Kallmann Syndrome

Current methods to model or correct mutations in live cells are inefficient, especially when multiplexing -- installing multiple point mutations simultaneously across the genome. Researchers have developed new, efficient genome editing tools called multiplexed orthogonal base editors (MOBEs) to install multiple point mutations at once. The human genome consists of around 3 billion base pairs and humans are all 99.6% identical in their genetic makeup. That small 0.4% accounts for any difference between one person and another. Specific combinations of mutations in those base pairs hold important clues about the causes of complex health issues, including heart disease and neurodegenerative diseases like schizophrenia. Current methods to model or correct mutations in live cells are inefficient, especially when multiplexing -- installing multiple point mutations simultaneously across the genome. Researchers from the University of California San Diego have developed new, efficient genome editing tools called multiplexed orthogonal base editors (MOBEs) to install multiple point mutations at once. Their work, led by Assistant Professor of Chemistry and Biochemistry Alexis Komor's lab, appears in Nature Biotechnology. Komor's team was especially interested in comparing genomes that differ at a single letter change in the DNA. Those letters -- C (cytosine), T (thymine), G (guanine), A (adenosine) -- are known as bases. Where one person has a C base, another person might have a T base. These are single nucleotide variants (SNVs) or single point mutations, a person might have 4-5 million variants. Some variants are harmless; some are harmful; and often it is a combination of variants that confers disease. One issue with using the genome in disease modeling is the sheer number of possible variations. If scientists were trying to determine which genetic mutations were responsible for heart disease, they could decode the genomes of a cohort that all had heart disease but the number of variations between any two people makes it very hard to determine which combination of variations causes the disease. "There is a problem interpreting genetic variants. In fact, most variants that are identified are unclassified clinically, so we don't even know if they're pathogenic or benign," stated Quinn T. Cowan, a recent Ph.D. graduate from the university's Department of Chemistry and Biochemistry and first author on the paper. "Our goal was to make a tool that can be used in disease modeling by installing multiple variants in a controlled laboratory setting where they can be studied further." An evolution in gene-editing To understand why MOBEs were created, we have to understand the limitations of the traditional gene-editing tool CRISPR-Cas9. CRISPR-Cas9 uses a guide RNA, which acts like a GPS signal that goes straight to the genomic location you want to edit. Cas9 is the DNA-binding enzyme that cuts both strands of the DNA, making a complete break. Although relatively straightforward, double-stranded breaks can be toxic to cells. This kind of gene-editing can also lead to indels -- random insertions and deletions -- where the cell is not able to perfectly repair itself. Editing multiple genes in CRISPR-Cas9 multiples the risks. Instead of CRISPR, Komor's lab uses a base-editing technique she developed, which makes a chemical change to the DNA, although only one type of edit (C to T or A to G, for example) can be made at a time. So rather than scissors that cut out an entire section at once, base-editing erases and replaces one letter at a time. It is slower, but more efficient and less harmful to cells. Simultaneously applying two or more base editors (changing a C to T at one location, and an A to G at another location in the genome), allows for better modeling of polygenic diseases -- those occurring due to more than one genetic variant. However, a technology didn't exist that could do this efficiently without guide RNA "crosstalk," which happens when base editors make unwanted changes. Cowan's MOBEs use RNA structures called aptamers -- small RNA loops that bind to specific proteins -- to recruit base-modifying enzymes to specific genomic locations enabling simultaneous editing of multiple sites with high efficiency and a lower incidence of crosstalk. This system is novel and is the first time someone used aptamers to recruit ABEs (adenosine base editors) in combination with CBEs (cytosine base editors) in an orthogonal pattern to make the MOBEs. The differences are stark: when CBE and ABE are given together not using MOBE, crosstalk occurs up to 30% of the time. With MOBE, crosstalk is less than 5%, while achieving 30% conversion efficiency of the desired base changes. The study was a proof of principle to test the feasibility of the MOBE system, which has been granted a provisional patent. To test them even further, the team conducted several case studies with real diseases, including Kallmann syndrome, a rare hormonal disorder. Their experiments revealed that MOBE systems could be used to efficiently edit relevant cell lines of certain polygenic diseases. "We're in the process of putting the plasmids up on AddGene so anyone can freely access them. Our hope is that other researchers will use the MOBEs to model genetic diseases, learn how they manifest and then hopefully create effective therapies," stated Cowan. This research was funded in part by the National Institutes of Health (1R35GM138317, T32 GM008326, and T32 GM112584) and the Research Corporation for Science Advancement (28385). Full list of authors: Quinn T. Cowan, Sifeng Gu, Wanjun Gu, Brodie L. Ranzau, Tatum S. Simonson, and Alexis C. Komor (all UC San Diego).

