The Growing Demand for Oligonucleotide Synthesis: Uses, Challenges, and Future Opportunities

Oligonucleotide synthesis has emerged as a cornerstone of modern biotechnology, with applications spanning from drug development to genetic research. As demand grows for more personalised treatments and advanced therapies, the role of oligonucleotides in the pharmaceutical and biotech industries becomes increasingly important. In this blog, we’ll explore the various uses of oligonucleotides, the challenges in their synthesis, and the market demand driving their growth. Additionally, we’ll discuss the importance of Process Mass Intensity (PMI) in ensuring high-quality oligonucleotide production.

 

1. Key Uses of Oligonucleotides

Oligonucleotides, short strands of nucleic acids, have become vital tools in both research and medicine. These versatile molecules are used in a wide range of applications, from genetic testing to drug development.

• Diagnostics and Research: Oligonucleotides are central to diagnostic tools such as PCR (Polymerase Chain Reaction), which amplifies DNA for the detection of genetic conditions and infectious diseases. They also play a role in RNA interference, where they help silence specific genes, paving the way for targeted therapies.
• Gene Therapy: In the realm of personalised medicine, oligonucleotides are used to develop therapies that can target and repair specific genetic mutations, offering hope for conditions previously considered untreatable.
• Drug Development: The application of oligonucleotides in the development of antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) has led to new classes of drugs aimed at treating conditions such as Duchenne muscular dystrophy and genetic disorders.

 

2. Challenges in Oligonucleotide Synthesis

Despite their vast potential, the synthesis of oligonucleotides presents several challenges that can affect both the quality and cost of production.

• Sequence Complexity: Longer oligonucleotides or those with repetitive sequences are harder to synthesise. These sequences are prone to errors, requiring additional purification steps to ensure high-quality products.
• Purity and Yield: Achieving the desired purity and yield is a constant challenge. Impurities can arise from incomplete sequences or side reactions during the synthesis process, which can compromise the effectiveness of the final product.
• Scalability: While small-scale synthesis is relatively straightforward, scaling up production to meet commercial demand requires advanced techniques and equipment to ensure consistency across larger batches.

 

However, ongoing innovations in oligonucleotide synthesis technology, such as Exactmer’s Nanostar Sieving and liquid-phase synthesis, are transforming the landscape. These cutting-edge methods address traditional challenges by enhancing scalability, improving purity, and reducing production costs. Nanostar sieving ensures precise separation of desired molecules, while liquid-phase synthesis streamlines the process, minimising errors and waste. These advancements are paving the way for more efficient and reliable large-scale production, meeting the growing demand in research and therapeutic applications.

 

3. Current Commercially Available Oligonucleotide Drugs

The therapeutic potential of oligonucleotides has already been realised with the approval of several commercially available drugs. These treatments are not only revolutionising the pharmaceutical landscape but are also driving the demand for oligonucleotide synthesis.

• Spinraza (nusinersen): This drug, used to treat spinal muscular atrophy, is one of the first antisense oligonucleotide-based drugs to gain FDA approval. Spinraza works by modifying the splicing of the SMN2 gene to increase the production of survival motor neuron protein.
• Exondys 51 (eteplirsen): Approved for the treatment of Duchenne muscular dystrophy, Exondys 51 is another antisense oligonucleotide therapy that targets a specific exon of the dystrophin gene to allow for the production of a functional protein.

 

These drugs represent just a glimpse into the potential of oligonucleotides in medicine, with many more oligonucleotide-based therapies currently in clinical trials. The growing approval and success of these treatments have significantly increased the demand for high-quality oligonucleotide synthesis.

 

4. Market Demand for Oligonucleotides

The demand for oligonucleotides is expected to continue growing as research and development in gene therapy and personalised medicine accelerate. Several factors contribute to this increasing demand:

• Personalised Medicine: As the healthcare industry moves toward personalised treatments, the need for custom-designed oligonucleotides tailored to individual genetic profiles grows.
• Expanding Applications: Oligonucleotides are no longer confined to academic research. Their use in commercial drug development, gene therapy, and diagnostic tools is driving market growth.

 

5. The Importance of PMI in Oligonucleotide Manufacturing

Process Mass Intensity (PMI) is a key metric in oligonucleotide manufacturing, measuring the amount of raw materials required to produce a unit of product. This metric is critical for assessing and optimising the efficiency of the production process. Lower PMI values indicate more sustainable and cost-effective manufacturing practices, a goal of increasing importance in large-scale oligonucleotide synthesis.

