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
-
- Genetic Therapy/methods*
- Cell Transformation, Neoplastic
- Genes, Transgenic, Suicide/genetics*
- Zebrafish
- Caspase 9/genetics*
- Genetic Vectors/genetics*
- Dependovirus/genetics*
- Humans
- Sialic Acid Binding Ig-like Lectin 3/genetics*
- Cell Line, Tumor
- Leukemia, Myeloid, Acute/genetics*
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/therapy
- Gene Expression
- Animals
- PubMed
- 31436412 Full text @ Bioconjug. Chem.
Citation
Khan, N., Bammidi, S., Jayandharan, G.R. (2019) A CD33 antigen targeted AAV6 vector expressing an inducible caspase-9 suicide gene is therapeutic in a xenotransplantation model of acute myeloid leukemia. Bioconjugate Chemistry. 30(9):2404-2416.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping