显著的副作用出现。 OTOF基因编码一种名为otoferlin的蛋白质，这种蛋白质在内耳毛细胞中发挥着关键作用，特别是在声音信号向听觉神经传递的过程中。当OTOF基因发生突变时，会导致otoferlin蛋白的功能障碍或缺失，从而引发严重的听力损失。然而，在针对OTOF基因进行基因治疗的技术难点主要在于该基因较大，其全长约为6kb。我们采用的基因疗法是使用腺相关病毒（AAV）载体进行基因置换。然而，AAV载体的有效载荷只有约4.7kb，这超出了单个AAV载体的递送上限。为了解决这个问题，我们采用了双AAV递送策略。具体来说，我们将OTOF基因一分为二，分别用两个AAV载体递送，然后在细胞内重组形成有功能的蛋白质。这种方法在全球范围内是首次利用双AAV载体实现遗传性疾病基因治疗并产生疗效的策略。 在整个药物研发过程中，我们还面临了许多其他困难。例如，如何确定将OTOF基因分成两部分的具体位点，以及如何确保这两个部分在细胞内正确重组并发挥功能。此外，还需要评估双AAV载体在体内的临床安全性和有效性。为了推进OTOF基因疗法进入临床阶段，我们还研发了一种给药装置，通过外耳道将基因治疗药物递送到耳蜗内耳。这包括整个手术路径的设计、药物给药方式的优化，以及临床前筛选和临床试验中的有效性和安全性指标的制定。 梅斯医学：未来，耳聋基因治疗还有哪些待解决的重要问题？您关注的热点方向有哪些？ 王天奇博士：遗传因素导致的耳聋仅占总耳聋病例的大约10%或更少，大多数耳聋情况实际上是由后天因素引发的。对于这类后天性耳聋患者，目前临床上缺乏有效的药物治疗方法，主要依赖助听器或人工耳蜗来改善听力状况。尽管这些设备能够在一定程度上帮助恢复听力，但它们的普及率并不高，部分原因在于长期使用可能会给佩戴者带来不便。 在遗传性耳聋领域，已知与该疾病相关的基因超过200种。然而，在这众多候选基因中，只有OTOF基因的治疗方案已经在临床试验中显示出了一定的疗效。相比之下，针对其他一些较为常见的致病基因（如GJB2、SLC26A4/Pendred综合征相关基因以及TMC1）的研究则仍处于较初级阶段，距离实现临床应用尚需时日。 此外，从基础研究到最终产品上市的过程充满了挑战。不仅需要解决科学和技术上的难题，还要克服监管审批、生产工艺优化及市场推广等一系列问题。因此，将实验室里的发现转化为真正能够惠及广大患者的医疗产品，是一条漫长而复杂的道路。在此过程中，持续不断地探索和创新将是推动这一领域向前发展的关键。 来源 | 梅斯医学官网 编辑 | Swagpp ● 深思！规培生从三甲学了腹腔镜手术，回到基层没法做！只会腹腔镜不会开腹，是误入歧途？腹腔镜已成主流，卫生院不开展，到底能做啥？ ● 睡了等于没睡！川大华西最新：碎片化睡眠损害代谢和认知能力，但补充这个东西能逆转 ● 重磅！在三明医改深刻变革下，选择大医院还是基层医院？当地医生爆料基层工资可超三甲，不拖欠！江浙沪城市社区医院必将越来越吃香！ 版权说明：梅斯医学（MedSci）是国内领先的医学科研与学术服务平台，致力于医疗质量的改进，为临床实践提供智慧、精准的决策支持，让医生与患者受益。欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。 点击下方「阅读原文」 立刻下载梅斯医学APP！

TÜBINGEN, Germany, Aug. 12, 2024 /PRNewswire/ -- Acousia Therapeutics GmbH, a Tübingen-based clinical stage biotech company focused on the enhancement and preservation of natural hearing, will be presenting the ACOU085 Phase 2 PROHEAR clinical study at the HansonWade 4th Inner Ear Disorders Therapeutics Summit in Boston (MA) from August 20–22, and at the 36th World Congress of Audiology from September 19–22, 2024. The PROHEAR study is a placebo-controlled Phase 2a study with split-body design investigating the otoprotective efficacy of ACOU085 in patients with testicular cancer undergoing high-dose, cisplatin-based chemotherapy regimens (cis-Pt ≥300 mg/m2). Formally endorsed by the Study Group of the German Society of Otorhinolaryngology (DSZ-HNO), the PROHEAR study is being conducted across major university clinics in Germany under a CTA granted by the German Federal Institute for Drugs and Medical Devices (BfArM) and European Medicines Agency (EMA). On August 21, Dr. Jonas Dyhrfjeld-Johnsen will be presenting the Phase 2 PROHEAR clinical study on ACOU085 at the industry-leading 4th Inner Ear Disorders Therapeutics Summit organized by HansonWade in Boston (MA) in the Discovering & Validating Brand-New Drug Targets For Noise-Induced, Age-Related & Chemically-Induced Deafness session. In addition, Dr. Dyhrfjeld-Johnsen will be chairing the Summit and participating in roundtable and panel discussions. On September 22, Dr. Dyhrfjeld-Johnsen will be presenting the Phase 2 PROHEAR clinical study of ACOU085 to an international audience of clinical specialists at the 36th World Congress of Audiology in Paris, France during the Clinical Trials in Audiology and Otoneurology session. "We are thrilled by the invitations to present our ongoing PROHEAR study testing the otoprotective efficacy of ACOU085 against cisplatin-induced hearing loss to the international clinical community and our industry peers. The great interest in our clinical development program is a reflection of the major unmet medical need and long-lasting health consequences facing patients suffering acute forms of hearing loss, such as the side effects induced by life-saving chemotherapy" said Dr. Jonas Dyhrfjeld-Johnsen, CDO and Managing Director of Acousia Therapeutics. ACOU085 (INN: Bimokalner) is a first-in-class, small-molecule, etiology-agnostic otoprotective drug candidate delivered using