PUBLICATION

A CD33 antigen targeted AAV6 vector expressing an inducible caspase-9 suicide gene is therapeutic in a xenotransplantation model of acute myeloid leukemia

Authors
Khan, N., Bammidi, S., Jayandharan, G.R.
ID
ZDB-PUB-190823-9
Date
2019
Source
Bioconjugate Chemistry   30(9): 2404-2416 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Animals
  • Caspase 9/genetics*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Dependovirus/genetics*
  • Gene Expression
  • Genes, Transgenic, Suicide/genetics*
  • Genetic Therapy/methods*
  • Genetic Vectors/genetics*
  • Humans
  • Leukemia, Myeloid, Acute/genetics*
  • Leukemia, Myeloid, Acute/pathology
  • Leukemia, Myeloid, Acute/therapy
  • Sialic Acid Binding Ig-like Lectin 3/genetics*
  • Zebrafish
PubMed
31436412 Full text @ Bioconjug. Chem.
Abstract
Current chemotherapeutic regimens for acute myeloid leukemia (AML) has been modestly effective in patients, and are associated with poor long term survival (<30% at 5 years). Viral vector-based suicide gene therapy is an attractive option, if these vectors can target the AML cells with high specificity and efficiency. In this study, we have developed a receptor specific Adeno-associated virus (AAV) based vector to target the CD33 antigen which is over-expressed in leukemic cells. A targeting peptide was rationally designed from the antigen-binding regions of a CD33 monoclonal antibody. This peptide was further expressed on the capsid of AAV6 vector, since this serotype was most efficient among AAV1-rh10 vectors to infect the pro-monocytic, human myeloid leukemia cells (U937). AAV6-CD33 vectors expressing a suicide gene, the inducible caspase 9 (iCasp9) and its prodrug AP20187 significantly reduced (~59%) the viability of U937 cells. To further test its efficacy and specificity in vivo, AAV6-CD33 vectors were administered into a xenotransplantation model of AML in zebrafish through systemic delivery. We observed a significant anti-leukemic effect with AAV6-CD33 vectors, with a markedly higher survival (100% for AAV6-CD33 vectors vs. 15% for mock-treated) and higher number of TUNEL positive apoptotic cells after systemic vector delivery. Taken together, our work demonstrates the efficacy and translational potential of CD33-targeted AAV6 vectors for cytotoxic gene therapy in AML.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes