C9orf72

此次医博会由同写意策划，以“发展新质生产力，共享健康新未来”为主题，用全新的视角瞄准国内外医药及大健康产业发展前沿。诚邀海内外医药及大健康各界嘉宾齐聚中国医药城，共赴时代之约。展位/报告火热征集中！ “CRISPR让个道，RNA编辑疗法要提速了”。 这是今年2月，发表在《Nauter》上的一篇文章标题（《Move over, CRISPR: RNA-editing therapies pick up steam》）。 正在走向前台的RNA编辑技术，因其更安全、更灵活的特性，被视为有望超越CRISPR的存在。 技术方兴未艾，MNC如礼来、GSK的押注，更是一度将其热度推向高潮。不过，成立于2012年的RNA编辑先驱Wave，用了10多年的时间，才将首个RNA编辑项目WVE-006推向临床。 期间，由于其他核酸药物的临床失利，Wave股价由高点的56美元/股一路跌至1美元/股左右，市场预期不再。 沉寂多年后，一场由临床数据带动的反攻，正在上演。 10月16日，Wave发布WVE-006临床1b/2a期积极数据。 数据显示，在两例PiZZ型AATD（α-1 抗胰蛋白酶缺乏症）患者中，单次皮下注射WVE-006使其平均血浆总AAT水平达到约11µM，患者血浆中循环野生型M-AAT蛋白在第15天达到平均6.9µM，占总AAT的60%以上。 与基线相比，中性粒细胞弹性蛋白酶抑制的增加与功能性M-AAT的产生一致。平均总AAT蛋白从基线时的不可量化水平增加到第15天的10.8µM，达到了监管部门批准AAT增强疗法的基础水平。 由于PiZZ型AATD患者无法自然合成M-AAT蛋白，因此，M-AAT蛋白的出现，证明了突变型Z-AAT mRNA被成功编辑。 换句话说，Wave的RNA编辑平台终于实现了机制验证。Wave CEO兴奋地称之为，“人类首次治疗性RNA编辑数据”。 数据发布后，Wave股价暴涨75%。 在此之前的9月24日，Wave另一款反义寡核苷酸（ASO）药物WVE-N531，在中期临床中展现出成为杜氏肌肉萎缩症BIC药物的潜力，公司股价随之暴涨53%。 不到一个月的时间，Wave股价涨幅超162%。看起来，Wave正在践行其Reimagine Possible（潜力重燃）的承诺。 1 超越“CRISPR”？ WVE-006临床1b/2a期的成功，意味着Wave的RNA编辑平台实现了机制验证。 众所周知，CRISPR技术的诞生，让基因编辑从直板机步入智能机时代，也让我们距离成功修补人类基因缺陷的目标越来越近。去年12月，FDA更是批准了全球首款CRPISPR-Cas9基因组编辑疗法CASGEVY的上市。 相比之下，RNA编辑疗法的发展要慢得多。不过，正在走向前台的RNA编辑技术，则被视为有望超越CRISPR的存在。 这两种主流的基因编辑手段，在基因治疗领域扮演着重要角色，尽管它们的最终目的都是为了实现对遗传信息的精确修改，但两者仍有显著不同。 CRISPR-Cas9技术是通过直接剪切DNA链上的特定基因序列，实现对基因的编辑。这种方法虽然高效，但修改是永久性的，一旦发生错误，可能导致不可逆转的遗传变异。 事实上，自诞生以来，CRISPR技术的一个主要问题就是其潜在的脱靶效应，如果CRISPR基因编辑技术对预期靶标以外的其他DNA片段进行了切割，可能会破坏非靶向基因的功能或调节，引发严重后果。 此外，CRISPR技术涉及到直接修改个体的基因组，这不仅引发了伦理上的争议，也使得其应用受到了一定的限制。 与CRISPR技术相比，RNA编辑技术提供了一种更安全、更灵活的治疗选择。 因为，后者是通过修改信使RNA（mRNA）的方式，比如敲除、替换或抑制突变RNA片段，来实现对基因表达的调控，治疗遗传疾病。 其基本原理是通过特定的酶或编辑因子，对mRNA上的碱基进行修改，从而影响蛋白质的合成。这一过程可以分为单碱基编辑和RNA外显子编辑两种主要类型。 以单碱基编辑为例，通过精确地编辑特定的单个碱基，可以修正错误的遗传信息，恢复正常的蛋白质表达。比如，将mRNA上的腺嘌呤（A）编辑为肌苷（I）。这也是WVE-006的药物机制。 可以看到，由于这是在mRNA水平上进行，不直接改变DNA序列，因此可以有效避免脱靶效应和伦理问题。此外，mRNA分子寿命较短，意味着通过RNA编辑介入的效果是可逆的。 《Nature》上的一篇文章评价道，RNA编辑技术的发展标志着我们对生命科学的理解已经进入了一个新的层次。成立于2012年的RNA编辑先驱，Wave也被寄予厚望。 只不过，大多时候，前沿技术的发展总是充满波折与挑战。在临床试验中，如何确保编辑的精确性和效率，如何评估和优化长期安全性和稳定性，还有待验证。 Wave更是用了10多年的时间，才将WVE-006推向临床，获得初步验证。 2 命途多舛 尽管Wave在核酸赛道深耕多年，核酸技术平台PRISM也独具特色，是唯一提供三种RNA靶向方式（编辑、剪接和沉默，包括siRNA和反义RNA）的寡核苷酸平台。 但Wave却命途多舛，上市以来多个项目失败，导致市场预期降至谷底。 比如2019年3月，Wave停止了两款处于I/II期临床的反义寡核苷酸（ASO）药物，WVE-120101和WVE-120102。这是两款治疗亨廷顿病的疗法。 亨廷顿是一种罕见的遗传性神经退行性疾病，该疾病从被医学提出至今已长达150余年，距确定病因至今也已有30年，但目前仍没有治愈之法。研究人员一度希望ASO疗法能够改变亨廷顿病的游戏规则。 然而，现实是多款针对亨廷顿病的ASO药物相继折戟。数据显示，WVE-120102和WVE-120101两个药物所有评估剂量均未显示统计学显著的临床疗效证据。在此之前，罗氏与Ionis合作研发的ASO 药物Tominersen停止III期临床，这被外界视为亨廷顿基因疗法希望破灭。 两则坏消息，导致Wave的股价暴跌46%。 然而，令人意想不到的是，这只是Wave厄运的开始。 2019年底，Wave在对I期OLE研究结果进行中期分析后，决定终止外显子51跳跃突变杜氏肌营养不良症（DMD）药物suvodirsen的开发。研究结果显示，使用药物后肌营养不良蛋白表达与基线相比没有变化。 消息公布后，Wave股价暴跌超50%。半个月前，市场还寄希望其能够超越Sarepta，但随着亨廷顿病和DMD的失败，希望破灭，其股价也从高点的56美元/股，跌至不足8美元/股。 在接连失败的打击中，Wave决定裁员1/4，降低运营成本，并削减了其他DMD的研发工作。 此后接近3年时间，Wave几乎没有任何提振市场的消息传来，股价甚至一路下跌至1美元/股左右。 当然，Wave并没有放弃研发。毕竟其有技术平台，也有多款药物在研。 WVE-N531(剪接)，用于治疗DMD的外显子53分子; WVE-006(编辑)，用于治疗AATD(α-1抗胰蛋白酶缺乏症)的SERPINA1分子； WVE-003(沉默)，用于治疗亨廷顿病的mHTT SNP3分子; WVE-004(沉默)，用于治疗相关的ALS和FTD(肌萎缩侧索硬化症和额颞叶痴呆)的C9orf72分子；以及INHBE项目治疗代谢疾病。 