SGCG

Atamyo has received approval to initiate a clinical trial of ATA-200 gene therapy in France and Italy ATA-200 is a single-injection gene therapy aimed to treat LGMD2C/R5 caused by mutations in the γ-sarcoglycan gene The phase 1b, dose-escalation study will evaluate the safety and efficacy of ATA-200 in children EVRY, France--(BUSINESS WIRE)-- Atamyo Therapeutics, a clinical-stage biotechnology company focused on the development of new-generation gene therapies targeting muscular dystrophies and cardiomyopathies, today announced the first authorization of a Clinical Trial Application (CTA) in Europe for ATA-200, its gene therapy for the treatment of the γ-sarcoglycan related limb-girdle muscular dystrophy Type 2C/R5 (LGMD2C/R5). This authorization was first granted by the Italian Medicines Agency (AIFA), then by the French Medicines Agency (ANSM). “We are thrilled to obtain our CTA approval in France and Italy for the devastating LGMD2C/R5 disease affecting primarily a pediatric population and for which there is no approved treatment,” said Dr Sophie Olivier, Chief Medical Officer of Atamyo. “Atamyo plans to initiate dosing in patients for ATA-200 in third quarter 2024.” “LGMD 2C/R5 is a severe muscular dystrophy with an onset in early childhood and loss of ambulation generally occurring before adolescence,” said Pr. Giacomo Comi, Full Professor of Neurology at the University of Milan (Italy), and principal investigator of this trial. “It is a great motivation to know that the work we are doing has the potential to make a life-changing difference for the patients affected by this disease.” “This is a significant milestone for LGMD-2C/R5 patients and for Atamyo as ATA-200 is the first treatment targeting LGMD-2C/R5 to enter clinical trials,” said Stéphane Degove, CEO of Atamyo Therapeutics. “With the ongoing clinical trial of ATA-100 in LGMD2I/R9, the initiation of the clinical program for ATA-200 confirms our unique capabilities in bringing to patients suffering from limb-girdle muscular dystrophies a new generation of safe and effective gene therapies.” This clinical trial (NCT05973630) is a multicenter, Phase 1b, open-label, dose escalation study evaluating safety, pharmacodynamic, efficacy, and immunogenicity of intravenous ATA-200, a single-dose Adeno-Associated Virus (AAV) vector carrying the human γ-sarcoglycan transgene. LGMD2C/R5 is a rare genetic disease caused by mutations in the gene that produces γ-sarcoglycan, a transmembrane protein that is involved in the connection between muscle fibers and their environment. It affects an estimated 2,000 people in Europe. In the classical form, symptoms appear in early childhood and patients suffer from progressive muscular weakness leading to loss of ambulation before adulthood. Cardiac involvement, typically presenting as dilated