The vestibulo-ocular reflex (VOR) induces a compensatory movement in the eye when the head is rotated, to maintain stable vision when we move. It originates in the peripheral vestibular system, which detects head movements. It is particularly effective for rapid head movements, as tested in the Head Impulse Test (HIT). In acute unilateral vestibular deficit (AUVD), the VOR deficit is compensated for by a substitution saccade, more commonly known as catch up saccade, that contribute to refocus the gaze and maintain vision during head rotations.
Recent technological advances have made it possible to make high-quality recordings during HIT (video Head Impulse Test, vHIT), leading to the identification of substitution saccades of variable latency. Our team has shown that saccades of shorter latency lead to better visual function (Hermann et al., 2017) and that the cerebellum is involved in the development of these saccades (Hermann et al., 2023), suggesting a learning effect rather than the de novo appearance of particular saccades.
The main hypothesis of this study is that the mechanisms underlying short-latency substitution saccades, which seems to guarantee good functional recovery, depend on learning occurring from the first days after an acute unilateral vestibular deficit. We also hypothesise that early physiotherapeutic rehabilitation of the VOR under Head Impulse Test conditions would promote this learning process and the development of early catch-up saccades.
One of the causes of AVD is the resection of cochleovestibular schwannomas. This procedure involves a neurotomy, i.e. complete vestibular deafferentation, which is precisely known due to the scheduled nature of the surgery. The exact moment of onset of vestibular damage is therefore known, unlike other vestibular pathologies. Hospitalisation is necessary in the immediate aftermath of surgery, with the presence of physiotherapists on the wards. In addition, there is no spontaneous recovery of the vestibular deficit. These patients therefore represent the ideal acute unilateral vestibular deficit model for testing our hypothesis. Two studies using vHIT in the aftermath of vestibular schwannoma resection surgery (Pogson et al. 2022; Mantokoudis et al. 2014) also allow us to confirm the safety and feasibility of our protocol in this patient population.

开始日期2025-01-01

申办/合作机构

Hospices Civils de Lyon

NCT06163664 / Not yet recruitingN/AIIT

Role of ChatGPT in Vestibular Schwannoma Management

Previous studies have demonstrated that patients frequently undergo significant decision conflict regarding major medical decisions in otolaryngology. There lack validated tools available for decision support for patients. While limited evidence has demonstrated that clinical decision support tools can alleviate decision conflict for patients with diagnosis in otolaryngology, conversational language models were not employed in these studies and may provide additional benefit in this context. This study seeks to evaluate the efficacy of using ChatGPT, a conversational language model with basic clinical knowledge, in alleviating decision conflict for patients with new diagnosis in otolaryngology. For this pilot study, vestibular schwannoma, a benign tumor that develops on the vestibular nerve with known clinical equipoise, has been chosen for the initial study diagnosis. Efficacy will be evaluated by comparison of responses to the Decisional Conflict Scale (DCS) and Satisfaction with Decision (SWD) scores between a group given training in ChatGPT and a control group (no ChatGPT training).

开始日期2024-12-15

申办/合作机构

University of Southern California

NCT06517888 / Recruiting临床1/2期

A Phase 1/2 Trial of AAVAnc80-antiVEGF Gene Therapy in Individuals With Unilateral Vestibular Schwannoma

This trial will evaluate the safety and tolerability of a single unilateral administration of one of three dose levels of AAVAnc80-antiVEGF and will evaluate the Akouos delivery device to safely achieve the intended product performance.

开始日期2024-09-01

申办/合作机构

Akouos, Inc.

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100 项与神经瘤相关的临床结果

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100 项与神经瘤相关的转化医学

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0 项与神经瘤相关的专利（医药）

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29,689

项与神经瘤相关的文献（医药）

2025-01-01·Journal of Orthopaedics

Functional and HIP survivorship outcomes of free Vascularized fibula graft in the management of post COVID-19 Osteonecrosis of femur head: A prospective case series

Article

作者: Goyal, Rohit ; Mathur, Ashwani Kumar ; Gomes, Nihal Adriel ; Bhambhu, Vivek ; Kumar, Sandeep ; Yadav, Priya ; Jain, Manish ; Berwal, Ayush

Aim & objectivesTo evaluate functional and radiological outcomes of Free Vascularized Fibula grafting in management of Covid-19 associated Osteonecrosis of Femur Head.DesignProspective Case Series.Methods14 hips (10 patients) with ONFH following COVID-19 were treated with Free Vascularized Fibula graft from June 2021 to December 2022 and were subsequently evaluated monthly for 6 months and then every 3 months post operatively for functionality (Harris Hip Score), Femur head collapse and related complications.ResultsMean age of patients was 29.3 years (Range: 20-38 years). 14 diseased hips were classified on the basis of Steinberg classification as 4 stage 2B, 4 stage 3B and 6 stage 3C. The average follow up period was 2.1 years (Range: 12 months-34 months).Eight of fourteen hips survived and six progressed to collapse. Mean HHS at final follow-up was 68.3 in comparison to 65.8 pre-operatively. 4 fair and 4 poor HH scores were converted to 4 excellent and 4 good scores post-operatively.Two late complications were noted-one FHL contracture and one CPN neuroma.ConclusionFree Vascularized Fibula Graft, as a hip salvage modality, showed optimal results in the treatment of COVID-19 related ONFH, which is associated with aggressive disease course and extensive involvement of femur head.

2025-01-01·World Neurosurgery: X

Gamma-knife radiosurgery for jugular foramen schwannomas. A systematic review and meta-analysis

Article

作者: Alexiou, George A ; Siempis, Timoleon ; Alexiou, George A. ; Voulgaris, Spyridon

IntroductionJugular Foramen Schwannomas (JFS) have been traditionally treated with surgical resection with an associated significant post-operative morbidity. Stereotactic radiosurgery has been investigated as potentially minimally invasive alternative to microsurgery. The aim of this study was to provide a systematic review and meta-analysis of the available literature regarding the outcomes of cases of JFS treated with radiosurgery.MethodsA literature review until 28th of March 2023 was performed. All studies looking at the outcomes of radiosurgery for the treatment of JFS were included. Studies including non-vestibular schwannomas without clear distinction of the tumour type were excluded. Risk of bias was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) scale.ResultsEight (8) studies with a total of 375 patients met the inclusion and exclusion criteria and were included in the analysis. Pooled overall tumour control rate was 93.2 % (95 % CI 89.8-96.6) after a weighted mean follow-up of 54.07 months (95 % CI 46.8-61.3). Patient free survival was reported only in 4 studies and ranged from 87 % to 97 % and 76.9-93.8 % in 5 and 10 years respectively. The radiation induced cranial nerve deficits rates after GKRS were 3.6 % (95%CI 1.7, 5.5 %).ConclusionAccording to our findings, radiosurgery for JFS has favourable clinical outcomes with a high rate of long-term tumour control and low complication rates.

2024-12-31·NMC Case Report Journal

Ulnar Neuropathy Caused by a Giant Epidermal Cyst at the Elbow: Case Report

Article

作者: ITO, Yutaka ; IKEDA, Naokado ; KAWANISHI, Masahiro ; YAMADA, Makoto ; HENMI, Namiko ; TANAKA, Hidekazu ; SUGIE, Akira ; YOKOYAMA, Kunio ; WANIBUCHI, Masahiko

Here, we report an unusual case of ulnar neuropathy at the elbow caused by a giant epidermal cyst. A 76-year-old man was assessed on an outpatient basis for ulnar numbness of the left hand that had persisted for 6 months. A soft, elastic subcutaneous mass 6 cm in size was noted on his left elbow. He felt numbness on the ulnar aspect of the left fourth and fifth fingers, corresponding to the area innervated by the ulnar nerve, which worsened upon elbow flexion. An electrophysiological study revealed ulnar neuropathy at the elbow. To remove the subcutaneous mass at the left elbow and open up the ulnar tunnel, surgery was performed. There were no signs of nerve impingement or a neuroma on the ulnar nerve. The histological diagnosis was an epidermal cyst. On the day after surgery, numbness on the ulnar aspect of the left hand upon elbow flexion was markedly abated.

