NDLI: Effects of CD49d-targeted antisense-oligonucleotide on α4 integrin expression and function of acute lymphoblastic leukemia cells: Results of in vitro and in vivo studies.

Content Provider	Directory of Open Access Journals (DOAJ)
Author	Yann Duchartre Stefanie Bachl Hye Na Kim Eun Ji Gang Solah Lee Hsiao-Chuan Liu Kirk Shung Ruth Xu Aaron Kruse George Tachas Halvard Bonig Yong-Mi Kim
Abstract	We recently demonstrated the effectiveness of blocking CD49d with anti-functional antibodies or small molecule inhibitors as a rational targeted approach to the treatment of acute leukemia in combination with chemotherapy. Antisense oligonucleotide promises to be no less specific than antibodies and inhibitors, but more interesting for pharmacokinetics and pharmacodynamics. We addressed this using the published CD49d antisense drug ATL1102. In vitro, we incubated/nucleofected the ALL cell line Kasumi-2 with ATL1102. In vivo, immunodeficient hosts were engrafted with primary ALL cells and treated with ATL1102. Changes in expression of CD49d mRNA and CD49d protein, and of cooperating gene products, including ß1 integrin and CXCR4, as well as survival in the mouse experiments were quantified. We observed dose-dependent down-regulation of CD49d mRNA and protein levels and its partner integrin ß1 cell surface protein level and, up-regulation of CXCR4 surface expression. The suppression was more pronounced after nucleofection than after incubation, where down-regulation was significant only at the higher doses. In vivo effects of ATL1102 were not sufficient to translate into "clinical" benefit in the leukemia model. In summary, antisense oligonucleotides are successful tools for specifically modulating gene expression but sufficient delivery to down-regulate CD49d in vivo may be difficult to achieve.
e-ISSN	19326203
DOI	10.1371/journal.pone.0187684
Journal	PLoS ONE
Issue Number	11
Volume Number	12
Language	English
Publisher	Public Library of Science (PLoS)
Publisher Date	2017-01-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Medicine Science
Content Type	Text
Resource Type	Article

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