Spotlight Therapeutics, Inc.

▎药明康德内容团队编辑 CRISPR-Cas9技术自问世以来仅十余年间，我们已经见证了基因编辑领域的显著进展。首例基于CRISPR基因编辑技术的药物Casgevy已获批用于治疗镰刀型细胞贫血病（SCD）与输血依赖性β地中海贫血（TDT）患者，同时，针对遗传性疾病和癌症的CRISPR基因编辑疗法的临床试验也在如火如荼地进行中。近日，知名行业媒体STAT发表了一篇文章，评选出10位在基因编辑领域崭露头角的青年才俊。他们的开创性工作不仅推动了基因编辑治疗应用的拓展，也为CRISPR技术在人类健康领域的积极影响增添了新的维度。在今天的文章中，药明康德内容团队将带领大家一同了解这些未来之星。点击文末“阅读全文/Read More”，即可查看原文内容。 图片来源：123RF Alexis Komor 加州大学圣地亚哥分校（UCSD） Alexis Komor博士目前担任UCSD的助理教授。在她的博士后研究期间，Komor博士成功开发了首个碱基编辑器，这一创新成果在2016年发表于《自然》杂志。自那以后，碱基编辑技术逐渐被应用于临床研究。例如，Beam Therapeutics公司已经开始利用这种技术进行SCD、癌症和α1抗胰蛋白酶缺乏症的临床试验。 今年夏天，Komor博士及其在UCSD的团队取得了另一项重大突破，他们开发了四种新型碱基编辑系统，这些多任务编辑器系统被称为MOBE。MOBE允许研究人员同时进行多种类型的单碱基编辑，而且它们之间不会相互干扰，从而降低了错误发生的风险。MOBE编辑器的这一特性对于建立更精确的复杂疾病模型至关重要，并且有望为免疫疗法领域设计出更强效的T细胞。这一进展不仅推动了基因编辑技术的发展，也为未来的医学治疗提供了新的可能性。 Jonathan Gootenberg & Omar Abudayyeh 哈佛大学医学院 Jonathan Gootenberg博士和Omar Abudayyeh博士目前是哈佛大学医学院的研究员。两人在研究生时期就结下了深厚的友谊，并成为了科研搭档。在师从CRISPR基因编辑领域的先驱之一张锋教授期间，他们发现了一种名为Cas13的新酶，并成功将其设计为一种用于编辑RNA的CRISPR系统。几年后，他们又发现了一种更安全的版本，即Cas7-11。基于这些创新成果，他们与张锋教授共同创立了两家公司：Sherlock Biosciences和Proof Diagnostics。这两家公司专注于利用CRISPR技术开发快速诊断测试，为医疗诊断领域带来了革命性的进步。 2022年，他们在麻省理工学院（MIT）麦戈文脑科学研究所（McGovern Institute for Brain Research）担任研究员期间，发明了一种名为PASTE的下一代基因编辑技术，能够实现大段DNA的精准插入，这一突破性成果被《自然》杂志评为“2024年值得关注的七大技术”之一。 Patrick Hsu 加州大学伯克利分校（University of California，Berkeley），Arc研究所（Arc Institute） Patrick Hsu博士是张锋教授的杰出门生之一，目前担任加州大学伯克利分校的助理教授，他同时还是Arc研究所的联合创始人。Hsu博士在将机器智能与生物学相结合的交叉领域走在了前列，致力于挖掘和设计新型CRISPR系统。 2018年，Hsu博士发现了CasRx，这是一种靶向RNA的CRISPR酶，它为治疗由RNA剪接错误引起的疾病（如额颞叶痴呆症）提供了新的治疗途径。今年夏天，他在Arc研究所的研究团队发现了一类新的引导RNA（gRNA），这些gRNA分子有潜力对DNA进行大规模的改变。 最近，Hsu博士与Arc研究所的同事们合作，开发了一个生成式人工智能模型，该模型能够设计出前所未有的新型CRISPR系统。尽管这些新系统仍需通过实验测试来验证它们的功能和安全性，但这项工作无疑为基因编辑领域开辟了新的研究方向，为未来探索更多治疗应用提供了可能性。 Alexander Marson Gladstone-UCSF Institute of Genomic Immunology，加州大学伯克利分校 Alexander Marson博士是将CRISPR技术与免疫疗法相结合的先驱之一，他专注于利用基因编辑工具设计T细胞，以增强其对抗血癌的能力。2018年，他开发了一种创新技术，利用脉冲电流将CRISPR元件迅速传递到T细胞中，从而重写其基因序列并赋予其新的功能。此外，他还运用CRISPR筛选技术——这项技术允许研究人员逐一关闭细胞中的每个基因——来识别新的靶点，进而创造出更具肿瘤杀伤能力的T细胞。这些工作极大地推动了体外细胞编辑的速度和精确度。 最近，Marson博士的研究团队又取得了新的进展，他们利用抗体和细胞穿透肽的组合，开发出了一种将CRISPR系统有效递送至体内特定细胞类型的方法。Marson博士与Patrick Hsu博士共同创立了Spotlight Therapeutics公司，该公司正在积极推进这些技术，旨在开发出超越现有病毒载体和脂质纳米颗粒的体内基因编辑递送方法，为基因治疗领域带来革命性的变革。 Britt Adamson 普林斯顿大学（Princeton University） Britt Adamson博士目前是普林斯顿大学的助理教授。在她的博士后研究期间，Adamson博士领导了Perturb-seq技术的研究工作——这是一种创新的基因扰动组学测序技术，它将CRISPR基因编辑技术与单细胞测序相结合，使得研究人员能够大规模地研究单个人类基因的功能及其协同工作的方式。 Adamson博士的研究团队发现了一些延缓先导编辑（prime editing）技术的分子障碍。为了克服这些障碍，她与David Liu（刘如谦）教授和Alexander Marson博士合作，开发出了更高保真度的新型先导编辑器版本。这些改进后的编辑器在相关人类细胞中的应用前景广阔，有望为治疗遗传疾病提供新的策略。其中的一些技术升级被《细胞》杂志评为2022年最令人兴奋的细胞生物学研究之一。 