By focusing on PMI, manufacturers can reduce material waste and enhance process efficiency while maintaining the high purity and consistency essential for therapeutic applications. Innovations like Exactmer’s Nanostar sieving and liquid-phase synthesis contribute significantly to achieving lower PMI, ensuring a balance between scalability and environmental responsibility.

 

Final Thoughts

Oligonucleotide synthesis is at the forefront of biotechnology, with applications that span diagnostics, gene therapy, and drug development. As the market for oligonucleotides continues to grow, manufacturers face both challenges and opportunities in meeting the increasing demand for these versatile molecules. Advances in synthesis technology, along with a focus on process optimisation, are paving the way for more efficient and cost-effective production.

At Exactmer, we understand the importance of high-quality oligonucleotide synthesis and are committed to delivering solutions that meet the demands of our clients and the broader biotech industry. To learn more about our services and how we can assist with your oligonucleotide synthesis needs, contact us today.

 

Exactly defined molecular weight poly(ethylene glycol) allows for facile identification of PEGylation sites on proteins

We are thrilled to announce the publication of our new research paper titled “Exactly defined molecular weight poly(ethylene glycol) allows for facile identification of PEGylation sites on proteins” in Nature Communications!

Diagram illustrating the differences between conventional PEGylation and PEGylation defined in this publication. Using Exactmer's PEG synthesis for defined molecular weights enables for easy identification of PEGylated regions within a protein using relatively straightforward techniques.

Diagram illustrating the differences between conventional PEGylation and PEGylation defined in this publication. Using Exactmer’s defined molecular weight PEG synthesis enables for easy identification of PEGylated regions within a protein using relatively straightforward techniques.

In this study, we propose a chromatography-free synthesis process to produce defined PEGs with a molecular weight of 5kDa.

This breakthrough approach enables the use of precisely defined molecular weight poly(ethylene glycol) to address current batch-to-batch variations and unpredictable impurities in PEGylated drugs — an essential consideration for advancing biopharmaceutical development.

Our findings could transform how PEGylation, a key method to improve protein stability and therapeutic efficacy, is studied and applied in drug development.

We invite you to read the full paper and explore how Exactmer’s innovation could impact the future of drug design and protein synthesis. Find out more about how our findings on PEG synthesis can help you by visiting Our Services – Exactmer.

Read the full paper here:

Exactly defined molecular weight poly(ethylene glycol) allows for facile identification of PEGylation sites on proteins | Nature Communications

Exactmer Partners with Asahi Kasei Bioprocess to Accelerate Growth of Nanostar Sieving Technology for Large-scale Oligo Manufacturing

LONDON — August 8th, 2024 — Oligonucleotide-based therapies have emerged as powerful tools in modern medicine, with several FDA-approved treatments already on the market. The global multibillion-dollar oligonucleotide synthesis market is expected to continue expanding at double-digit growth rates over the coming years as drug manufacturers look for new ways to advance life-saving therapeutics.

Exactmer, a pioneer in polymer synthesis and manufacturing services, has received investment from Asahi Kasei Medical (AKM) to accelerate the growth of its innovative “Nanostar Sieving” technology within the oligonucleotide space. In conjunction with the investment, Exactmer and Asahi Kasei Bioprocess, part of Asahi Kasei Medical, offering technology platforms for oligonucleotide synthesis, have agreed to explore technical collaboration aimed at rapidly scaling Exactmer’s technology to meet emerging customer applications.

Exactmer’s proprietary platform technology, Nanostar Sieving, allows large-scale manufacturing of exact polymers, including oligonucleotides, fully in solution. This innovative approach overcomes current limitations in oligonucleotide production, making advanced therapies more accessible to patients in need.

“Asahi Kasei Bioprocess’ support will be instrumental in scaling our Nanostar Sieving technology and helping us address the growing demand for oligonucleotide-based therapies that contribute to the next wave of breakthrough treatments,” said Andrew Livingston, Chief Executive Officer and Co-Founder of Exactmer.

The investment and technical collaboration will support the commercial development of large-scale synthesis solutions that significantly reduce solvent usage, addressing both economic and environmental concerns in oligonucleotide pharmaceutical manufacturing. Both Exactmer and Asahi Kasei Bioprocess are committed to advancing the field of oligonucleotide therapeutics and look forward to the positive impact this partnership will have on the industry and patient care.

