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European Biopharmaceutical Review

Produce Potential

Custom-made oligonucleotides are commonly produced by solid phase synthesis, where the sequence is grown chemically on a resin in a 3’-5’ direction (1). Each amidite/nucleotide monomer has a 5’ trityl-blocking group to prevent addition of more than one nucleotide in each synthesis step that is cleaved off prior to the start of next coupling reaction (2). The completed oligonucleotide is released from the solid support by ammonolysis. Although the solid-phase technology gives a very low synthesis error rate, a small percentage of sequences where the oligonucleotide has deletions are always present, such as N-1 sequences and depurinations (where the nucleic base has been cleaved off), or extra insertions of elements (eg, N+1) (3). The frequency of failures increases with length of the synthesised oligonucleotide.

Antisense oligonucleotides (ASOs) are DNA sequences designed to bind complementary RNA targets (mainly mRNAs) to affect gene expression. Antisense gene therapy is emerging as one of the most promising therapeutics for various diseases, such as cancer (4-5). As of 2017, six FDAapproved ASO-based therapies are on the market, and many are in clinical trials (6). Most of the ASO molecules currently in clinical trials are phosphorothioates: modified nucleic acids in which one of the non-bridging oxygens on the phosphate backbone is replaced by a sulphur (7). This modification increases the half-life of the oligonucleotide. In addition to the mentioned synthesis errors, the phosphorothioate linkage of phophorotioates might be oxidised to a phosphodiester linkage, (P=O)x.

Due to the stringent requirements in therapeutic applications, efficient purification schemes to produce oligonucleotides with a minimum of erroneous sequences are a necessity.

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Dr Cecilia Unoson is a Senior Application Scientist at Bio-Works Technologies and has a PhD from the Department of Cellular and Molecular Biology at Uppsala University, Sweden. Cecilia has 15 years’ experience working with oligonucleotides, especially within the RNA field, where she has focussed on regulatory RNAs and the CRISPR-Cas9 system. She also has a strong background in proteomics and has worked in both small and large biotech companies. Today, Cecilia is responsible for the oligonucleotide applications at Bio-Works Technologies.

Dr Lars Haneskog is the R&D director at Bio-Works Technologies, with a PhD in bioseparation and membrane proteins from Uppsala University, Sweden. The research focus was bioseparation and membrane proteins. He has more than 20 years of experience in chromatographic purification of biomolecules, and development of chromatography products.
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Dr Cecilia Unoson
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Dr Lars Haneskog
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