JCR Pharmaceuticals Co., Ltd.

编者按：近年来，寡核苷酸类药物凭借其直接调控基因表达的独特机制，在中枢神经系统（CNS）疾病治疗领域展现出巨大潜力，受到业内广泛关注。迄今为止，美国FDA已批准多款寡核苷酸药物用于CNS疾病的治疗，如脊髓性肌萎缩症（SMA）和肌萎缩侧索硬化症（ALS），显著改善了众多患者的生活质量。然而，寡核苷酸药物在CNS疾病领域的开发依然面临诸多挑战，其中，如何高效穿越血脑屏障（BBB）是实现疗效的关键难题，行业正积极探索多种递送策略，以提升寡核苷酸在CNS组织中的递送效率和特异性。为满足全球合作伙伴日益增长的研发需求，药明康德旗下专注于寡核苷酸、多肽及相关化学偶联药物的WuXi TIDES围绕寡核苷酸疗法，建立了化合物合成、工艺开发及生产的一站式服务平台，覆盖从药物发现、CMC开发，到商业化生产的全生命周期，助力全球创新加速落地。本文将聚焦寡核苷酸治疗CNS疾病的机遇和挑战，并介绍药明康德如何通过其平台能力赋能这一前沿疗法的开发。 寡核苷酸药物治疗CNS疾病的主要进展 近年来，寡核苷酸药物在CNS疾病治疗领域取得了诸多突破。寡核苷酸疗法包括siRNA、反义寡核苷酸（ASO）和适配体（aptamer），这类疗法可通过直接调节mRNA水平而非蛋白功能，实现对CNS疾病分子机制的精准干预。 目前，美国FDA已批准两款治疗CNS疾病的寡核苷酸药物：Spinraza（nusinersen）是首款获批用于治疗SMA的疗法，Qalsody（tofersen）则是首个获批用于治疗具有超氧化物歧化酶1突变的肌萎缩侧索硬化（SOD1-ALS）的药物。 除上市产品外，全球范围内多款寡核苷酸药物正在推进临床开发，适应症涵盖ALS、亨廷顿舞蹈症、帕金森病、阿尔茨海默病等多种CNS疾病。一些项目还在尝试个体化治疗策略，开发针对特定突变的“n-of-1”疗法。得益于其高度可编程性和特异性，寡核苷酸药物为传统手段难以触达的疾病开辟了新路径，尤其在神经系统遗传病和罕见病治疗中潜力巨大。 ▲部分处于临床开发阶段，治疗CNS疾病的寡核苷酸疗法（数据来源：公开资料） 挑战与应对：突破血脑屏障的关键策略 尽管寡核苷酸药物在CNS疾病治疗中具有广阔前景，但其临床转化仍受限于难以穿越血脑屏障这一难题。由于分子量大且亲水性强，寡核苷酸难以通过被动扩散进入CNS。目前，多数获批和在研疗法仍依赖鞘内或脑室内注射将药物注入脑脊液中。这些方法虽然能够绕过BBB，但具有侵袭性和潜在的副作用，且给患者接受治疗带来不便。因此，研发人员正在加快开发穿越血脑屏障的非侵入性递送技术。 其中一项备受关注的技术是基于转铁蛋白受体（TfR）介导的靶向递送系统。TfR在脑血管内皮细胞上高度表达，是大脑获取铁元素的重要通道。通过将寡核苷酸与可结合TfR的载体偶联，可利用该机制穿越血脑屏障，实现高效靶向递送。 罗氏医药研究与早期开发（pRED）神经科学及罕见病领域全球负责人Azad Bonni博士在与药明康德的独家对话中表示，基于TfR开发的脑穿梭技术有可能彻底革新脑部药物递送方式，为脑部疾病的治疗开辟全新的可能性。 目前，该技术已经在递送蛋白酶和抗体方面取得了显著进展。2021年，JCR Pharmaceuticals推出的JR-141酶替代疗法成功将艾杜糖醛酸-2-硫酸酯酶（IDS）送入大脑，成为全球首个获批的脑穿梭药物。罗氏基于脑穿梭技术开发的创新抗体分子trontinemab在临床试验中表现出了快速而强大的淀粉样蛋白斑块清除能力，远超传统抗体。 此外，Denali Therapeutics公司基于其TfR递送系统开发的tividenofusp alfa已获得FDA授予的突破性疗法认定和优先审评资格。该公司的研发管线中还包括两款利用这一系统递送的寡核苷酸疗法，用于治疗阿尔茨海默病和帕金森病。已开发多款获批ASO疗法的Ionis Pharmaceuticals公司已与Bicycle Therapeutics展开研发合作，探索TfR靶向双环肽作为创新载体，以提高寡核苷酸的递送效率。 此外，脂质修饰也被广泛研究。通过将寡核苷酸与脂肪酸链偶联，可增强与脑内细胞膜的相互作用，提高穿膜能力。以Alnylam公司为例，其开发的C16脂肪酸偶联平台可以显著提高siRNA药物在CNS组织中的分布和吸收能力。 尽管这些偶联技术提高了寡核苷酸药物CNS递送的效率，但其复杂的化学合成过程为开发带来了重大挑战。WuXi TIDES的寡核苷酸平台针对性地提供从药物发现到商业化生产的一体化CRDMO服务。药物发现阶段的合成服务支持高通量库合成和定制合成，涵盖多种类型的寡核苷酸及其单体、连接子、配体和偶联物，助力合作伙伴快速推进临床前研究。同时，可无缝衔接到工艺开发阶段，放大到从mmol到mol的任何规模，充分满足从临床前、临床到商业化阶段的需求。 新一代递送技术涌现，CNS药物研发迎来复兴 此外，研究人员在不断优化基于转铁蛋白受体的第一代脑穿梭系统的同时，也在积极探索其他天然血脑屏障转运机制，以期实现更广谱、更精准的大脑药物递送。例如，在TfR之外，CD98hc蛋白和γ-分泌酶等与转运相关的蛋白成为开发新一代脑穿梭平台的基础。 在脂质纳米颗粒（LNP）载体系统方面，西奈山伊坎医学院的研究团队今年在Nature Materials上发表论文，通过将BBB穿越模块与脂质分子偶联，合成了72种能够穿越BBB的脂质分子，基于这些分子制备的LNP在动物实验中成功穿越BBB，将mRNA药物递送到大脑中。 ▲穿越BBB的LNP递送技术（图片来源：参考资料[9]） 在该领域，WuXi TIDES的一体化LNP平台提供涵盖脂质发现、制剂和工艺开发、分析开发以及不同规模的生产，可提供具有特定功能脂质（如可电离脂质和聚乙二醇化脂质）以及新型脂质的设计、合成和生产服务。该平台以其稳健的可扩展性和可重复性的新型多通道微混合器为特色，生产规模灵活可控。 CNS药物研发曾因失败率高、作用机制复杂，使众多企业望而却步。如今，随着脑科学基础的积累、成像技术与生物标志物的进步，以及脑穿梭技术的涌现，CNS领域正在快速复兴。今年发表在《自然》期刊上的一篇文章指出，过去六年间，资本和药企纷纷回流CNS赛道，推动行业快速扩张。数据显示，2018年至2023年，全球CNS药物研发管线增长超过30%。罗氏pRED神经科学及罕见病领域全球负责人Azad Bonni博士在与药明康德的独家对话中也表示，他相信神经科学治疗领域正在迈入一个具有实质性进展的新纪元。未来，药明康德将继续依托其一体化、端到端的CRDMO模式，持续赋能合作伙伴包括寡核苷酸在内的CNS药物开发，加速将科学创新转化为惠及全球患者的突破性疗法。 Crossing the Blood-Brain Barrier: Delivery Technologies Fuel CNS Innovation In recent years, oligonucleotide therapeutics have emerged as a promising class of treatments due to their unique ability to directly modulate gene expression. This modality has shown significant potential in addressing central nervous system (CNS) disorders. The U.S. FDA has already approved several oligonucleotide-based drugs for CNS indications, including spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), significantly improving patients’ quality of life. However, the development of