“This groundbreaking technology has the potential to transform how these critical therapeutics are manufactured, offering increased efficiency, reduced costs, and improved environmental sustainability,” said Chris Rombach, Executive Vice President at Asahi Kasei Bioprocess. He added: “With this investment and the planned collaboration – both of which align with Asahi Kasei Bioprocess’ mission to help customers achieve long term productivity gains by pushing the boundary of tomorrow’s technology today – we’re jointly accelerating our growth in the oligonucleotide synthesis market by leveraging Exactmer’s technology to build cutting-edge equipment and provide consultative expertise to customers.”

Learn more about how Nanostar Sieving works.

 

About Exactmer

Exactmer is a life sciences company with the mission to manufacture exact polymeric pharmaceuticals, enabling advanced therapies to be provided to all patients in need. Exactmer specializes in the synthesis of biopolymers (oligonucleotides, peptides) and synthetic polymers (polyethylene glycols) using its patented Nanostar Sieving Technology, which allows the synthesis of polymers with exactly defined monomer sequences in liquid phase. Exactmer produces polymers of unprecedented precision by using this completely new approach, opening the way to manufacture at scale supremely accurate polymers for use as pharmaceuticals. For more information please visit: https://exactmer.com/.

 

About Asahi Kasei

The Asahi Kasei Group contributes to life and living for people around the world. Since its foundation in 1922, it has consistently grown its business portfolio to meet the evolving needs of every age. Now with more than 49,000 employees worldwide, it aims to provide solutions to the world’s sustainability challenges through its three business sectors of Health Care, Homes, and Material. Asahi Kasei Medical is a core operating company in the group’s Health Care sector. Its bioprocess business arm – Asahi Kasei Bioprocess – is devoted to solving product safety, efficiency, and purity challenges within the pharmaceutical and bioprocessing industries. Along with its technology platforms for oligonucleotide synthesis, buffer formulation, chromatography and filtration, its bioprocess systems, columns and automation solutions advance GMP manufacturing of critical drug substances around the world. For more information, please visit: https://fluidmgmt.ak-bio.com. 

Asahi Kasei Bioprocess – Built with pride, built with quality, built to exceed expectations. “Built for You.”

 

Contact

[email protected]

Exactmer Secures FASST Grant to Revolutionize Oligonucleotide Synthesis

Exactmer is excited to announce that it has been awarded a Flexible, Agile, Scalable and Sustainable medicines manufacturing (FASST) grant from the Innovate UK Transforming Medicine Manufacturing program. The grant, valued at £1,234,617, supports the 24-month BioNanostar project, a collaborative effort between Exactmer, the University of Manchester and Imperial College London. This consortium is uniquely positioned to develop a streamlined bioprocess for oligo assembly that promises increased efficiency, sustainability, and cost-effectiveness. 

About BioNanostar: 

The Sustainable Bioprocess for Oligonucleotide Manufacture using Nanostar Sieving (BioNanostar) project aims to revolutionize the synthesis of oligonucleotides (oligos), which are crucial in gene therapy, diagnostics, and drug delivery. Current manufacturing methods, such as Solid Phase Synthesis (SPS), face significant challenges, including high Process Mass Intensity (PMI) and cost inefficiencies, limiting large-scale production. 

Exactmer’s innovative Nanostar Sieving technology offers a transformative solution to oligo synthesis. By employing a liquid-phase process and membrane filtration, Nanostar Sieving facilitates the precise and scalable iterative addition of nucleotide monomers to a growing Nanostar hub. The BioNanostar grant will combine this technology with enzyme chemistry to create a greener, more sustainable manufacturing process. Advanced modeling techniques will be employed to fully optimize reaction and process parameters. 

Project Objectives: 

The BioNanostar project aims to enhance process efficiency by combining Nanostar Sieving with enzyme technology for linear oligo assembly in aqueous media, guided by advanced digital modelling techniques. It also seeks to promote sustainability by reducing the use of organic solvents and other chemicals, utilizing natural nucleotides as building blocks.  

Jason Micklefield, Professor of Chemical Biology at the University of Manchester said, “current oligonucleotides synthesis is highly step and atom inefficient, relies on large quantities of deleterious reagents and creates a huge amount of harmful waste. We aim to address this by developing more sustainable and cleaner oligonucleotides synthesis using enzymes operating under benign aqueous conditions.” 

Additionally, the project focuses on ensuring scalability by developing advanced membranes optimized for aqueous media and designing bio-synthesizers for commercial-scale production. 