此外，Adamson博士的实验室还取得了另一项重要成就：他们成为了首个在小鼠胚胎中高效进行先导编辑的实验室。这一成就对于遗传疾病建模和哺乳动物发育研究具有重大意义，为这些领域的研究提供了强大的新工具。 Ben Kleinstiver 麻省总医院（Massachusetts General Hospital） Ben Kleinstiver博士是麻省总医院的助理教授，他专注于利用蛋白质工程技术来扩展CRISPR技术的临床应用。在过去几年中，Kleinstiver博士在将基因编辑技术转化为新型基因药物方面做出了多项重要贡献。 Kleinstiver博士及其团队设计构建了新型CRISPR酶，这种酶能够识别和编辑人类DNA中更多的片段。这一创新是相对于第一代CRISPR系统的重大进步，因为第一代CRISPR系统能够进入并编辑的区域有限，从而限制了其能够解决的疾病类型。今年早些时候，Kleinstiver博士的团队又开发了“点击编辑器”（click editors），这是一种利用人体细胞内现有蛋白质来实现多种DNA改变的技术。 此外，Kleinstiver博士还领导或参与了多项研究，旨在优化基因编辑技术，以治疗慢性肉芽肿病、脊髓性肌萎缩症（SMA）、亨廷顿病和遗传性听力损失等遗传性疾病。这些研究为将基因编辑技术应用于临床试验铺平了道路，为患者带来了新的治疗希望。 Kiran Musunuru 宾夕法尼亚大学Perelman医学院 Kiran Musunuru博士是宾夕法尼亚大学Perelman医学院心血管疾病研究所疾病遗传和表观遗传起源计划的负责人。在2010年，他发现了一种特定的DNA变异，这种变异能够关闭ANGPTL3基因，携带这种变异的个体因此获得了对血管斑块堆积、心脏病和中风的保护。基于这一发现，Musunuru博士参与创办了Verve Therapeutics公司，该公司目前正在进行临床试验，测试基于碱基编辑技术复制这种保护性变异的治疗方法，以帮助家族性高胆固醇血症患者。 由于在基因编辑领域的杰出贡献，Musunuru博士在2016年荣获了美国青年科学家总统奖，并在2021年获得了美国心脏协会的Joseph A. Vita奖。今年早些时候，Musunuru博士与费城儿童医院的同事们证明了在胎猴出生前进行子宫内基因编辑可以治疗其致命的肝病，这是基因编辑技术在胎儿治疗领域的一个重要突破。 此外，Musunuru博士还是美国国立卫生研究院（NIH）资助的一个耗资1400万美元项目的主要研究者之一。该项目的目标是建立一个平台，为患有尿素循环障碍的婴儿提供量身定制的个体化碱基编辑疗法和先导编辑疗法。这项试验预计将于明年开始治疗首位患者，这将是基因编辑个体化治疗的又一重要里程碑。 Charles Gersbach 杜克大学（Duke University） Charles Gersbach教授是杜克大学生物医学工程学系的一名杰出学者，他正在领导“表观编辑”（epi-editing）研究项目，这项技术利用CRISPR系统，通过改变控制基因表达的化学标签和DNA结构，而不是直接改变基因本身，来影响基因表达。这一创新方法有望解决由调控元件错误引起的复杂疾病。 Gersbach教授一直致力于绘制表观遗传网络图谱，并开发能够调控这些网络的分子工具。他所研发的表观编辑器技术已被授权给Tune Therapeutics。该公司去年宣布，其科学家成功地在猴子体内关闭了PCSK9基因的表达，从而降低了动物血液中的低密度脂蛋白胆固醇水平。目前，Tune Therapeutics公司正准备启动一项临床试验，旨在开发一种一次性永久灭活治疗慢性乙型肝炎感染病毒的方法。 Krishanu Saha 威斯康星大学麦迪逊分校（University of Wisconsin–Madison） Krishanu Saha博士是威斯康星大学麦迪逊分校的副教授，他的研究工作集中于将基因编辑工具与干细胞技术相结合，以深入理解人类疾病并探索其治疗方法。目前，他正领导一个致力于开发基于CRISPR技术的治疗方案，以治疗两种导致失明的遗传性眼病的项目。此外，Saha博士还担任美国NIH体细胞基因组编辑联盟的联合主席，该联盟正在推动多个类似的项目，目标是在不久的将来实现由学术界主导的CRISPR药物的临床试验。 在推动CRISPR科学发展的同时，Saha博士也积极参与促进公众对这项技术使用的广泛讨论。2020年，他协助成立了全球基因编辑观察站，该观察站定期组织会议，聚焦讨论基因编辑相关的伦理、公平和社会正义问题。 文中图片均来自上榜者工作机构或个人主页官网 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料： [1] These 10 scientists are leading a new generation of gene editors developing CRISPR medicines，Retrieved November 6, 2024 from https://www.statnews.com/2024/10/31/who-to-know-series-10-scientists-crispr-gene-editing/ 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。 版权说明：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。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

