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Compositions and Methods for Treating Glioblastoma GBM

a glioblastoma and composition technology, applied in the field of compositions and methods for treating glioblastoma multiforme, can solve the problems of increased aggressiveness, poor prognosis, increased malignancy and poor prognosis

Inactive Publication Date: 2013-08-15
VASCULAR BIOGENICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a use of a viral vector for the treatment of malignant glioma. The vector comprises a nucleic acid construct that includes a first polynucleotide sequence encoding a Fas-chimera (Fas-c) and a second polynucleotide sequence encoding an endothelial cell-specific promoter or a periendothelial cell-specific promoter. The vector can be administered to a subject in need thereof in a therapeutically effective amount. The technical effect of the invention is to provide an effective treatment for malignant glioma by using a viral vector to deliver a therapeutic nucleic acid sequence to the brain tumor cells.

Problems solved by technology

Various malignant gliomas, such as glioblastomas, exhibit epidermal growth factor receptor (EGFR) overexpression leading to increased aggressiveness and poor prognosis.
Malignant gliomas may also display over-expression of platelet-derived growth factor receptor, a phenomenon which has also been correlated with increased malignancy and poor prognosis.
It is effective in inhibiting tumor growth but not in actually eliminating them.
In comparison with drugs targeting VEGF or VEGFR, agents inhibiting other angiogenic pathways have produced less success.
Drugs that inhibit PDGF receptors such as imatinib mesylate (Gleevec) were ineffective, due partly to its poor penetration across the blood-brain barrier.

Method used

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  • Compositions and Methods for Treating Glioblastoma GBM
  • Compositions and Methods for Treating Glioblastoma GBM
  • Compositions and Methods for Treating Glioblastoma GBM

Examples

Experimental program
Comparison scheme
Effect test

example 1

Effect of VB-111 in an Animal Model of Glioblastoma

[0336]Materials and Methods

[0337]Construction and Cloning of the Viral Vector:

[0338]The vector was constructed using a backbone containing most of the genome of adenovirus type 5, as well as partial homology to an adaptor plasmid, which enables recombination.

[0339]The E1 early transcriptional unit was deleted from the backbone plasmid, and further modified by deleting the pWE25 and the Amp resistance selection marker site.

[0340]The adaptor plasmid, containing sequences of the Ad5, CMV promoter, MCS, and SV40 polyA was modified to delete deleting the CMV promoter, and the PPE-1 promoter and Fas-c fragment were inserted by restriction digestion.

[0341]The modified PPE-1 promoter (PPE-1-3X, SEQ ID NO: 12) and the Fas-chimera transgene (Fas-c, SEQ ID NO: 4) were utilized for construction of the adenoviral vector. The PPE-1-(3X)-Fas-c element (2115 bp) was constructed from the PPE-1-(3X)-luc element. This element contains the 1.4 kb of th...

example 2

Effect of VB-111 in Glioblastoma Patients

[0359]Treatment Plan:

[0360]VB-111 will be administered as a single intravenous infusion of 1×1012 or 3×1012 Dose.

[0361]Study consists of 2 cohorts.

[0362]Cohort 1a: 3-6 subjects, safety (1×1012 VPs);

[0363]Cohort 1b: 3-6 subjects, safety (3×1012 VPs);

[0364]Cohort 2: 23-26 subjects, efficacy & safety (3×1012 VPs)

[0365]Cohort 1a & Cohort 1b: Study subjects will be enrolled sequentially. The first subject of each cohort will be treated and observed for 14 days; if no dose-limiting toxicities (DLT) are observed, then another two subjects will be recruited to that cohort. All six subjects of cohort 1 need to be observed for a minimum of 14 days and show no DLT for the start of the next cohort. If a DLT is observed in one patient in a specific dosing cohort, three additional subjects will be accrued for the same dosing cohort, and safety will be reassessed. If DLT is confirmed, i.e. two out of six subjects experience a DLT, then the study will be dis...

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Abstract

Methods of treating a malignant glioma in a subject are disclosed. The methods comprise administering to the subject a therapeutically effective amount of a viral vector comprising: (i) a first polynucleotide sequence encoding a Fas-chimera (Fas-c), said first polynucleotide sequence comprising SEQ ID NOs: 2 and 3; and (ii) a second polynucleotide sequence encoding an endothelial cell-specific promoter or a periendothelial cell-specific promoter.

Description

FIELD AND BACKGROUND OF THE INVENTION[0001]The present invention, in some embodiments thereof, relates to compositions and methods for treating malignant gliomas and, more particularly, but not exclusively, for treating Glioblastoma multiforme (GBM).[0002]Malignant gliomas, the most common adult-onset neurological neoplasms, encompass a family of primary central nervous system tumors including glioblastoma, astrocytoma, oligodendroglioma, and ependymoma, along with the juvenile onset neoplasms such as juvenile pilocystic astrocytoma.[0003]Malignant gliomas are typically characterized by over-expression of growth factors / tumor associated antigens believed to significantly contribute to the unchecked growth of such tumors. Various malignant gliomas, such as glioblastomas, exhibit epidermal growth factor receptor (EGFR) overexpression leading to increased aggressiveness and poor prognosis. Malignant gliomas may also display over-expression of platelet-derived growth factor receptor, a ...

Claims

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Application Information

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IPC IPC(8): A61K38/17A61K39/395A61N5/10A61K48/00A61K38/16A61K39/00
CPCA61K38/162A61K2039/5258C07K14/70578C12N2799/022Y02E60/36A61N2005/1087A61K39/39558A61K48/005A61N5/1001A61N5/1077A61K38/177A61P25/00A61P35/00A61K31/7088A61K48/00C12N15/00C12N15/861
Inventor COHEN, YAELBANGIO, LIVNATBRENNER, ANDREW J.BREITBART, EYAL
Owner VASCULAR BIOGENICS
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