UNC13A

撰文丨王聪 RNA结合蛋白TDP-43的功能丧失（TDP-LOF）是肌萎缩侧索硬化症（ALS，也叫做渐冻症）和额颞叶痴呆（FTD）等神经退行性疾病的标志性特征，因此，被认为是一个有希望的治疗靶点。 TDP-43在调控mRNA剪接过程中发关键作用，保护转录组免受有毒的“隐秘外显子”（Cryptic Exon，CE）的影响，这些隐秘外显子在健康细胞中很少被检测到，但在TDP-43缺失时会明显表达。隐秘外显子通常会在转录本中引入提前终止密码子（PTC），从而阻止包括STMN2和UNC13A在内的关键蛋白质的表达。 之前的研究显示，对单个特定的隐秘外显子进行基因调节可以影响疾病的进展，许多临床前研究旨在减少与TDP-43相关的毒性，例如通过使用反义寡核苷酸（ASO）或转基因技术阻止隐秘外显子表达或通过直接靶向TDP-43的聚集过程。 将基因疗法应用于临床的主要障碍是缺乏有效调控转基因表达的方法。在神经退行性疾病患者中，只有一小部分运动神经元会在任何特定时间显示出明显的病理变化。因此，传统的靶向策略（例如将靶向中枢神经系统的AAV血清型与神经元特异性启动子结合）会导致大量非退行性细胞表达治疗转基因。这种表达不仅没有必要，反而会通过干扰原本健康细胞的正常功能，从而而恶化病情，尤其是考虑到这些基因方法往往具有持久性。 因此，开发一种能够在病变细胞中特异性表达治疗性蛋白质的系统，将是革命性的，这将极大地提高基因疗法的安全性，并有可能实现在发病前的预防性治疗。 2024年10月3日，伦敦大学学院的研究人员在国际顶尖学术期刊 Science 上发表了题为：Creation of de novo cryptic splicing for ALS and FTD precision medicine 的研究论文。 该研究开发了一种名为TDP-REG的精准医学方法，利用细胞中TDP-43功能丧失（TDP-LOF）时发生的隐秘剪接事件，以在病变细胞中特异性表达，用于治疗肌萎缩侧索硬化症（ALS）和额颞痴呆症（FTD）。 在这项最新研究中，研究团队基于对TDP-43剪接调控的理解，以及基于深度学习的剪接预测工具，开发了一种具有新型隐秘剪接位点的基因治疗载体。 该研究开发了一种针对肌萎缩侧索硬化症（ALS）和额颞痴呆症（FTD）的精准医学方法——TDP-REG，利用细胞中TDP-43功能丧失（TDP-LOF）时发生的隐秘剪接事件，以在病变细胞中特异性表达。 TDP-REGv1——通过调控上游隐秘外显子控制下游转基因表达 除了对现有的隐秘外显子进行修改以达到上述目的外，研究团队还开发了一种基于深度学习（Deep Learning）的算法，用于生成可定制的隐秘剪接事件，这些事件可以嵌入任何编码序列中。 TDP-REGv2——人工智能指导的新型隐秘剪接事件设计 通过将部分编码序列置于一个新型隐秘外显子中，可以将蛋白质表达与TDP-LOF紧密耦合。在体外和体内实验中，TDP-43功能丧失（TDP-LOF）激活了蛋白质表达，包括由细胞质中TDP-43聚集引起的TDP-LOF。这种方法限制了治疗性转基因在有TDP-LOF的细胞中表达，这与患者的TDP-43聚集同时发生，因此大大降低了脱靶副作用的风险。 除了产生各种荧光和磷光报告分子外，研究团队还利用该系统进行TDP-LOF依赖的先导编辑（Prime Editing），以消除UNC13A秘供体剪接位点。此外，研究团队设计了一组编码TDP-43/Raver1融合蛋白的严格门控、自动调节载体，以挽救关键的病理性隐秘剪接事件。 除了在体外和体内证明了TDP-REG高效的TDP-LOF依赖性表达，研究团队还将这种方法应用于肌萎缩侧索硬化症（ALS）和额颞痴呆症（FTD）的治疗，为这些毁灭性疾病的更安全、更有效的治疗铺平了道路。 总的来说，该研究将深度学习与理性设计相结合，创造出复杂的剪接传感器，从而构建了一个平台，为神经退行性疾病提供了更安全的治疗方法，甚至可能实现对高风险个体的预防性治疗。 论文链接： https://www-science-org.libproxy1.nus.edu.sg/doi/10.1126/science.adk2539 快讯！Victor Ambros教授和Gary Ruvkun教授凭microRNA研究成果荣获2024年诺贝尔生理学或医学奖 这些诺奖得主，竟然也是成功的连续创业家！ 一家临床前、老靶点biotech初创公司要IPO了！原来创始人是诺贝尔奖得主 点击查看更多精彩！

PASADENA, Calif., Sept. 3, 2024 /PRNewswire/ -- AcuraStem, a patient-based biotechnology company advancing treatments for amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative diseases, announced today that it has successfully secured $4 million in grant funding from the California Institute for Regenerative Medicine (CIRM). Continue Reading This latest funding will specifically support AcuraStem's continued efforts to advance its targeted therapeutic program for the UNC13A gene, using its iNeuroRx® technology platform. iNeuroRx® has been instrumental in the company's development of targeted therapeutics focused on the UNC13A gene, which plays a crucial role in the pathophysiology of ALS and FTD. "This funding will enable us to leverage our advances to help revolutionize the treatment landscape for ALS and FTD." Post this An overwhelming majority of ALS cases, and roughly half of FTD cases, are characterized by TDP-43 pathology. TDP-43, an RNA-binding protein typically found in the nucleus, is mislocalized to the cytoplasm in affected neurons, leading to RNA processing errors. These errors result in the incorporation of a cryptic exon into the UNC13A messenger RNA, causing a loss of UNC13A protein. This loss is further exacerbated by a risk variant in the UNC13A gene, closely linked to the TDP-43 binding site and associated with reduced survival in ALS and FTD patients. AcuraStem's iNeuroRx® platform has successfully replicated UNC13A pathology in patient neurons, enabling the rapid development and testing of antisense oligonucleotides (ASOs). These ASOs effectively suppress the cryptic exon and restore normal UNC13A function, offering a promising