CRISPR/Cas9(Jingchu University of Technology)

A new CRISPR-based gene-editing tool has been developed which could lead to better treatments for patients with genetic disorders. The tool is an enzyme, AsCas12f, which has been modified to offer the same effectiveness but at one-third the size of the Cas9 enzyme commonly used for gene editing. The compact size means that more of it can be packed into carrier viruses and delivered into living cells, making it more efficient. A new CRISPR-based gene-editing tool has been developed which could lead to better treatments for patients with genetic disorders. The tool is an enzyme, AsCas12f, which has been modified to offer the same effectiveness but at one-third the size of the Cas9 enzyme commonly used for gene editing. The compact size means that more of it can be packed into carrier viruses and delivered into living cells, making it more efficient. Researchers created a library of possible AsCas12f mutations and then combined selected ones to engineer an AsCas12f enzyme with 10 times more editing ability than the original unmutated type. This engineered AsCas12f has already been successfully tested in mice and has the potential to be used for new, more effective treatments for patients in the future. By now you have probably heard of CRISPR, the gene-editing tool which enables researchers to replace and alter segments of DNA. Like genetic tailors, scientists have been experimenting with "snipping away" the genes that make mosquitoes malaria carriers, altering food crops to be more nutritious and delicious, and in recent years begun human trials to overcome some of the most challenging diseases and genetic disorders. The potential of CRISPR to improve our lives is so phenomenal that in 2020, researchers Jennifer Doudna and Emmanuelle Charpentier, who developed the most precise version of the tool named CRISPR-Cas9, were awarded the Nobel Prize in chemistry. But even Cas9 has limitations. The common way to deliver genetic material into a host cell is to use a modified virus as a carrier. Adeno-associated viruses (AAVs) are not harmful to patients, can enter many different types of cells to introduce CRISPR enzymes like Cas9, and have a lower likelihood of provoking an undesired immune response compared to some other methods. However, like any parcel delivery service, there is a size limit. "Cas9 is at the very limit of this size restriction, so there has been a demand for a smaller Cas protein that can be efficiently packaged into AAV and serve as a genome-editing tool," explained Professor Osamu Nureki from the Department of Biological Sciences at the University of Tokyo. Its large size means that Cas9 can lack efficiency when used for gene therapy. So, a large multi-institutional team worked to develop a smaller Cas enzyme that is just as active, but more efficient. The researchers selected an enzyme called AsCas12f, from the bacteria Axidibacillus sulfuroxidans. The advantage of this enzyme is that it is one of the most compact Cas enzymes found to date and less than one-third the size of Cas9. However, in previous tests it showed barely any genome activity in human cells. "Using a screening method called deep mutational scanning, we assembled a library of potential new candidates by substituting each amino acid residue of AsCas12f with all 20 types of amino acids on which all life is based. From this, we identified over 200 mutations that enhanced genome-editing activity," explained Nureki. "Based on insights gained from the structural analysis of AsCas12f, we selected and combined these enhanced-activity amino acid mutations to create a modified AsCas12f. This engineered AsCas12f has more than 10 times the genome-editing activity compared to the usual AsCas12f type and is comparable to Cas9, while maintaining a much smaller size." The team has already carried out animal trials with the engineered AsCas12f system, partnering it with other genes and administering it to live mice. Administering treatments directly into the body is preferable to extracting cells, editing them in a lab and reinserting them into patients, which is more time-intensive and costly. The success of the tests showed that engineered AsCas12f has the potential to be used for human gene therapies, such as treating hemophilia, a disease in which the blood does not clot normally. The team discovered numerous potentially effective combinations for engineering an improved AsCas12f gene-editing system, so the researchers acknowledge the possibility that the selected mutations may not have been the most optimal of all the available mixes. As a next step, computational modeling or machine learning could be used to sift through the combinations and predict which might offer even better improvements.