cardiomyopathy is reported in approximately half of patients. There is no curative treatment. The management of LGMD2C/R5 is solely supportive. ATA-200, a gene therapy candidate for LGMD2C/R5, delivers a normal copy of the gene for production of γ-sarcoglycan protein. In preclinical models, a single systemic injection of ATA-200 demonstrated its tolerability and capability to correct symptoms and biomarkers of the pathology. ATA-200 has been granted Orphan Medicinal Product Designation by the European Medicines Agency (EMA). The therapy is based on the research of Atamyo Chief Scientific Officer Isabelle Richard, Ph.D., Research Director at National Center of Scientific Research (CNRS) in France and head of the Progressive Muscular Dystrophies Laboratory at Genethon. In addition to its LGMD2C/R5 gene therapy, Atamyo is developing a clinical trial with ATA-100 gene therapy for LGMD2I/R9, related to deficiencies in FKRP; and is in IND-enabling studies for LGMD2A/R1, related to deficiencies in calpain protein. About Atamyo Therapeutics Atamyo Therapeutics is a clinical-stage biopharma focused on the development of a new generation of effective and safe gene therapies for neuromuscular diseases. A spin-off of gene therapy pioneer Genethon, Atamyo leverages unique expertise in AAV-based gene therapy and muscular dystrophies from the Progressive Muscular Dystrophies Laboratory at Genethon. Atamyo’s most advanced programs address different forms of limb-girdle muscular dystrophies (LGMD), with two clinical-stage programs targeting respectively LGMD2I/R9 and LGMD2C/R5. The name of the company is derived from two words: Celtic Atao which means “Always” or “Forever” and Myo which is the Greek root for muscle. Atamyo conveys the spirit of its commitment to improve the life of patients affected by neuromuscular diseases with life-long efficient treatments. For more information visit . View source version on businesswire.com: Contacts U.S. Contact: Charles Craig, Opus Biotech Communications Charles.s.craig@gmail.com, 404-245-0591 European Contact: contact@atamyo.com Source: Atamyo Therapeutics View this news release online at:

追求长生不老，是人类亘古不变的梦想。抗衰，也成为现代人经久不衰的永恒话题。据统计，2022年全球抗衰老药物市场规模已达670.46亿元（人民币），预测到2028年，全球市场规模将会扩增至1568.71亿元，年均复合增长率约14.86%。目前衰老生物学机制主要分为基因程序性衰老和基因损失理论两大类，基于这两大理论，全球虽未有已上市的专门针对抗衰的药品，但共有14款药物在研（表1），其中临床2期1款、临床1期1款、临床前7款、药物发现5款，涉及的国家地区有美国、中国、韩国、加拿大等，药物类型中小分子药物数量排名第一，共7款。在研抗衰药物目前公开的靶点且处于临床阶段的有TNF-α、SIRT6、GSNOR、TERT + Telomerase和Erα（目前无进展)，下文将对以上靶点的作用机制及代表性药物分别介绍。表1.全球在研抗衰药物1TNF-α（肿瘤坏死因子）TNF-α是一种T细胞和活化的巨噬细胞分泌的多功能细胞因子,在调节细胞免疫反应中起着多种生理和病理作用。TNF-α能够诱导多种细胞的增殖或凋亡,且可与受体结合后通过细胞内多种信号转导途径引发自由基的过量产生等,进而促进机体的衰老；TNF-α在炎症反应中诱发“次级”细胞因子如IL-6、IL-8等的产生,由此激发细胞因子级联反应和炎症连锁反应而损失细胞功能；TNF-α通过炎症连锁反应具有阻抑长时程记忆和神经中毒作用。从结构上看，TNF-α是一种由157个氨基酸组成的同型三聚体蛋白，主要由活化的巨噬细胞、T淋巴细胞和自然杀伤细胞产生。从功能上讲，它可以触发一系列不同的炎症分子，包括其他细胞因子和趋化因子。