standard, transtympanic administration of a proprietary, slow-release gel formulation. Ototoxic hearing loss is a typical, severe, and permanent side effect of cisplatin treatment and is a consequence of irreversible damage to the sensory cells in the inner ear, the so-called outer hair cells (OHCs). ACOU085 modulates a biologically validated target, the KCNQ4-encoded Kv7.4 potassium channel of the OHCs and has demonstrated significant potential to reduce cisplatin-induced hearing loss and preserve outer hair cells from ototoxicity in preclinical models. Contact Tim Boelke, M.D. [email protected] SOURCE Acousia Therapeutics GmbH

German pioneer biotech accelerates hearing loss solution development with fresh capital boost TÜBINGEN, Germany, Jan. 9, 2024 /PRNewswire/ -- Acousia Therapeutics GmbH, a clinical-stage biotech company developing drug candidates against acute and chronic forms of hearing loss, proudly announces Esperante Ventures as the latest addition to its esteemed group of investors. The infusion of fresh capital is set to boost the progress of Acousia's Kv7.4 activator programs, with a focus on advancing the ongoing clinical development of ACOU085. ACOU085 is a proprietary, small-molecule, etiology-agnostic otoprotective drug candidate, which recently entered Phase 2 clinical testing for the prevention of chemotherapy-induced hearing loss and sensory hair cell death in cancer patients. The significant otoprotective potential of ACOU085 is broadly supported by results from a number of preclinical studies in relevant models. Sustained target exposure by ACOU085 in the cochlea is achieved through local application of a novel, proprietary slow-release gel formulation using standard transtympanic injection. Tim Boelke, CEO of Acousia Therapeutics, said, "Adding Esperante Ventures with their existing position in inner ear therapeutics to our investor syndicate – amidst a challenging macro-economic environment and despite recent drawbacks in competing hearing loss drug development programs – is a testament to the confidence in our unique and proprietary Kv7.4 activator approach. Our lead candidate ACOU085, currently in Clinical Phase 2, aims to set a new standard for treating acute and subacute forms of hearing loss." Dean Slagel, Managing Director of Esperante Ventures, said "We are excited to invest in Acousia's novel and compelling approach to treating the significant unmet indication of chemotherapy-induced hearing loss, supported by its excellent leadership, robust data and experienced investors." About Acousia Therapeutics GmbH Acousia Therapeutics GmbH is a privately held, clinical-stage biotech company based in Tübingen, Germany. The company is dedicated to the identification of small molecules for the effective prevention and treatment of different hearing loss etiologies. Acousia is focused on the development of proprietary drug candidates, which are designed to affect the sensory outer hair cells (OHC) in the cochlea of the inner ear. The unique dual mode of action of its small-molecule Kv7.4 activators combines acute functional OHC enhancement and sustained OHC protection aim to both enhance and preserve a patient's natural hearing. Acousia Therapeutics develops drugs for both local and systemic administration. Contact Tim Boelke, M.D. [email protected] About Esperante Ventures Esperante is a corporate venture capital company and part of a family-controlled global life science group. Its leadership is experienced in the management of life science companies with an emphasis on the development and commercialisation of prescription pharmaceuticals. Its investment focus is mainly from Phase 2 clinical development onwards with a geographical focus in Europe and North America. Further information is available at