Wave的技术平台和相关药物也得到了GSK的青睐。2022年12月13日，双方达成合作。首先是利用Wave的PRISM平台以及GSK在遗传学与基因组学的专业进行发现合作，以推进GSK最多8个以及Wave最多3个项目。 除了这些项目，GSK也将获得Wave临床前项目WVE-006的全球独家权利。根据协议，Wave将从GSK获得1.7亿美元的预付款，以及关于WVE-006项目的开发与里程碑启动款项等款项，最高可达33亿美元。 3 潜力重燃 在与GSK达成合作后一周，Wave公布了WVE-N531治疗DMD男孩的1b/2a期积极数据。 在Wave的WVE-N531试验的A部分中，WVE-N531展示出行业领先的外显子跳跃水平，达53%。 并且，相比已获批的ASO药物，WVE-N531的药代动力学参数显示药物的半衰期为25天。这可能支持其每月给药，高于现有药物的1周一次。 这得益于其新型化学修饰技术PN化学。与更传统的磷酸硫酯或磷酸二酯连接相比，含有PN化学的寡核苷酸连接更稳定，因此，有实现更长的药物半衰期和长期效果的潜力。 上述数据公布及与GSK的合作宣布后，Wave股价接连大涨。而今年9月24日，最新的临床数据显示，除了继续保持领先的外显子跳跃水平（57%），WVE-N531也实现了9%的平均肌肉含量调整后的抗肌萎缩蛋白，安全性与耐受性良好。这再次带动Wave股价暴涨53%。 与此同时，尽管在亨廷顿病领域遭遇沉重打击，但Wave仍保留了一款ASO药物，WVE-003。 可以说，WVE-003承载着已停止研究的WVE-120101和WVE-120102这两款药物的希望。其特别之处在于，高针对性。 WVE-003能够识别并针对变有害的亨廷顿蛋白（mHTT），不影响正常的亨廷顿蛋白（wtHTT）。由于wtHTT的功能对中枢神经系统的健康至关重要，且mHTT可能干扰wtHTT的功能， 今年6月，Wave公布了WVE-003的I/II期SELECT-HD研究数据。结果显示，WVE-003组患者的mHTT水平相比安慰剂组显著下降（治疗第24周时，mHTT降低了46%；治疗第28周时，mHTT降低了44%）。 Wave认为WVE-003的销售峰值有望达到50亿美元。不过，武田已于10月11日决定放弃行使包括WVE-003在内的亨廷顿氏病疗法的期权。 双方的合作始于2018年，武田已向Wave支付了约2.6亿美元。WVE-003是之前的合作协议产生的最后一个未宣告失败的成果，但武田决定放弃引进该药物。 而相比其他核酸疗法，Wave更是高度重视开发RNA靶向药物，首个RNA编辑项目WVE-006也获得了GSK的押注。 WVE-006是针对AATD的RNA编辑寡核苷酸疗法。AATD是一种常见的遗传性基因疾病，通常由SERPINA1基因中G到A的点突变（Z等位基因）引起，会引发严重的肺和肝疾病。 目前AATD肺病的唯一治疗选择是通过每周静脉输注以递送AAT蛋白，仅针对肺病（2023年全球销售额超过14亿美元）；AATD肝病目前尚无治疗方法，许多患者最终需要接受肝脏移植。 因此，包括WVE-006在内的新疗法颇受市场关注。WVE-006的原理是通过设计特定的小分子RNA，针对性地引导细胞内的ADAR酶对特定mRNA上的错配碱基进行精准编辑，从而修正错误的遗传信息，恢复AAT蛋白的正常表达。 同时，WVE-006作为全球首个进入临床试验的RNA编辑化合物，也在一定程度上影响着市场对于RNA编辑疗法的想象与预期。 10月16日，Wave公布Ib/IIa期RestorAATion-2研究积极数据。 尽管数据仅来自两名患者，但Wave表示这些数据显示了令人信服的证据，其药物成功地编辑了细胞用来将DNA转化为蛋白质的信使分子，即其RNA编辑平台实现了机制验证。 Wave CEO兴奋地称之为，人类首次治疗性RNA编辑数据。 数据发布后，Wave股价暴涨75%。完成RestorAATion-2研究后，WAVE将把WVE-006的开发和商业化权益转移给GSK，并有资格获得高达5.25亿美元的里程碑付款，以及分层版税。 如果从9月算起，其股价已经上涨162%，打了一个漂亮的翻身仗。 如果有什么秘诀，恐怕指向一点：尽管一度跌至谷底，但Wave并没有就此沉沦，而是有选择的坚持与改进管线研发，沉淀平台技术。目前看，其正在用积极的临床进展数据，践行其Reimagine Possible（潜力重燃）的承诺。 当然，对于Wave来说，这边RNA编辑技术刚刚获得验证，那边武田退回合作，意味着其在核酸药物这条道路上，还有很多未知与挑战。 同写意媒体矩阵，欢迎关注↓↓↓

TPN-101 had lowering effects on key biomarkers of neurodegeneration and neuroinflammation, including neurofilament light chain (NfL) and interleukin 6 (IL-6) Treatment with TPN-101 also showed clinical benefits on the Revised ALS Functional Rating Scale (ALSFRS-R) and Vital Capacity, key clinical outcome measures for ALS SAN DIEGO, Oct. 9, 2024 /PRNewswire/ -- Transposon Therapeutics, a biotechnology company developing a platform of novel, orally administered therapies for the treatment of neurodegenerative and aging-related diseases, including Alzheimer's disease, today announced that results from its Phase 2 study of TPN-101 in patients with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) related to hexanucleotide repeat expansion in the C9orf72 gene (C9orf72-related ALS/FTD) have been accepted for both oral and poster presentation at the 2024 Annual Northeastern Amyotrophic Lateral Sclerosis Consortium (NEALS) Meeting. The hybrid meeting will take place October 21-24, 2024, in Clearwater, Florida, and virtually. "Given the