Brinretigene vesgedparvovec

成立了11年，Editas Medicine顶着“张锋长子”的名头，管线开发一款，放弃一款，兜兜转转又成为了一家临床前阶段公司。 在近日的更新中，Editas宣布进行战略转型为体内基因编辑公司，计划在2年内实现人体概念验证。 此外，上一代核心管线reni-cel（之前名为EDIT-301）未能找到商业合作伙伴，reni-cel的开发结束；以及公司向体内基因编辑转型，体外项目的中止；为了节约成本，Editas宣布将裁员65%。 没人接盘的管线 reni-cel是一款体外的、自体的、CRISPR-Cas12a基因编辑药物，被开发用于治疗镰状细胞病（SCD）和β-地中海贫血。reni-cel是Editas目前唯一一款临床阶段管线。 早在今年10月，Editas就已经宣布要为reni-cel寻找合伙伙伴或买家，但是经过2个月的努力之后，发现无人问津。 Editas在ASH 2024年会上披露了reni-cel针对重症镰状细胞病的RUBY试验的最新数据，数据显示，自reni-cel治疗以来，28例患者中有27例没有血管闭塞事件（VOE），观察到患者总血红蛋白早期恢复正常，平均总血红蛋白从基线的9.8 g/dL增加到第6个月的13.8 g/dL（n=18）。此外，在患者报告的疼痛、身体功能、社会角色和活动中观察到具有持续临床意义的改善。 但是由于reni-cel没有找到合作方，Editas正在停止对reni-cel的开发，将与临床试验中心、监管机构和其他各方密切合作，以确定RUBY试验和EdiTHAL试验中参与者的未来道路。 延伸阅读：兜售唯一临床管线，张锋公司的再次转向 实际上，这已经不是Editas第一次想要卖管线。 早在2022年11月，Editas就想将其当时研发进度最快的AAV体内CRISPR项目EDIT-101授权出去。但是因为疗效的不佳、未来商业前景的不足，EDIT-101没能成功找到下家，在Editas的研发管线中默默消失。 延伸阅读：商业潜力堪忧，Editas领先的体内CRISPR疗法停止临床开发 多款管线惨遭放弃 除了卖不出去的EDIT-101和reni-cel之外，Editas还在2023年1月宣布放弃2款在研管线。 EDIT-103：一款AAV体内CRISPR项目，被开发用于治疗视紫红质相关的常染色体显性视网膜色素变性 (RHO-adRP)。EDIT-103在此前发布的非人灵长类动物临床前数据较为积极，具体放弃原因不明。 EDIT-202：一款多重编辑诱导多能干细胞（iPSC）衍生的NK（iNK）细胞疗法，被开发用于治疗实体瘤。除了有名有姓的EDIT-202之外，Editas还停止了一系列的iNK项目的内部投资。 此外，随着Editas向体内基因编辑的转型，Editas其余的体外项目估计也会停止。 事实上，顶着“张锋长子”名号的Editas，在业内鼎鼎有名，但是管线开发总是戛然而止，让很多人大失所望，Editas的股价也一跌再跌。 兜兜转转，还是体内 在Editas过去的研发中，其实可以看到其重心在体内或体外疗法中不断摇摆。 小编研究了一下，发现还是蛮有意思的——从AAV体内-到HSPC体外-再到LNP体内。 最早先，Editas更多押注在AAV体内项目上，包括其最先推进临床的眼科项目EDIT-101。 但是EDIT-101的疗效数据不佳，Editas在2023年初宣布放弃AAV项目的开发（同期Editas当时的首席科学官Mark S. Shearman离职），转向HSPC体外项目。 结果HSPC体外项目也没能做多久（大概一年半），Editas现在又宣布放弃体外基因编辑（伴随着Editas的首席医疗官Baisong Mei离任），转型到LNP体内。 Editas将利用专有的新型靶向脂质纳米颗粒（tLNP）开发下一代CRISPR体内疗法，第一个目标是SCD和β-地贫的CRISPR-tLNP。 根据Editas公司所披露的进度来看，SCD和β-地贫的CRISPR-tLNP已经在小鼠模型中完成了临床前概念验证，在人源化小鼠模型（植入人类造血干细胞且缺乏自身造血细胞的小鼠）中，体内疗法诱导了胎儿血红蛋白 （HbF）产生。 此外，CRISPR-tLNP制剂已经完成了在非人类灵长类动物肝脏高效编辑的体内概念验证。 小结 令人失望的Editas，股价已经跌到了1.89美元/股。 此外，接连转型的Editas，也失去了在CRISPR疗法开发的领先地位。 延伸阅读： 张锋旗下公司百态，被出售、被合并、被裁员 张锋旗下8家公司，3家启动裁员 参考资料： 1.https://ir.editasmedicine.com/news-releases/news-release-details/editas-medicine-announces-strategic-transition-vivo-gene-editing 2.https://ir.editasmedicine.com/news-releases/news-release-details/editas-medicine-reports-updated-clinical-data-ruby-trial-reni 本周好文推荐 如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·

According to a report by Yole Développement, the CRISPR technology market is projected to reach $5 billion by 2023, marking its rapid global development and widespread application. By 2027, the global CRISPR technology market is expected to grow to $3.94 billion, with a compound annual growth rate (CAGR) of 24.2%. This forecast underscores the sustained growth of CRISPR technology across various fields, particularly in therapeutic applications. Key therapeutic uses of CRISPR include gene editing, gene therapy, and immunotherapy, which hold promise for offering new treatment solutions for numerous genetic disorders and cancers. Mechanism of CRISPR-Cas9The development of CRISPR-Cas9 technology can be traced back to 1987, when Japanese scientists first identified CRISPR sequences in Escherichia coli, though their significance was not realized at the time. In 2005, researchers discovered that CRISPR sequences matched viral DNA infecting bacteria, revealing the relationship between CRISPR and bacterial defense against viruses. By 2007, researchers at Danisco demonstrated that the CRISPR system could function as an adaptive immune mechanism in bacteria, protecting against foreign genetic material. Mechanism of CRISPR/Cas9 system[1]In 2012, Jennifer Doudna, Emmanuelle Charpentier, and their team unveiled the functional mechanism of the CRISPR-Cas9 system. They discovered that the Cas9 protein, guided by RNA molecules, could precisely identify and cleave specific DNA sequences, highlighting its immense potential for precise gene editing. This breakthrough rapidly made CRISPR-Cas9 a prominent tool in scientific research, finding applications in gene function studies, genetic disease treatments, and more. A brief history of CRISPR/Cas9 system development and associated gene editing tools[1]In the