109

项与神经瘤相关的新闻（医药）

2024-10-30

·CPHI制药在线

晶锐医药可入脑的BET抑制剂获批临床，拥挤赛道是否还有突围机会

关注并星标CPHI制药在线近日，中国国家药监局药品审评中心（CDE）官网公示，晶锐医药1类新药JRD-018片获批临床，拟开发治疗晚期恶性肿瘤。 JRD-018是一款可入脑的BET抑制剂，今年4月已经获美国FDA批准开展1期临床研究。晶锐医药拟开启1期临床试验并将针对晚期实体瘤患者进行招募，继而扩展到血液瘤、脑转移或原发性脑瘤，旨在探索JRD-018在患者中的安全性、耐受性、药代动力学以及初步抗肿瘤活性。体内药效研究结果表明，JRD-018单独使用在脑胶质瘤模型、小细胞肺癌模型、非小细胞肺癌模型、髓性单核细胞白血病模型以及乳腺癌模型中均表现出良好的抗肿瘤活性。在临床前动物模型研究中，JRD-018已显示出良好的对脑转移或原发性脑瘤、恶性脑肿瘤的抑制效果。表观遗传学靶点之BET 溴结构域和超末端结构域（bromodomain and extra terminal domain，BET）属于溴结构域蛋白家族，BET蛋白家族包含四个异构体BRD2、BRD3、BRD4、BRDT，它们的结构相似，在N端有2个串联的溴结构域（BD1和BD2）以及一个超末端结构域（ET）。BD1和BD2识别并结合乙酰化赖氨酸残基，与染色质重塑和基因转录的调控过程相关；ET结构域与多种转录因子相互作用。BET蛋白家族通过溴结构域与乙酰化的染色质结合，从而实现在表观遗传学水平上对基因表达进行调控。 BET蛋白家族在人体内表达广泛，与多种实体瘤和恶性血液性肿瘤、炎症、肥胖、肺纤维化等多种疾病的发生和发展密切相关。如原癌基因Myc在超过一半的肿瘤中过表达，BET抑制剂通过竞争性结合阻止BRD4与染色质结合，进而抑制Myc的转录，从而实现抑制肿瘤的目的。 BET抑制剂是一类新型抗癌药，这类药物在治疗血液癌症如白血病和淋巴瘤方面具有良好的前景。BET抑制剂能够通过阻断BET蛋白的功能从而抑制肿瘤生长。研发BET蛋白选择性抑制剂是目前的新方向。目前，一系列BET抑制剂正在临床试验中检验它们治疗包括白血病、淋巴瘤、脑瘤和骨髓瘤在内的多种癌症的疗效。 BET抑制剂：诺华高调购入，加思科、正大天晴加速推进 BET被认为是抗肿瘤药物研发潜力靶点。目前，全球药企针对该靶点已开发出多款药物，详见下表。在研BET抑制剂大多为小分子化学药，此外还包括蛋白水解靶向嵌合体（PROTACs）。适应症上，BET抑制剂主要被开发用于实体瘤和血液性肿瘤，其中部分还被开发用于治疗炎症性疾病如白癜风等。全球至今还尚无BET抑制剂获批，进度最快的就是MorphoSys的Pelabresib，是首个三期临床试验取得成功的BET抑制剂。MorphoSys围绕该药物布局了骨髓纤维化、恶性外周神经鞘瘤、多发性骨髓瘤等多项适应症。 Pelabrisib是由MorphoSys AG公司研制的first-in-class BET抑制剂，近期Pelabrisib治疗骨髓纤维化III期达到了主要研究终点SVR35（脾脏缩小超过35%），从214例患者的临床数据来看， Pelabrisib与JAK抑制剂芦可替尼联用24周，有65.9%的患者脾脏缩小超过35%，而对照组（芦可替尼与安慰剂）仅有35.2%的患者达到SVR35，实验组的疗效比对照组高30.4%。今年年初，诺华以29亿美元收购MorphoSys AG从而拥有了pelabresib这款BET抑制剂。诺华将基于III期MANIFEST-2研究的积极数据在今年下半年向FDA和EMA提交pelabresib联合芦可替尼治疗骨髓纤维化的上市申请。 ZEN-3694是一种领先的差异化BET抑制剂，被开发联合免疫检查点抑制剂、PARP抑制剂、MEK抑制剂、CDK4/6抑制剂、HDAC抑制剂治疗多种肿瘤。