DYNE-101

– Continued favorable safety profile for DYNE-251 – – DELIVER Registrational Expansion Cohort is fully enrolled; data from this cohort planned for late 2025 – – Potential for Biologics License Application submission for U.S. accelerated approval in early 2026 – WALTHAM, MA, USA I March 16, 2025 I Dyne Therapeutics, Inc . (Nasdaq: DYN), a clinical-stage company focused on advancing life-transforming therapeutics for people living with genetically driven neuromuscular diseases, today announced new long-term clinical data from its ongoing Phase 1/2 DELIVER trial of DYNE-251 demonstrating unprecedented and sustained functional improvement at the selected registrational dose of 20 mg/kg Q4W (approximate PMO dose). The DELIVER trial is evaluating DYNE-251 in individuals with Duchenne muscular dystrophy (DMD) who are amenable to exon 51 skipping, and updated results from the trial are being presented this week at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference. “With Dyne-251, we have the opportunity to deliver a durable and redosable therapy demonstrating clinically meaningful and sustained functional improvement in DMD. The consistency of these new data across multiple endpoints and timepoints underscores the potential of DYNE-251 to meaningfully address the significant unmet need in Duchenne despite available therapies,” said John Cox, president and chief executive officer of Dyne. “We are rapidly advancing DYNE-251 toward a readout later this year with the potential to submit for U.S. accelerated approval in early 2026 based on a well-established regulatory pathway leveraging dystrophin expression as a surrogate endpoint. If approved, we believe there is an opportunity for rapid adoption by physicians and currently treated patients, as well as those naïve to therapy.” “I am very encouraged by these new, long-term data for DYNE-251 in the exon 51 skip amenable population and the promise of sustained functional improvement which has continued to elude the DMD community,” said Pat Furlong, founder and president of Parent Project Muscular Dystrophy. “The investment and innovation in DMD are delivering, and this is a prime example of how the accelerated approval pathway may swiftly enable a new generation of therapies that address unmet and urgent medical needs.” “The amount of expression of near-full length dystrophin induced by DYNE-251 has not been previously seen with exon 51 skipping agents and is associated with evidence for clinical efficacy,” said Kevin Flanigan M.D., Director, Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children’s Hospital. “I look forward to the opportunity to present new functional data and updated safety data at the 2025 MDA Clinical & Scientific Conference.” This updated assessment of the DELIVER trial evaluating DYNE-251 includes new functional data out to 12 months from 6 patients enrolled in the 