CRISPR-Cas system, CRISPR loci are initially transcribed into a long precursor RNA (pre-crRNA). This process occurs within bacterial or archaeal cells in response to the invasion of viruses or other foreign genetic material. CRISPR loci consist of multiple repeat sequences and spacer sequences, the latter of which are derived from fragments of previously encountered viral genes. Typically, CRISPR loci include a leader region rich in AT bases, which acts as a promoter. Following the leader region, alternating repeat and spacer sequences form a pattern of "repeat-spacer-repeat," transcribed under the leader region's regulation into pre-crRNA containing multiple repeats and spacers. Each spacer corresponds to an integrated viral gene fragment. Naturally occurring Cas proteins and the engineered Cas proteins[2]Pre-crRNA requires processing to form mature crRNA, a process aided by trans-activating crRNA (tracrRNA). TracrRNA is a longer RNA molecule that contains a domain binding to Cas proteins and a sequence complementary to the repeat regions of pre-crRNA. Through complementary pairing, tracrRNA binds to the repeat regions of pre-crRNA to form a double-stranded RNA structure. This structure is cleaved by endogenous enzymes like RNase III, producing multiple mature crRNA molecules. Each crRNA includes a spacer sequence complementary to a previously integrated viral gene fragment. Mature crRNA, approximately 20 nucleotides long, specifically recognizes target DNA sequences. Schematic diagram of in vitro or in vivo CRISPR screening[1]The mature crRNA is produced from pre-crRNA and includes a spacer sequence complementary to the integrated viral gene fragment. TracrRNA facilitates the complementary pairing of its sequence to the repeat regions of pre-crRNA, forming a double-stranded RNA structure. Enzymes such as RNase III cleave this structure to produce mature crRNA, which includes a spacer sequence complementary to the target DNA sequence. Mature crRNA pairs with tracrRNA to form a double-stranded RNA complex, structurally resembling a "Y" shape. The spacer sequence of crRNA remains single-stranded, while the remainder forms a double strand with tracrRNA. This double-stranded RNA complex stabilizes the crRNA and provides the necessary structure for subsequent binding to the Cas9 protein. Pooled CRISPR/Cas9 screening approachesCas9 protein is a nuclease capable of cleaving DNA at specific locations. It has two primary domains: RuvC-like and HNH, which cleave the two DNA strands, respectively. The double-stranded RNA complex binds to Cas9, forming a ribonucleoprotein (RNP) complex essential for precise gene editing. The RNP complex is stabilized through Cas9's specific domains binding to tracrRNA. The spacer sequence of crRNA is exposed and pairs complementarily with the target DNA sequence. The RNP complex recognizes and binds to the target DNA sequence through the spacer sequence of crRNA. The target DNA sequence must contain a Protospacer Adjacent Motif (PAM), essential for Cas9 recognition and binding. Once the crRNA pairs with the target DNA sequence, it forms an R-loop structure, a prerequisite for DNA cleavage by Cas9. Cas9 cleaves the double-stranded DNA at specific positions upstream of the PAM sequence, creating double-strand breaks (DSBs). The RuvC-like and HNH domains of Cas9 cleave the non-target and target strands, respectively. DSBs are repaired via non-homologous end joining (NHEJ) or homology-directed repair (HDR). NHEJ introduces random insertions or deletions (indels), leading to gene inactivation or loss of function, while HDR enables precise insertion or replacement of specific DNA fragments for accurate gene editing Market Drivers for CRISPR TechnologyIn recent years, CRISPR technology has seen significant advancements in genome editing platforms, particularly in optimizing Cas9 proteins. For instance, optimized versions like eSpCas9 and SpCas9-HF have significantly reduced off-target effects and improved editing efficiency. These innovations have expanded CRISPR's applications across