打破大脑“难以进入”的魔咒，药明康德为小核酸疗法按下加速键 | Bilingual

长期以来，中枢神经系统（CNS）药物的开发面临着独特挑战：血脑屏障的存在使得绝大多数药物难以进入中枢神经系统；神经网络的复杂性则使药物开发面临较高的脱靶风险。

但如今，这一局面正在发生变化。

随着一系列新分子疗法的发展，越来越多曾被视为“不可成药”的神经系统靶点开始进入药物开发视野。在这场变革中，寡核苷酸药物逐渐走向舞台中央。

包括siRNA和反义寡核苷酸（ASO）在内的寡核苷酸药物，能够利用碱基互补配对原则直接作用于靶RNA，从而对疾病相关蛋白进行精准调控。通过鞘内注射等给药方式，寡核苷酸药物能够绕过血脑屏障，在中枢神经系统实现广泛分布，从而触及传统分子难以覆盖的疾病靶点。

这一潜力已经在临床实践中得到验证。治疗脊髓性肌萎缩症（SMA）的ASO药物Spinraza（nusinersen）已于2016年获批上市，证实了寡核苷酸药物能够为CNS疾病患者带来明确临床获益。此后，针对SOD1基因突变肌萎缩侧索硬化（ALS）患者的ASO药物Qalsody（tofersen）也获得批准，进一步证明了RNA靶向策略在神经系统疾病中的临床价值。此外，多款寡核苷酸药物已进入临床开发阶段，涵盖亨廷顿病、帕金森病、阿尔茨海默病等多种CNS疾病。

化零为整，搭建一体化发现平台

随着寡核苷酸药物研发热度的持续攀升，如何加速药物发现，将寡核苷酸的生物学潜力快速转化为具有临床价值的候选药物，正成为行业关注的重要课题。

寡核苷酸药物研发的早期发现阶段，通常涉及序列设计、化学合成、体外筛选、药效评价等多个环节，每个环节都具备独特的技术要求。此时，让各个环节更加协同，衔接效率更高的策略成为了许多研发人员期待突破的方向之一。

一些客户在与药明康德开展寡核苷酸合作项目时，就分享了研发中遇到的实际感受：在以往的项目中，生物学早期发现涉及到多个环节，它们需要不同的赋能能力支撑。并且，这些环节会经过跨团队甚至跨机构的协调。这不仅增加了沟通成本，也让这些环节之间的衔接变得复杂。

正是基于这样的行业需求，药明康德生物学平台（WuXi Biology）搭建了寡核苷酸药物一体化发现平台，将靶点验证、序列设计、化学合成与修饰优化、体外筛选、递送体系评估、体内验证等能力纳入同一体系之中。

以序列设计与化学修饰环节为例，平台已累计支持200余个靶点的寡核苷酸序列设计，探索超过80种化学修饰模式，可提供特殊修饰、手性寡核苷酸及各类偶联寡核苷酸的设计与开发服务。

围绕以下关键环节，平台同样构建了系统化的技术能力：

• 在体外筛选环节，结合大量细胞资源及多类型细胞模型，平台可快速识别具有高敲降效率和良好特异性的候选分子；

• 在安全性与机制研究方面，平台整合RNA转录组分析、免疫原性与细胞毒性检测，实现对脱靶效应与潜在安全风险的系统评估；

• 在递送技术方面，除肝靶向GalNAc策略外，平台还支持肝外递送工具的发现，包括抗体和多肽等配体，并通过优化偶联位点提升递送效率。

在寡核苷酸药物一体化发现平台上，所有阶段的结果、经验可以实现无缝衔接，从而加速了药物发现进程，以满足客户日益增长的寡核苷酸药物研发需求。对大多数项目而言，从最初的序列设计到获得临床前候选化合物，周期通常只需要一年。

自2021年以来，药明康德生物学平台已支持全球客户超过1000项寡核苷酸相关研发项目，覆盖300多个靶点，并助力超过60项IND项目推进。

一体化平台助力挖掘潜力分子

平台能力的价值，最终仍需要通过具体项目来验证。在一个针对ATXN2基因的案例中，药明康德生物学平台团队验证了寡核苷酸药物一体化发现平台发掘CNS潜力分子的能力。

作为近年来神经退行性疾病领域备受关注的治疗靶点，ATXN2突变导致的脊髓小脑性共济失调2型（SCA2）是一种罕见的神经退行性疾病，其病理进程主要发生于脑干和小脑深处。

