Contact Information: Contact Name: Dara O’Brien E-mail: dara.obrien@exactmer.com Website: www.exactmer.com
Funding required: £2.5m
Pioneers in exact polymer synthesis, Exactmer is redefining what is possible in controlling monomer sequences; developing Nanostar Sieving technology to produce high-purity polymers bound for use in medicine. The Problem Oligonucleotide (oligo) therapeutics target disease at RNA-level, reaching targets beyond those generally accessible to conventional pharmaceuticals. While initially oligos targeted the treatment of rare diseases, they are now being developed to treat conditions with large patient populations. However, tonne-per-annum scale oligo production methods are not available; sustainable, cost-effective methods are now urgently required to ensure these innovative medicines are made available to all patients who need them. Solid Phase Synthesis (SPS) is the dominant technique used to manufacture oligos. SPS solves key separation problems associated with iterative polymer synthesis; but brings penalties: The biggest oligo synthesisers are limited to batch sizes of a few kg; and intra-particle diffusional limitations lead to incomplete reactions resulting in impurities. The result is crude oligo purities between 60-90%, requiring further chromatographic processing which contributes 30%-50% of the £800-£1,000/g manufacturing price (at kg-scale). This purification step also accounts for ~50% of the material used in the process, which is incredibly wasteful. Collectively, these issues limit the global manufacturing capacity to ~4t/ year. Together with the high price and large solvent consumption (1,200 L/kg), this represents not only a substantial environmental burden, but a significant barrier to bringing these medicines to all patients in need.
The Solution Exactmer’s Nanostar Sieving technology addresses the limitations of current commercial oligo synthesis, producing purer crude-oligo products, at scale, more economically. At multi-tonne scale, Nanostar Sieving could show a 10x reduction in cost with a 10x increase in batch capacity. This disruptive new technology is capable of high synthesis purity, and could render chromatography redundant, dramatically cutting medicine costs to patients, and waste of materials by some 30-50%. The technique involves growing polymers from a hub molecule, chain-extending monomers one at a time, creating a soluble ‘nanostar’ complex. This complex is then sieved from reaction debris after each cycle using a molecular separation membrane. Using membranes for the crucial separation step overcomes current state-of-the-art: (i) it takes place in the liquid phase, removing issues of intra-particle diffusional limitations; (ii) it is scalable; and (iii) it allows for in-line monitoring for reaction completion, essential to obtaining high purity. The current early- stage, non-optimised nanostar synthesiser produces a 20mer oligo with purity 90%, compared to 70- 80% crude-purity for the same oligo from SPS. Furthermore, Nanostar Sieving is chemistry-agnostic, meaning it is compatible with a wide variety of conditions and chemical syntheses, safeguarding the technology as synthetic routes are developed and improved.
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