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Treatment of disease using an improved regulated expression system

A technology for expression system and treatment of diseases, applied in nervous system diseases, cardiovascular system diseases, digestive system, etc., can solve problems such as not suitable for clinical application, unable to express cells for a long time

Inactive Publication Date: 2008-08-06
BAYER SCHERING PHARMA AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of the known nucleic acid delivery systems are not suitable for clinical application and cannot produce regulated or long-term expression in cells
Only a few known nucleic acid delivery systems have been reported to be capable of modulating transgene expression under laboratory conditions, but the applicability and operability of these delivery systems for clinical applications is unknown (see e.g. M. Gossen and H. Bujard Science 268:1766 -69; D.No et al., (1996) Proc.Natl.Acad.Sci.USA 93:3346-51; J.F.Amara et al., (1997) Proc.Natl.Acad.Sci.USA 94:10618-23; Y. Wang (1994) Proc. Natl. Acad. Sci. USA 91: 8180-84; J.L. Nordstrom (2002) 13: 453-58)

Method used

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  • Treatment of disease using an improved regulated expression system
  • Treatment of disease using an improved regulated expression system
  • Treatment of disease using an improved regulated expression system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0438] Example 1: Construction of carriers for IFN-β or GMCSF gene therapy

[0439] A. Plasmid carrier: The murine IFN-β (mIFN-β) gene from the bacterial expression carrier pbSER189 was amplified by PCR, immunoglobulin kappa (IgK) (for protein purification) or mIFN-β (for gene expression treatment) signal sequence was added to the 5' primer. The PCR products were inserted downstream of the cytomegalovirus (CMV) promoter in the expression vectors pCEP4 / WPRE and pgWiz, respectively, to generate pGER90 (Figure 2A) for recombinant protein expression and purification and pGER101 for gene therapy ( Figure 2B).

[0440]The human IFN-β gene from the bacterial expression vector pbSER178 was PCR amplified and inserted into pCEP4 / WPRE and pgWiz, respectively, following the same procedure as the mIFN-β gene (except for the hIFN signal sequence for gene therapy vectors) In order to generate pGER123 for recombinant protein expression and purification (Fig. 2C) and pGER125 for gene therapy...

Embodiment 2

[0445] Example 2: Pharmacokinetic study of IFN-β gene delivery

[0446] A. Pharmacokinetic studies of human IFN-β: Pharmacokinetic studies were performed in normal mice to compare human IFN-β (hIFN-β) bolus protein delivery with gene-based delivery.

[0447] 1) Human IFN-β1a protein pharmacokinetic study: Pharmacokinetics in C57 / BI6 mice using bolus injection of recombinant hIFN-β1a delivered by intramuscular (i.m.) or intravenous (i.v) injection In this study, the serum levels of hIFN-β were detected by a commercially available ELISA. Figure 3 shows the pharmacokinetic curves of hIFN-β1a protein in mouse serum after a single intramuscular or intravenous injection of 25ng (1 μg / kg) or 250ng (10 μg / kg) hIFN-β1a protein. After intravenous injection, hIFN-β1a was detected in serum in a dose-dependent manner at the first time point (30 min) and then rapidly cleared, with levels approaching the limit of detection (LOD) of the assay by 6 h (LOD = 12.5 pg / ml). Serum levels of hIFN...

Embodiment 3

[0449] Example 3: Identification and Application of IFN-β Biomarkers for Gene Therapy

[0450] A: Development of mIFN-β biomarker: To detect murine IFN-β (mIFN-β) activity in vivo with higher sensitivity, after injection of mIFN-β protein or a gene therapy vehicle encoding mIFN-β in mice, Identification of biomarkers of mIFN-β activity. Biomarkers are available to monitor human IFN-β activity in clinical samples from patients treated with Betaseron (IFN-β1b) (see e.g. Arnason, BG (1996) Clin Immunol Immunopathol 81:1-11; Deisenhammer, F et al., (2000 ) Neurology 54:2055-60; Knobler, RL et al., (1993) J Interferon Res 13:333-40; Kracke, A et al., (2000) Neurology 541:193-9). A major biomarker for IFN-beta clinical studies is MxA (see e.g. Kracke, A et al., (2000) Neurology 541:193-9; Bertoloto, A et al., (2001) JImm Meth 256:141-152), Because it is specifically induced by type I IFN (see eg von Wussow, P et al. (1990) J Imm 20:2015-19). In this study, the MxA mouse homologue...

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Abstract

The present invention provides improved expression systems for the regulated expression of encoded protein or nucleic acid therapeutic molecules in cells of a subject to treat disease. In particular, the present invention provides improved systems and pharmaceutical compositions for modulating gene expression and their use in the treatment of disease.

Description

[0001] This application claims priority to US Provisional Application 60 / 682,761, filed May 19, 2005, which is hereby incorporated by reference in its entirety. field of invention [0002] The present invention relates to improved expression systems for the regulated expression of encoded protein or nucleic acid therapeutic molecules for disease treatment. In particular, the present invention relates to improved systems for modulating gene expression, their pharmaceutical compositions and uses for the treatment of diseases. Background of the invention [0003] Delivery of nucleic acids encoding therapeutic molecules (TMs) for disease treatment is considered a therapeutic modality with greater potential than conventional therapeutic approaches. Specifically, the delivery of nucleic acids encoding therapeutic proteins in gene therapy has the potential to offer significant advantages over conventional therapies that require the administration of large amounts of protein. These...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/63A61K48/00
CPCA61K48/00A61K48/0066C12N15/63C12N15/85C12N15/86C12N2750/14143C12N2799/04C12N2800/107C12N2800/108C12N2830/002C12N2830/42C12N2830/48C12N2830/60C12N2830/80C12N2840/20A61P1/16A61P25/00A61P31/12A61P35/00A61P43/00A61P9/00A61P9/10
Inventor M·鲍宗R·N·哈金斯T·赫米斯顿P·克雷特施默P·西曼斯基
Owner BAYER SCHERING PHARMA AG
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