oligonucleotide therapies for CNS diseases still faces notable challenges. Chief among them is the difficulty of delivering these molecules efficiently across the blood-brain barrier (BBB)—a critical obstacle for therapeutic efficacy. To address this bottleneck, the biopharmaceutical industry is actively investigating a variety of delivery strategies aimed at improving both specificity and efficiency within CNS tissues. To meet growing global R&D demands, WuXi TIDES, a unique CRDMO platform that is part of WuXi AppTec, has established an integrated service platform around oligonucleotides and conjugates, covering from drug discovery and CMC development to commercial-scale manufacturing. This article explores the opportunities and challenges of using oligonucleotides to treat CNS diseases, and how WuXi AppTec is enabling progress in this frontier area. Major Advances in Oligonucleotide Therapies for CNS Diseases Oligonucleotide therapies have made substantial progress in recent years in the field of CNS disorders. These therapies—including small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and aptamers—enable precise intervention at the mRNA level rather than the protein level, offering a novel approach to modulate disease mechanisms. To date, the FDA has approved two oligonucleotide-based drugs for CNS conditions: Spinraza (nusinersen), the first approved treatment for SMA, and Qalsody (tofersen), the first approved treatment specifically targeting ALS caused by SOD1 mutations. Beyond these approved therapies, a robust pipeline of oligonucleotide candidates is under clinical development worldwide. These programs target a range of neurological conditions, including ALS, Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. Notably, some efforts are advancing personalized “n-of-1” treatments for patients with specific mutations. With their programmability and high specificity, oligonucleotides are breaking new ground in treating diseases long considered undruggable—particularly in the realm of genetic and rare neurological disorders. Challenge and Response: Key Strategies to Overcome the Blood-Brain Barrier Despite their therapeutic promise, oligonucleotides face significant translational hurdles—foremost among them, the inability to efficiently cross the BBB. Due to their large molecular size and strong hydrophilicity, these molecules cannot passively diffuse into the CNS. As a result, most approved and investigational therapies still rely on invasive intrathecal or intraventricular administration to deliver the drug into cerebrospinal fluid. While effective in bypassing the BBB, these approaches are invasive, pose potential safety risks, and may reduce patient compliance. To overcome these limitations, researchers are pursuing non-invasive delivery strategies. Among the most promising is transferrin receptor (TfR)-mediated delivery. TfR is highly expressed on brain endothelial cells and facilitates iron transport into the brain. By conjugating oligonucleotides to ligands that bind TfR, therapies can harness this pathway for efficient BBB penetration and targeted delivery. This strategy has already demonstrated success in delivering macromolecules such as proteins and antibodies. In 2021, the regulatory agency in Japan approved the first enzyme replacement therapy using a brain shuttle system, enabling successful IDS enzyme delivery into the brain. Similarly, brain shuttle-enabled antibody and enzyme replacement therapies have shown impressive results in clinical trials for neurodegenerative diseases and rare diseases.  