20 mg/kg Q4W cohort, and 18-month functional data from 6 patients in the 10 mg/kg Q4W cohort (these participants began transitioning to the 20 mg/kg Q4W regimen after month 6). In addition, updated safety data as of February 7, 2025, continue to demonstrate a favorable safety profile for DYNE-251. Key findings from the DELIVER Phase 1/2 trial presentation include: Key Milestones for the DELIVER Trial Dyne Presentations at the 2025 MDA Clinical & Scientific Conference The new assessment of the DELIVER trial is being presented in an oral presentation “Safety and Efficacy from the Ongoing Phase 1/2 DELIVER Trial of DYNE-251 in Males with DMD Mutations Amenable to Exon 51 Skipping” on Wednesday, March 19, at 8:30-8:45 a.m. CT by Kevin Flanigan, M.D., Director, Center for Gene Therapy, Abigail Wexner Research Institute of Nationwide Children’s Hospital in Columbus, Ohio and Principal Investigator for the DELIVER Trial. A poster with the same title will be available starting at 6:00 p.m. CT Sunday, March 16, 2025, through Tuesday, March 18, 2025, in the conference exhibit hall. Both the oral presentation and poster are now available in the Scientific Publications & Presentations section of Dyne’s website, along with several other posters and presentations including an encore presentation of the most recent positive results for DYNE-101 from the Phase 1/2 ACHIEVE trial in myotonic dystrophy type 1 (DM1). About the DELIVER Trial DELIVER is a randomized, placebo-controlled, double-blind, Phase 1/2 clinical trial evaluating the safety, tolerability and efficacy of DYNE-251 in patients with Duchenne muscular dystrophy (DMD) who are amenable to exon 51 skipping. The multiple ascending dose (MAD) portion of the study resulted in the selection of a registrational dose and regimen of 20 mg/kg every four weeks. A registrational expansion cohort to support potential regulatory submissions for expediated approvals, including accelerated approval in the U.S., is fully enrolled. The primary endpoint for this cohort is the change from baseline in dystrophin protein levels as measured by Western blot. For more information on the DELIVER trial, visit clinicaltrials.gov (NCT05524883) and euclinicaltrials.eu (2023-510351-31-00). About DYNE-251 DYNE-251 is an investigational therapeutic being evaluated in the Phase 1/2 global DELIVER clinical trial for people living with DMD who are amenable to exon 51 skipping. DYNE-251 consists of a phosphorodiamidate morpholino oligomer (PMO) conjugated to a fragment antibody (Fab) that binds to the transferrin receptor 1 (TfR1) which is highly expressed on muscle. It is designed to enable targeted muscle tissue delivery and promote exon skipping in the nucleus, allowing muscle cells to create internally shortened, near full-length dystrophin protein, with the goal of stopping or reversing disease progression. DYNE-251 has been granted fast