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.
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.
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027, United States ; Division of Hematology-Oncology, Department of Pediatrics, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA 90027, United States ; Translational and Clinical Sciences Program, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA 90027, United States.
Fatih M
FM
Uckun
RetroTherapy LLC, Bethesda, MD 20814, United States.
Lloyd G
LG
Mitchell
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027, United States ; Bioinformatics Program, Gustavus Adolphus College, 800 W College Avenue, St. Peter, MN 56082, United States.
Sanjive
S
Qazi
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign (UIUC) Bioengineering Department, Urbana, IL 61801, United States.
Yang
Y
Liu
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign (UIUC) Bioengineering Department, Urbana, IL 61801, United States.
Nan
N
Zheng
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027, United States.
Dorothea E
DE
Myers
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign (UIUC) Bioengineering Department, Urbana, IL 61801, United States.
Ziyuan
Z
Song
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027, United States.
Hong
H
Ma
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign (UIUC) Bioengineering Department, Urbana, IL 61801, United States.
Jianjun
J
Cheng
D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002999:Clone Cells; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010455:Peptides / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D057285:Precision Medicine; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D020543:Proteome / Q000378:metabolism; D012313:RNA / Q000235:genetics; D012307:Risk Factors; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000378:metabolism*; D020040:Trans-Splicing / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D010455:Peptides; D010750:Phosphoproteins; D020543:Proteome; D051918:Sialic Acid Binding Ig-like Lectin 2; D012313:RNA
Alternative splicing; Cancer; Driver lesion; Gene therapy; Leukemia; Leukemogenesis; Nanomedicine; Personalized medicine; RNA therapeutics; RNA trans-splicing