Walking Fish Therapeutics has closed despite being on the precipice of entering the clinic. (Getty/zoom-zoom) Walking Fish Therapeutics has closed after a lead investor backed out of a critical series B round.  CEO Rusty Williams, M.D., Ph.D., said in an interview with Fierce Biotech that the company was on the precipice of securing fresh capital to enter the clinic when an unnamed top investor backed out, citing concerns about the cost of a multiyear lease. The decision, which came after Walking Fish secured two federal ARPA-H grants to help take the pressure off internal financiers, stunned Williams. “It was a shock,” the CEO said. “T​​his investor just pulled out abruptly and said they wanted to shut down the company.” As a result, 35 employees were laid off, which followed two other layoff rounds to help dwindle costs.  Endpoints News first reported Walking Fish’s closure.  Walking Fish was more than two years removed from a $73 million series A co-led by Northpond Ventures and First Spark Ventures. The biotech previously received funding from Illumina’s venture arm, Quan Capital and the Emerson Collective.  Less than a year ago, the company was adding to its leadership team, hiring Julie Kim as chief business officer and Nallakkan Arvindan, Ph.D., as chief technology officer. Kim joined from Quan after stints at Genentech and Roche, while Arvindan was the former CTO at Spotlight Therapeutics.  The financing and new hires were meant to help advance a three-asset portfolio of B-cell-based therapies, with a lead candidate designed to treat Fabry disease. That asset, WFX-001, was most recently in IND-enabling studies, according to Walking Fish’s website. The biotech intended to reconfigure B cells to help build proteins, including a deficient enzyme in patients with Fabry disease. The biotech also had two additional preclinical assets aimed at undisclosed targets. There’s “a fair amount of interest” in those assets, according to Williams, and conversations are ongoing to find a buyer.  Previously, Williams served as Five Prime Therapeutics' CEO for more than 15 years before its acquisition by Amgen. Before that, he was the chief scientific officer at Chiron, which ultimately was bought by Novartis for $5.1 billion. Now, he’s helming a new venture, Ten30 Bio, which is working on oral molecules.  Reflecting on Walking Fish’s work, Williams concedes that the cost of cell therapy manufacturing and associated clinical trial costs were difficult to overcome. It’s a painful conclusion that many others in cell therapy have realized as they pivot to treat autoimmune conditions.  “I think that B-cell therapy is likely to have its day; I think that what we were doing would have worked,” he said. “But it was just too expensive to get the phase 1 done in that financing environment.” 