ZEN-3694可以降低BRCA1/2和RAD51等蛋白的DNA修复活性，以提高肿瘤细胞对PARP抑制的敏感性，当前用以治疗转移性去势抵抗性前列腺癌II期临床正在开展中。2019年8月，Zenith Epigenetics 与恒翼生物就该药签订超7800万美元的许可协议，授权恒翼生物获得ZEN-3694在中国（包括中国香港、中国台湾和中国澳门地区）的权益。 JAB-8263是加科思自主研发、具有全球知识产权的小分子BET抑制剂，临床前研究显示其对多种实体瘤和血液瘤均能发挥抗肿瘤作用。从公开数据来看，JAB-8263是同类临床项目中活性最强的BET抑制剂，有望在极低剂量下有效抑制多种肿瘤生长，和Pelabrisib相比具有巨大的差异化优势。目前，加科思正在中美两地开展JAB-8263的多中心、开放性I/IIa期临床研究，适应症涉及白血病及实体瘤。 TQB3617是正大天晴自主研发的一款具有全新化学结构的BET抑制剂，能够通过抑制BET蛋白功能减少c-Myc、NF-κB、Aurora B和BCL-2等致癌基因的异常表达，进而发挥抗肿瘤作用。临床前研究结果显示，TQB3617对BET家族的BRD2、BRD3、BRD4、BRDT蛋白均具有较强的抑制活性。TQB3617用于晚期恶性肿瘤的I期临床试验显示，2例骨髓纤维化患者在治疗第12周结束时，脾脏体积较基线分别缩小13%和30%，展现出潜在的抗骨髓纤维化疗效。在28例接受疗效评估的淋巴瘤中，总缓解率（ORR）为39.3%（11/28），其中4例CR，7例PR。 Trotabresib（CC-90010）是一种新型、口服、可逆性、小分子BET抑制剂，可穿透高级别胶质瘤患者的脑肿瘤组织，临床前研究显示其可增强替莫唑胺（TMZ）的抗肿瘤作用。已公布的1b/2期开放标签、剂量探索研究结果显示：在长期随访中，新诊断胶质母细胞瘤（GBM）患者接受Trotabresib+TMZ辅助治疗或Trotabresib+TMZ+RT（放疗）同步治疗耐受性良好，未出现新的不良反应。结语整体来看，BET是进展相对较慢的一个表观遗传学药物靶点。BET蛋白家族在人体内表达广泛，与多种实体瘤和恶性血液性肿瘤、炎症、肥胖、肺纤维化等多种疾病的发生和发展密切相关，是非常有潜力的药物靶点，全球首个BET抑制剂pelabresib III期临床试验的成功宣告了该靶点的成效性，目前全球围绕BET靶点研发火热，值得一提的是，随着科学技术的发展，BET抑制剂的研发不再局限于小分子化药，已有多家企业、机构研发出BET靶向PROTACs。目前国内药企也积极布局BET靶点，而布局方式除了自主研发，还从外部企业引进，如恒翼生物。期待在药企的不懈努力下，BET靶点可以早日迎来重大突破。参考来源 1.Raajit Rampal, Sebastian Grosicki, Dominik Chraniuk et al.Updated safety and efficacy data from the phase 3 MANIFEST-2 study of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-na?ve patients with myelofibrosis.?JCO?42,?6502-6502(2024).DOI:10.1200/JCO.2024.42.16_suppl.6502 2.2024 ASCO. Abstract?#6502: Updated safety and efficacy data from the phase 3 MANIFEST-2 study of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-na?ve patients with myelofibrosis. END 来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

