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Composition and methods of RNAi therapeutics for treatment of cancer and other neovascularization diseases

a technology of neovascularization disease and rnai, which is applied in the field of composition and methods, can solve the problems of ineffective agents for many patients, insufficient benefits for most patients, and difficult observation of rnai effects in adult animal models

Inactive Publication Date: 2008-06-26
INTRADIGM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0020]One aspect of the present invention provides compositions and methods for treatment of cancer, arthritis, blindness, infectious diseases and inflammatory diseases. In another aspect of the present invention nucleic acid agents inducing RNAi are used in concert with other therapeutic agents, such as but not limited to small molecules and monoclonal antibodies (mAb), in the same therapeutic regimen.
[0021]Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Problems solved by technology

Some of these agents act by binding to and inhibiting the action of Vascular Endothelial Growth Factor (VEGF), but these agents are not effective for many patients.
However, these benefits are still inadequate for most patients and better therapeutic means to control the VEGF pathway still are needed.
One problem that has emerged with use of antagonists appears to be a response by the pathological tissues to increase production of VEGF.
However, RNAi effects have been difficult to observe in adult animal models(57).
Although RNAi has potential applications in both gene target validation and nucleic acid therapeutics, progress of the technology has been hindered due to the poor delivery of RNAi molecules into animal disease models.

Method used

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  • Composition and methods of RNAi therapeutics for treatment of cancer and other neovascularization diseases
  • Composition and methods of RNAi therapeutics for treatment of cancer and other neovascularization diseases
  • Composition and methods of RNAi therapeutics for treatment of cancer and other neovascularization diseases

Examples

Experimental program
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Effect test

example 1

Tumor Growth Inhibition with Combination Use of siRNA Duplexes Targeting VEGFR2 and Bevacizumab (Avastin) against VEGF

Material and Methods.

[0113]Reagents: Avastin, monoclonal antibody against VEGF (25 mg / ml, Genetech); siRNA against mouse VEGFR2, sequence ((a) AAGCTCAGCACACAGAAAGAC (SEQ ID NO: 247); (b) AATGCGGCGGTGGTGACAGTA) (SEQ ID NO: 248); siRNA against luciferase (Qiagen); Avertin made of 1.5 gram 2,2,2,Tribromoethanol and 1.5 ml t-amyl alcohol (Cat# T4840-2, Cat#24048-6, Aldrich) in 100 ml distill water, St. Louis, Mo.]. Mice: athymus female nude mice, 5 to 6 weeks old, were purchased from TACONIC and housed conventionally. All investigations followed guidelines of the Committee on the Care of Laboratory Animals Resources, Commission of Life Sciences, National Research Council. The animal facility of Biomedical Research Institute in Rockville Maryland is fully accredited by the American Association of Laboratory Animal Care. Cells: Colon carcinoma cell line, DLD-1 (CCL-221, AT...

example 2

siRNA-Mediated VEGF Silencing In Vitro and In Vivo

[0123]Human VEGF 165 specific siRNA was transfected into the MCF-7 / VEGF 165 cell (hVEGF over-expression) by Lipofectamine resulting in knockdown of hVEGF mRNA in the cell (FIG. 2 upper panel). Using an electroporation procedure, MCF-7 / VEGF 165 cells were transfected by hVEGF 165 specific siRNA, resulting in down regulation of hVEGF expression as determined with an ELISA analysis.

[0124]When the hVEGF165 specific siRNA were delivered through intratumoral administration repeatedly, the growth of MCF-7 / VEGF 165 cell induced xenograft tumors were significantly inhibited. This inhibition was further validated when the tumor tissues were collected for testing hVEGF mRNA expression which resulted in significant down regulation based on RT-PCR analysis. Using the same hVEGF165 specific siRNA, we are also able to demonstrate tumor growth inhibition with head and neck squamous cell carcinoma (HNSCC, 1483 cell) xenograft model, through 5 repeate...

example 3

25 Basepair Blunted Double-Stranded siRNA is More Potent than Regular 19 Basepair siRNA with 3′-Overhangs in Silencing Target Gene Expression

[0125]In one of in vitro siRNA transfection studies, the MCF / 165 breast cancer cells overexpressing human VEGF (hVEGF) were transfected with either 25 basepair blunted double-stranded siRNA (hVEGF-25-siRNA-a, hVEGF-25-siRNA-b, hVEGF-25-siRNA-c, Luc-25-siRNA) or 19 basepair siRNA with 3′ overhangs (hVEGF-siRNA-a, GFP-siRNA-a) using an electroporation mediated transfection method. 4×106 MCF7 / 165 cells were resuspended in 200 μl of siPORT siRNA Electroporation Buffer (Ambion) mixed with 5 μg siRNA and then subjected to electroporation treatment using an Electro Square Porator ECM830 (BTX, Fisher Scientific). The parameters for the electroporation are: voltage 500 v; duration of pulse 60 us; pulse number 2; pulse interval 1 second. The transfected cells were seeded to 24-well plate at a density of 5×104 cell / well and cultured at 37° C. incubator wi...

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Abstract

Compositions and methods are provided for treatment of diseases involving unwanted neovascularization (NV). The invention provides treatments that control NV through selective inhibition of pro-angiogenic biochemical pathways, including inhibition of the VEGF pathway gene expression and inhibition localized at pathological NV tissues. Tissue targeted nanoparticle compositions comprising polymer conjugates and nucleic acid molecules that induce RNA interference (RNAi) are provided. The nanoparticle compositions of the invention can be used alone or in combination with other therapeutic agents such as VEGF pathway antagonists. The compositions and methods can be used for the treatment of NV diseases such as cancer, ocular disease, arthritis, and inflammatory diseases.

Description

[0001]This application is a continuation application of International Application No. PCT / US06 / 13645, filed Apr. 12, 2006, which designates the United States and which claims priority under 35 U.S.C. §119(e) from U.S. Provisional Application No. 60 / 670,717, filed Apr. 12, 2005, the contents of which are hereby incorporated by reference in their entirety. The application also relates to the following applications, the contents of which are also incorporated by reference in their entireties: International Application No. PCT / US05 / 03858, filed Feb. 7, 2005; International Application No. PCT / US05 / 03857, filed Feb. 7, 2005; and International Application No. PCT / US03 / 24587, filed Aug. 6, 2003.FIELD OF THE INVENTION[0002]The invention provides compositions and methods for treatments of diseases with unwanted neovascularization (NV), often an abnormal or excessive proliferation and growth of blood vessels. The development of NV itself often times has adverse consequences or it can be an ear...

Claims

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Application Information

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IPC IPC(8): A61K31/70C12N15/113
CPCA61K9/0019A61K9/0048A61K9/5146A61K31/70A61K48/00C12N2320/32C12N15/1138C12N2310/14C12N2310/53C12N2320/31C12N15/1136A61P19/02A61P27/02A61P29/00A61P31/00A61P35/00A61P43/00A61P9/00
Inventor LIU, YIJIALU, PATRICK Y.WOODLE, MARTIN C.XIE, FRANK Y.
Owner INTRADIGM CORP
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