图1. TNFRs下游的信号形式和生物活性来源：网络公开资料正因为TNF-α能促进机体衰老，所以TNF-α抑制剂也被用于抗衰药物的开发。目前全球共有297款TNF-α上市药物，虽然排名前列的适应症主要为各类免疫疾病，包括类风湿关节炎、强直性脊柱炎、银屑病关节炎、溃疡性结肠炎、葡萄膜炎等，但Science于2021年就刊文表明免疫T细胞能调节机体的健康和寿命，如果阻断由细胞引起的炎症或增加关键代谢分子的供应，就可以减轻机体衰老相关症状的严重程度。研究人员给实验小鼠注射伊那西普（TNF-α抑制剂，阻断T细胞释放TNF-α的药物）后，小鼠的肌肉力量增强、大脑认知功能改善、心脏功能也得改善，由此可见，TNF-α药物在治疗炎症的同时，也能延缓身体衰老。回顾药物研发史，全球首款TNF-α药物英夫利西单于1998年上市，开启了生物治疗RA等免疫疾病的时代，随后国内百奥泰、信达、复宏汉霖等都先后涌入该赛道。2005年，国内首个TNF-α药物——三生国健研发的依那西普生物类似药被批准上市用于治疗自免疾病。弗若斯特沙利文报告显示，中国TNF-α抑制剂市场预计至2030年达到约380亿元，复合年增长率约16.5%，期待已上市的药物一定会有更多抗衰这一新适应症的成果问世。2SIRT6SIRT6又被称为“长寿蛋白”，是一种多功能酶，作为第三家族长寿蛋白中的一员，具有多种催化酶活性，且在抗衰老、染色质调节、转录调控、糖脂代谢、DNA损伤修复等生物学过程中起着重要的作用，因此不少学者认为，激活SIRT6基因能延长人类寿命。相关研究屡见报道，比如2021年布朗大学在PNAS上发表表题为“SIRT6 regulates lifespan in Drosophila melanogaster”的文章，该文章发现dSIRT6在分子和生化水平上与哺乳动物SIRT6的功能非常相似，且dSIRT6过表达可通过对抗Myc的活性延长寿命；2022年东南大学中大医院科学家在Nature Communications 发表文章，表明SIRT6通过抑制 IL-15/JAK3/STAT5信号通路可以减轻软骨细胞衰老，靶向SIRT6有望成为一种非常有前途的治疗骨关节炎的新方法。近期，著名心脏病学家、复旦大学葛均波院士团队，在Aging and Disease上刊发综述文章，阐述了NAD+依赖性酶SIRT6在衰老、代谢、炎症等病理生理过程中发挥的作用，文章主要对三大类SIRT6激活剂的药理作用进行了介绍：其中不乏淫羊藿苷、槲皮素等天然植物提取物，也有NAD+前体（NMN、NR）等分子化合物，还包括SGLT2抑制剂、GLP-1受体激动剂等已上市临床药物，都可能通过激活SIRT6，在改善代谢紊乱、炎症和衰老方面发挥益处，从而对心血管疾病起到治疗效果。就MDL-800药物而言，上海交通大学等研发人员首次证明MDL-800(一种新开发的选择性SIRT6激活剂)通过激活两种DNA修复途径——非同源末端连接(NHEJ)和碱基切除修复(BER)在老鼠源性iPSC中提高基因组稳定性，而且发现用MDL-800预处理通常表现出有限分化潜能的老鼠iPSC促进了由所有三个胚层组成的畸胎瘤的形成,并强烈刺激了嵌合体的产生，表明SIRT6的药理学激活在使用基于iPSC的细胞疗法治疗与衰老相关的疾病方面具有很大的前景（图2）。来源：Aging Cell3GSNORGSNOR（S-亚硝基化谷胱甘肽还原酶）由ADH5基因编码，是乙醇脱氢酶（ADH）家族中的成员。谷胱甘肽一直以来在各美容护肤产品中作为功效成分广为所知，谷胱甘肽是重要的细胞抗氧化物，除了有一定美白效果，也可以改善皮肤老化。2017年的一项研究中受试者补充谷胱甘肽后由紫外线引发的黑斑减少，部分受试者的皮肤皱纹减少且弹性增加。而谷胱甘肽还原酶是利用还原型NAD（P）将氧化型谷胱甘肽（GS－SG）催化反应成还原型（GSH）的酶，目前也被证实在抗衰中发挥有效作用，生物体内的GSNOR能调控多种蛋白的S-亚硝基化，参与多种生理和病理过程。2022年中科院姚永刚团队发表研究成果，在动物模型实验中，GSNOR基因敲除小鼠明显改善了MPTP诱导的帕金森样症状诸如运动障碍、多巴胺神经元的死亡，而敲除GSNOR后，CDK5的S-亚硝基化修饰增加，抑制了CDK5激酶活性，进而抑制CDK5介导的细胞自噬，最终表现为改善了MPTP诱导的帕金森样症状，而且应用GSNOR抑制剂N6022能针对GSNOR靶点进行帕金森样疾病的预防和治疗。2019年北京脑科学与类脑研究中心就刊文，衰老小鼠的海马体中的S-亚硝基谷胱甘肽还原酶（GSNOR）显著增加，而神经元特异性GSNOR转基因小鼠在行为测试中表现出认知障碍，首次发现是GSNOR的增加降低了CREB信号传导因此导致小鼠出现认知障碍，而Nobiletin（川陈皮素）能上调CREB信号通路挽救GSNOR转基因小鼠的认知困难，所以揭开了抗衰药川陈皮素改善衰老认知功能损伤的作用机理。4TERT + Telomerase早在2009年，诺贝尔生理学或医学奖获得者Elizabeth Blackburn、Carol Greider、Jack Szostak就开始了端粒和端粒酶是如何保护染色体的研究，此后端粒也被大众熟知。端粒现在被视为细胞寿命的“有丝分裂钟”，随着年龄增长，DNA损伤的积累会随机影响基因组，而端粒作为覆盖每个染色体臂末端的核蛋白结构，特别易受到增龄性损伤。当端粒因细胞分裂持续缩短时，会加剧体内细胞的凋亡和死亡，最终导致机体衰老，而通过实验干预这一过程，可使细胞规避衰老，并实现无限增殖。有研究表明，通过激活端粒酶逆转录酶（telomerase reverse transcriptase，TERT），可以增加端粒酶的产生，减慢端粒缩短进程，进而延缓衰老。总之，端粒伴随着机体衰老而持续缩短，而通过实验手段干预则可实现延缓衰老。2012年，西班牙著名学者Maria Blasco教授在实验中使用端粒酶逆转录酶基因，成功为小鼠延寿24%，开创了基因疗法抗衰的先河。2015年，时年44岁的美国生物科技公司BioViva的CEO Elizabeth Parrish身先士卒，接受了向自己的细胞中注入TERT基因的实验，该基因能促进细胞生产端粒酶延长端粒长度。经过半年实验期，Parrish的端粒长度从6.71kb增加到7.33kb，换算成细胞生理年龄，大约年轻了20岁。不论该壮举是否是噱头，但端粒检测技术确实在衰老及衰老相关疾病中已有广泛应用。5Erα全球目前仅有一款Erα靶点相关的抗衰药HM-144,且当前状态并无进展。实际上，此前，学界已对ERα的功能进行了广泛深入的研究，尤其在细胞核内调控转录过程中如何影响乳腺癌病程等方面积累了大量工作。