SOUTH SAN FRANCISCO, Calif., May 10, 2023 (GLOBE NEWSWIRE) -- Tenaya Therapeutics, Inc. (NASDAQ: TNYA), a clinical-stage biotechnology company with a mission to discover, develop and deliver potentially curative therapies that address the underlying causes of heart disease, today reported financial results and provided a corporate update for the first quarter ended March 31, 2023. “Tenaya is making meaningful progress across multiple fronts of our business while maintaining a solid cash position. We are pleased to have recently received Fast Track designation for TN-201 and completed dosing in our Phase 1 trial of TN-301. We remain on track to achieve our 2023 development and regulatory milestones for TN-201, TN-301 and TN-401, including the release of clinical data for TN-301 in the second half of 2023,” said Faraz Ali, Chief Executive Officer of Tenaya. “In addition to our focus on achieving near-term catalysts, we continue to invest in our future. We look forward to highlighting the depth and breadth of our core capabilities at the upcoming ASGCT conference. We have also added leading industry and academic experts to our Scientific Advisory Board and to our newly created Technical Advisory Board. These efforts will collectively help Tenaya lay the foundation for commercial-ready manufacturing for our existing product candidates and support the expansion of Tenaya’s pipeline into new modalities, including gene editing, so that we can bring the promise of genetic medicines to individuals and families fighting heart disease.” Business and Program Updates TN-201 – Gene Therapy for MYBPC3-Associated Hypertrophic Cardiomyopathy (HCM) Tenaya received notification that the U.S. Food and Drug Administration (FDA) granted Fast Track designation to TN-201. The FDA Fast Track program is designed to facilitate the development and expedite the review of drug candidates intended to treat serious conditions and for which nonclinical data demonstrates the potential to address unmet medical need. In January 2023, the FDA notified Tenaya that clinical testing of TN-201 may proceed based on review of the company’s Investigational New Drug (IND) application. Tenaya plans to commence a Phase 1b multi-center, open-label, dose-escalation clinical trial in the third quarter of 2023. The Phase 1b clinical trial is designed to assess the safety, tolerability and pharmacodynamics of a one-time intravenous infusion of TN-201 in symptomatic adults with MYBPC3-associated HCM. Initial data from the Phase 1b clinical trial are anticipated in 2024. TN-301 – Small Molecule HDAC6 Inhibitor for Heart Failure with Preserved Ejection Fraction (HFpEF) Tenaya recently completed dosing of healthy participants in its Phase 1 clinical trial. Initial target engagement, measured by the biomarker tubulin acetylation, was achieved and no dose-limiting toxicities were reported. The Phase 1 clinical trial was designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of escalating oral doses of TN-301. Tenaya expects to report results from both the single and multiple ascending dose stages of the Phase 1 clinical trial in the second half of 2023. TN-401 – Gene Therapy for PKP2-Associated Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Tenaya plans to submit an IND application for TN-401 to the FDA in the second half of 2023. TN-401 is being developed for the potential treatment of ARVC caused by PKP2 genetic mutations and is designed to deliver a fully functional PKP2 gene to prevent arrhythmia and reverse disease following a single dose. Research Updates In May 2023, Tenaya researchers will present six abstracts at the American Society of Gene and Cell Therapy (ASGCT) 26th Annual Meeting detailing the company’s expanded capabilities for manufacturing and discovering genetic medicines for heart disease. Tenaya’s continued growth and optimization across its enabling technologies supports current pipeline candidates and is expected to increase opportunities for future programs. The presentations will highlight innovations in manufacturing, capsid engineering and gene editing. Leadership Tenaya expanded its Scientific Advisory Board with the appointments of Christine Edry Seidman, M.D., and Alexander Marson, M.D., Ph.D. Dr. Seidman leads a laboratory that aims to define genetic causes, mechanisms, treatments and cures for human heart disease. Her work enabled development of the first mechanism-based