various fields. In basic research, high-precision CRISPR tools help scientists study gene functions, identify biomarkers, and discover drug targets. In clinical applications, reduced off-target effects enhance therapeutic safety, minimizing adverse reactions and providing more effective treatments. Additionally, optimized Cas9 proteins are useful for complex gene editing tasks such as multi-gene editing and large-scale genomic screening, driving CRISPR's broader adoption in research and medicine. As the understanding of genetic diseases and cancer deepens, the demand for precision medicine and personalized therapies continues to grow. CRISPR technology, with its high efficiency and precision, has become a critical tool to meet these needs. Genetic diseases are often caused by specific gene mutations, and traditional therapies struggle to provide cures. In contrast, CRISPR technology enables precise gene editing to correct pathogenic mutations, offering curative treatment options. For instance, CRISPR has been successfully used in early-stage treatments for genetic disorders such as β-thalassemia and sickle cell disease. In cancer therapy, CRISPR technology allows the editing of immune cells, such as CAR-T cells, enhancing their ability to recognize and eliminate cancer cells, thereby improving the efficacy of immunotherapy. Moreover, CRISPR is being used to develop novel gene therapies, including gene-editing vaccines and gene-drive systems, paving the way for new approaches in disease prevention and treatment. The increasing demand for CRISPR-based solutions not only drives innovation and technological advancement but also fosters the formation of related industrial chains, delivering significant economic and social benefits. Regional Development of CRISPR TechnologyThe United States leads the research and development of CRISPR technology. Prominent institutions and biotech companies, such as Harvard University, MIT, the Broad Institute, CRISPR Therapeutics, and Intellia Therapeutics, are at the forefront of advancing this technology. The U.S. Food and Drug Administration (FDA) has approved several clinical trials for CRISPR-based therapies, targeting conditions such as sickle cell disease (SCD), transfusion-dependent β-thalassemia (TDT), and hereditary blindness. On December 8, 2023, the FDA approved Casgevy (exa-cel), a CRISPR-based gene-editing therapy developed by CRISPR Therapeutics and Vertex Pharmaceuticals, for treating SCD and TDT. The United Kingdom is also at the forefront of CRISPR regulation and approvals. On November 16, 2023, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) approved Casgevy (exa-cel) for treating SCD and TDT. Institutions like the University of Cambridge and Imperial College London have made significant contributions to the basic and applied research of CRISPR technology. Several European Union countries are actively advancing CRISPR research and clinical applications. The European Medicines Agency (EMA) approved Casgevy (exa-cel) for treating SCD and TDT on December 15, 2023. Research institutions and biotech firms in Germany, France, and the Netherlands have achieved notable progress in clinical trials and applications of CRISPR technology. Competitive Landscape of the CRISPR Gene Editing Therapy MarketCRISPR Therapeutics, based in Basel, Switzerland, is a leading gene editing company focused on utilizing CRISPR-Cas9 technology to treat various genetic disorders. Its flagship product, Casgevy (exa-cel), is a gene editing therapy for sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT). This therapy received approval from both the FDA and EMA in 2023. The company is also advancing CTX001, an autologous cell therapy for β-thalassemia and SCD, which has demonstrated promising safety and efficacy in multiple clinical trials. Intellia Therapeutics, headquartered in Cambridge, Massachusetts, specializes in the development and application of CRISPR-Cas9-based therapies. The company is advancing both in vivo and ex vivo gene editing treatments for various genetic diseases. Key