临床1期临床3期蛋白降解靶向嵌合体临床2期临床结果

2024-10-16

·生物探索

Nature | 神经肽SP通过细胞外ssRNA-TLR7轴驱动肿瘤转移

引言几十年来，学界持续在恶性组织中发现神经纤维【1-3】。大多数实体瘤受外周神经系统支配，接收来自自主神经（交感神经和副交感神经）和/或感觉神经的信号。原发性肿瘤还可以通过分泌神经营养因子募集神经纤维，这些神经营养因子不仅包括神经营养因子家族成员，还包括轴突引导分子【4,5】。然而，其他基质细胞在调节肿瘤神经支配中的作用尚不清楚。越来越多的研究关注肿瘤神经支配与肿瘤发生的关系。神经胶质瘤细胞与促进肿瘤生长的神经元可以形成功能性突触【6-8】。自主神经系统已被证明能促进胃和前列腺肿瘤的发生。最近有报道还指出，自主神经和感觉神经在黑色素瘤中具有免疫调节作用【11,12】。健康乳腺组织有丰富的感觉神经纤维【13,14】，病理证据也表明乳腺肿瘤中存在神经支配【2】。肿瘤神经支配与多种癌症患者预后较差有关【1,2】，这表明可能具有调节肿瘤转移的功能，但是，感觉神经支配在乳腺癌转移中的作用仍然知之甚少。近日，来自美国纽约The Rockefeller University的Sohail F. Tavazoie研究组在Nature上发表题为Neuronal substance P drives metastasis through an extracellular RNA–TLR7 axis的文章，通过三维共培养、遗传修饰和体内转移试验等方法，定义一个复杂的旁分泌机制，通过该机制，感觉神经可以直接作用于癌细胞，并驱动乳腺癌转移。作者近期发现轴突引导分子SLIT2在转移性肿瘤的内皮中表达。与此一致的是，作者观察到，与低转移性肿瘤相比，SLIT2在高转移性乳腺肿瘤的内皮中高表达。鉴于其在轴突引导中的作用，作者，假设内皮来源的SLIT2可能调节原发性乳腺肿瘤的神经支配。为了验证这一假设，作者将4T1乳腺癌细胞原位移植到诱导敲除模型中，他莫昔芬用于驱动内皮特异性的Slit2缺失。内皮源性SLIT2缺失导致肿瘤神经支配，包括感觉神经支配明显减少，而肿瘤腔室中SLIT2的缺失并没有改变肿瘤的神经支配。这些数据表明SLIT2起源于肿瘤血管系统，是乳腺肿瘤神经支配的上游驱动因素。癌细胞会沿着神经迁移，这一过程被称为神经周围浸润，需要细胞之间直接接触。然而，在三维共培养模型中，作者没有检测到神经元和癌细胞之间的物理相互作用。因此，作者假设DRG神经元可能通过分泌分子介导促转移作用。为了验证这一点，作者从肿瘤- DRG共培养体系中收集培养基（DRG-CM）。与肿瘤纯培养基相比，DRG-CM可以诱导DRG神经元的侵袭和增殖。DRG神经元所分泌神经肽包括CGRP, 神经肽P物质(SP)和galanin，作者发现SP可以促进乳腺肿瘤的生长、侵袭和转移。乳腺癌细胞诱导感觉神经元自发钙活性，引发SP的释放。此外，SP升高的患者肿瘤表现出淋巴结转移扩散的增强。SP作用于肿瘤速激肽受体(TACR1)，驱动TACR1高含量癌细胞亚群的死亡。为了系统地分析SP驱动转移的分子基础，作者用DNase、RNase A或热失活处理DRG-CM。用RNase A处理DRG-CM显著削弱了DRG-CM促进肿瘤细胞球侵袭的能力，而用DNase或热失活处理则没有。这说明ssRNA可以作为DRG-CM对乳腺癌细胞的促侵袭作用的介质。作者还发现，SP可以诱导一部分癌细胞凋亡和随后的ssRNA释放。在TACR1高含量的癌细胞亚群中，神经肽SP导致细胞死亡，导致ssRNAs的释放，从而驱动转移。在小鼠中，ssRNA通过toll样受体7 (TLR7) 来介导RNA感知和先天免疫响应。作者发现，从垂死细胞释放的ssRNA作用于邻近肿瘤TLR7，从而激活转移基因表达程序。这种SP-和ssRNA诱导的Tlr7基因表达特征与乳腺癌生存结果降低有关。TACR1拮抗剂阿瑞吡坦是一类获批的抗恶心药物。最后，作者还确定阿瑞吡坦可以靶向神经肿瘤轴，在多种模型中抑制了乳腺癌的生长和转移。综上所述，作者发现神经肽SP促进乳腺肿瘤的生长、侵袭和转移。SP作用于TACR1，驱动癌细胞死亡。从垂死细胞释放的ssRNA作用于邻近TLR7，激活转移基因。作者的研究结果表明，神经元可以通过神经肽SP/细胞外ssRNA传感轴，调节乳腺癌转移进展。