Development of Polypeptide-based Nanoparticles for Non-viral Delivery of CD22 RNA Trans-splicing Molecule as a New Precision Medicine Candidate Against B-lineage ALL

Fatih M. Uckun, Lloyd G. Mitchell, Sanjive Qazi, Yang Liu, Nan Zheng, Dorothea E. Myers, Ziyuan Song, Hong Ma, Jianjun Cheng

Research output: Contribution to journalArticle

Abstract

CD22δE12 has emerged as a driver lesion in the pathogenesis of pediatric B-lineage acute lymphoblastic leukemia (ALL) and a new molecular target for RNA therapeutics. Here we report a 43-gene CD22δE12 signature transcriptome that shows a striking representation in primary human leukemia cells from patients with relapsed BPL. Our data uniquely indicate that CD22δE12 is a candidate driver lesion responsible for the activation of MAPK and PI3-K pathways in aggressive forms of B-lineage ALL. We also show that the forced expression of a CD22 RNA trans-splicing molecule (RTM) markedly reduces the capacity of the leukemic stem cell fraction of CD22δE12+ B-lineage ALL cells to engraft and cause overt leukemia in NOD/SCID mice. We have successfully complexed our rationally designed lead CD22-RTM with PVBLG-8 to prepare a non-viral nanoscale formulation of CD22δE12-RTM with potent anti-cancer activity against CD22δE12+ B-lineage leukemia and lymphoma cells. CD22-RTM nanoparticles effectively delivered the CD22-RTM cargo into B-lineage ALL cells and exhibited significant anti-leukemic activity in vitro.

Original languageEnglish (US)
Pages (from-to)649-659
Number of pages11
JournalEBioMedicine
Volume2
Issue number7
DOIs
StatePublished - Jul 1 2015

Keywords

  • Alternative splicing
  • Cancer
  • Driver lesion
  • Gene therapy
  • Leukemia
  • Leukemogenesis
  • Nanomedicine
  • Personalized medicine
  • RNA therapeutics
  • RNA trans-splicing

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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