Silencing the leukaemic fusion gene RUNX1/ETO by siRNA-loaded lipid nanoparticles restores myeloid differentiation

Leukeamias are often driven by the expression of leukaemic-specific fusion genes. Exclusive targeting using RNA interference is therefore an attractive therapeutic concept, but lacks so far suitable delivery systems. Here, we use targeted lipid nanoparticles (LNPs) containing siRNA (siRE) to reduce RUNX1/ETO protein expression in patient-derived AML cells.

We generated LNPs using microfluidic mixing followed by decoration with a modified short LDV peptide that has high affinity towards the very late antigen-4 (VLA-4). Compared to non-targeted LNPs, LDV-LNPs showed an enhanced uptake in RUNX1/ETO positive cell lines and patient-derived cells within the first 8 hours. In addition, a single dose of LDV-LNPsiRE resulted in significant knockdown of RUNX1/ETO transcripts. Sequential treatment prolonged and enhanced this effect. Multiparameter flow cytometry analysis of patient cells show the restoration of myeloid differentiation upon RUNX1/ETO depletion. Currently, in vivo biodistribution and efficacy studies using orthotopic mouse models are ongoing.

Thus, targeted LNP-mediated delivery of siRNAs might be a promising new approach for the treatment of fusion gene-driven leukaemias.

Publication History

Article published online:
17 May 2022