Impact: 

“We are thrilled to partner with the University of Manchester and Imperial College London on this groundbreaking project,” said Piers Gaffney, CSO of Exactmer. “BioNanostar has the potential to significantly advance oligonucleotide synthesis, making it more efficient and environmentally friendly, ultimately benefitting a wide range of therapeutic applications.” 

The BioNanostar project aims to create a novel, adaptable method for oligonucleotide biomanufacture, addressing a broad spectrum of diseases and reducing final product costs. The integration of cutting-edge technologies aligns with the competition’s goals, promising significant advancements in the bioprocessing and biomanufacturing of oligos. 

Exactmer joins forces with leading institutions to secure Innovative Technologies Award

Exactmer is excited to announce the successful application to the Innovative Technologies for Nucleic Acid Medicines Manufacturing competition, delivered by the Innovate UK Transforming Medicine Manufacturing programme. Exactmer will work in collaboration with CPI, Queen Mary University of London and AstraZeneca, forming a consortium of leading experts in membrane production, nanofiltration, oligo manufacture and commercialisation. 

The consortium will receive £1.8 million funding for a 24-month long project aimed at Maximising Efficiency of Liquid Phase Oligo Synthesis (MELOS). The project will focus on improving the process efficiency and sustainability of Exactmer’s Nanostar Sieving technology for liquid-phase synthesis of oligonucleotides at large scale. 

Oligonucleotides, or oligos, are short chains of nucleotides that are used in a variety of applications, including gene therapy, diagnostics, and drug delivery. The current methods for manufacturing oligos are often inefficient and environmentally unfriendly. Nanostar Sieving technology is a new approach to oligo synthesis that uses a membrane to separate the growing oligo from unreacted monomers, allowing for more efficient and sustainable production of oligos. 

The MELOS project will focus on improving the following aspects of the Nanostar Sieving technology: 

  • Process efficiency: The team will develop new chemistries and process conditions to improve the yield and throughput of the Nanostar Sieving process. 
  • Sustainability: The team will develop methods to reduce the use of solvents and other chemicals in the Nanostar Sieving process. 
  • Scalability: The team will develop methods to scale up the Nanostar Sieving process for commercial production of oligos. 

“We are excited to be working on this project with such a talented team of partners,” said Piers Gaffney, CSO of Exactmer. “The MELOS project has the potential to revolutionize the way oligos are manufactured, making them more affordable and accessible to patients.” 

This is a significant step forward in the development of the Nanostar Sieving technology. The MELOS project is expected to lead to improved process efficiency, sustainability, and scalability of the technology, and in the future it could benefit millions of patients worldwide.

Exactmer Awarded £2M for Alternative Oligo Chemistries

Exactmer is delighted to announce it has been awarded €2.49M (£2.15M) from the European Innovation Council (EIC) through its Transition programme, to fund ground-breaking research in the synthesis and manufacture of oligonucleotide (oligo) therapeutics. The funding will fast-track the development of new oligo chemistries for Exactmer’s patented Nanostar Sieving technology, which enables the large-scale manufacture of exact polymeric pharmaceuticals.

‘Alternative Chemistry for Oligonucleotide Synthesis using Nanostar Sieving’, ALTOLIGO, will develop innovative synthesis routes to revolutionise the production of oligos, using greener and cheaper methodologies, and alleviating burdensome supply-chains. In contrast to current methodologies, which rely on the classical phosphoramidite approach using solid-phase platforms, Nanostar Sieving employs the liquid phase for synthesis, making the process inherently scalable. Moving away from dependence on solid supports allows for novel, non-classical syntheses to be developed and optimised, pushing the boundaries for efficiency in oligo production.

Exactmer’s CEO, Prof. Andrew Livingston said: “Exactmer is a technology innovator in oligo manufacture. Our Nanostar Sieving platform harnesses over a decade of research at the forefront of membrane technologies, from the Livingston Group at Queen Mary University of London, and provides a step-change in exact polymer manufacturing. This makes it the ideal platform to address the needs of the oligo synthesis market. This EIC Transition funding will enable us to deliver cheaper and more-efficient oligo manufacturing methods, ultimately bringing these innovative therapeutics to all patients in need.”

The EIC Transition programme offers start-ups and small to medium enterprises (SMEs) grants of up to €2.5 million to fund activities that go beyond the experimental proof of principle, addressing both technology and market development. The programme is being financed through the UKRI Horizon Europe Guarantee funding in the UK.

Exactmer began as a spin-out company from Imperial College in December 2017, and is now a fast-growing SME based in Londoneast-UK Technical Park in Dagenham, East London. Contact us at [email protected] if you are interested in partnering on our oligo synthesis work developing through ALTOLIGO, or to find out more about our work in this area.