▎药明康德内容团队报道3月15日，中国国家药监局（NMPA）官网公示，由苏庇医药（Sobi）申报的阿那白滞素注射液新适应症上市申请已获得批准。公开资料显示，这是一种白细胞介素1（IL-1）受体拮抗剂。本次获批的适应症为斯蒂尔病（Still’s disease）。截图来源：NMPA官网斯蒂尔病是一种病因不明的严重罕见炎症性疾病，包括成人斯蒂尔氏病（adult-onset Still’s disease，AOSD）和全身性幼年特发性关节炎（sJIA）。斯蒂尔病潜在致命并发症包括肺动脉高压、急性呼吸衰竭、心肌炎、血栓性血小板减少性紫癜等。斯蒂尔病常用治疗方式包括非甾体类抗炎药（NSAID）、皮质类固醇和改善病情的抗风湿药（DMARD）。研究发现，斯蒂尔病患者常伴有炎症因子的升高，这些炎症因子参与了疾病的发生和发展。研究人员开始针对关键炎性细胞因子开发靶向治疗药物。而针对IL-1的抑制剂可有效控制斯蒂尔病患者的炎症反应，改善症状。根据Sobi公司官网介绍，阿那白滞素（anakinra）正是一种IL-1受体拮抗剂，它能通过与多种组织和器官中表达的IL-1的1型受体结合，阻断IL-1的生物活性，中和这些免疫和炎症过程的关键介质的活性。该药此前已经在中国获批治疗冷吡啉相关周期性综合征（CAPS）、家族性地中海热（FMF）。在全球范围内，阿那白滞素获批的适应症包括CAPS、FMF、类风湿关节炎（RA）、白介素-1受体拮抗剂缺乏症（DIRA）、斯蒂尔病（包括sJIA和成人斯蒂尔病）。据文献报道，在针对斯蒂尔病患者的临床和真实世界研究中，阿那白滞素治疗可使患者达到临床缓解/应答，达成全身和实验室表现的快速、持续改善，患者得以减少或停用皮质类固醇和改善病情抗风湿药物（DMARD）治疗，从而降低与此类治疗相关的药物不良反应风险。参考资料：[1]2024年03月15日药品批准证明文件送达信息发布. Retrieved Mar 15, 2024 from https://www.nmpa.gov.cn/zwfw/sdxx/sdxxyp/yppjfb/20240315151015114.html[2]苏庇医药官网. From https://www.sobi.com/en/pipeline[3]Lyseng-Williamson KA. （2018）Anakinra in Still's disease: a profile of its use. Drugs Ther Perspect. doi: 10.1007/s40267-018-0572-5. 本文来自药明康德内容团队，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。转发授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

Part 1国内仿制药研发批准动态01新注册分类品种首家批准上市情况根据药渡数据调研，本次统计周期（2024.03.02-03.08）无新增新注册分类首家过评受理号。与上次统计周期相比，本次减少2个新注册分类首家过评品种。02一致性评价品种首家批准上市情况根据药渡数据调研，本次统计周期（2024.03.02-03.08）无新增一致性评价首家过评受理号，与上次统计周期持平。03新注册分类品种批准上市情况根据药渡数据调研，本次统计周期（2024.03.02-03.08）新注册分类新增4个过评受理号，涉及3个品种，包括1个片剂，2个注射剂。与上次统计周期相比，本次减少39个新注册分类过评品种。新注册分类品种过评情况（部分）注射用米卡芬净钠米卡芬净钠安斯泰来开发的一款1,3-β-葡聚糖合酶抑制剂和细胞壁抑制剂，也是继卡泊芬净之后全球第二个获批上市的棘白菌素类抗真菌药物。米卡芬净钠作用机制独特，副作用小，抗菌谱广，有效覆盖临床常见念珠菌以及曲霉菌，可用于血液病/恶性肿瘤患者侵袭性真菌感染的各个环节，并可应用于ICU抢救中发生的大规模真菌感染。米卡芬净钠最早于2002年10月8日获PMDA批准在日本首发上市；随后 2005年3月16日获FDA批准上市，2006年9月1日获NMPA批准在国内上市，2008年4月25日获EMA批准上市。