研究发现，ERα（核内荷尔蒙受体雌激素受体α，estrogen receptor）在70%乳腺癌病人的体内都处于活化状态，而ERα拮抗剂它莫昔芬在临床上是治疗乳腺癌的一线药物，它可以通过抑制ERα的活性来调节转录过程，延长病人的生存周期。2021年Cell上也刊文称，ERα是一类核质穿梭蛋白（nucleocytoplasmic shuttling protein），可以在细胞核与细胞质之间自由而迅速的移动，ERα被发现可以与多种RNA结合蛋白发生蛋白质相互作用，由此确定ERα亦是一类RNA结合蛋白。在乳腺癌细胞系MCF7 和T47D中， ERα都可以与大量poly(A) RNA相结合，最终支持肿瘤细胞生存和抵抗抗癌药物，再次证实ERα拮抗剂有治疗乳腺癌，延长肿瘤患者生命周期的作用。虽然衰老不可逆转，但庆幸的是，越来越多的药物可以延缓及预防衰老，不论是减少年龄相关的炎症药物、调控能量代谢药物还是直接靶向衰老基因药物或修复损伤基因药物，都可以看到在全球范围内相关研发正如火如荼地开展，期待未来有更多高价值的“长生抗老药”及早上市，满足人们逆龄生长的愿望。参考文献：1.https://www.163.com/dy/article/HOFO2VJA05329KGN.html2.https://zhuanlan.zhihu.com/p/3693134733.https://baijiahao.baidu.com/s?id=1770654033432799807&wfr=spider&for=pc4.https://baijiahao.baidu.com/s?id=1714746913411813252&wfr=spider&for=pc免责声明“药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！

A multicenter phase 1b study will evaluate safety, pharmacodynamic and efficacy of ATA-200 ATA-200 is the second Atamyo’s next generation gene replacement therapy entering the clinic ATA-200 is eligible to receive up to €8m ($8.6m) of non-dilutive financing from France 2030 program EVRY, France--(BUSINESS WIRE)-- Atamyo Therapeutics, a biotechnology company focused on the development of new-generation gene therapies targeting neuromuscular diseases, today announced the filing of a Clinical Trial Application (CTA) in Europe for ATA-200, its gene therapy targeting γ-sarcoglycan (SGCG) related limb-girdle muscular dystrophy Type 2C/R5 (LGMD2C/R5). The company also announced that ATA-200 has been granted a non-dilutive financing up to €8m ($8.6m) from France 2030 public program managed by Bpifrance, to support its clinical trials and manufacturing development programs. This clinical trial (EUCT 2023-506440-16-00) is a multicenter, Phase 1b, open-label, dose escalation study evaluating safety, pharmacodynamic, efficacy, and immunogenicity of intravenous ATA-200, a single-dose Adeno-Associated Virus (AAV) vector carrying the human γ-sarcoglycan transgene. “LGMD-R5 is the most rapidly progressive and debilitating form of LGMDs with onset of symptoms in early childhood, a loss of ambulation before adulthood, and frequent cardiac impairment. No curative treatment exists for this disease,” said Dr Sophie Olivier, Chief Medical Officer of Atamyo. “ATA-200 incorporates a new promoter that enhances the liver and cardiac safety of gene therapy,” said Isabelle Richard, Ph.D., Co-founder and Chief Scientific Officer of Atamyo. “This first-in-class experimental treatment represents a new hope for the patients.” “We are thrilled to European Clinical trial and to receive such a strong public financing for the devastating LGMD2C/R5 disease,” said Stephane Degove, Co-Founder and Chief Executive Officer of Atamyo. “With the ongoing clinical trial in LGMD-R9, the initiation of the clinical program for LGMD-R5/2C confirms our unique capabilities in bringing to patients suffering from