Multiple companies are expanding the brain shuttle system into oligonucleotide delivery. In 2024, a study published in Science Translational Medicine demonstrated a transferrin receptor-binding molecule that enabled successful delivery of an oligonucleotide across large regions of the brains of mice and macaque monkeys, reducing synthesis of a target protein. Another delivery strategy under active investigation is lipid conjugation. By attaching fatty acid chains to oligonucleotides, researchers can enhance their membrane affinity and transcellular transport, significantly improve oligonucleotide distribution and uptake in CNS tissues. While these conjugation strategies improve delivery, they also introduce new complexities in chemical synthesis. WuXi TIDES offers integrated CRDMO services for oligonucleotides, supporting high-throughput and custom synthesis of various oligo types and their monomers, linkers, ligands, and conjugates. With over 50,000 oligonucleotide compounds produced annually, WuXi TIDES empowers partners to accelerate preclinical research and bring innovative drugs to patients faster.  Next-Generation Delivery Technologies Fuel CNS Innovation While optimizing TfR-based brain shuttle systems remains a priority, researchers are also exploring alternative endogenous BBB transport mechanisms to achieve broader and more precise CNS delivery. New targets such as CD98hc and γ-secretase are being investigated as potential foundations for next-generation shuttle platforms. In parallel, the lipid nanoparticle (LNP) delivery field is evolving rapidly. A 2024 Nature Materials publication by researchers at the Icahn School of Medicine at Mount Sinai described the synthesis of 72 lipid molecules capable of crossing the BBB. By linking BBB-penetrating modules to lipids, these LNPs successfully delivered mRNA into the brain in animal models. WuXi TIDES’ integrated LNP platform offers services spanning lipid design, formulation, process development, analytics, and production at various scales. The large-scale LNP GMP production line features novel multi-channel micro-mixers, which result in high scalability and reproducibility.  Once considered a high-risk field due to complex mechanisms and low success rates, CNS drug development is now experiencing a renaissance. Advances in neuroscience, biomarker technologies, and brain delivery platforms are breathing new life into the field. A recent Nature article reported that from 2018 to 2023, the global CNS drug pipeline grew by over 30%, driven by renewed capital and pharmaceutical interest. Looking ahead, WuXi AppTec will continue to leverage its fully integrated, end-to-end CRDMO model to support the development of CNS therapies—including oligonucleotides—and accelerate the transformation of scientific discoveries into life-changing treatments for patients worldwide. 