Deafness

Convenience is one area Sling Therapeutics may have an edge over the incumbent in thyroid eye disease. \n Sling Therapeutics’ oral challenger to Amgen’s intravenous Tepezza has hit the mark in a phase 2b/3 thyroid eye disease (TED) trial, teeing the biotech up to run a confirmatory study of its ex-Astellas asset. But a cross-trial comparison suggests Amgen’s blockbuster may have the advantage on the efficacy front.Astellas studied the small-molecule IGF-1R inhibitor linsitinib as a cancer treatment. However, with the anti-IGF-1R antibody Tepezza showing the benefits of targeting the receptor in TED, Sling spied a chance to use linsitinib in the eye disease. The biotech launched with $35 million to run a phase 2b trial in TED, a complication of Graves’ disease that causes the eyes to bulge, in 2022.About 18 months later, Sling has evidence linsitinib works in TED. Investigators randomized 90 patients to receive one of two doses of linsitinib or placebo. After 24 weeks, 52% of people on the high dose had a big enough reduction in eye bulging to meet the response criteria.The response rate was significantly higher than in the placebo group, causing the high dose to achieve the primary endpoint. Sling made no mention of the performance of the low dose. The biotech is now preparing to start a confirmatory phase 3 trial this year. Horizon Therapeutics, which brought Tepezza to market before selling up to Amgen, reported a higher response rate in its phase 3 program. After eight infusions across 24 weeks, the response rates in the two Tepezza trials were (PDF) 71% and 83%. Cross-trial comparisons can be misleading, but the available data suggest Sling may need to focus on areas other than efficacy to compete.Convenience is one area Sling may have an edge over the incumbent. Tepezza patients receive 60- to 90-minute infusions every three weeks. Linsitinib is taken orally twice a day. Amgen began a phase 3 trial of a subcutaneous formulation of Tepezza last year, positioning it to potentially free patients from lengthy infusions in the future.Safety and tolerability is another potential battleground. In Tepezza’s phase 3 program, 10% of patients on the drug developed hearing impairment, a catch-all term for conditions such as deafness and tinnitus. Sling said no drug-related hearing impairment was reported in its trial, although there was one unrelated report, and the placebo-adjusted tinnitus rate was 0%. Hyperglycemia was rarer than for Tepezza, too.Sling saw elevated liver enzymes, but they resolved quickly and caused no signs of drug-induced injury, leading the biotech to conclude linsitinib was well tolerated. The planned phase 3 trial will shed more light on the molecule’s safety and efficacy profile and potentially position Sling to challenge Amgen for the TED market. 