越来越多的研究表明，降低ATXN2的表达能够干扰应激颗粒的形成，阻止病理性蛋白TDP-43的错误定位，从而减少对神经细胞的损伤。除了改善SCA2的症状，ATXN2的调控策略对于帕金森病、阿尔茨海默病等更广泛的CNS疾病类型同样具有治疗潜力。如今，已有旨在降低ATXN2表达的寡核苷酸药物进入临床试验阶段。

基于持续增长的客户需求，利用寡核苷酸药物一体化发现平台，药明康德生物学平台团队围绕ATXN2靶点筛选了一款ASO候选分子，用以验证一体化平台在序列设计、优化及体内外评估等环节的协同能力。

在设计阶段，团队仅通过一轮序列设计与筛选，就获得了一批对靶基因抑制水平可观的分子，其中约20%的分子活性达到了与对照组在研分子相当，甚至更优的水平。

这些高活性分子被迅速合成并推进至后续验证环节，由体外筛选团队进一步评估其生物学功能。在模拟TDP-43蛋白病的病理模型中，高活性分子显著抑制了应激颗粒的异常形成，其效果同样与对照组分子相当。

随后，对于ASO药物至关重要的脱靶问题，安全评估团队接手开展脱靶风险分析。结果显示，这些高活性分子整体脱靶信号较弱，在检测体系中与背景噪声接近。这些结果验证了该平台用于发掘高潜力ASO分子的技术能力，为后续赋能客户寡核苷酸项目的研发奠定了基础。

赋能创新走向舞台

过去十年间，以Spinraza和Qalsody为代表的药物已经证明，寡核苷酸药物能够为CNS疾病患者带来真实的临床获益。当下，行业也正不断探索更广泛的潜在靶点，布局更多研发管线。

面对这一趋势，药明康德依托一体化平台协同优势，构建了覆盖药物发现、机制研究、药代动力学评价以及开发与生产的一体化寡核苷酸研发体系，为合作伙伴提供端到端支持。

其中，药明康德生物学平台建立了覆盖设计、筛选、评价与转化研究的一体化寡核苷酸药物发现平台，可为合作伙伴提供端到端的研发支持。药明康德DMPK团队建立了系统化的体外代谢研究平台，通过多模型协同策略对寡核苷酸药物的稳定性与降解行为进行全面评估，为候选分子的优化与临床前决策提供关键数据支持。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CRDMO平台WuXi TIDES，则为寡核苷酸原料药和制剂提供从药物发现到商业化生产的一体化服务，帮助合作伙伴加速推动寡核苷酸创新疗法迈向市场。

当下，对于许多创新者而言，真正稀缺的并非科学创意，而是将创意转化为候选药物所需的系统能力。

药明康德持续建设的一体化寡核苷酸研发体系，承担的正是这样的角色：让经验丰富的企业提升研发效率，也帮助刚进入这一领域的新锐公司降低研发门槛，从而使全球的医药创新者更多地聚焦于科学判断和转化洞察之中，推动药物早日抵达患者手中。

▲欲了解WuXi Biology如何赋能药物研发，请长按扫描上方二维码，与药明康德生物学业务平台联系

How does WuXi AppTec accelerate oligonucleotide drug discovery for CNS diseases?

Oligonucleotide therapeutics are unlocking historically inaccessible disease targets. WuXi AppTec accelerates oligonucleotide drug discovery for central nervous system (CNS) diseases through an integrated discovery platform that bridging key capabilities required to move efficiently from target biology to candidate selection. This approach reduces discovery complexity and enables faster progression of promising programs.

Oligonucleotide therapeutics, including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), are expanding the range of targets through direct modulation of disease-associated RNA.

The success of therapies such as Spinraza (nusinersen) and Qalsody (tofersen) has demonstrated the therapeutic potential of RNA-targeting approaches in neurological disorders. Moreover, a growing pipeline of oligonucleotide therapies has advanced to clinical stages, covering CNS indications such as Huntington's disease, Parkinson's disease, and Alzheimer's disease.

Integrated platform improves discovery efficiency

To improve efficiency across oligonucleotide discovery, WuXi Biology, a business unit of WuXi AppTec, has established an integrated discovery platform for oligonucleotides that bridges target validation, RNA design, synthesis, screening, safety assessment, delivery evaluation, and in vivo validation within a coordinated workflow.

