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

作者：Uckun Fatih M^*; Mitchell Lloyd G; Qazi Sanjive; Liu Yang; Zheng Nan; Myers Dorothea E; Song Ziyuan; Ma Hong; Cheng Jianjun

来源：EBioMedicine, 2015, 2(7): 649-659.

DOI：10.1016/j.ebiom.2015.04.016

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

CD22 Delta E12 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 CD22 Delta E12 signature transcriptome that shows a striking representation in primary human leukemia cells from patients with relapsed BPL. Our data uniquely indicate that CD22 Delta E12 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 CD22 Delta E12+ 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 CD22 Delta E12-RTM with potent anti-cancer activity against CD22 Delta E12+ 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.

• 出版日期2015-7