track, orphan drug and rare pediatric disease designations by the U.S. Food and Drug Administration for the treatment of DMD mutations amenable to exon 51 skipping. In addition to DYNE-251, Dyne is building a global DMD franchise and has preclinical programs targeting other exons, including 53, 45 and 44. About Duchenne Muscular Dystrophy (DMD) DMD is a rare disease caused by mutations in the gene that encodes for dystrophin, a protein critical for the normal function of muscle cells. These mutations, the majority of which are deletions, result in the lack of dystrophin protein and progressive loss of muscle function. DMD occurs primarily in males and affects an estimated 12,000 to 15,000 individuals in the U.S. and 25,000 in Europe. Loss of strength and function typically first appears in pre-school age boys and worsens as they age. As the disease progresses, the severity of damage to skeletal and cardiac muscle often results in patients experiencing total loss of ambulation by their early teenage years and includes worsening cardiac and respiratory symptoms and loss of upper body function by the later teens. There is no cure for DMD, and currently approved therapies provide limited benefit. About Dyne Therapeutics Dyne Therapeutics is discovering and advancing innovative life-transforming therapeutics for people living with genetically driven neuromuscular diseases. Leveraging the modularity of its FORCE™ platform, Dyne is developing targeted therapeutics that deliver to muscle and the central nervous system (CNS). Dyne has a broad pipeline for neuromuscular diseases, including clinical programs for myotonic dystrophy type 1 (DM1) and Duchenne muscular dystrophy (DMD) and preclinical programs for facioscapulohumeral muscular dystrophy (FSHD) and Pompe disease. For more information, please visit https://www.dyne-tx.com/ , and follow us on X , LinkedIn and Facebook . SOURCE: Dyne Therapeutics

本文转自测序中国公众号 一名7岁罕见病患者，症状为进行性肌无力，肌酸激酶增高，既往各种遗传检测均显示阴性结果。通过全基因组测序（WGS）和转录组测序（RNA-seq）分析，在该患者肌病相关基因和常染色体隐性遗传基因中发现了127个非编码区变异，其中86个变异可以进行剪接识别。此外，在患者的LMNA基因内含子区域发现一个新发26bp深度缺失，导致6号内含子滞留。LMNA基因与多种肌病相关，这些疾病与该患者的表型一致[1]。 这只是测序技术帮助罕见病患者实现精准诊疗的众多案例中的一个。 罕见病由于发病率极低，且临床表现复杂多样，通常诊断困难。传统的临床诊断方法不仅耗时费力，且准确性较低。测序技术作为精准医学的核心支柱，为罕见病的精准诊疗带来了革命性改变，使人们对罕见病分子机制的认知达到了前所未有的深度。基于WGS、RNA-seq等测序技术，研究人员不仅可以提高罕见病的诊断效率和准确性，还能鉴别疾病亚型，指导个性化治疗和预后评估，并推动药物研发进展。 罕见病诊断中的测序策略 上述案例中使用了WGS和RNA-seq，是罕见病诊疗中常用的测序策略，此外还包括全外显子测序（WES）、靶向测序、单细胞测序等。不同测序策略的靶标区域、类型和适用场景各不相同，本文将着重探讨WGS和RNA-seq在罕见病诊疗中的应用。 01 WES：有效诊断罕见病，但仍存在局限性 WES是对编码序列的外显子区域进行测序，是临床中应用较多的罕见病诊断手段，在已知致病基因变异和新致病基因挖掘方面均发挥着重要作用。目前WES的平均罕见病诊断率约在25%-50%[2]。但WES很难检测结构变异（SV）、重复扩增和深度内含子区变异等，导致很多通过其他方法诊断（肌肉活检、代谢检测等）的案例无法得到明确分子诊断。 02 WGS：提高罕见病诊断率，做为一线检测具成本效益 理论上，WGS能够检测基因组的所有潜在变异，包括单核苷酸多态性（SNP）、插入缺失（Indel）和SV。基于目前的回顾性研究分析，WGS的诊断率在19.1%-68.3%之间[3]。一项荟萃分析显示，在罕见病患者的基因检测中，WGS诊断率比WES高1.2倍，WGS发现了更多的新基因，且临床效用高于WES[4]。 2021年10月，BMJ期刊报道了第一次在国民医疗服务体系（NHS）中验证WGS的罕见病诊断有效性的结果[5]。