「  本文共：15条资讯，阅读时长约：3分钟 」今‍日‍头条拓臻THR-β激动剂NASH临床积极。拓臻生物甲状腺激素受体β（THR-β）激动剂TERN-501单药或联合法尼酯X受体激动剂TERN-101治疗非酒精性脂肪性肝炎（NASH）的IIa期DUET研究结果积极。治疗第12周时，与安慰剂相比，TERN-501（1mg、3mg和6mg）单药显著降低患者的肝脏脂肪含量（-15%、-27%和-45%，vs-4%），三个剂量组患者达到肝脏脂肪含量至少降低30%的比例均显著高于安慰剂组（26%、39%和64%，vs4%）。TERN-501与TERN-101联合治疗组达到肝脏脂肪含量至少降低30%的比例较安慰剂组也显著更高。‍‍‍国‍‍‍‍‍‍‍‍‍内‍‍‍‍药‍‍讯‍‍‍‍1.辉瑞启动偏头痛鼻喷雾剂亚洲III期临床。辉瑞偏头痛新药Zavegepant鼻喷雾剂登记启动一项III期研究（CTR20232410），拟在亚洲成人中评估ZAVEGEPANT鼻腔给药(IN) 用于偏头痛急性期治疗的疗效和安全性。该项研究计划入组980例中国患者，1400例其它国家的成人患者。主要研究者由中国人民解放军总医院于生元医学博士担任。zavegepant是一款CGRP受体拮抗剂，今年3月已获FDA批准上市，用于急性治疗偏头痛成人患者。2.博安启动PD-1生物类似药III期临床。博安生物PD-1疗法纳武单抗类似药LY01015登记启动一项III期临床（CTR20232393），旨在比较LY01015与欧狄沃®（纳武利尤单抗注射液）分别联合氟尿嘧啶和顺铂用于治疗晚期或转移性食管鳞癌患者的有效性和安全性。LY01015是国内首个按照治疗用生物制品3.3类注册分类获批临床的纳武利尤单抗生物类似药。除中国市场外，博安生物还将在全球其他国家和地区开展LY01015的注册工作。3.明济Claudin 18.2单抗国内报IND。明济生物1类生物制品M108单抗注射液的临床试验申请获CDE受理。M108是一款靶向Claudin 18.2的单抗药物，能充分利用抗体的免疫学抗肿瘤机制，通过增强型的ADCC效应充分调动患者机体的免疫细胞来杀伤肿瘤细胞。目前，该新药正在I期临床中评估用于治疗晚期不可切除实体瘤的安全性和有效性；以及在一项I/II期临床中评估单药或联合特瑞普利单抗治疗晚期实体瘤的潜力。4.辉大基因与恺佧生物达成战略合作。辉大基因宣布与恺佧生物签署新型基因编辑工具酶hfCas12Max®的生产销售许可协议，授予恺佧生物hfCas12Max®研发级蛋白在大中华区的生产销售独家权益。与广泛使用的CRISPR-Cas9以及Cas12a、Cas12b和Cas12e相比，hfCas12Max®具有更高的中靶编辑活性和更低的脱靶编辑活性，在科学研究、作物育种、细胞与基因治疗等领域具有巨大的应用潜力及前景。5.珐博进罗沙司他Q2中国收入7640万美元。8月7日，FibroGen公布2023年第二季度财报。数据显示，2023年第二季度罗沙司他（Roxadustat，爱瑞卓）在中国销售额为7640万美元，合5.32亿元人民币，同比增长44%。Roxadustat是一款口服小分子缺氧诱导因子脯氨酰羟化酶 (HIF-PH) 抑制剂，于2018年12月在中国获得全球首批，用于治疗正在接受透析治疗的患者因慢性肾脏病（CKD）引起的贫血，目前该新药适用人群已扩大至非透析CKD患者。‍‍‍‍国‍‍‍‍‍‍‍‍‍‍际‍‍‍‍药‍讯‍‍1.诺华BTK抑制剂荨麻疹Ⅲ期临床积极。诺华布鲁顿酪氨酸激酶（BTK）抑制剂remibrutinib治疗慢性自发性荨麻疹（CSU）的两项Ⅲ期临床（REMIX-1和REMIX-2）均达到所有主要和次要终点。Remibrutinib可阻断BTK级联反应，并阻止组胺释放引起的瘙痒、荨麻疹/伤痕和肿胀。结果显示，remibrutinib在第12周时每周荨麻疹活动评分（UAS7）较基线的绝对变化、瘙痒严重程度评分和荨麻疹严重程度评分的绝对变化方面相比安慰剂据统计学改善。2.杨森FGFR抑制剂实体瘤Ⅱ期临床积极。杨森FGFR抑制剂erdafitinib治疗FGFR基因变异、晚期实体瘤（不限瘤种）的国际Ⅱ期研究（RAGNAR）结果发表在《柳叶刀》子刊The Lancet Oncology上。中位随访为17.9个月时，erdafitinib达到30%的客观缓解率，疾病控制率为74%，临床获益率为46%，中位无进展生存期（PFS）为4.2个月，中位总生存期（OS）为10.7个月。