therapeutic approach for TDP-43 proteinopathies and a deeper understanding of UNC13A's role in disease progression. "The support from CIRM is a testament to the potential of our research and its capacity to address critical challenges in neurodegenerative disease treatment," said Sam Alworth, MS, MBA, co-founder and CEO of AcuraStem. "This funding will facilitate the development of our UNC13A program toward clinical trials, enabling us to leverage our advances to potentially revolutionize the treatment landscape for ALS and FTD." Funding from CIRM was awarded following a highly competitive and rigorous peer-review process, reflecting the strength of AcuraStem's research and potential impact on the treatment of ALS and FTD. For additional information, please visit acurastem.com and follow on LinkedIn, Facebook, and X. About AcuraStem AcuraStem is a patient-based biotechnology company pioneering treatments for neurodegenerative diseases including sporadic ALS and FTD. AcuraStem's best-in-class disease modeling platform, iNeuroRx®, enables the discovery of innovative, effective, and broadly acting treatments. The team's strong expertise in ASO technology provides for the rapid advancement of treatments to the clinic. AcuraStem's research is funded in part by support from the Alzheimer's Drug Discovery Foundation, Harrington Discovery Institute, Alzheimer's Association, Rainwater Charitable Foundation, Department of Defense and the National Institute of Neurological Disorders and Stroke. About the California Institute for Regenerative Medicine (CIRM) At CIRM, we never forget that we were created by the people of California to accelerate stem cell treatments to patients with unmet medical needs, and act with a sense of urgency to succeed in that mission. To meet this challenge, our team of highly trained and experienced professionals actively partners with both academia and industry in a hands-on, entrepreneurial environment to fast track the development of today's most promising stem cell technologies. With $5.5 billion in funding and more than 150 active stem cell programs in our portfolio, CIRM is one of the world's largest institutions dedicated to helping people by bringing the future of cellular medicine closer to reality. Contacts: Kissy Black Director of Communications, AcuraStem [email protected] 615.310.1894 Roxan Olivas Lotos Nile [email protected] 520-954-1634 SOURCE AcuraStem - Patient-Based Therapeutics

HONG KONG, June 12, 2024 /PRNewswire/ -- Even with the ever-changing situation, technological innovation is still the most critical component for biopharmaceutical companies' long-term development. This continuous innovation keeps companies up to date and promotes the evolution of R&D and the success of commercialization. Recently, Viva Biotech's portfolio companies have new updates. Keep reading for more details. VivaVision Forges Strategic Alliance with Renhe Shanliang, and Intitated Their Domestic Phase III Trial for VVN001 On June 6th, World Eye Health Day, a themed event was held in Shanghai. At this grand occasion, guests witnessed the signing of a joint venture agreement between VivaVision, invested and incubated by Viva BioInnovator (VBI), and Jiangxi Shanliang Pharmaceutical Co., Ltd. The two parties will join forces to build a renowned Chinese brand for contact lens care products. Back on March 16th, VivaVision had announced that the initiation meeting for the domestic Phase III clinical trial of VVN001 eye drops - their independently developed dry eye treatment, a LFA-1 antagonist - was successfully convened