从罕见病到阿尔茨海默病、帕金森病等常见病，反义寡核苷酸如何变革神经退行性疾病治疗？

编者按：神经退行性疾病影响着全球超过5000万人的生活，而目前有效治疗手段非常有限，存在巨大的未被满足的医疗需求。这类疾病治疗困难的主要原因之一，在于难以直接靶向引发疾病的遗传因素。反义寡核苷酸（ASO）疗法通过与编码蛋白的mRNA或mRNA前体结合，促使mRNA降解或调控其前体的剪接（splicing）过程，为精准靶向神经退行性疾病的遗传根源提供了有效途径。迄今为止，美国FDA批准的11款ASO疗法中，有4款用于治疗神经退行性疾病，显示出其在延缓甚至逆转病程方面的巨大潜力。为了更好地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ASO等寡核苷酸疗法，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，加速将合作伙伴的创新构想转化为现实，更好地造福全球病患。本文将重点介绍这一平台如何加速合作伙伴ASO药物开发，以及ASO药物在神经退行性疾病领域的进展。

针对神经退行性疾病根本原因的有效策略

神经退行性疾病既包括阿尔茨海默病、帕金森病等影响老年人认知、运动以及日常生活能力的常见疾病，也包括杜氏肌营养不良、肌萎缩侧索硬化等罕见疾病。据世界卫生组织（WHO）统计，全球有超过5000万人受到神经退行性疾病的困扰。此类疾病多数由编码特定蛋白的基因突变导致毒性蛋白积累或功能性蛋白缺失所引起。然而，传统手段往往难以有效靶向疾病的遗传根源。

反义寡核苷酸药物通过与目标mRNA或其前体结合，直接干预靶蛋白的合成过程。一方面，ASO可利用基于RNase H的机制促进mRNA降解，从而抑制毒性蛋白产生；另一方面，也可通过调节mRNA前体的剪接，使细胞生成具有治疗作用的蛋白。这些多样化的作用机制使ASO成为靶向神经退行性疾病遗传因素的重要工具。截至2025年7月，FDA批准的11款ASO疗法中，有4款用于神经退行性疾病领域，其中多款更是相关疾病的首个获批疗法。

▲反义寡核苷酸药物可通过多种作用机制调节靶点蛋白的合成（图片来源：参考资料[1]）

天然的寡核苷酸极易被人体内的酶降解，因此临床应用面临较大挑战。近年来，对ASO的化学修饰显著提高了药物的亲和力、效力和稳定性。然而，这些复杂的修饰工艺也为ASO药物的合成带来了新的技术难题。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，放大到任何规模（mmol到mol），充分满足从临床前、临床到商业化阶段的需求。下面，我们将通过一个具体案例，进一步说明这一平台如何助力合作伙伴加速ASO药物的开发进程。

12个月内完成ASO候选化合物优化和GMP生产

2023年，一家生物技术公司与WuXi TIDES合作进行ASO药物的早期筛选研究，WuXi TIDES的药物化学团队为其提供了超过400种携带骨架化学修饰的ASO化合物，以协助确定最具前景的分子。然而，早期研究发现，创新骨架修饰导致候选化合物中出现新的杂质。在最初的合成过程中，这些杂质占比高达25%，不仅降低了产率和纯化效率，还可能带来潜在毒性，给后续临床开发带来挑战。

面对这一难题，WuXi TIDES药物化学团队和工艺研发团队密切配合，从两个方向入手解决问题。一方面，药物化学团队与合作伙伴共同探索杂质产生的潜在原因，设计出定制化的amidite和分子砌块，规避杂质产生的关键合成机制，并快速生产这些新分子砌块，协助工艺研发团队加速验证工艺设计策略，以有效地控制杂质。此外，工艺研发团队通过优化工艺参数，系统性地降低了杂质的产生。最终，经过持续工艺优化，杂质占比成功从25%降低至5%，同时最终收率也从最初的0.5 g/mol提高到3.4 g/mol。

在该项目中，WuXi TIDES各团队高效协作，不仅在12个月内完成了先导化合物的优化、工艺开发及GMP生产，更帮助合作伙伴基于数据进行快速决策，选出综合效力、稳定性和开发潜力俱佳的ASO候选化合物，为后续临床研究奠定了坚实基础。随着越来越多的ASO药物进入临床开发，这种产业协同模式将成为加快研发步伐的重要推动力。

从罕见病到常见病，ASO治疗迈向新时代

1978年，Zamecnik和Stephenson博士的研究首次显示ASO分子能够抑制病毒复制，为这一创新治疗模式提供了理论依据。如今，ASO技术经过多次迭代，已成为治疗多种罕见神经退行性疾病的重要选择。在FDA已批准的ASO疗法中，渤健（Biogen）和Ionis Pharmaceuticals联合开发的Spinraza（nusinersen），是FDA批准的首款治疗脊髓性肌萎缩症的创新疗法。同样由这两家公司合作开发的，则是首个针对肌萎缩侧索硬化（ALS）遗传病因的获批疗法。

▲FDA批准用于治疗神经退行性疾病的ASO疗法（数据来源：公开资料，点击可见大图）

随着ASO分子设计和递送技术的不断突破，其适用范围逐渐从罕见病扩展至患者人数众多的常见病领域。去年，Wave Life Sciences公司宣布，其等位基因选择性ASO疗法WVE-003在治疗亨廷顿病的1/2期临床试验中取得，在降低突变亨廷顿蛋白表达的同时保留健康的野生型亨廷顿蛋白水平。此外，Ionis公司靶向淀粉样蛋白前体（APP）和LRRK2的ASO药物也已进入2期临床研究，用于治疗阿尔茨海默病和帕金森病。

麻省理工学院药物递送领域专家Robert Langer教授等学者曾经在

Nature Reviews Drug Discovery

Overcoming the Efficacy Challenge: How WuXi AppTec Supports Antisense Oligonucleotide Development for Neurodegenerative Diseases

Neurodegenerative diseases affect more than 50 million people worldwide, yet effective treatment options remain limited, creating significant unmet medical needs. Antisense oligonucleotide (ASO) therapies offer a promising approach to precisely address the root causes of neurodegenerative diseases. Of the more than a dozen ASO therapies approved globally, approximately one-third are indicated for neurodegenerative conditions, underscoring the modality’s potential to slow or even reverse disease progression.

To meet the increasing global demand for oligonucleotide R&D, WuXi TIDES, part of WuXi AppTec, has established a CRDMO platform for ASO and other oligonucleotide therapies. The platform provides high-throughput library synthesis and custom synthesis, covering all types of oligonucleotides, their monomers, linkers, ligands and conjugates. It supports all stages of development, from drug discovery and CMC development to commercial-scale manufacturing, accelerating the translation of innovative ideas into clinical reality for partners worldwide.

A Precise Strategy Targeting the Root Cause of Neurodegenerative Diseases

Neurodegenerative diseases are often driven by the accumulation of toxic proteins or the loss of functional proteins caused by mutations. ASO therapies work by directly modulating the expression levels of these underlying defects. This distinguishes ASOs from conventional therapies that typically act downstream of disease pathways.

However, natural oligonucleotides are highly susceptible to degradation in the body, posing a challenge for clinical application. Advances in chemical modification have greatly improved ASO binding affinity, efficacy, and stability. These modifications, though essential, introduce new synthetic complexities. WuXi TIDES empowers partners to bring innovative drugs to patients faster.

From Hit-to-Lead Optimization to GMP Production: Advancing an ASO Candidate in 12 Months

In 2023, a biotech company partnered with WuXi TIDES to conduct early-stage ASO screening. The discovery synthesis team undertook extensive SAR (Structure-Activity Relationship) exploration—screening more than 400 ASO variants with various types of backbone and ribose modifications to help identify the most promising candidates. However, early-stage studies revealed that novel backbone modifications introduced new impurities—up to 25% in some initial batches—significantly lowering yield and purification efficiency, while raising concerns about potential toxicity that could hinder clinical development.

To address these challenges, WuXi TIDES’ Discovery Chemistry team and Process Development (PRD) team collaborated closely on two fronts. The Discovery Chemistry Team worked with the client to investigate the source of impurities and designed specialized amidites and building blocks to circumvent the pathway leading to key impurities. In parallel, the PRD team rapidly synthesized these components and supported swift validation of the optimized strategy. Additionally, the PRD team systematically optimized multiple process parameters to further reduce impurities.

Ultimately, through a series of process refinements, the impurity level was reduced from 25% to just 5%, and the final yield increased from 0.5 g/mol to 3.4 g/mol.

Thanks to efficient cross-functional collaboration, WuXi TIDES completed hit-to-lead optimization, process development, and GMP manufacturing within 12 months. The partner was able to make data-driven decisions and select a lead ASO candidate with optimal potency, stability, and development potential—laying a strong foundation for clinical studies. As more ASO therapies enter development, this model of collaborative development will be critical for accelerating future breakthroughs.

Advances in chemical modification and delivery technology have enabled oligonucleotide therapeutics to reach previously inaccessible tissue targets—offering new hope for rare and hard-to-treat diseases. Looking ahead, the continued evolution of ASO therapies is expected to deliver more innovative treatments to benefit patients worldwide. WuXi TIDES remains committed to leveraging its integrated CRDMO platform to empower the development of ASO therapies, helping partners translate scientific innovation into life-changing medicines.

参考资料：

[1] Mansour and El-Khatib. (2025). Oligonucleotide-based therapeutics for neurodegenerative disorders: Focus on antisense oligonucleotides. European Journal of Pharmacology, https://doi.org/10.1016/j.ejphar.2025.177529

[2] Sumner and Miller. (2024). The expanding application of antisense oligonucleotides to neurodegenerative diseases. JCI, doi: 10.1172/JCI186116

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