根据药渡数据调研，目前米卡芬净钠已在全球绝大多数主要国家上市，上市剂型均为注射用冻干粉针剂。药渡数据-仿制药库调研信息显示，包括原研企业安斯泰来在内，国内共有11家企业拥有注射用米卡芬净钠的生产批文。篇幅原因，仅展示前五家企业申报进展情况，更多信息，请查看药渡数据-仿制药库目前国内注射用米卡芬净钠的申报格局为“5+5”，药渡数据-一致性评价库统计信息显示，过评格局为“5+4”。目前只有齐鲁制药于今年1月递交的报产申请已获受理等待审评审批。药渡数据-中国销量库统计数据显示，注射用米卡芬净钠连续多年销售情况稳步增长，2021年度销售额高达5.48亿元。2022年6月纳入集采后，全年销售额虽略有下滑，但仍然达到4.71亿元。值得一提的是，随着国产注射用米卡芬净钠陆续获批上市，销售额年年暴增，原研药市场份额被快速抢占，2020年原研企业安斯泰来的市场份额跌落六成，2022年艰难守住四成大关。米卡芬净钠是美国感染病学会（IDSA）念珠菌病临床实践指南推荐一线用药，，且在同类产品中，米卡芬净钠安全性良好，对肝肾功能不全患者及儿童、老年人无需调整剂量，并可与免疫抑制剂等多种药物联用，极少出现药物间相互作用，且价格相对低廉，市场潜力大。04一致性评价品种批准上市情况根据药渡数据调研，本次统计周期（2024.03.02-03.08）一致性评价新增7个过评受理号，涉及6个品种，包括4个注射剂，2个片剂。与上次统计周期相比，本次一致性评价过评品种与上周齐平。一致性评价品种过评情况（部分）05仿制药品种批准临床情况Part 2国内仿制药研发批准动态01新注册分类品种申报上市情况根据药渡数据调研，本次统计周期（2024.03.02-03.08）新注册分类数据新增83个新报受理号，涉及61个品种，包括4个滴眼剂，1个混悬剂，5个胶囊剂，2个颗粒剂，3个口服溶液剂，2个凝胶贴膏，20个片剂，3个乳膏剂，3个吸入溶液剂，1个直肠栓，17个注射剂。与上次统计周期相比，本次增加4个新注册分类申报品种。新注册分类品种申报受理情况（部分）02一致性评价品种申报上市情况根据药渡数据调研，本次统计周期（2024.03.02-03.08）一致性评价数据新增20个新报受理号，涉及13个品种，包括1个胶囊剂，4个片剂，8个注射剂。与上次统计周期相比，本次减少2个一致性评价申报品种。一致性评价申报受理情况（部分）03仿制药补充申请情况04仿制药申报上市专利声明信息汇总Part 3国内仿制药研发领域热点聚焦01国内仿制药研发领域政策法规相关动态国家药监局中药保护品种公告(第15号)(2024年第19号)根据《中药品种保护条例》规定，国家药品监督管理局批准浙江佐力药业股份有限公司生产的灵泽片为首家中药二级保护品种，保护品种编号为：ZYB2072024002，保护期限自公告日起七年。特此公告。02国内仿制药研发领域热点新闻药业：关于获得药品注册批件的公告2024 年3月4日，深圳大佛药业股份有限公司发布公告称，公司于近日收到国家药品监督管理局核准签发的《药品注册证书》。现将相关情况公告如下：一、药品注册证书主要内容药品名称：盐酸多巴胺注射液剂型 ：注射剂规格：2.5ml:50mg；5ml:100mg注册分类：化学药品 3 类药品批准文号：国药准字 H20243229；国药准字 H20243228批准日期：2024 年 2 月 23 日上市许可持有人：深圳大佛药业股份有限公司生产企业：浙江赛默制药有限公司二、药品基本情况盐酸多巴胺是一类儿茶酚胺化合物， 为中枢性递质之一， 长期以来被认为是生物体内去甲肾上腺素和肾上腺素的前体，具有升高血、兴奋β-受体、α-受体和多巴胺受体的作用，兴奋心脏β-受体可增加心肌收缩力，增加心输出量。临床上用于心肌梗死、创伤、内毒素败血症、心脏手术、肾功能衰竭、充血性心力衰竭等引起的休克综合征。三、 对公司的影响及风险提示公司获得盐酸多巴胺注射液药品注册证书，进一步丰富了公司专科药产品线，提升公司市场竞争力，对公司的经营发展具有积极作用。小D有话说为方便读者阅读及保存，我们将周报原文整理成了PDF版本，如需获取全文，可点击最上方蓝字，在“药渡仿制”公众号后台回复“0312仿制药周报”获取全文。