参考资料（可上下滑动查看） [1] 2025 Annual Shareholders Meeting Corporate Update. Retrieved July 18, 2025, from https://ir.ionis.com/static-files/332c6f45-b685-4337-b066-92da0688e5b6 [2] DNLI CORPORATE PRESENTATION - JUNE 2025. Retrieved July 18, 2025, from https://investors.denalitherapeutics.com/static-files/11aecea4-da13-42bf-a9cf-d58097553fc3 [3] Arrowhead Pharmaceuticals Corporate Presentation. Retrieved July 18, 2025, from https://ir.arrowheadpharma.com/static-files/25007351-232f-400a-bc0e-0fd4e2906fe8 [4] Alnylam R&D Day 2025. Retrieved July 18, 2025, from https://capella.alnylam.com/wp-content/uploads/2025/02/Alnylam-RD-Day-2025.pdf [5] GTX-102 for AS. Retrieved July 21, 2025, from https://www.ultragenyx.com/our-research/pipeline/gtx-102-for-angelman-syndrome/ [6] McCartan et al., (2023). Nucleic acid-based therapeutics for the treatment of central nervous system disorders. Front. Genet., https://doi-org.libproxy1.nus.edu.sg/10.3389/fgene.2023.1250276 [7] Brain drugs can now cross the once impenetrable blood–brain barrier. Retrieved July 22, 2025, from https://www-nature-com.libproxy1.nus.edu.sg/articles/d41586-025-01569-z [8] Wang et al., (2025). Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system. Nature Materials, https://doi-org.libproxy1.nus.edu.sg/10.1038/s41563-024-02114-5 [9] New Lipid Nanoparticle Platform Delivers mRNA to the Brain Through the Blood-Brain Barrier. Retrieved July 23, 2025, from https://www.mountsinai.org/about/newsroom/2025/new-lipid-nanoparticle-platform-delivers-mrna-to-the-brain-through-the-blood-brain-barrier 免责声明：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：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，传递医学新知

编者按：近年来，寡核苷酸类药物凭借其直接调控基因表达的独特机制，在中枢神经系统（CNS）疾病治疗领域展现出巨大潜力，受到业内广泛关注。迄今为止，美国FDA已批准多款寡核苷酸药物用于CNS疾病的治疗，如脊髓性肌萎缩症（SMA）和肌萎缩侧索硬化症（ALS），显著改善了众多患者的生活质量。然而，寡核苷酸药物在CNS疾病领域的开发依然面临诸多挑战，其中，如何高效穿越血脑屏障（BBB）是实现疗效的关键难题，行业正积极探索多种递送策略，以提升寡核苷酸在CNS组织中的递送效率和特异性。为满足全球合作伙伴日益增长的研发需求，药明康德旗下专注于寡核苷酸、多肽及相关化学偶联药物的WuXi TIDES围绕寡核苷酸疗法，建立了化合物合成、工艺开发及生产的一站式服务平台，覆盖从药物发现、CMC开发，到商业化生产的全生命周期，助力全球创新加速落地。本文将聚焦寡核苷酸治疗CNS疾病的机遇和挑战，并介绍药明康德如何通过其平台能力赋能这一前沿疗法的开发。 寡核苷酸药物治疗CNS疾病的主要进展 近年来，寡核苷酸药物在CNS疾病治疗领域取得了诸多突破。寡核苷酸疗法包括siRNA、反义寡核苷酸（ASO）和适配体（aptamer），这类疗法可通过直接调节mRNA水平而非蛋白功能，实现对CNS疾病分子机制的精准干预。 目前，美国FDA已批准两款治疗CNS疾病的寡核苷酸药物：Spinraza（nusinersen）是首款获批用于治疗SMA的疗法，Qalsody（tofersen）则是首个获批用于治疗具有超氧化物歧化酶1突变的肌萎缩侧索硬化（SOD1-ALS）的药物。 除上市产品外，全球范围内多款寡核苷酸药物正在推进临床开发，适应症涵盖ALS、亨廷顿舞蹈症、帕金森病、阿尔茨海默病等多种CNS疾病。一些项目还在尝试个体化治疗策略，开发针对特定突变的“n-of-1”疗法。得益于其高度可编程性和特异性，寡核苷酸药物为传统手段难以触达的疾病开辟了新路径，尤其在神经系统遗传病和罕见病治疗中潜力巨大。 ▲部分处于临床开发阶段，治疗CNS疾病的寡核苷酸疗法（数据来源：公开资料） 挑战与应对：突破血脑屏障的关键策略 尽管寡核苷酸药物在CNS疾病治疗中具有广阔前景，但其临床转化仍受限于难以穿越血脑屏障这一难题。由于分子量大且亲水性强，寡核苷酸难以通过被动扩散进入CNS。目前，多数获批和在研疗法仍依赖鞘内或脑室内注射将药物注入脑脊液中。这些方法虽然能够绕过BBB，但具有侵袭性和潜在的副作用，且给患者接受治疗带来不便。因此，研发人员正在加快开发穿越血脑屏障的非侵入性递送技术。 其中一项备受关注的技术是基于转铁蛋白受体（TfR）介导的靶向递送系统。TfR在脑血管内皮细胞上高度表达，是大脑获取铁元素的重要通道。通过将寡核苷酸与可结合TfR的载体偶联，可利用该机制穿越血脑屏障，实现高效靶向递送。 罗氏医药研究与早期开发（pRED）神经科学及罕见病领域全球负责人Azad Bonni博士在与药明康德的独家对话中表示，基于TfR开发的脑穿梭技术有可能彻底革新脑部药物递送方式，为脑部疾病的治疗开辟全新的可能性。 目前，该技术已经在递送蛋白酶和抗体方面取得了显著进展。2021年，JCR Pharmaceuticals推出的JR-141酶替代疗法成功将艾杜糖醛酸-2-硫酸酯酶（IDS）送入大脑，成为全球首个获批的脑穿梭药物。罗氏基于脑穿梭技术开发的创新抗体分子trontinemab在临床试验中表现出了快速而强大的淀粉样蛋白斑块清除能力，远超传统抗体。 此外，Denali Therapeutics公司基于其TfR递送系统开发的tividenofusp alfa已获得FDA授予的突破性疗法认定和优先审评资格。该公司的研发管线中还包括两款利用这一系统递送的寡核苷酸疗法，用于治疗阿尔茨海默病和帕金森病。已开发多款获批ASO疗法的Ionis Pharmaceuticals公司已与Bicycle Therapeutics展开研发合作，探索TfR靶向双环肽作为创新载体，以提高寡核苷酸的递送效率。 此外，脂质修饰也被广泛研究。通过将寡核苷酸与脂肪酸链偶联，可增强与脑内细胞膜的相互作用，提高穿膜能力。以Alnylam公司为例，其开发的C16脂肪酸偶联平台可以显著提高siRNA药物在CNS组织中的分布和吸收能力。 尽管这些偶联技术提高了寡核苷酸药物CNS递送的效率，但其复杂的化学合成过程为开发带来了重大挑战。WuXi TIDES的寡核苷酸平台针对性地提供从药物发现到商业化生产的一体化CRDMO服务。药物发现阶段的合成服务支持高通量库合成和定制合成，涵盖多种类型的寡核苷酸及其单体、连接子、配体和偶联物，助力合作伙伴快速推进临床前研究。同时，可无缝衔接到工艺开发阶段，放大到从mmol到mol的任何规模，充分满足从临床前、临床到商业化阶段的需求。 