Antibody-Antisense Oligonucleotide Conjugate Downregulates a Key Gene in Glioblastoma Stem Cells

Amy E. Arnold; Elise Malek-Adamian; Phuong U. Le; Anika Meng; Saúl Martínez-Montero; Kevin Petrecca; Masad J. Damha; Molly S. Shoichet

doi:10.1016/j.omtn.2018.04.004

Molecular Therapy: Nucleic Acids (Jun 2018)

Antibody-Antisense Oligonucleotide Conjugate Downregulates a Key Gene in Glioblastoma Stem Cells

Amy E. Arnold,
Elise Malek-Adamian,
Phuong U. Le,
Anika Meng,
Saúl Martínez-Montero,
Kevin Petrecca,
Masad J. Damha,
Molly S. Shoichet

Affiliations

Amy E. Arnold: Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada
Elise Malek-Adamian: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada
Phuong U. Le: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
Anika Meng: Division of Engineering Science, University of Toronto, 35 St. George Street, Toronto, ON M5S 1A4, Canada
Saúl Martínez-Montero: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada
Kevin Petrecca: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
Masad J. Damha: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada
Molly S. Shoichet: Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada

DOI: https://doi.org/10.1016/j.omtn.2018.04.004
Journal volume & issue: Vol. 11, no. C
pp. 518 – 527

Abstract

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Glioblastoma stem cells (GSCs) are invasive, treatment-resistant brain cancer cells that express downregulated in renal cell carcinoma (DRR), also called FAM107A, a genetic driver of GSC invasion. We developed antibody-antisense oligonucleotide (AON) conjugates to target and reduce DRR/FAM107A expression. Specifically, we used antibodies against antigens expressed on the GSCs, such as CD44 and EphA2, conjugated to chemically modified AONs against DRR/FAM107A, which were designed as chimeras of DNA and 2′-deoxy-2′-fluoro-beta-D-arabinonucleic acid (FANA) for increased nuclease stability and mRNA affinity. We demonstrate that these therapeutic conjugates successfully internalize, accumulate, and reduce DRR/FAM107A expression in patient-derived GSCs. This is the first example of an antibody-antisense strategy against cancer stem cells.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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