effects of TPN-101 on key biomarkers of neurodegeneration and neuroinflammation, including NfL and IL-6, and clinical outcome measures of disease progression and respiratory function in patients with C9orf72-related ALS, we are very pleased these data were accepted for presentation at NEALS," said Andrew Satlin, M.D., Chief Medical Officer at Transposon. "Based on these promising results, we are advancing TPN-101 into a Phase 3 registration study for the treatment of C9orf72-related ALS, while also continuing to develop TPN-101 for other neurodegenerative diseases." Oral presentation details The poster will also be on view during Poster Session 2 on Wednesday, October 23, 2024, from 4:00 to 6:00 pm EDT. For more information, please visit the 2024 Annual NEALS Meeting website. About the Phase 2 Study in C9orf72-related ALS/FTD The Phase 2 study in patients with C9orf72-related ALS/FTD was a multi-center, randomized, double-blind, placebo-controlled parallel-group, two-arm study with an open-label treatment period. Participants (n=42) were randomized 3:2 to receive daily doses of 400 mg of TPN-101 or placebo. The study included a six-week screening period, a 24-week double-blind treatment period, a 24-week open-label treatment period, and a follow-up visit four weeks post-treatment. Further information on the study can be accessed at ClinicalTrials.gov. About TPN-101 TPN-101 specifically inhibits the LINE-1 reverse transcriptase that promotes LINE-1 replication. LINE-1 elements are a class of retrotransposable elements that in humans are uniquely capable of replicating and moving to new locations within the genome. When this process becomes dysregulated, LINE-1 reverse transcriptase drives overproduction of LINE-1 cDNA, triggering innate immune responses that contribute to neurodegenerative, neuroinflammatory, and aging-related disease pathology. About ALS and FTD ALS is a neurodegenerative disease characterized by progressive muscle weakness, and loss of ability to speak, eat, move or breathe. FTD is a progressive frontal/temporal cortex disease associated with behavior and personality changes, emotional problems, and difficulty walking, communicating, or working. A C9orf72 hexanucleotide repeat mutation accounts for 10-15% of both disorders. With onset commonly in middle age or earlier, patients with ALS have a mean survival of two to three years. Patients with FTD have a mean survival of nine years. About Transposon Transposon Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing a platform of novel therapies for the treatment of neurodegenerative and aging-related diseases, including Alzheimer's disease. The company's lead clinical compound, TPN-101, is first-in-class to address LINE-1 reverse transcriptase for treating neurodegenerative and autoimmune diseases. The company also has a discovery platform supporting a deep pipeline of novel therapies to address additional indications. Contact: Rick Orr Transposon Therapeutics, Inc. (858) 