Exactmer awarded with SMART Grant from Innovate UK

Exactmer is pleased to announce that it has been awarded a SMART Grant from Innovate UK. Innovate UK drives productivity and economic growth by supporting businesses to develop and harness the potential of new ideas.

Through this 16-month long project, due to start later this year, Exactmer will develop a disruptive new approach for the synthesis of multi-functional Polyethylene Glycols (mfPEGs).

PEGs help to regulate the transport and retention of medicine in the body and can be used as linkers in Antibody Drug Conjugates (ADCs). ADCs have been developed as a ‘magic-bullet’ for cancer treatment, delivering toxic payloads directly to cancer cells; however, the linkers currently used in ADCs are unadaptable and ‘cargos’, such as drugs, dyes, or cell-penetrating agents, cannot be attached to the linker, ultimately limiting the efficacy of ADC therapeutics.

Through this SMART project Exactmer will use its proprietary Nanostar Sieving technology platform to produce PEGs, comprising sequences of Exactmer’s completely-new, EG-based monomers, each containing a side-group designed to attach useful cargos. When polymerised, these monomers will form multi-functional PEGs (mfPEGs) and will be used as linkers in ADCs. By increasing water-solubility, drug-to-antibody ratios and enabling incorporation of multifunctional components, mfPEGs could revolutionise ADC therapeutics.

Exactmer looks forward to contributing to the development of improved ADCs in the next years. Contact us at [email protected] if you would like to know more about our work in this area.

New Facilities

Exactmer is excited to announce the opening of new facilities at our premises in the Londoneast-UK Business and Technical Park in Dagenham, East London. The new space will house a Membrane Casting facility, for the manufacture and production of proprietary membranes used in our Nanostar Sieving platform. The facility will also accommodate membrane-related R&D activities. This marks the beginning of an exciting expansion for Exactmer as we begin growing our Membrane Manufacturing operations, and will streamline the commercialisation of the Nanostar Sieving platform and products.

Exactmer has grown rapidly over the last year, having also acquired new R&D lab and office space. This has enabled the company to establish new partnerships and research activities, and expand our manufacturing capabilities across both our oligonucleotide and exact-PEG syntheses services.

Exactmer awarded Knowledge Transfer Partnership with Queen Mary University of London

Exactmer, together with Queen Mary University of London (QMUL), has been awarded its first Knowledge Transfer Partnership (KTP), from Innovate UK.

Through this KTP, Exactmer and QMUL will develop new synthesis methods for exact Polyethylene Glycol polymers (PEGs), using Exactmer’s proprietary Nanostar Sieving platform. When added to therapeutics drugs, PEGs help to regulate the transport and retention of the medicine in the body. Their water solubility also lends them useful in drug delivery scaffolds and nanomedicine. However, current manufacturing limitations means that producing PEGs is difficult to do accurately; to do so is challenging, time-consuming and expensive.

To solve this, Exactmer is developing its breakthrough technology, Nanostar Sieving, to revolutionise PEG manufacturing. Through the KTP, QMUL and Exactmer will address manufacturing and analytical challenges and will accelerate the commercialisation of exact-PEGs for applications in the PEGylated drugs and Antibody Drug Conjugates markets.

The KTP programme is a collaboration between universities and businesses in the UK, to help overcome challenges of innovation and address specific obstacles to technology development. It is a partially-government funded initiative which gives companies access to the know-how and expertise of academic institutions, through a project designed to address a specific business need.

For more information on the Nanostar Sieving platform and our exact-PEG polymers, please contact the Exactmer team at [email protected].

 

Exactmer wins Startup Pitch and Partner Award at BioVaria, Munich

Exactmer is delighted to have been awarded the Startup Pitch and Partner award in the ‘Emerging’ category, at BioVaria 2022.

Exactmer’s winning pitch on the development of our proprietary Nanostar Sieving technology for oligonucleotide synthesis was chosen by a jury of leading investors, in a showcase of 13 hand-picked start ups from across Europe.

BioVaria is Europe’s leading showcasing event for life-science technologies, targeting technology scouts, business developers and investors, and bringing together Europe’s leading tech transfer professionals, innovators from academia and representatives of the global biotech and pharma industry.

This year’s event was held in Munich in May, bringing together over 230 life-science innovators to the two-day event, with more than 60 licensable innovations presented by leading players from all over Europe, from therapeutic and diagnostic approaches to platform technologies.

Read the full feature here.