Oligonucleotide-based therapeutics are rapidly emerging as a transformative class of drugs, capable of targeting previously untreatable diseases at their genetic roots. These molecules, encompassing antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and mRNA-based therapies, work by modulating gene expression with unparalleled precision. The global antisense oligonucleotide (ASO) drug market has experienced significant growth, reaching approximately USD 2.8 billion in sales in 2023 and projected to grow to around USD 10.6 billion by 2030, with a compound annual growth rate (CAGR) of 21.5%. Recent innovations, such as AI-driven drug design and advanced delivery systems, are overcoming challenges in delivery, stability, and immunogenicity. By addressing unmet medical needs and unlocking personalized medicine’s potential, oligonucleotide-based therapies promise to redefine modern medicine, offering new hope for patients worldwide.
Oligonucleotide-based therapeutics represent a paradigm shift in medicine, offering tools to directly modulate gene expression and tackle diseases at their source. Unlike traditional small molecules or protein-based drugs, oligonucleotides act at the RNA level, enabling precise therapeutic interventions. Since their emergence in the late 20th century, these therapies have evolved from proof-of-concept experiments to approved treatments addressing diseases ranging from rare genetic disorders to prevalent conditions like cardiovascular disease and cancer. With a growing pipeline and significant investment from biotech and pharmaceutical leaders, oligonucleotides are set to become a cornerstone of future therapeutic strategies, complementing advanced gene-editing technologies like Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR).
What Are Oligonucleotide-Based Therapeutics? – Oligonucleotide-based drugs are short, synthetic sequences of nucleotides designed to interact with RNA molecules. Their mechanisms of action include:
• Antisense Oligonucleotides (ASOs): Bind to complementary RNA sequences to degrade target mRNA or modify splicing.
• Small Interfering RNAs (siRNAs): Utilize the RNA interference (RNAi) pathway to silence specific genes.
• mRNA Therapies: Deliver mRNA encoding therapeutic proteins, enabling direct protein production in cells.
These modalities have been successfully applied to treat genetic disorders, infectious diseases, and metabolic conditions. Examples include ONPATTRO (patisiran) (Alnylam Pharmaceuticals) for hereditary transthyretin-mediated amyloidosis and SPINRAZA (nusinersen) (Ionis/Biogen) for spinal muscular atrophy. Emerging technologies, such as circular RNAs (circRNAs) and self-amplifying mRNAs, are expanding the therapeutic toolkit.
Challenges in Development – Despite their promise, oligonucleotide-based therapies face significant hurdles:
1. Delivery and Intellectual Property (IP): Efficient and targeted delivery to tissues and cells remains the biggest challenge. Strategies like lipid nanoparticles (LNPs) and conjugates, such as Avidity Biosciences’ antibody–oligonucleotide conjugates (AOCs), are showing promise in improving tissue-specific delivery.=. Tissue-specific delivery requires precision engineering of delivery systems to avoid off-target effects and enhance therapeutic efficacy. IP challenges further complicate the landscape, as key delivery technologies are often patented, leading to potential licensing hurdles and delays in development.
2. Stability: Oligonucleotides are prone to degradation by nucleases in the body. Chemical modifications, such as phosphorothioate backbones and locked nucleic acids, have improved stability, but scalability remains a bottleneck.
3. Immunogenicity: Unintended immune activation can limit therapeutic utility. Optimized sequences and chemical modifications are reducing these risks, enabling safer applications.
4. Manufacturing Complexity and Capacity: The synthesis and scalability of oligonucleotides demand advanced technologies, and capacity for large-scale manufacturing remains a significant bottleneck. Current methods, such as solid-phase synthesis, are labor-intensive and costly when scaled up. Addressing this challenge requires the development of more efficient, automated systems and robust infrastructure to meet growing demand.
5. Regulatory Barriers: Accelerating regulatory pathways and harmonizing global standards are necessary to maintain the industry’s momentum.
