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
Affiliations
Fatih M. Uckun
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027, United States
Lloyd G. Mitchell
RetroTherapy LLC, Bethesda, MD 20814, United States
Sanjive Qazi
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027, United States
Yang Liu
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign (UIUC) Bioengineering Department, Urbana, IL 61801, United States
Nan Zheng
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign (UIUC) Bioengineering Department, Urbana, IL 61801, United States
Dorothea E. Myers
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027, United States
Ziyuan Song
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign (UIUC) Bioengineering Department, Urbana, IL 61801, United States
Hong Ma
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027, United States
Jianjun Cheng
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign (UIUC) Bioengineering Department, Urbana, IL 61801, United States
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.