点击“蓝字”关注我们 概述：薄基底膜肾病（TBMN）指以肾小球基底膜（GBM）显著弥漫变薄为特征，临床上以持续性镜下血尿为主要表现的一种与遗传密切相关的肾小球疾病。TBMN是导致儿童和成人持续性镜下血尿的最常见病因，其人群患病率约为1%，其中30%~50%的患者有明确的血尿家族史。TBMN由McConville于1966年首先报道，该组患儿中大部分有血尿家族史，临床上以孤立性持续性血尿为特点，泌尿系统影像学无显著异常，因此被称为“良性家族性血尿”。随后1973年Rogers在一个4代34例患者的家系中发现患病成员电镜可见GBM弥漫变薄。此后，陆续有学者开始从病理学角度将该病命名为TBMN。20世纪90年代开始，国外学者运用基因测序和连锁分析发现约40%的TBMN患者携带Ⅳ型胶原α3、α4链编码基因COL4A3、COL4A4杂合突变。近年来对TBMN患者进行长程随访后发现，TBMN患者的肾脏预后并非均为“良性”，有15%~30%的TBMN患者在平均50~60岁进展至终末期肾病（ESRD）[1]。由于我国临床医生对本病的认识不足，同时血尿、蛋白尿常引起患者的不适及医生的忧虑，常导致过度治疗和不合理用药，反而伤及肾脏。 一、发病率 TBMN并不少见，是儿童和成人血尿最主要的病因之一（最高分别约占其中的15%和30%）。来自自体肾或移植肾活检病理资料显示，TBMN占所有肾活检病例的3.7%~9%。据国外文献报道，TBMN的发病率较高，学龄前儿童的发病率可达0.5%~2.0%，是较常见的肾脏疾病。国内报道TBMN的发病率也较高，但低于国外，可能与国内肾活检的比例较低及以往对该病的认识不足有关[2]。近年来，随着对TBMN认识的不断提高、临床和病理的结合不断加强，以及合理的诊断标准的建立，国内对TBMN的确诊率不断提高，接近国外诊断水平。 二、发病机制 遗传因素在TBMN的发病中起重要作用。TBMN的遗传方式多为常染色体显性遗传，致病基因是位于2号染色体的Ⅳ型胶原α3和α4链编码基因COL4A3和COL4A4。约40%的TBMN患者可检出COL4A3/COL4A4基因杂合突变。但也有学者发现，TBMN并不完全与COL4A3/COL4A4基因连锁，提示可能存在其他致病基因。此外文献报道LMX1B、MYH9、COL4A1、FN、WT1、ITGA3、LAMB2基因发生突变亦可导致GBM病变。除遗传因素外，药物（如金制剂）或其他病理性原因（如继发于肺出血肾炎综合征）可引起GBM变薄[3]。 除了GBM弥漫变薄外，TBMN在光镜下常合并局灶节段性肾小球硬化（FSGS），其机制假说包括：①GBM病变影响邻近足细胞的黏附、导致足细胞骨架结构异常；②足细胞表面Ⅳ型胶原受体如α2β1整合素和盘状结构域受体通过识别异常Ⅳ型胶原与GBM互相作用，导致足细胞内多种促炎症因子和促纤维化因子如结缔组织生长因子、TGF-β1、MMP-2和MMP-9等表达上调；③COL4A3/COL4A4基因错义突变蛋白错误折叠后滞留于足细胞内质网触发内质网应激和未折叠蛋白反应。 三、临床特点 TBMN可发生于任何年龄，根据已有的报道，最小年龄为1岁，最大年龄为86岁，以青中年最为常见；男女比例约为1∶（2~3）。 绝大部分TBMN患者以血尿为主要临床表现，其中大多数患者为持续性镜下血尿；肉眼血尿并不常见，少数患者偶在上呼吸道感染或剧烈运动后可出现肉眼血尿。儿童以无症状性单纯血尿常见，成人患者中有45%~60%合并轻度蛋白尿，亦有报道TBMN患者有大量蛋白尿或肾病综合征者，但对激素反应较好。多数研究表明，TBMN患者通常血压正常，但有报道部分成人患者（<20%）可有轻度高血压。绝大部分TBMN患者长期随访预后良好，肾功能可长期维持在正常范围。但少数患者（<10%）多年后可出现肾功能不全，而且极个别患者可发展为终末期肾功能衰竭而需要透析治疗。绝大多数患者尿红细胞位相显微镜检查为大小不一、多种形态的肾小球源性血尿，少数病人可有红细胞管型[2,4]。 四、病理特点 病理检查是TBMN确诊的依据，尤其是电镜检查具有高度特异性。根据国际版《Alport综合征以及薄基底膜肾病的诊治指南建议》，对不典型TBMN患者建议行肾组织活检：24 h蛋白尿>1.0 g或肾小球滤过率<90 ml/（min·1.73m2）；不能除外X连锁型AS；有显著肾小球或肾小管间质损害[5]。 1、光镜 可有少量系膜细胞增生和基质扩张，约30%患者合并FSGS和不同程度的肾小管纤维化。 2、电镜 GBM弥漫性变薄是TBMN唯一的或最重要的病理特征，肾小球内无电子致密物沉积，部分病例有节段性上皮细胞足突融合现象。TBMN肾小球毛细血管袢GBM呈广泛一致菲薄，如线状，不同毛细血管袢及同一毛细血管袢GBM厚度无明显差异；有的GBM局部极度变薄，十分纤细，但很少见GBM断裂；偶然观察到菲薄的GBM内有足突或内皮插入；部分病例可观察到足突呈节段性融合现象。电镜下GBM的厚度是诊断TBMN最重要的依据。但关于GBM的正常厚度国内外文献报道数据不一。多数文献认为TBMN患者GBM厚度约为正常GBM厚度的2/3~1/3。现在认为各年龄段应达到以下标准才能诊断：成人GBM厚度<250 nm；6~10岁儿童GBM厚度<200 nm；5岁以内儿童GBM厚度<150 nm。 3、免疫荧光 常规免疫荧光检查也没有明确的具有诊断意义的病理指标。大多数TBMN患者肾活检标本免疫荧光检查阴性，仅少数患者在系膜区有微量免疫球蛋白和补体C3沉积，提示免疫因素在该病的发生中不起主要作用。 4、Ⅳ型胶原α链免疫荧光或免疫组化染色 TBMN患者的肾脏和皮肤组织Ⅳ型胶原α链染色通常无异常，因此也是区别TBMN与AS的重要手段。 五、诊断及鉴别诊断 1、诊断 TBMN临床以单纯镜下血尿为主要表现，部分患者可合并轻度蛋白尿和肾功能减退。肾脏病理以>50%的GBM弥漫变薄为特征（成人GBM<250 nm，2~11岁儿童<180 nm），且无GBM厚薄不均、致密层撕裂或分层或虫蚀样等改变。基因检测除了明确TBMN患者有无携带COL4An基因突变外，还可帮助与其他以血尿为主要表现的遗传性肾脏病（如MYH9相关肾病、遗传性C3肾小球病等）进行鉴别。这里需指出的是，TBMN仅为病理学诊断，对于明确致病基因或其他病因的TBMN患者，需相应对诊断进行修正[3,6]。TBMN在青少年血尿患者中并不少见，需注意提高对该病的认识，对于青少年出现血尿，家族中有类似病例的，需行肾活检以排除，以免漏诊、误诊。 2、鉴别诊断 TBMN需要与以血尿为主要表现的遗传性肾小球疾病如AS以及原发性肾小球疾病如IgA肾病（IgAN）、原发性FSGS等进行鉴别诊断。 （1）AS：AS以持续性镜下血尿、进行性肾功能衰竭、合并耳聋及眼部病变等肾外表现为临床特征，同时具有明确的遗传方式（85%的患者呈X连锁显性遗传，10%的患者呈常染色体显性遗传，另有约5%的患者呈常染色体隐性遗传）和典型的肾组织病理学改变（GBM可见厚薄不均，致密层撕裂、分层、虫蚀样或篮网样改变）。肾组织和皮肤Ⅳ型胶原α链染色在诊断Alport综合征中有重要的辅助作用。儿童AS患者可仅表现为单纯性血尿且GBM变薄可为唯一病理改变。 （2）IgAN：IgAN是全球最常见的原发性肾小球疾病之一，特征性病理改变为以IgA为主的免疫球蛋白在肾小球系膜区沉积继而引起弥漫性系膜细胞增生及不同程度系膜基质增多。IgAN多见于男性，肉眼血尿、合并蛋白尿以及发生肾功能不全的比例均高于TBMN。近20%的TBMN患者可合并IgA肾病，此外10%~39%的IgAN可出现GBM弥漫性变薄或局部断裂分层增厚及双轨样改变。少部分IgAN患者呈家族聚集性，其中约30%的病因实质为COL4An基因突变所导致。 （3）原发性FSGS：FSGS是基于病理的诊断，近年来在FSGS尤其是在家族性FSGS中发现COL4An是其主要的致病基因。近30%的成人遗传性FSGS和5%~10%的散发性FSGS为COL4A3-COL4A5基因突变所致。