Industry Momentum and Key Partnerships – The field of oligonucleotide therapeutics is experiencing unprecedented growth, marked by major partnerships and investments:
• Arrowhead Pharmaceuticals and Sarepta Therapeutics: Arrowhead and Sarepta partnered to develop RNAi therapies for rare genetic diseases affecting muscles, the central nervous system, and lungs. The agreement includes programs targeting specific proteins linked to conditions like muscular dystrophy, myotonic dystrophy, pulmonary fibrosis, spinocerebellar ataxias, and Huntington’s disease. They will also explore up to six additional disease targets using Arrowhead’s advanced gene-silencing technology. Arrowhead will receive $500 million upfront, a $325 million equity investment, and up to $10 billion in potential future milestone payments and royalties (November 2024).
• Novartis and PTC Therapeutics: Novartis entered a global license and collaboration agreement with PTC Therapeutics for the development of PTC518, an oral small molecule targeting Huntington’s disease. The agreement included a $1 billion upfront payment and up to $1.9 billion in development, regulatory, and sales milestones (December 2024).
• Eli Lilly and HAYA Therapeutics: Lilly entered into a multi-year collaboration with Haya to discover RNA-based drug targets for obesity and related metabolic disorders using RNA-guided genome platforms. HAYA received an upfront payment, including an equity investment, and is eligible to receive up to an aggregate $1 billion in pre-clinical, clinical and commercial milestone payments, as well as royalties on product sales (September 2024).
• Roche and Ascidian Therapeutics: Roche partnered with Ascidian Therapeutics to develop RNA exon editing gene therapies targeting neurological diseases. Ascidian received an initial payment of $42 million, with potential milestone payments up to $1.8 billion, plus royalties on future sales (June 2024).
• GSK and Elsie Biotechnologies: GSK acquired San Diego-based Elsie Biotechnologies for up to $50 million. This acquisition aims to accelerate GSK’s oligonucleotide platform, enhancing their capabilities in gene expression modulation (June 2024).
•Eli Lilly and QurAlis: Lilly secured rights to ASO QRL-204 and other compounds targeting the UNC13A gene for ALS and frontotemporal dementia in a $45 million upfront deal, with milestones reaching $577 million (June 2024).
These recent collaborations highlight the growing confidence and investment in oligonucleotide-based therapeutics, with deal sizes reaching unprecedented levels. The increasing adoption of ASO and siRNA therapeutics for rare diseases and neurodegenerative conditions is a key driver of market growth.
Opportunities in Personalized Medicine – Oligonucleotide-based therapeutics align with the trend toward personalized medicine, offering solutions tailored to an individual’s genetic makeup. Advances in sequencing technologies and bioinformatics are enabling the identification of actionable targets and the design of bespoke therapies. Applications include:
• Rare Genetic Disorders: Custom ASOs to correct specific mutations.
• Oncology: siRNAs targeting tumor-specific mutations or pathways.
• Neurological Diseases: Modulation of splicing in conditions like Huntington’s disease.
Ethical considerations, including equitable access and affordability, remain critical as these therapies transition into broader clinical use.
Future Outlook – The future of oligonucleotide therapeutics lies in integrating cutting-edge technologies such as:
• Advanced Delivery Systems: Nanotechnology and viral vectors to improve tissue specificity.
• CRISPR and Base Editing: Combining oligonucleotides with gene-editing tools for permanent corrections.
• Artificial Intelligence (AI): Enhancing target identification and drug design through predictive modeling.
• Next-Generation Chemistry: Developing novel nucleotide analogs to overcome current limitations.
• Manufacturing Innovations: Investments in automation, continuous processing, and large-scale production facilities will be crucial to meeting the growing demand for oligonucleotide therapies and ensuring cost-efficiency.
As these innovations mature, oligonucleotides are expected to expand their therapeutic impact, transforming the management of both common and rare diseases.
Oligonucleotide-based therapeutics are ushering in a new era of precision medicine.
By addressing diseases at their genetic core, they hold the potential to tackle conditions previously deemed untreatable. The market for oligonucleotide therapeutics is projected to grow rapidly, driven by increased investment, technological advancements, and a supportive regulatory environment. While challenges such as high development costs and manufacturing complexities remain, the convergence of scientific innovation and industry momentum signals a bright future for this transformative class of drugs. With continued collaboration and innovation, oligonucleotides are poised to redefine the therapeutic landscape, offering hope to millions worldwide.
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Author: Dr. Jean Chatellier, PhD
Partner, EVP & Managing Director
KYBORA
Email: jean@kybora.com