新一代递送技术涌现，CNS药物研发迎来复兴 此外，研究人员在不断优化基于转铁蛋白受体的第一代脑穿梭系统的同时，也在积极探索其他天然血脑屏障转运机制，以期实现更广谱、更精准的大脑药物递送。例如，在TfR之外，CD98hc蛋白和γ-分泌酶等与转运相关的蛋白成为开发新一代脑穿梭平台的基础。 在脂质纳米颗粒（LNP）载体系统方面，西奈山伊坎医学院的研究团队今年在Nature Materials上发表论文，通过将BBB穿越模块与脂质分子偶联，合成了72种能够穿越BBB的脂质分子，基于这些分子制备的LNP在动物实验中成功穿越BBB，将mRNA药物递送到大脑中。 ▲穿越BBB的LNP递送技术（图片来源：参考资料[9]） 在该领域，WuXi TIDES的一体化LNP平台提供涵盖脂质发现、制剂和工艺开发、分析开发以及不同规模的生产，可提供具有特定功能脂质（如可电离脂质和聚乙二醇化脂质）以及新型脂质的设计、合成和生产服务。该平台以其稳健的可扩展性和可重复性的新型多通道微混合器为特色，生产规模灵活可控。 CNS药物研发曾因失败率高、作用机制复杂，使众多企业望而却步。如今，随着脑科学基础的积累、成像技术与生物标志物的进步，以及脑穿梭技术的涌现，CNS领域正在快速复兴。今年发表在《自然》期刊上的一篇文章指出，过去六年间，资本和药企纷纷回流CNS赛道，推动行业快速扩张。数据显示，2018年至2023年，全球CNS药物研发管线增长超过30%。罗氏pRED神经科学及罕见病领域全球负责人Azad Bonni博士在与药明康德的独家对话中也表示，他相信神经科学治疗领域正在迈入一个具有实质性进展的新纪元。未来，药明康德将继续依托其一体化、端到端的CRDMO模式，持续赋能合作伙伴包括寡核苷酸在内的CNS药物开发，加速将科学创新转化为惠及全球患者的突破性疗法。 Crossing the Blood-Brain Barrier: Delivery Technologies Fuel CNS Innovation In recent years, oligonucleotide therapeutics have emerged as a promising class of treatments due to their unique ability to directly modulate gene expression. This modality has shown significant potential in addressing central nervous system (CNS) disorders. The U.S. FDA has already approved several oligonucleotide-based drugs for CNS indications, including spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), significantly improving patients’ quality of life. However, the development of oligonucleotide therapies for CNS diseases still faces notable challenges. Chief among them is the difficulty of delivering these molecules efficiently across the blood-brain barrier (BBB)—a critical obstacle for therapeutic efficacy. To address this bottleneck, the biopharmaceutical industry is actively investigating a variety of delivery strategies aimed at improving both specificity and efficiency within CNS tissues. To meet growing global R&D demands, WuXi TIDES, a unique CRDMO platform that is part of WuXi AppTec, has established an integrated service platform around oligonucleotides and conjugates, covering from drug discovery and CMC development to commercial-scale manufacturing. This article explores the opportunities and challenges of using oligonucleotides to treat CNS diseases, and how WuXi AppTec is enabling progress in this frontier area. Major Advances in Oligonucleotide Therapies for CNS Diseases Oligonucleotide therapies have made substantial progress in recent years in the field of CNS disorders. These therapies—including small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and aptamers—enable precise intervention at the mRNA level rather than the protein level, offering a novel approach to modulate disease mechanisms. To date, the FDA has approved two oligonucleotide-based drugs for CNS conditions: Spinraza (nusinersen), the first approved treatment for SMA, and Qalsody (tofersen), the first approved treatment specifically targeting ALS caused by SOD1 mutations. Beyond these approved therapies, a robust pipeline of oligonucleotide candidates is under clinical development worldwide. These programs target a range of neurological conditions, including ALS, Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. Notably, some efforts are advancing personalized “n-of-1” treatments for patients with specific mutations. With their programmability and high specificity, oligonucleotides are breaking new ground in treating diseases long considered undruggable—particularly in the