535-4821 [email protected] SOURCE Transposon Therapeutics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Grant to support the in vivo development of first-in-class condensate-modifying drugs (c-mods) targeting the TDP-43 condensatopathy in ALS BOSTON, Aug. 26, 2024 (GLOBE NEWSWIRE) -- Dewpoint Therapeutics Inc., the leading biotechnology company that develops therapeutics by targeting biomolecular condensates, announced today that it was awarded for the second time a Target ALS Foundation grant to validate its leading condensate-modifying compound (c-mod) in a mouse model of slow-progressing amyotrophic lateral sclerosis (ALS). This in-kind grant is a collaboration with Biospective contract research organization. Today, there are no disease-modifying therapeutic options for the ~ 20,000 patients that suffer from ALS in the US. The lack of efficacious drugs is reflected in the poor life expectancy of patients, at 2-5 years post diagnosis. Dewpoint is approaching ALS drug discovery and development from a new angle, by taking advantage of a pathology-driving aberration shared by over 97% of all patients – the wrongful localization of the protein TDP-43 from the nucleus to membrane-less cytoplasmic bodies, called biomolecular condensates. The TDP-43 mislocalization causes loss of TDP-43 splicing function and gain of toxic function caused by aberrant localization of other proteins into the TDP-43 cytoplasmic condensates. Together, these lead to systemic defects and the complex pathophysiology of ALS. Dewpoint’s lead c-mod was discovered through a high-content, high throughput approach that selected compounds that dissolve the aberrant TDP-43 condensates. Repairing the disease-driving aberrant condensate (condensatopathy), also repairs systemic TDP-43 loss of function and restores neuronal health, as well as clinically relevant ALS biomarkers in animal models. The slow-progressing ALS NLS8 mouse model offered by Biospective and Target ALS recapitulates the TDP-43 cytoplasmic mislocalization, neurodegeneration and motor deficit phenotypes experienced by patients. Validation of Dewpoint’s c-mod into the NLS8 model will complement the existing data package, and the ongoing work in a C9orf72 mouse model, supported through another grant awarded by Target ALS, to better understand the efficacy, safety and mechanism of action of this pre-clinical candidate. "Target ALS is thrilled to have the opportunity to help advance Dewpoint's mission to deliver a novel, effective treatment to ALS patients. Their molecule will be one of the first to test a central hypothesis regarding the role of TDP-43 in motor neuron degeneration and may have the potential to treat both sporadic and familial forms of ALS," said Dr. Amy Easton, Senior Director of Scientific Programs at Target ALS. “We are excited to expand our partnership with Target ALS and are appreciative of the foundation’s transformational effort to bring the academic and biotech communities together. This