Early-stage oligonucleotide discovery often involves multiple specialized stages, each requiring distinct expertise and technologies. Traditionally, these stages may be distributed across different teams or organizations, creating additional coordination requirements and complicating the handoffs between stages.

WuXi Biology, a business unit of WuXi AppTec, could help clients to address these challenges.In RNA design and chemistry optimization alone, WuXi Biology has supported more than 200 targets of oligonucleotide designed and explored over 80 modification strategies.It also supports the design and development of specialized modifications, chiral oligonucleotides, and various conjugated oligonucleotide formats.

The platform further incorporates capabilities for in vitro evaluation, safety assessments, and delivery technology research, providing integrated support throughout the discovery process.

Since 2021, WuXi Biology has supported more than 1,000 oligonucleotide-related projects covering more than 300 targets, and has facilitated the advancement of over 60 IND programs.

Integrated workflows accelerate candidate identification for CNS diseases

By enabling seamless progression from design through evaluation, WuXi AppTec helps accelerate the identification and optimization of promising oligonucleotide candidates with its integrated discovery platform. A case study validated the platform’s capability to develop potent and safe ASOs with therapeutic potential for CNS diseases.

One example involves ATXN2, a therapeutic target receiving increasing attention in neurodegenerative disease research. Mutations in ATXN2 are associated with spinocerebellar ataxia type 2 (SCA2), while modulation of ATXN2 expression has also shown potential relevance for broader neurological disorders.

To evaluate the capabilities of its integrated discovery platform, the WuXi Biology team developed an ASO program targeting ATXN2.

Following a single round of RNA design and evaluation, the team identified multiple molecules with strong target suppression activity.Approximately 20% of candidates inhibit the target at similar or better levels than a positive control.

These candidates were rapidly synthesized and advanced into functional evaluation. In disease models, highly active molecules significantly reduced abnormal stress granule formation and demonstrated performance comparable to the positive control.

The same candidates were subsequently evaluated for off-target effects. Results showed generally low off-target signals, with measurements approaching background levels within the testing system.

On the integrated discovery platform, the seamless flow of results and insights across all stages accelerates the drug discovery process. For most projects, the timeline from initial RNA design to preclinical candidate is typically just one year.

Support programs from discovery to manufacturing

The industry is continuously exploring a broader range of potential targets and advancing oligonucleotide pipelines. In response to this trend, WuXi AppTec has established an integrated oligonucleotide platform covering drug discovery, mechanism studies, pharmacokinetic evaluation, as well as development and manufacturing, thereby providing end-to-end support to its clients.

WuXi Biology has established an end-to-end oligonucleotide discovery platform covering design, screening, evaluation, and translational research, providing comprehensive oligonucleotide development support for global clients.

WuXi AppTec DMPK team has established a comprehensive in vitro metabolic stability platform tailored to the unique biochemical properties of oligonucleotide drugs, enabling systematic characterization of degradation behavior and improved prediction of in vivo disposition.

In addition, WuXi TIDES provides integrated CRDMO services for oligonucleotides, peptides, and related conjugated therapeutics, supporting programs from research through commercial manufacturing.

Together, these capabilities create an integrated oligonucleotide R&D&M ecosystem that supports innovation across multiple stages and helps clients advance promising therapies more efficiently.

As the therapeutic potential of oligonucleotides continues to expand, success increasingly depends on the ability to efficiently transform scientific insights into viable drug candidates.

By continuously building an integrated platform for oligonucleotides, WuXi AppTec is enabling global innovators to focus on scientific and translational insights, ultimately accelerating the delivery of novel therapies to patients.

Key Takeaways

• WuXi Biology, a business unit of WuXi AppTec, improves research efficiency through an integrated oligonucleotide discovery platform that connects design, synthesis, evaluation, and translational studies within a coordinated workflow.

• Since 2021, WuXi Biology has supported more than 1,000 oligonucleotide-related projects, covering more than 250 targets, and has facilitated the advancement of over 50 IND programs.

• WuXi Biology helps accelerate the identification and optimization of promising oligonucleotide candidates for CNS diseases, as demonstrated by an ASO program targeting ATXN2 that identified potent candidates in a single design round.

• Through integrated capabilities spanning research, development and manufacturing, WuXi AppTec has established an integrated oligonucleotide platform and provides end-to-end support to its clients.

• WuXi AppTec enables most oligonucleotide discovery projects to progress from initial RNA design to preclinical candidate selection in approximately one year through its seamless integrated workflow.

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