Efficient Gene Silencing in Brain Tumors with Hydrophobically Modified siRNAs.

Autor:	Osborn MF; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts.; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts., Coles AH; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts.; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts., Golebiowski D; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts.; Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts., Echeverria D; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts.; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts., Moazami MP; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts.; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts., Watts JK; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts.; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts., Sena-Esteves M; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts. Anastasia.Khvorova@umassmed.edu Miguel.Esteves@umassmed.edu.; Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts., Khvorova A; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts. Anastasia.Khvorova@umassmed.edu Miguel.Esteves@umassmed.edu.; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2018 Jun; Vol. 17 (6), pp. 1251-1258. Date of Electronic Publication: 2018 Apr 13.
DOI:	10.1158/1535-7163.MCT-17-1144
Abstrakt:	Glioblastoma (GBM) is the most common and lethal form of primary brain tumor with dismal median and 2-year survivals of 14.5 months and 18%, respectively. The paucity of new therapeutic agents stems from the complex biology of a highly adaptable tumor that uses multiple survival and proliferation mechanisms to circumvent current treatment approaches. Here, we investigated the potency of a new generation of siRNAs to silence gene expression in orthotopic brain tumors generated by transplantation of human glioma stem-like cells in athymic nude mice. We demonstrate that cholesterol-conjugated, nuclease-resistant siRNAs (Chol-hsiRNAs) decrease mRNA and silence luciferase expression by 90% in vitro in GBM neurospheres. Furthermore, Chol-hsiRNAs distribute broadly in brain tumors after a single intratumoral injection, achieving sustained and potent (>45% mRNA and >90% protein) tumor-specific gene silencing. This readily available platform is sequence-independent and can be adapted to target one or more candidate GBM driver genes, providing a straightforward means of modulating GBM biology in vivo Mol Cancer Ther; 17(6); 1251-8. ©2018 AACR . (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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