与原发性FSGS相比，合并FSGS的TBMN患者除多数有家族史外，临床上以非肾病综合征范围蛋白尿为主，且对激素及免疫抑制剂治疗反应差，足突多为节段性融合。 （4）与其他肾脏疾病鉴别：TBMN还必须与外科性血尿（如结石、肿瘤、结核等）、泌尿系感染、某些以血尿为主要表现的原发性肾小球疾病（如系膜增殖性肾炎、急性链球菌感染后肾炎等）以及继发性肾小球疾病（如紫癜肾、狼疮肾、血管炎肾损害等）相鉴别，可依据上述各病的临床特点、实验室检查和病理改变一一加以排除。 六、治疗 绝大部分TBMN呈良性肾小球疾病过程，预后良好。对于仅表现为血尿，而血压正常、肾功能正常的患者，无需特殊药物治疗；而对于出现大量蛋白尿或肾病综合征者，可用激素治疗；如合并有高血压，应将血压控制在正常范围；已有慢性肾功能衰竭者，可按肾衰治疗。避免感冒和过度劳累，定期监测血压和肾功能，避免不必要的治疗和肾毒性药物的应用，对本病无疑是有益的[7]。 七、预后 TBMN的预后虽较之AS相对较好，但相较普通人群发生高血压、蛋白尿以及肾功能进展的风险显著增加。TBM女性患者在生育前需临床评估有无高血压、蛋白尿或肾功能损害，并建议行基因检测明确有无携带致病基因突变。 参考文献 （上下滑动可查看） [1] Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY. Thin basement membrane nephropathy.Kidney Int. 2003;64(4):1169-1178. [2] Tryggvason K, Patrakka J. Thin basement membrane nephropathy.J Am Soc Nephrol. 2006;17(3):813-822. [3] Hirabayashi Y, Katayama K, Mori M, et al. Mutation Analysis of Thin Basement Membrane Nephropathy.Genes (Basel). 2022;13(10):1779. Published 2022 Oct 2. [4] Ramakrishnan M, Leslie SW. Thin Basement Membrane Nephropathy (Benign Familial Hematuria). In:StatPearls. Treasure Island (FL): StatPearls Publishing; August 2, 2023. [5] Foster K, Markowitz GS, D'Agati VD. Pathology of thin basement membrane nephropathy.Semin Nephrol. 2005;25(3):149-158. [6] Kashtan CE. The nongenetic diagnosis of thin basement membrane nephropathy.Semin Nephrol. 2005;25(3):159-162. [7] Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy.J Am Soc Nephrol. 2013;24(3):364-375.  声明：本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。 最新《国际糖尿病》读者专属微信交流群建好了，快快加入吧！扫描左边《国际糖尿病》小助手二维码（微信号：guojitnb），回复“国际糖尿病读者”，ta会尽快拉您入群滴！ （来源：《肾医线》编辑部）

The companies and health systems aim to collect genetic data from consenting volunteers numbering in the tens of millions, by analyzing the leftover specimens taken from routine lab tests. \n Illumina and Regeneron are taking stakes in health data company Truveta to help fund research that may dwarf the efforts of the National Institutes of Health’s All of Us million-person program and other massive DNA sequencing projects.The companies—supported by more than a dozen major health systems—aim to collect genetic data from consenting volunteers numbering in the tens of millions by analyzing the leftover specimens taken from routine lab tests.The goal is to build the most diverse database possible, with Truveta serving as home to a catalog of genotypes and phenotypes linked to de-identified medical records. In addition, the project may generate enough data to support the training of large language models, the company said during the J.P. Morgan Healthcare Conference in San Francisco.“Nations have spent decades and billions of dollars to try and uncover the mysteries of biology to advance healthcare,“ Truveta co-founder and CEO Terry Myerson said in a statement. “Just like volunteering to be an organ donor on your driver’s license is a simple act of service with a profound impact, the Truveta Genome Project enables each of us to anonymously contribute to dramatically accelerate progress in discovering the science of humanity, improving the health of our families and communities, and lowering the cost of care.”