Our annual survey of some of the best (and most handsomely financed) science that was commercialized from academia in 2021 kicks off with orna_tx, the most visible company advancing the technology of circular RNA therapeutics
The success of the Pfizer/BioNTech and Moderna COVID-19 mRNA vaccines has galvanized research on mRNA therapeutics. Rather than use mRNA to make antigens, the objective of mRNA therapeutics is to make proteins on demand inside patients’ cells within a tissue of interest at a level and duration sufficient to achieve treatment benefit.
Wesselhoeft confirmed that these circRNAs persist in cells longer than modified mRNA typified by the Pfizer and Moderna vaccines. The circRNA also produced larger amounts of protein than modified linear mRNA, over a longer period, in part due to the discovery of new cap-independent RNA translation sequences , RNA elements that recruit ribosomes to internal regions of RNA.
Orna’s lead program is ‘in situ CAR’ therapy for cancer. CARs, or chimeric antigen receptors, express an antibody-like fusion protein linked to a T cell receptor intracellular domain, using antigen binding to activate T cells against the target. Five autologous engineered CAR-T cell therapies are FDA approved for blood cancers, all involving ex vivo cellular engineering via lentiviral transduction before reinfusion.
CircRNA has two main theoretical concerns. One is that Orna’s circularization method unavoidably leaves behind small fragments of cyanobacterial ribozyme mRNA at the ligation junction. “It’s possible that some of those remnants may, at least in some contexts, be immunogenic,” says Thoreen. “That would be bad from any kind of therapeutic standpoint because they’ll limit any kind of protein that could be produced from those RNAs.” Such an outcome is very unlikely, counters Wesselhoeft.
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