products include NTLA-2001, an in vivo gene editing therapy for transthyretin amyloidosis (ATTR), which has shown significant efficacy and safety in clinical trials, and NTLA-2002, an in vivo therapy for hereditary angioedema (HAE), which has received FDA approval for clinical trials and demonstrated positive results in early-stage studies. Editas Medicine, also based in Cambridge, Massachusetts, is a prominent player in the gene editing field, leveraging CRISPR-Cas9 technology to address genetic diseases. Its lead product, EDIT-101, is an in vivo gene editing therapy for Leber congenital amaurosis type 10 (LCA10). Using an AAV5 vector to deliver the CRISPR-Cas9 system, this therapy targets pathogenic mutations in the CEP290 gene to restore photoreceptor function. It has shown good safety and preliminary efficacy in Phase 1/2 clinical trials. Another key product, EDIT-301, treats SCD and TDT by editing hematopoietic stem cells to produce high levels of fetal hemoglobin, reducing or eliminating disease symptoms. EDIT-301 is currently under evaluation in several clinical trials, showing favorable safety and efficacy. Mammoth Biosciences, located in San Francisco, California, was co-founded by CRISPR pioneer Dr. Jennifer Doudna. The company focuses on applying CRISPR technology for disease diagnosis and gene editing. Notable offerings include the DETECTR platform, a CRISPR-based diagnostic tool that leverages Cas enzymes and guide RNA to deliver genetic diagnostic results within 20 minutes. This platform gained prominence during the COVID-19 pandemic through the RADx initiative and collaborations with the U.S. Department of Defense, showcasing its potential in public health emergencies. Mammoth is also developing gene editing therapies for genetic disorders using its proprietary ultra-small Cas enzymes (e.g., Cas14 and Cas12), which are smaller, more thermally stable, and exhibit faster reaction kinetics, enabling efficient delivery and gene editing. Collaborations with companies like Bayer and Regeneron are accelerating Mammoth’s therapeutic development efforts. Beam Therapeutics, headquartered in Cambridge, Massachusetts, is a biotechnology company specializing in base editing technology. This approach enables precise genetic modifications, providing tailored treatments for genetic disorders. Its key products include BEAM-101 and BEAM-102. BEAM-101 is an ex vivo gene-editing therapy designed for the treatment of sickle cell disease (SCD). It works by editing hematopoietic stem cells to increase fetal hemoglobin (HbF) levels, thereby mitigating or eliminating SCD symptoms. BEAM-101 has received FDA IND approval and is currently undergoing the Phase 1/2 BEACON-101 clinical trial. Early data indicate its ability to significantly elevate HbF levels while reducing HbS levels, demonstrating both safety and efficacy. BEAM-102 targets transfusion-dependent β-thalassemia (TDT), similarly using edited hematopoietic stem cells to increase HbF levels and alleviate or eliminate disease symptoms. BEAM-102 is currently in the IND feasibility study phase, laying the groundwork for future clinical trials. SummaryThe market outlook for CRISPR technology is promising, with expanding applications in gene editing, gene therapy, and immunotherapy. Advances in technical optimization, safety improvements, growing market demand, and supportive policies are driving the rapid development of CRISPR technologies. As more clinical trials succeed and regulatory approvals increase, CRISPR holds the potential to offer precise and effective treatments for genetic disorders and cancers. This progress is also expected to stimulate the growth of related industries, delivering positive economic and social impacts. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery! Reference： 1.Wang, S.W., et al., Current applications and future perspective of CRISPR/Cas9 gene editing in cancer. Mol Cancer, 2022. 21(1): p. 57. 2.Liu, Z., et al., Recent advances and applications of CRISPR-Cas9 in cancer immunotherapy. Mol Cancer, 2023. 22(1): p. 35.