realm of genetic and rare neurological disorders. Challenge and Response: Key Strategies to Overcome the Blood-Brain Barrier Despite their therapeutic promise, oligonucleotides face significant translational hurdles—foremost among them, the inability to efficiently cross the BBB. Due to their large molecular size and strong hydrophilicity, these molecules cannot passively diffuse into the CNS. As a result, most approved and investigational therapies still rely on invasive intrathecal or intraventricular administration to deliver the drug into cerebrospinal fluid. While effective in bypassing the BBB, these approaches are invasive, pose potential safety risks, and may reduce patient compliance. To overcome these limitations, researchers are pursuing non-invasive delivery strategies. Among the most promising is transferrin receptor (TfR)-mediated delivery. TfR is highly expressed on brain endothelial cells and facilitates iron transport into the brain. By conjugating oligonucleotides to ligands that bind TfR, therapies can harness this pathway for efficient BBB penetration and targeted delivery. This strategy has already demonstrated success in delivering macromolecules such as proteins and antibodies. In 2021, the regulatory agency in Japan approved the first enzyme replacement therapy using a brain shuttle system, enabling successful IDS enzyme delivery into the brain. Similarly, brain shuttle-enabled antibody and enzyme replacement therapies have shown impressive results in clinical trials for neurodegenerative diseases and rare diseases.  Multiple companies are expanding the brain shuttle system into oligonucleotide delivery. In 2024, a study published in Science Translational Medicine demonstrated a transferrin receptor-binding molecule that enabled successful delivery of an oligonucleotide across large regions of the brains of mice and macaque monkeys, reducing synthesis of a target protein. Another delivery strategy under active investigation is lipid conjugation. By attaching fatty acid chains to oligonucleotides, researchers can enhance their membrane affinity and transcellular transport, significantly improve oligonucleotide distribution and uptake in CNS tissues. While these conjugation strategies improve delivery, they also introduce new complexities in chemical synthesis. WuXi TIDES offers integrated CRDMO services for oligonucleotides, supporting high-throughput and custom synthesis of various oligo types and their monomers, linkers, ligands, and conjugates. With over 50,000 oligonucleotide compounds produced annually, WuXi TIDES empowers partners to accelerate preclinical research and bring innovative drugs to patients faster.  Next-Generation Delivery Technologies Fuel CNS Innovation While optimizing TfR-based brain shuttle systems remains a priority, researchers are also exploring alternative endogenous BBB transport mechanisms to achieve broader and more precise CNS delivery. New targets such as CD98hc and γ-secretase are being investigated as potential foundations for next-generation shuttle platforms. In parallel, the lipid nanoparticle (LNP) delivery field is evolving rapidly. A 2024 Nature Materials publication by researchers at the Icahn School of Medicine at Mount Sinai described the synthesis of 72 lipid molecules capable of crossing the BBB. By linking BBB-penetrating modules to lipids, these LNPs successfully delivered mRNA into the brain in animal models. WuXi TIDES’ integrated LNP platform offers services spanning lipid design, formulation, process development, analytics, and production at various scales. The large-scale LNP GMP production line features novel multi-channel micro-mixers, which result in high scalability and reproducibility.  