通过对疑似线粒体疾病患者的外周血DNA进行WGS分析（Illumina TruSeq、HiSeq 2500和HiSeq X），31%获得了明确或可能的基因诊断，证实WGS在疑似线粒体病患者中是一种有用的诊断方法。 图：NHS研究分析概述和诊断信息。来源：BMJ 英国国家医疗系统13,037名参与者（9802人患有罕见病）的WGS分析（Illumina TruSeq，HiSeq2500）结果显示[6]，WGS为1138名广泛表型参与者提供了遗传诊断，并发现了4种新的非编码变异，证实在常规医疗保健中，使用WGS可以简化诊断并发现基因组编码区和非编码区未知的致病变异。 图：英国国家医疗系统研究概述。来源：Nature 在临床中，除了诊断率外，成本效益也是需要考虑的重要因素。WGS、WES与常规标准检测在疑似罕见遗传病儿童中的成本效益评估结果显示，与WES和标准检测相比，将WGS作为一线诊断检测更具成本效益[7]。 03 RNA-seq：WES/WGS的有效补充手段 对于部分无法确诊的患者，RNA-seq可以作为WES/WGS的有效补充手段，快速准确地进行基因表达量的测定，识别未知转录本、SV、可变剪接、基因融合等，从而得到全面的遗传信息，可提高罕见病诊断率和发现新候选基因。RNA-seq在许多肌病及线粒体疾病中已有许多成功应用案例。 例如，在一项将RNA-seq用于罕见病诊断的研究中，利用RNA-seq从遗传学角度诊断罕见肌肉疾病，检测骨骼肌样本RNA，表明RNA-seq能有效鉴别位于外显子区或深内含子区的有害剪接位点变异，总体诊断率可达35%[3]。Yépez, V.A.等利用皮肤成纤维细胞RNA-seq，帮助205例WES未诊断的病例中16%（32例）的患者获得了诊断[2]。 图：RNA-seq在孟德尔遗传病诊断中的临床应用。来源：Genome Med 在临床环境下，部分患者的疾病相关组织（如肌肉活检）和成纤维细胞都较难获得，这限制了组织特异性RNA-seq的应用范围。因此，基于外周血的RNA-seq在样本获取受限的未诊断罕见病患者的遗传诊断中得以广泛探索。 Frésard等评估了血液RNA-seq作为罕见疾病诊断手段的效用[8]。血液RNA-seq在6例未诊断患者（7.5%）中识别并验证了致病基因，提高了16.7%患者候选基因的诊断效力。值得注意的是，对于神经系统相关疾病，虽然血液并不是代表性的组织样本，但RNA-seq仍在5例神经系统异常患者发现了候选基因。此外，基于血液的bulk-RNA-seq能够评估71%的意义不明变异（VUS），对于DNA测序中没有候选VUS的患者或候选VUS不影响剪接的患者，SpliceAI（Illumina）联合RNA-seq还可检测到新的发育障碍相关候选基因[9]。 图：利用血液RNA-seq分析罕见病基因。来源：Natrue Medicine 04 WGS+RNA-seq：助力罕见病诊断更上一层楼 在实际临床应用中，需要综合考虑患者的临床表现、家族遗传史、检测成本、时间等因素来选择合适的测序策略。对于疑难复杂的罕见病，可能需要多种测序策略的联合应用。近年来，许多团队在尝试WGS与RNA-seq联合应用，以获得不同程度的分子诊断率提高。 Genetics in Medcine报道了WGS联合RNA-seq的测序策略在罕见孟德尔遗传病诊断中的临床应用[1]。研究显示，WGS联合RNA-seq可以将阳性诊断率从31%提高到38%，同时RNA-seq帮助18%的病例提高了致病性证据等级。 图：WGS联合RNA-seq检测到SEPSECS外显子跳跃。来源：Genetics in Medcine 罕见病治疗及药物开发中的测序应用 2019年，顶级医学期刊NEJM发文报道了罕见病患者Mila Makovec经WGS和RNA-seq成功找到致病基因突变[10]。研究团队基于该突变快速研发靶向药物，使Mila得到了有效治疗。 Mila患有致命性的极罕见Batten病。美国波士顿儿童医院团队利用trio WGS，发现在CLN7基因内，Mila及其母亲同时携带一个特殊的插入序列SVA（SINE - VNTR - Alu）结构，并通过RNA-seq证实SVA结构会干扰正常的基因剪接功能。基于此，研究团队研发了一款针对Mila特定突变的新药“milasen”，并经过了临床试验和FDA的批准。经过一年的milasen治疗，Mila的症状得到明显改善，且没有不良反应发生。 图：Mila的基因诊断，来源：NEJM 在Mila的诊疗案例中，药物研发在WGS和RNA-seq的帮助下加速进行。传统的药物研发过程需要进行大量的试验和筛选，耗时费力，而且成功率较低。测序技术的进步打破了传统药物研发过程中的技术瓶颈，不仅可以快速找到药物靶点，还能筛选适合某种药物治疗的患者亚群，监测药物不良反应，降低成本，提高研发成功率。 总体而言，测序技术主要从以下几个方面促进罕见病药物研发： 01 药物靶点发现与筛选应用： 测序技术可以对罕见病相关基因进行全面分析，帮助研究人员发现新的药物靶点并进行筛选，以及探索药物与基因之间的作用关系，进而开发出更加精准、高效的药物治疗方案。PCSK9抑制剂是展示基因测序促进药物研发的经典案例。2003年，研究人员利用基因测序在家族性高胆固醇血症患者的PCSK9基因中发现了功能获得性突变[11]。12年后，美国FDA年批准了第一个PCSK9抑制剂Evolocumab，用于家族性高胆固醇血症的治疗。 02 临床前研究应用： 传统的罕见病药物临床前评估所需时间和成本过高，测序技术可帮助快速识别生物标记物、阐明药物的作用机制或耐药性，加速体外细胞实验和动物模型实验，验证药物的有效性和安全性。例如利用罕见病患者来源的类器官模型评估个性化反义寡核苷酸（ASO）疗法。在针对两位DMD患者的个性化ASO设计和类器官检测分析中，RNA-seq确认了剪接恢复正常[12]。 03 临床试验应用： 测序技术还可用于优化临床试验设计，提高罕见病药物研发效率和成功率。在测序技术的帮助下，研发人员可以筛选出适合某种治疗方案的患者亚群，并预测可能出现的副作用。此外，测序技术还可以帮助识别患者分层的生物标记物、监测药物反应和疾病进展。在抗体偶联寡核苷酸疗法DYNE-101治疗1型肌强直性营养不良（DM1）的临床试验中，利用RNA-seq发现接受DYNE-101治疗患者的DMPK基因RNA水平显著下降[13]。  展 望  目前，罕见病诊疗仍面临着诸多挑战。随着测序技术的不断发展，相信罕见病的精准诊断能力将进一步提升，相关药物研究也将取得突飞猛进的发展。据不完全统计，仅2024年，全球批准了近200个罕见病药或新适应症[14]，中国全年批准罕见病药39个，覆盖34种罕见病[15]。 除本文探讨的WGS和RNA-seq外，其它测序及分析技术对促进罕见病诊疗和药物研发也有巨大的潜力。