研究中最常发生的严重不良事件（≥3级）为口腔炎（2%）和腹泻（1%）。3.FDA拒绝批准口腔粘膜炎新药上市。Galera公司小分子歧化酶模拟物Avasopasem manganese（Avasopasem，GC4419）用于治疗接受标准治疗的头颈癌（HNC）患者因放疗引起的严重口腔粘膜炎（SOM）的新药上市申请（NDA）收到FDA的完整回复函（CRL）。FDA认为需要重新递交额外的临床试验数据。来自Ⅲ期试验ROMAN和Ⅱb期临床GT-201的汇总数据显示，avasopasem能显著降低患者包括SOM发生率和天数、SOM严重程度等关键指标，且不影响标准放化疗的治疗效果。4.澳大利亚EBV疫苗临床前研究积极。澳大利亚伯格霍费尔医学研究所的研究人员开发的靶向淋巴结的EB病毒（EBV，属于疱疹病毒家族）候选疫苗，在用于小鼠模型的临床前研究结果积极。研究发现，接种该疫苗能产生强效的EB病毒特异性抗体和T细胞，而且效力维持至少7个月；其中在一个淋巴瘤小鼠模型中显示调动免疫，并能阻止EB病毒相关肿瘤的扩散并控制肿瘤生长。研究成果发表于Nature Communications 期刊。5.默沙东联手大冢开发p53靶点小分子。默沙东与大冢制药旗下全资子公司Astex Pharmaceuticals将利用后者基于片段的药物发现平台，针对多种形式肿瘤抑制蛋白p53，合作开发小分子候选药物。根据协议，Astex将获得3500万美元的预付款，临床前、临床、监管和销售里程碑相关的潜在款项，每个项目的里程碑付款约为5亿美元。默沙东将获得候选小分子的进一步开发和商业化的独家全球许可。6.tRNA寡核苷酸药物公司完成Ｂ轮融资。Alltrna公司宣布完成1.09亿美元Ｂ轮融资，用于进一步搭建其机器学习驱动的技术平台，以解锁tRNA序列和修饰的巨大组合力量，将首个tRNA靶向寡核苷酸候选药物推向临床研究，用于治疗终止密码子病（Stop Codon Disease）。tRNAs不仅在mRNA翻译成蛋白质中起核心作用，并且为具序列和修饰生物学多样性的可编程分子。Alltrna的目标是工程化tRNA药物，通过读取这些PTC突变并递送所需的氨基酸，从而恢复全长蛋白的产生。‍‍‍‍‍‍‍‍‍医‍‍‍‍‍‍药‍‍‍‍‍‍‍‍‍‍‍‍‍热‍‍‍‍‍‍‍点‍‍‍‍‍‍‍‍‍1.首批宫颈癌规范诊疗质控试点公布。8月9日，国家癌症中心公布首批宫颈癌规范诊疗质量控制试点单位名单，全国共146家医院入选。首批名单中医院入选数目位列前五的省份分别为，广东（14家）、山东（13家）、河南（10家）、四川（9家）、浙江（9家）。北京、天津、上海和重庆四个城市的医院入选数目分别为6家、4家、3家和3家。2.WHO将EG.5列为“需要留意的”新冠。8月9日，世卫组织（WHO）宣布将新冠病毒变异株EG.5列为“需要留意的”变异株，但基于目前可用的证据，WHO仍认为EG.5在全球层面对公共卫生造成的风险为“低”级别。EG.5是奥密克戎变异株XBB.1.9.2谱系的一个后代谱系，首次报告于2023年2月17日。目前，根据WHO分析，EG.5仍是在美洲、欧洲和西太平洋地区流行的新冠变异株中增长最快的。3.每日走4000步可显著降低死亡风险。《欧洲预防心脏病学杂志》8日发布的最新研究报告显示，每日至少走4000步，可以显著降低死亡风险。此外，每天每增加500步，死于心血管疾病的风险会降低7%，每增加1000步，死于任何原因的风险会降低15%。60岁以下人群每天步行7000至13000步，死亡风险降低49%。‍‍‍‍‍‍‍评‍‍‍‍‍审‍‍‍‍动‍‍态‍‍‍‍‍‍‍  1. CDE新药受理情况（08月10日) 2. FDA新药获批情况（北美08月09日）股市资讯上个交易日 A 股医药板块 -0.31%涨幅前三     跌幅前三科源制药+20.00%  康 希 诺 -5.46%圣诺生物 +7.35%  东诚药业-4.75%恩威医药 +6.80%  赛托生物-4.73%  【上海医药】盐酸美金刚片获得药品注册证书和批准生产，主要用于治疗中重度至重度阿尔茨海默型痴呆。【信立泰】腔静脉滤器系统获得医疗器械注册证，用于预防下腔静脉系统栓子脱落而引起的肺动脉栓塞(PE)。【复旦张江】2023年上半年实现营业收入5.22亿元，同比增长92.74%;实现归属于上市公司股东的净利润 6843.75万元;实现归属于上市公司股东的扣除非经常性损益的净利润5490.54万元。- The End -戳“阅读原文”，了解更多医药研发及股市资讯。