Efficient Gene Silencing in Brain Tumors with Hydrophobically Modified siRNAs
AuthorsOsborn, Maire F.
Coles, Andrew H.
Moazami, Michael P.
Watts, Jonathan K.
UMass Chan AffiliationsDepartment of Biochemistry and Molecular Pharmacology
Horae Gene Therapy Center
Department of Neurology
Program in Molecular Medicine
RNA Therapeutics Institute
KeywordsBiochemistry, Biophysics, and Structural Biology
Genetics and Genomics
MetadataShow full item record
AbstractGlioblastoma (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 vivoMol Cancer Ther; 17(6); 1251-8. ©2018 AACRin vivo.
Mol Cancer Ther. 2018 Jun;17(6):1251-1258. doi: 10.1158/1535-7163.MCT-17-1144. Epub 2018 Apr 13. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/48855