alliance will accelerate the path to the clinic for Dewpoint’s revolutionary TDP-43 condensatopathy-targeted c-mod, which we believe holds great promise for patients,” said Isaac Klein, MD PhD, CSO of Dewpoint Therapeutics. ABOUT CONDENSATES Condensates are membraneless organelles that form dynamically throughout the cell via a process called phase separation. These subcellular compartments organize and concentrate molecules within cells to enable a diversity of key biochemical processes. The dysregulation of biomolecular condensates has been observed in many diseases, including cancer, diabetes, and neurological disorders. Condensate-modifying drugs (c-mods) potentially provide novel therapeutic options for complex diseases and historically undruggable targets. ABOUT DEWPOINT THERAPEUTICS Dewpoint is the leading biotech company in the application of biomolecular condensate biology towards the development of a new generation of therapeutics to address diseases of high unmet need. The realization that a vast range of conditions are regulated by or arise from the dysfunction of condensates has provided new possibilities for modulating the function of high-value targets previously deemed ‘undruggable,' opening unexplored avenues to identify hundreds of novel therapeutic targets. Dewpoint’s proprietary AI/ML-powered state-of-the-art platform underlies a drug discovery pipeline that spans multiple therapeutic areas, including oncology, neurodegenerative, cardiopulmonary, and metabolic diseases. Through collaborations with Bayer, Novo Nordisk and Evotec, Dewpoint pushes the boundaries to accelerate the translation of condensate biology into medicine for patients suffering from difficult to treat diseases. Learn more at Dewpointx.com and follow us on X and LinkedIn. ABOUT TARGET ALS Target ALS is a 501(c)(3) medical research foundation committed to the search for effective treatments for Amyotrophic Lateral Sclerosis (ALS). Founded in 2013 by former New York City deputy mayor Dan Doctoroff — who lost both his father and uncle to ALS and was himself diagnosed in 2021 – Target ALS has transformed ALS research through their landmark Innovation Ecosystem model. The organization has fostered unprecedented collaborations between academia and the pharma and biotech industry, lowered barriers to access for critical research tools, and become a hub of communication and networking for the worldwide scientific community, resulting in the launch of 7 clinical trials and several drug discovery programs over the last decade. Building upon this momentum, Target ALS launched a groundbreaking Seven Pillar Strategy that will expand the breadth and depth of their ecosystem to accelerate ALS drug discovery with the goal of realizing a world where Everyone Lives. For more information and to get involved, visit www.targetals.org. Media contact: media@dewpointx.com Investor contact: Michael Fenn, Ph.D.Head of External Innovation & Investor Relations mfenn@dewpointx.com