“Discoveries from smaller datasets before today’s AI have led to important new approaches to help prevent heart disease and restore hearing in children with certain forms of congenital deafness—it is so exciting to envision where a complete representative genomic dataset will guide us,” Myerson added. To kick off the project, Regeneron made an upfront strategic investment of $119.5 million into Truveta, while Illumina chipped in $20 million as part of a series C financing. They’re joining previous backer Microsoft, which will be providing its Azure cloud computing infrastructure to the project. The Regeneron Genetics Center, meanwhile, has signed up to sequence the exomes of the first 10 million volunteers and will have exclusive rights to access the de-identified EHR data provided by the study participants. “With nearly three million exomes sequenced at RGC to date, Regeneron scientists have already identified dozens of genetic-based drug targets for a wide range of conditions—including chronic liver disease, obesity, cancer and neurodegenerative conditions—that have led to multiple clinical-stage treatments,” said Regeneron Genetics Center head Aris Baras, M.D.. “As we continue to scale our genomics initiatives, we seek more targets and medicines, while expanding the potential impact of our research to optimize clinical trials and personalize healthcare delivery.”“Big Data—combined with human ingenuity—is the key to driving next-generation scientific advancements,” added George Yancopoulos, M.D., Ph.D., president and chief scientific officer of Regeneron. “By combining Regeneron’s expertise in genetics and drug development with Truveta\'s extensive phenotypic data and collaboration of leading U.S. health systems, we hope to create the ‘Big Data’ that will empower the next generation of drug discovery, as well as enable new approaches to healthcare analytics and healthcare management.”According to Truveta, 17 health systems have also made investments in the company—that, all told, and with Regeneron and Illumina’s coin, amount to about $320 million. Advocate Health, CommonSpirit Health, Henry Ford Health, Northwell Health, Providence and Trinity Health have all agreed to contribute samples to the research. “Improving our understanding of the genome can transform healthcare by unlocking both the causes and cures of diseases—and we’re now helping build the world’s largest anonymized genetic database to deliver on that promise,” said Advocate Health CEO Eugene Woods. “With this research into how genetic factors affect our health, based on tens of millions of records and harnessing the power of AI, we can then deliver tailored treatments based on patients’ unique genetic makeup.”“And because this dataset is drawn from the most diverse spectrum of volunteers, the resulting medical breakthroughs will have the power to benefit everyone,” Woods said.Truveta launched in 2020 and has already collaborated with 30 health systems to collect de-identified electronic health records from more than 120 million patients.