模式图（Credit: Nature）参考文献 1. Ayala, G. E. et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin. Cancer Res. 14, 7593–7603 (2008). 2. Huang, D. et al. Nerve fibers in breast cancer tissues indicate aggressive tumor progression. Medicine 93, e172 (2014). 3. Oertel, H. Innervation and tumour growth: a preliminary report. Can. Med. Assoc. J. 18, 135–139 (1928). 4. Renz, B. W. et al. β2 adrenergic-neurotrophin feedforward loop promotes pancreatic cancer. Cancer Cell 34, 863–867 (2018). 5. Latil, A. et al. Quantification of expression of netrins, slits and their receptors in human prostate tumors. Int. J. Cancer 103, 306–315 (2003). 6. Osswald, M. et al. Brain tumour cells interconnect to a functional and resistant network. Nature 528, 93–98 (2015). 7. Venkatesh, H. S. et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 161, 803–816 (2015). 8. Venkatesh, H. S. et al. Electrical and synaptic integration of glioma into neural circuits. Nature 573, 539–545 (2019). 9. Zhao, C. M. et al. Denervation suppresses gastric tumorigenesis. Sci. Transl. Med. 6, 250ra115 (2014). 10. Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013). 11. Balood, M. et al. Nociceptor neurons affect cancer immunosurveillance. Nature 611, 405–412 (2022). 12. Globig, A. M. et al. The β1-adrenergic receptor links sympathetic nerves to T cell exhaustion. Nature 622, 383–392 (2023). 13. Gerendai, I. et al. Transneuronal labelling of nerve cells in the CNS of female rat from the mammary gland by viral tracing technique. Neuroscience 108, 103–118 (2001). 14. Hebb, C. & Linzell, J. L. Innervation of the mammary gland. A histochemical study in the rabbit. Histochem. J. 2, 491–505 (1970). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-024-07767-5 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