in Shanghai, marking the official setting sail of the Phase III clinical trial. QurAlis Grants Lilly Exclusive Global License for QRL-204 CAMBRIDGE, Mass., June 3rd, 2024–QurAlis Corporation ("QurAlis"), invested and incubated by Viva BioInnovator (VBI), recently announced that it has entered into an exclusive license agreement with Eli Lilly and Company ("Lilly") in which QurAlis is granting Lilly global rights to develop and commercialize QRL-204, a potentially best-in-class splice-switching antisense oligonucleotide (ASO) designed to restore UNC13A function in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative diseases. Under the terms of the agreement, QurAlis granted Lilly an exclusive, worldwide license to develop and commercialize QRL-204 and other UNC13A-targeting compounds in exchange for an upfront payment of $45 million to QurAlis, plus an additional equity investment. QurAlis is also eligible for future milestone payments of up to $577 million and tiered royalties on net sales. Arthrosi Announces Multiple Presentations at the European League Against Rheumatism (EULAR) Congress 2024 SAN DIEGO, May 30th, 2024 /PRNewswire/ -- Arthrosi Therapeutics, Inc., invested and incubated by Viva BioInnovator (VBI), is a late-stage biotechnology company developing a potentially best-in-class, highly potent and selective next generation URAT1 inhibitor to reduce serum urate levels, flares and Tophi in patients with gout. Recently they announced the acceptance of two presentations, including one poster tour at the European League Against Rheumatism (EULAR) Congress 2024 meeting, being held in Vienna, Austria on June 12-15. Lucy Therapeutics Secures New Funding to Advance New Alzheimer's and Parkinson's Treatments WALTHAM, Mass.--(BUSINESS WIRE)--Lucy Therapeutics, Inc. (LucyTx), incubated and invested by Viva BioInnovator (VBI), announced it has raised $12.5 million in additional funding led by existing investors Engine Ventures and Safar Partners with new participation from Bill Gates, Parkinson's UK, and the Michael J. Fox Foundation, which provided a $2 million non-dilutive grant. The fresh capital brings LucyTx's total funding to date to more than $36 million. The investments will further the company's research programs for Alzheimer's and Parkinson's diseases and continue its development of a novel drug target for Rett syndrome. Technoderma Medicines Initiates Phase 2 Clinical Trial for TDM-180935, a Novel Drug for Atopic Dermatitis/Eczema, and Officially Establishes Presence at Chengdu Tianfu International Bio-Town On April 29th, 2024, Technoderma Medicines Inc., ("Technoderma Medicines"), a clinical-stage biotech company developing innovative drugs that is invested and incubated by Viva BioInnovator (VBI), officially announced the initiation of its Phase 2 clinical trial (NCT 06363461) for TDM-180935, a topical ointment for atopic dermatitis/eczema, with patients beginning treatment. Previously, on April 20th, Thyrologics officially established its presence at the Chengdu Tianfu International Bio-Town. Multipeptide Screening Integrated with Biochips, Unveiling New Strategies of XLEMENT and Healthytide On March 27th, 2024, two leading companies in the biopharmaceutical industry - Hangzhou Healthytide Biotechnology Co., LTD. (hereinafter referred to as "Healthytide") and XLEMENT, which is invested incubated by Viva BioInnovator (VBI), announced a strategic cooperation agreement to jointly advance technological innovation and breakthroughs in the field of peptide drug development. Healthytide brings its