Clinical experience with tyrosine kinase inhibitors (TKIs) over the past two decades has shown that, despite the apparent therapeutic benefit, nearly 30% of patients with chronic myelogenous leukemia (CML) display primary resistance or intolerance to TKIs, and approximately 25% of those treated are forced to switch TKIs at least once during therapy due to acquired resistance.

Despite excellent progress in the past two decades with the introduction of targeted molecular therapies, new strategies to address TKI resistance and reduce the leukemic burden could be a game changer in the professional management of patients with CML unresponsive to current therapies.

Here, we report the results of a therapeutic oligonucleotide of original design that showed the ability to reduce BCR-ABL1 mRNA levels with remarkable efficiency by >99% after a single application and to induce cell death in all TKI-resistant cells, including those with the clinically relevant T315I mutation, by day 5 after redosing. The effect was selective for cancer cells, indicating a favorable safety profile for this therapeutic modality. The spontaneous cellular uptake of ASP210 and the high intracellular concentrations achieved suggest that ASP210 has the potential to be biologically effective at relatively low applied doses.

The present findings suggest that ASP210 is a promising therapeutic avenue for patients with CML who fail to respond to TKI therapy.

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