Once considered a high-risk field due to complex mechanisms and low success rates, CNS drug development is now experiencing a renaissance. Advances in neuroscience, biomarker technologies, and brain delivery platforms are breathing new life into the field. A recent Nature article reported that from 2018 to 2023, the global CNS drug pipeline grew by over 30%, driven by renewed capital and pharmaceutical interest. Looking ahead, WuXi AppTec will continue to leverage its fully integrated, end-to-end CRDMO model to support the development of CNS therapies—including oligonucleotides—and accelerate the transformation of scientific discoveries into life-changing treatments for patients worldwide. 参考资料： [1] 2025 Annual Shareholders Meeting Corporate Update. Retrieved July 18, 2025, from https://ir.ionis.com/static-files/332c6f45-b685-4337-b066-92da0688e5b6 [2] DNLI CORPORATE PRESENTATION - JUNE 2025. Retrieved July 18, 2025, from https://investors.denalitherapeutics.com/static-files/11aecea4-da13-42bf-a9cf-d58097553fc3 [3] Arrowhead Pharmaceuticals Corporate Presentation. Retrieved July 18, 2025, from https://ir.arrowheadpharma.com/static-files/25007351-232f-400a-bc0e-0fd4e2906fe8 [4] Alnylam R&D Day 2025. Retrieved July 18, 2025, from https://capella.alnylam.com/wp-content/uploads/2025/02/Alnylam-RD-Day-2025.pdf [5] GTX-102 for AS. Retrieved July 21, 2025, from https://www.ultragenyx.com/our-research/pipeline/gtx-102-for-angelman-syndrome/ [6] McCartan et al., (2023). Nucleic acid-based therapeutics for the treatment of central nervous system disorders. Front. Genet., https://doi-org.libproxy1.nus.edu.sg/10.3389/fgene.2023.1250276 [7] Brain drugs can now cross the once impenetrable blood–brain barrier. Retrieved July 22, 2025, from https://www-nature-com.libproxy1.nus.edu.sg/articles/d41586-025-01569-z [8] Wang et al., (2025). Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system. Nature Materials, https://doi-org.libproxy1.nus.edu.sg/10.1038/s41563-024-02114-5 [9] New Lipid Nanoparticle Platform Delivers mRNA to the Brain Through the Blood-Brain Barrier. Retrieved July 23, 2025, from https://www.mountsinai.org/about/newsroom/2025/new-lipid-nanoparticle-platform-delivers-mrna-to-the-brain-through-the-blood-brain-barrier 免责声明：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：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

一般而言，孤儿药常常反映了一个存在未满足需求的空白市场。有些时候甚至会在其中发现一些很“妖”的思路，闻所未闻，让人啧啧称奇，另外由于整个2025年FDA的高层基本处于变动状态，对于一些孤儿药的态度也可能出现变化。本文就将简单介绍2025年以来被FDA授予孤儿药称号的抗体药物，期望能反映未来孤儿药抗体开发的具体思路，当然其中也能看到大量的中国声音。 1.什么？用于神经退行行疾病PD-L1抗体 你没看错，ImmunoBrain公司开发了一款用于神经性退行性疾病的PD-L1抗体IBC-Ab002，早先的临床前研究表明IBC-Ab002能降低Aβ和Tau这两种阿尔兹海默症有毒蛋白。在神经退行性疾病的临床前模型中，抗体的短期外周暴露诱导了中枢神经系统的长期有益变化。 这一药物的特性是半衰期短，能从循环中快速被清除。 IBC-Ab002的发现基于以色列魏茨曼科学研究所哈尔·施瓦茨教授的研究，除了阿尔兹海默症外，公司还打算开发帕金森症的派生疾病PSP，此次被授予孤儿药称号的就是PSP适应症。 2.TNFR2抗体 瑞典公司BioInvent International开发了一款靶向肿瘤坏死因子受体2（TNFR2）的抗体BI-1808，获得孤儿药称号的适应症为T细胞淋巴瘤。目前正在尝试单药和联用K药治疗T细胞淋巴瘤，在实体瘤中也有进行尝试。 去年该药物在T细胞淋巴瘤的II期临床数据不错，出现了CR，值得关注。 