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
Year: 2015
Type: article
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.
Source: EBioMedicine
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,780
Funders: National Science Foundation, U.S. Department of Health and Human Services, Ronald McDonald House Charities, V Foundation for Cancer Research, North Carolina Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Cairo University, National Cancer Institute, Division of Chemistry
Awards: G130212128, G1745093857, Amplifying Radiation Potency Against Leukemic Stem Cells, Poly(alpha-hydroxy acids) via Ring-Opening Polymerization of O-Carboxyanhydrides, Developing Clinically Applicable, Cancer-Targeting Polymeric Nanoconjugates, Targeting SYK Tyrosine Kinase to Overcome Radiation Resistance in ALL, G59106282, G7076870511, Targeting SYK Kinase in B-Lineage ALL with CD19-Specific C-61 Nanoparticles, G8960800728, University of Southern California Norris Comprehensive Cancer Center Support Grant (CCSG), Correcting Aberrant Splicing of the Human CD22 Gene, G930688475
OpenAlex ID: W2077753291