treatment for hypertrophic cardiomyopathy. Among her current roles, she serves as the Director of the Cardiovascular Genetics Center at Brigham and Women's Hospital, and a professor of genetics and medicine at Harvard Medical School. Previously, Dr. Seidman was a scientific co-founder of MyoKardia, a precision medicine cardiovascular company focused on cardiomyopathies (acquired by BMS). Dr. Marson’s research focuses on understanding the genetic circuits that control human immune cell function and deploying genome editing technologies such as CRISPR to create engineered cells capable of detecting, resisting and eliminating disease. He currently serves as Director of the Gladstone-UCSF Institute of Genomic Immunology and professor of medicine at UCSF. He is also co-founder of Spotlight Therapeutics, an in vivo genome editing company using non-viral delivery. Tenaya announced the formation of a Technical Advisory Board (TAB) to provide expert perspective on manufacturing, quality, regulatory process development and analytical development strategies across a range of modalities. Members of the TAB each bring significant expertise in the manufacture of genetic medicines and include: Mark Angelino, Ph.D., Venture Partner at Third Rock Ventures. Dr. Angelino brings broad operational experience, most recently as co-founder and Chief Operating Officer of Generation Bio, a non-viral delivery genetics medicine company, and prior as the Senior Vice President of Pharmaceutical Sciences at bluebird bio, an ex vivo autologous lentiviral vector gene therapy company. Guangping Gao, Ph.D., Director of the Li Weibo Institute for Rare Diseases and professor at UMass Chan Medical School. Dr. Gao is widely recognized for his significant contributions to the field of discovery and manufacturing of viral vector gene therapies for rare diseases. Victoria Sluzky, Ph.D., is founder and principal of Lucid Biotechnology Advisors with more than 30 years of biotechnology industry experience. Dr. Sluzky formerly served as the Senior Vice President of Technical Development at BioMarin Pharmaceutical where she was directly involved in advancing product development in many rare diseases, and providing expertise in quality, process and assay development, formulation and regulatory strategy. Angela Thedinga, MBA, MPH, is presently a Board member of Nkarta, Inc. Previously, Ms. Thedinga was the Chief Technology Officer at Adverum and led manufacturing strategy and program management at AveXis (now Novartis Gene Therapies). First Quarter 2023 Financial Highlights Cash Position and updated cash guidance: As of March 31, 2023, cash, cash equivalents and investments in marketable securities were $173.6 million. Tenaya expects current cash, cash equivalents and investments in marketable securities (current and noncurrent) will be sufficient to fund the company into the first half of 2025. Research & Development (R&D) Expenses: R&D expenses for the quarter ended March 31, 2023, were $25.6 million. Non-cash stock-based compensation included in R&D expense was $1.6 million for the quarter ended March 31, 2023. General & Administrative (G&A) Expenses: G&A expenses for the quarter ended March 31, 2023, were $8.1 million. Non-cash stock-based compensation included in G&A expense was $1.9 million for the quarter ended March 31, 2023. Net Loss: Net loss for the quarter ended March 31, 2023, was $31.7 million, or $0.43 per share. About Tenaya Therapeutics Tenaya Therapeutics is a clinical-stage biotechnology company committed to a bold mission: to discover, develop and deliver potentially curative therapies that address the underlying drivers of heart disease. Leveraging its integrated and interrelated Gene Therapy, Cellular Regeneration and Precision Medicine platforms and proprietary core capabilities, the company is advancing a pipeline of novel therapies with diverse treatment modalities for rare genetic cardiovascular disorders and more prevalent heart conditions. Tenaya’s most advanced candidates include TN-201, a gene therapy for MYBPC3-associated hypertrophic cardiomyopathy (HCM), TN-401, a gene therapy for PKP2-associated arrhythmogenic right ventricular cardiomyopathy (ARVC), and TN-301, a small molecule HDAC6 inhibitor being initially developed for heart failure with preserved ejection fraction (HFpEF). Tenaya also has multiple early-stage programs progressing through preclinical development.