CRDMO: Overcoming the Efficacy Challenge: How WuXi AppTec Supports Antisense Oligonucleotides 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, more than half 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 expression level 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 of formation of 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.