2024-10-06

·生物探索

Cell Rep Med | 余发星团队报道胸膜间皮瘤基因治疗新策略

引言胸膜间皮瘤是一种罕见且高度恶性的肿瘤，起源于胸膜表面的间皮细胞，通常与石棉暴露密切相关【1】。现阶段针对胸膜间皮瘤的临床治疗主要以姑息疗法为主。尽管免疫检查点抑制剂等免疫疗法能在一定程度上改善患者的生存状况，但整体疗效有限，患者的中位总生存期仅约为18个月，预后不理想。因此，亟需进一步探索和开发新的策略用于胸膜间皮瘤的治疗。近年来的研究表明，胸膜间皮瘤的发病机制涉及多种抑癌基因的失活突变。胸膜间皮瘤患者样本的全外显子测序结果显示，NF2、BAP1、CDKN2A/B和TP53等多种抑癌基因在患者中经常发生突变或缺失【2】。此外，LATS2失活突变在间皮瘤患者中也较为常见【2】。NF2和LATS2分别是Hippo抑癌信号通路中的重要接头蛋白和激酶，这些基因的高频突变表明Hippo信号通路在胸膜间皮瘤的发生发展中发挥重要作用，提示Hippo信号通路有潜力成为胸膜间皮瘤治疗靶点。 2024年10月4日，复旦大学生物医学研究院/附属儿科医院余发星团队在Cell Reports Medicines上发表了题为“Gene therapy for diffuse pleural mesotheliomas in preclinical models by concurrent expression of NF2 and SuperHippo”的研究论文。该研究报道了一种基于腺相关病毒（AAV）的胸膜间皮瘤基因治疗新策略，并通过小鼠胸膜间皮瘤的遗传肿瘤模型验证了该策略的有效性。 Hippo信号通路通常被视为是一个“线性”激酶级联反应，即MST1/2激酶和MAP4Ks激酶通过作用于LATS1/2激酶来调控YAP/TAZ转录共激活因子【3】。为深入理解LATS1/2和YAP/TAZ如何整合上游信号，余发星团队系统梳理了该信号通路的核心分子网络，提出了HPO1和HPO2两个双信号模块架构，其中WWC和NF2分别介导两个信号模块的活化，并且基于WWC蛋白的作用机制开发了SuperHippo迷你基因分子工具【4,5】。 NF2在胸膜间皮瘤中的失活突变频率高达40%，提示HPO2信号在该疾病中具有潜在调节作用，这一观点已在前人研究中得到验证。本研究通过间皮瘤细胞系和小鼠遗传模型探究了HPO1信号（WWC和SAV1）在间皮瘤中的功能，结果表明：当HPO1信号缺失后，间皮瘤细胞的体外增殖和体内成瘤能力明显增强；而当HPO1和HPO2信号同时缺失时，小鼠胸膜间皮明显增厚并呈现胸膜间皮瘤的特征。因此，HPO1信号同样参与胸膜间皮瘤的疾病进程，活化HPO1信号应该具有抗癌潜力。的确，在小鼠胸膜间皮瘤遗传模型中过表达SuperHippo能够显著抑制肿瘤进展。基于这些发现，研究团队提出一种“双管齐下”的膜间皮瘤治疗新策略：一方面通过回补NF2恢复HPO2的正常功能，另一方面通过过表达SuperHippo使HPO1超活化，同时提升HPO1和HPO2活性，最大程度地激活Hippo信号通路，从而充分发挥其抑癌功能。由于NF2和SuperHippo基因较小，能够被同一AAV病毒载体携带并表达，实现“一石二鸟”的功效。研究还表明，AAV6可以有效感染间皮细胞，团队最终制备了AAV6-SuperHippo-NF2 病毒用于临床前研究。在Nf2/Trp53小鼠胸膜间皮瘤模型中，该病毒显著抑制了肿瘤进展并延长了小鼠生存期，展现了显著的抗癌潜力。综上，该研究通过胸膜间皮瘤的细胞系及小鼠模型验证了Hippo信号通路，特别是HPO1信号模块，在胸膜间皮瘤中的抑癌作用。此外，研究还提出了一种全新的基因治疗新方案，并在小鼠遗传模型中验证了其可行性。这些发现为通过基因治疗靶向Hippo信号通路治疗胸膜间皮瘤提供了概念性验证，并为后续的临床转化研究奠定了基础。参考文献 1. Febres-Aldana CA, Fanaroff R, Offin M, et al. Annu Rev Pathol, 2024, 19:11-42. 2. Badhai J, Pandey GK, Song JY, et al. Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice. J Exp Med. 2020, 217(6):e20191257. 3. Yu FX, Zhao B, Guan KL. Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. Cell. 2015, 163(4):811-28. 4. Qi S, Zhu Y, Liu X, Li P, Wang Y, Zeng Y, Yu A, Wang Y, Sha Z, Zhong Z, Zhu R, Yuan H, Ye D, Huang S, Ling C, Xu Y, Zhou D, Zhang L, Yu FX. WWC proteins mediate LATS1/2 activation by Hippo kinases and imply a tumor suppression strategy. Mol Cell. 2022, 82(10):1850-1864.e7. 5. Qi S, Zhong Z, Zhu Y, Wang Y, Ma M, Wang Y, Liu X, Jin R, Jiao Z, Zhu R, Sha Z, Dang K, Liu Y, Lim DS, Mao J, Zhang L, Yu FX. Two Hippo signaling modules orchestrate liver size and tumorigenesis. EMBO J. 2023, 42(11):e112126. https://www-cell-com.libproxy1.nus.edu.sg/cell-reports-medicine/fulltext/S2666-3791(24)00493-2 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

免疫疗法基因疗法