limb-girdle muscular dystrophies a new generation of safe and effective gene therapies.” LGMD2C/R5 is a rare genetic disease caused by mutations in the gene that produces γ-sarcoglycan, a transmembrane protein that is involved in the connection between muscle fibers and their environment. It affects an estimated 2,000 people in Europe only. In the classical form, symptoms appear in early childhood and patients suffer from progressive muscular weakness leading to loss of ambulation before adulthood. Cardiac involvement, typically presenting as dilated cardiomyopathy is reported in approximately half of patients. There is no curative treatment. The management of LGMDR5 is solely supportive. ATA-200, the gene therapy for LGMD2C/R5, delivers a normal copy of the gene for production of γ-sarcoglycan. In preclinical mice models, ATA-200 demonstrated its tolerability and capability to correct symptoms and biomarkers of the pathology. Atamyo plans to initiate dosing in patients for ATA-200 in the first half of 2024. In addition to its LGMD2C/R5 gene therapy, Atamyo is developing a clinical trial with ATA-100 gene therapy for LGMD2I/R9, related to deficiencies in FKRP; and is in IND-enabling studies for LGMD2A/R1, related to deficiencies in calpain protein. About Atamyo Therapeutics Atamyo Therapeutics is a clinical-stage biopharma focused on the development of a new generation of effective and safe gene therapies for neuromuscular diseases. A spin-off of gene therapy pioneer Genethon, Atamyo leverages unique expertise in AAV-based gene therapy and muscular dystrophies from the Progressive Muscular Dystrophies Laboratory at Genethon. Atamyo’s most advanced programs address different forms of limb-girdle muscular dystrophies (LGMD), with two clinical-stage programs targeting respectively LGMD-R9 and LGMD-R5. The name of the company is derived from two words: Celtic Atao which means “Always” or “Forever” and Myo which is the Greek root for muscle. Atamyo conveys the spirit of its commitment to improve the life of patients affected by neuromuscular diseases with life-long efficient treatments. For more information visit About France 2030 Launched by the President of France Republic in October 2021, France 2030 is a €54 ($58) billion program which aims to accelerate the transformation of key sectors of the French economy through innovation. From fundamental research, emergence of an idea, and up to the production of a new product or service, France 2030 supports the entire life cycle of innovation until its industrialization. More information on : france2030.gouv.fr View source version on businesswire.com: Contacts U.S. Contact: Charles Craig, Opus Biotech Communications charles.s.craig@gmail.com, 404-245-0591 European contact: contact@atamyo.com Source: Atamyo Therapeutics View this news release online at: