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Polymorphisims in the human cyp2d6 gene promoter region and their use in diagnostic and therapeutic applications

a technology of cyp2d6 and promoter region, which is applied in the direction of enzymology, drug composition, cardiovascular disorder, etc., can solve the problems of individual um phenotype at risk of therapeutic failure, adverse side effects, etc., and achieves improved drug tolerance, reduced overhead, and improved health care

Inactive Publication Date: 2012-10-25
TRANSGENOMIC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is based on the discovery of new variations in the nucleotide sequences of the CYP2D6 gene promoter and the distribution of these alleles in different populations. This knowledge has been used to design diagnostic tests and reagents for detecting and genotyping these alleles in humans. The determination of the CYP2D6 promoter allele status is useful for optimizing therapies with drugs that are substrates of CYP2D6. The invention provides polynucleotides, vectors, and host cells containing the new variants of CYP2D6 gene promoter. These variants have the potential to create a pharmacodynamic profile for a given patient, which can help in developing personalized medicine.

Problems solved by technology

Individuals with the UM phenotype are at risk to experience therapeutic failure due to abnormally fast clearance of the drug whereas IMs may be comparable to PMs in their risk to develop adverse side effects and toxicity.

Method used

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  • Polymorphisims in the human cyp2d6 gene promoter region and their use in diagnostic and therapeutic applications
  • Polymorphisims in the human cyp2d6 gene promoter region and their use in diagnostic and therapeutic applications
  • Polymorphisims in the human cyp2d6 gene promoter region and their use in diagnostic and therapeutic applications

Examples

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example 1

[0059]Genomic samples, isolated by standard techniques from human blood samples were obtained from healthy volunteers under consideration of all legal, ethical and medical requirement of the local ethics committee. Blood samples from >50 individuals were obtained and processed by ion exchange chromatography methods (Qiagen) to isolate DNA.

1. Description of Methods:

[0060]DNA Samples and PCR Conditions:

[0061]Leucocyte DNA from Caucasian individuals was isolated from blood samples by standard methods. All indiciduals included in this study had been previously phenotyped with sparteine and genotyped for the CYP2D6-polymorphism using published methods (StUven et al., 1996; Griese et al., 1998). To investigate the promoter region of the CYP2D6 gene, genomic DNA was amplified using a pair of primers upf14 and upr1669, designed to specifically amplify a 1656 by fragment which contains almost the entire known 5′-flanking sequence (FIG. 1, Table 1). Aliquots of each PCR product were subjected...

example 2

[0072]CYP2D6 was quantitated immunologically and enzymatically in liver biopsies from 76 individuals with known sparteine oxidation phenotype. All important known alleles including the −1584 C / G promoter polymorphism were determined.

1. Description of Methods:

[0073]Patients and Liver Samples. Liver tissue was obtained as wedge biopsy specimens from patients undergoing cholecystectomy between 1983 and 1986 and stored at −80° C. All patients included here had been phenotyped with respect to their sparteine metabolizer phenotype before laparotomy (Osikowska-Evers et al., 1987).

[0074]CYP2D6 Genotypinq. CYP2D6 alleles were assigned based on the determination of the appropriate key mutations using established PCR assays for alleles *2, *3, *4, *5, *6, *7, *8, *9, and *10 (Steven et al., 1996; Griese et al., 1998). The C / G mutation was determined using a novel real-time PCR method (Zanger et al., 2001).

[0075]Preparation of DNA and of Liver Microsomes. Genomic DNA was isolated from a fractio...

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PUM

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Abstract

Provided are polynucleotides of molecular variant promoters of the CYP2D6 gene which, for example, are associated with abnormal drug response or individual predisposition to several common diseases and disorders caused by drug under- or over-metabolization, and vectors comprising such polynucleotides. Furthermore, methods of diagnosing the status of disorders related to intermediate metabolization of drugs are described. In addition, kits comprising oligonucleotides hybridizing to the CYP2D6 promoter and / or being capable of being extended into this region useful for diagnosing subjects that are ultrarapid or intermediate metabolizer of drugs are provided.

Description

FIELD OF THE INVENTION[0001]The present invention relates generally to means and methods of diagnosing and treating the phenotypic spectrum as well as the overlapping clinical characteristics with several forms of inherited abnormal expression and / or function of the cytochrome P-450 (CYP)2D6 gene. In particular, the present invention relates to polynucleotides of molecular variant promoters of the CYP2D6 gene which, for example, are associated with abnormal drug response or individual predisposition to several common diseases and disorders caused by drug under- or overmetabolization, and to vectors comprising such polynucleotides. Furthermore, the present invention relates to host cells comprising such polynucleotides or vectors. Moreover, the present invention relates to methods for identifying and obtaining drug candidates for therapy of disorders related to the malfunction of the CYP2D6 gene as well as to methods of diagnosing the status of such disorders. The present invention f...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N15/11C12N1/00C12N15/63A61K31/137A61P25/00A61P9/06A61P25/24A61P35/00A61P25/04C12Q1/68C07C211/27C12N15/09A61K45/00A61P43/00C07K14/47C12N1/15C12N1/19C12N1/21C12N5/10C12N9/02C12Q1/26C12Q1/6883
CPCC12N9/0077C12Q2600/156C12Q1/6883A61P25/00A61P25/04A61P25/24A61P35/00A61P43/00A61P9/06
Inventor RAIMUNDO, SEBASTIANZANGER, ULRICH
Owner TRANSGENOMIC
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