长读长测序技术可以克服短读长测序在检测复杂SV方面的局限性；多组学分析可将基因组学、转录组学、蛋白质组学、代谢组学等结合，获得更全面的疾病信息。人工智能技术可以帮助提高测序数据的挖掘分析和解读效率，减少漏诊和假阳性。此外，研究机构与企业、医疗机构之间的合作，可通过共享数据和专业知识，使整个研究过程更加协同高效。期望未来能有更多罕见病患者获得有效治疗，改善预后。 参考资料（上下滑动查看） [1] Hane Lee, PhD, Alden Y. Huang, PhD, Lee-kai Wang, et al. Diagnostic utility of transcriptome sequencing for rare Mendelian diseases. Genetics in Medcine, Volume 22, Issue 3, March 2020, Pages 490-499. https://doi.org/10.1038/s41436-019-0672-1 [2] Yépez, V.A., Gusic, M., Kopajtich, R. et al. Clinical implementation of RNA sequencing for Mendelian disease diagnostics. Genome Med 14, 38 (2022). https://doi.org/10.1186/s13073-022-01019-9 [3] Jaramillo Oquendo, C., Wai, H.A., Rich, W.I. et al. Identification of diagnostic candidates in Mendelian disorders using an RNA sequencing-centric approach. Genome Med, 2024 Sep 9; 16;  https://doi.org/10.1186/s13073-024-01381-w [4] Claudia Ching Yan Chung,Shirley Pik Ying Hue, Nicole Ying Ting Ng, et al. Meta-analysis of the diagnostic and clinical utility of exome and genome sequencing in pediatric and adult patients with rare diseases across diverse populations. Genetics in Medicine, 13 May 2023. https://www.gimjournal.org/article/S1098-3600(23)00909-7/pdf [5] Katherine R Schon, Wei Wei, Arianna Tucci, et al. Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study. BMJ 2021; 375 doi: https://doi.org/10.1136/bmj-2021-066288 [6]Turro, E., Astle, W.J., Megy, K. et al. Whole-genome sequencing of patients with rare diseases in a national health system. Nature 583, 96–102 (2020). https://doi.org/10.1038/s41586-020-2434-2 [7] Mario Cesare Nurchis, Francesca Clementina Radio, Luca Salmasi, et al. Cost-Effectiveness of Whole-Genome vs Whole-Exome Sequencing Among Children With Suspected Genetic Disorders. JAMA Netw Open. 2024;7(1):e2353514. doi:10.1001/jamanetworkopen.2023.53514 [8]Frésard, L., Smail, C., Ferraro, N.M. et al. Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts. Nat Med 25, 911–919 (2019). https://doi.org/10.1038/s41591-019-0457-8 [9] Jaramillo Oquendo, C., Wai, H.A., Rich, W.I. et al. Identification of diagnostic candidates in Mendelian disorders using an RNA sequencing-centric approach. Genome Med, 2024 Sep 9; 16;  https://doi.org/10.1186/s13073-024-01381-w [10] Kim J, Hu C, Moufawad El Achkar C, et al. Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. N Engl J Med. 2019; 381(17): 1644-1652. doi:10.1056/NEJMoa1813279 https://www.nejm.org/doi/full/10.1056/NEJMoa1813279 [11] Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet, 2003, 34(2): 154-156. [12] Means, J.C., Martinez-Bengochea, A.L., Louiselle, D.A. et al. Rapid and scalable personalized ASO screening in patient-derived organoids. Nature (2025). https://doi.org/10.1038/s41586-024-08462-1 [13] https://mp.weixin.qq.com/s/7qLN49y-rOlbADypHKYoPA [14] https://mp.weixin.qq.com/s/qkNzZYLAWPOIBq_N0d-VqA [15] https://mp.weixin.qq.com/s/vhnsiVRswEudAJzhKe4ozw .