Abstract:
Leukemias are often driven by the expression of leukemic-specific fusion genes. Exclusive targeting of these fusion genes using RNA interference is therefore an attractive therapeutic concept. Lipid nanoparticles (LNPs) have evolved rapidly as promising delivery systems for oligonucleotides, including siRNAs. Current approaches, however, show high liver accumulation after systemic administration thereby limiting treatment of extrahepatic diseases including leukemia. In this thesis, I developed targeted LNPs for the treatment of leukemia. LNPs were generated using microfluidic mixing followed by surface functionalization with a modified short peptide that displays high affinity towards the very late antigen-4 (VLA-4) receptor. LDV-targeted LNPs showed an enhanced uptake in patient-derived leukemia cells, compared to non-targeted LNPs. In addition, a single dose resulted in significant knockdown of the fusion gene transcript and altered target genes. Sequential treatment prolonged and enhanced this effect. Moreover, in vivo biodistribution studies showed that surface-modified LNPs displayed significantly improved uptake by immature hematopoietic stem cells, also suggesting similarly improved uptake by leukemic stem cells. To conclude, this thesis thereby supports the further development of LNPs for targeted therapeutic interventions for leukemia.