single-molecule peptide diversity library to the table, while XLEMENT contributes its innovative and industry-leading biochip technology platform to support the collaboration. About VivaVision Biotech VivaVision is a clinical stage pharmaceutical company focused on best-in-class and first-in-class therapies for ocular diseases. VivaVision's current pipeline includes VVN001 for treating dry eye syndrome, VVN539 for the treatment for Glaucoma or Ocular Hypertension, and VVN461 for the treatment of non-infectious ocular inflammation of Uveitis. VivaVision is also engaged in discovery and development of novel therapies for the treatment of other anterior and posterior eye diseases. For more info, visit . About QurAlis Corporation QurAlis is trailblazing the path to conquering amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases with genetically validated targets with next-generation precision medicines. QurAlis' proprietary platforms and unique biomarkers enable the design and development of drugs that act directly on disease-causing genetic alterations. Founded by an internationally recognized team of neurodegenerative biologists from Harvard Medical School and Harvard University, QurAlis is advancing a deep pipeline of antisense oligonucleotides and small molecule programs including addressing sub-forms of ALS that account for the majority of ALS patients. For more information, please visit or follow us on Twitter @QurAlisCo. About Arthrosi Arthrosi Therapeutics, Inc. was founded in San Diego, CA, in 2018 with a mission to create a revolutionary treatment option to target uric acid levels and reduce joint damage for people living with gout. With its vast therapeutic and treatment knowledge, Arthrosi has accumulated a comprehensive and robust intellectual property portfolio and impressive Phase 1 and Phase 2b data showing industry-leading efficacy rates and superior safety profiles. About Lucy Therapeutics Lucy Therapeutics is a private biotechnology company in Waltham, MA, founded by Amy Ripka, Ph.D., in 2017, dedicated to unraveling the complex and interrelated biological processes driving mitochondrial dysfunction and addressing them to slow and stop the diseases they cause. Sitting at the center of genetics and metabolism, Lucy Therapeutics is leading the change in how we think about mitochondria and the intersecting pathways that play critical roles in human health and disease, particularly those of the central nervous system, including Parkinson's disease and Rett syndrome. For more information, visit lucytherapeutics.com. About Technoderma Medicines Technoderma Medicines, Inc. is a privately held clinical stage biopharmaceutical company. The Company was originally located in Jiaxing Xiuzhou Biomedicine Guoqian Park, China, and recently relocated to Chengdu Biomed Town, Chengdu, Sichuan Province, China. Its current core programs focus on development of innovative therapies for Androgenetic Alopecia, Atopic Dermatitis, Psoriasis and Lupus Erythematosus. Its "first-in-class" small molecule thyromimetic drug candidate TDM-105795 for Androgenetic Alopecia is currently in Phase 2a clinical testing. Technoderma's novel JAK1/TYK2 inhibitor TDM-180935 for Atopic Dermatitis is now in Phase 1 clinical testing. The pipeline targets dermatologic indications. About XLEMENT As an Innovator in the field of biopharmaceutical R&D and health diagnostics, Liangzhun has independently developed and launched the pioneering next-generation ultra-surface plasmon resonance detection "MetaSPR Biochip Technology". SOURCE Viva Biotech Holdings