3.GSK的PAPP-A抗体 GSK有一款妊娠相关血浆蛋白A（PAPP-A）抗体被授予孤儿药称号，适应症为常染色体显性多囊肾病（ADPKD），ADPKD是一种常见的遗传性肾脏疾病，由PKD1（16号染色体）或PKD2（4号染色体）基因突变引起。PKD1突变占85%-90%，病情更重；PKD2突变占10%-15%，病程较缓。其特征为双肾多发囊肿进行性增大，最终破坏肾功能。 该药物的机制是通过抑制PAPP-A的活性，阻断IGF-1信号通路，减少囊肿生长。艾伯维也在开发相关竞品管线ABBV-CLS-628。 4.拜耳的SEMA3A抗体 拜耳开发了一款SEMA3A抗体，适应症为Alport综合征，Alport综合征又称遗传性肾炎，由COL4A3、COL4A4或COL4A5基因突变引起，导致肾小球基底膜（GBM）中Ⅳ型胶原异常，进而引发血尿、蛋白尿和肾功能衰竭。SEMA3A抗体通过中和SEMA3A，阻断其与受体（如neuropilin-1）的结合，从而抑制下游信号通路的激活。这可能减少足细胞损伤、减轻肾小球炎症和纤维化，从而保护肾功能。 礼邦医药此前开发过同类型竞品AP303，去年就被授予了孤儿药称号。 5.普米斯/BioNtech排面BNT327 在BioNtech收购普米斯后，该公司在不遗余力推进PD-L1/VEGF双抗，获得孤儿药称号的适应症为小细胞肺癌。该药物之前在小细胞肺癌的数据惊艳，已至三期，确实值得关注。 6.TfR人源化抗体 自从人转铁蛋白受体在神经疾病中作为靶点得到大量应用以来，已经有大量公司围绕该靶点开发药物。日本公司JCR Pharmaceuticals开发了一款利用人转铁蛋白受体运输NAGLU酶（α-N-乙酰葡糖胺酶）的疗法。适应症为黏多糖贮积症IIIB型（MPS IIIB），在MPS III中，由NAGLU基因突变导致NAGLU酶缺乏，硫酸肝素在细胞内积累，引发进行性神经退行性病变。因此需要抗体药物运输NAGLU酶穿透血脑屏障到大脑。 7.ROR1 ADC 中美华东开发了一款ROR1-ADC HDM2005，获得孤儿药称号的适应症为套细胞淋巴瘤。同类竞品为默沙东的MK-2140。 8.CD228 ADC 山东博安生物开发了一款CD228 ADC BA1302，目前已获得FDA授予的鳞状非小细胞肺癌和胰腺癌的孤儿药资格认定。这是全球首个获批临床的CD228 ADC。辉瑞此前有展示CD228 ADC PF-08046031的临床前PPT。 9.CEACAM6 ADC 我国台湾地区的Ji Yan Biomedical开发了一款CEACAM6人源化重链抗体药物偶联物（HCAb-ADC） ADC002，毒素为MMAE。适应症为胰腺癌。 10.GPRC5D单抗 赛诺菲开发了一款GPRC5D单抗SAR446523，适应症为多发性骨髓瘤（MM），看来赛诺菲也想在多发性骨髓瘤和强生拼一拼？ 11.TCTP单抗 韩国公司NEX-I开发了一款TCTP单抗（研发代码可能是NXI-101或NXI-201），适应症为肝细胞癌（HCC），该药物可特异性结合肝细胞癌（HCC）细胞表面高表达的TCTP蛋白。 12.MUC1 ADC Xyone Therapeutics开发了一款MUC1 ADC XYA02，适应症为胰腺癌。Payload为Exatecan，采用7B8 Linker。 13.FRα ADC Medicovestor开发了一款FRα ADC MC001，适应症为胰腺癌，Payload使用MMAE。 14.Claudin 18.2 ADC 信达生物的美国子公司Fortvita Biologics获得了Claudin 18.2 ADC IBI34的孤儿药称号，IBI343采用了Fc沉默技术通过突变Fc段减少非特异性免疫反应，降低全身毒性。适应症为胰腺癌，Payload采用Exatecan，如今已经进入III期临床。 15.康宁杰瑞HER2双抗ADC 康宁杰瑞获得了HER2双抗ADC JSKN003在胃癌及胃食管交界癌（GC/GEJC）的孤儿药称号。 16.ALK1和BMPRII双特异性聚集激动剂抗体 Diagonal Therapeutics开发了一款ALK1和BMPRII双特异性聚集激动剂抗体DIAG723，适应症为遗传性出血性毛细血管扩张症，通过同时靶向ALK1（ACVRL1）和BMPRII受体，激活TGF-β/BMP信号通路，促进血管正常化，从而治疗HHT。 17.康诺亚BCMAxCD3双抗 在去年11月，康诺亚将BCMAxCD3双抗CM336以Newco模式授权给了Ouro Medicines，适应症为自身免疫性溶血性贫血（AIHA）。 AIHA是自身免疫性疾病，由B细胞产生自身抗体（多为IgG）攻击红细胞，导致溶血。约50%的患者经一线治疗（糖皮质激素）和二线治疗（抗CD20抗体、免疫抑制剂）后仍复发，且长期使用免疫抑制药物副作用显著（如感染、骨质疏松）此前在NEJM发表的研究为CM336在AIHA中的疗效和安全性提供了临床验证，支持其作为AIHA潜在创新疗法的地位。 18.FGFR3 ADC 韩国公司AIMEDBIO和启德医药共同开发了FGFR3 ADC GQ1011/AMB302，适应症为恶性胶质瘤。其技术基于启德医药的新型TOPO1i抑制剂Topolx+AIMEDBIO的智能连续偶联技术iLDC。 恶性胶质瘤（如胶质母细胞瘤，GBM）是预后极差的脑肿瘤，5年生存率不足10%。尤其是在青少年多形性低级别神经上皮肿瘤，FGFR3和FGFR2基因融合与肿瘤的发生和进展有关。 19.抗ACTH IgG1单抗 丹麦制药公司Lundbeck开发了一款ACTH（促肾上腺皮质激素） IgG1单抗Lu AG13909，适应症为先天性肾上腺增生症（CAH）。CAH是常染色体隐性遗传病，最常见类型为21-羟化酶缺乏症（占90%-95%）。患者因皮质醇和醛固酮合成障碍，导致ACTH反馈性升高，引发肾上腺增生和雄激素过多。 而ACTH抗体通过结合ACTH，可以阻断其与肾上腺皮质细胞上的黑皮质素2型受体（MC2R）结合，从而抑制ACTH诱导的信号传导。 同时由于该药物采用了人源化IgG1亚型，因此降低了免疫原性。 20.STEAP1 ADC 德烽药业开发了一款STEAP1（六跨膜前列腺上皮抗原1） ADC ADRX-0405，选用抗体为靶向STEAP1的人源化IgG1抗体Payload为拓扑异构酶1抑制剂，Linker采用了该公司Adcentrx的i-Conjugation®技术，可以优化Linker稳定性与药物释放效率。适应症为胃癌。 21.溶瘤性猪糖基化人源化多克隆抗体 法国公司Xenothera开发了一款溶瘤性猪糖基化人源化多克隆抗体（研发代码可能为XON7），适应症为软组织肉瘤，靶点不明。抗体本身来源是猪。官网也并未披露更多信息。 22.复宏汉霖HER2单抗 复宏汉霖的HER2单抗HLX22获得孤儿药资格认定，HLX22与传统的HER2靶向疗法相比存在差异化优势，可通过结合与曲妥珠单抗不同的HER2的胞外亚结构域IV，产生协同作用。这一点使得HLX22有望成为未来胃癌的标准疗法。 23.再鼎DLL3 ADC 再鼎医药的DLL3 ADC ZL-1310获得孤儿药资格认定，Payload采用的是喜树碱衍生物C24。适应症为小细胞肺癌。之前在ASCO上公布的数据相当积极，横向对比数据优于安进的已获批药物DLL3/CD3 TCE tarlatamab。 24.天广实GPRC5D×BCMA×CD3三抗 天广实和康源博创合作的GPRC5D×BCMA×CD3三抗MBS314获得孤儿药资格认定，之前还和辉瑞达成了合作，适应症为多发性骨髓瘤。看来辉瑞对于强生的多发性骨髓瘤药物龙头地位也有想法。 25.抗vWF抗体 荷兰公司TargED Biopharmaceuticals开发了抗von Willebrand因子（vWF）单链抗体融合尿激酶催化结构域，适应症为血栓性血小板减少性紫癜（TTP）。可特异性结合vWF（von Willebrand因子），vWF是一种参与血栓形成的关键蛋白，尤其在TTP中因ADAMTS13酶缺乏导致vWF多聚体异常积累。 参考来源： 各公司官网