Compositions and methods using siRNA molecules for treatment of gliomas
Inventors
Yan, Hai • Lu, Patrick Y. • Bigner, Darell D.
Assignees
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Publication Number
US-8541568-B2
Publication Date
2013-09-24
Expiration Date
Abstract
The present invention provides small interfering RNA (siRNA) molecules, compositions containing the molecules, and methods of using the compositions to treat gliomas.
Core Innovation
The disclosed composition comprises at least three isolated siRNA molecules directed to mRNAs encoding VEGF, EGFR, and MGMT. These specified siRNAs bind mRNAs encoding the respective human proteins and mRNAs encoding the corresponding mouse proteins. The description also presents nanoparticle and polymer carrier formulations, targeting ligands, and compositions that include anticancer agents.
The disclosure identifies glioma treatment, including glioblastoma multiforme, as an application and reports findings identifying active siRNAs against multiple targets. Documented figures show target-gene knockdown screening results in human and mouse cells, compare angiogenesis following implantation, and depict microcellular siRNA delivery into lung, kidney, and tumor tissues. The description presents these screening results as evidence of biological activity, reporting target mRNA inhibition of up to 60 percent.
Claims Coverage
The claim coverage includes four inventive features centered around an independent claim and associated dependent claims directed to formulations and therapeutic combinations.
Multi-target siRNA composition
The composition comprises at least three isolated siRNA molecules, wherein at least one binds mRNAs encoding human and mouse VEGF, at least one binds mRNAs encoding human and mouse EGFR, and at least one binds mRNAs encoding human and mouse MGMT.
Nanoparticle formulation with a targeting ligand
Dependent claims describe formulating the siRNAs in a nanoparticle with a pharmaceutically acceptable carrier and a targeting ligand, including RGD, RVG, or FROP peptides.
Composition with a therapeutic agent
A dependent claim specifies the composition in combination with a therapeutic agent selected from bevacizumab, sunitinib, sorafenib, temsirolimus, or temozolomide.
Biodegradable polyester carrier
A dependent claim identifies PLA, PGA, or PLGA as biodegradable polyester materials in the carrier formulation.
The claims center on a multi-target siRNA composition directed to VEGF, EGFR, and MGMT mRNAs in humans and mice. Dependent claims add nanoparticle and carrier formulations, targeting ligands, biodegradable polyester materials, and specified therapeutic agents.
Stated Advantages
The reported experiments identify active siRNAs against multiple targets and report target mRNA inhibition of up to 60 percent.
Documented Applications
The composition is described for glioma treatment, including treatment of glioblastoma multiforme.
The composition is described for use with anticancer agents, including bevacizumab, sunitinib, sorafenib, temsirolimus, and temozolomide.
Target-gene knockdown screening by siRNA in human and mouse cells, including screening involving Ratf1, mTOR, TGF-β, and COX-2.
Microcellular siRNA delivery depicted in lung, kidney, and tumor tissues.
Comparison of angiogenesis following implantation between control groups and groups receiving VEGF-A/VEGFR-targeting siRNAs or mixed siRNA.
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