Automated Fast-Flow Synthesis of Antisense Phosphorodiamidate Morpholino Oligomers
2020
The
antisense phosphorodiamidate morpholino oligomer (PMO) drugs Eteplirsen and Golodirsen
are improving the lives of some Duchenne muscular dystrophy (DMD) patients, but
treating all DMD subtypes would require the development of over 50 novel
antisense therapies. To rapidly prototype personalized PMO for diseases such as
DMD, we designed a fully automated flow-based oligonucleotide synthesizer. Our
optimized high temperature synthesis platform reduces coupling times by up to
22-fold compared to previously reported batch methods. We demonstrate the power
of our new automated technology with the synthesis of milligram quantities of
an 18-mer reporter PMO sequence in 3.5 hours, three new potential therapeutic
PMO sequences targeted to exon 46 of the dystrophin gene in a single day, and a
candidate antiviral PMO sequence targeted to the SARS-CoV-2 genomic mRNA in 3.5
hours. This flexible flow synthesis platform can be used for on-demand
production of a broad range of personalized therapeutic polymers.
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