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

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


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.

Inventors: Sebastian Raimundo, Ulrich Zanger
USPTO Applicaton #: #20120270948 - Class: 514654 (USPTO) - 10/25/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >Nitrogen Containing Other Than Solely As A Nitrogen In An Inorganic Ion Of An Addition Salt, A Nitro Or A Nitroso Doai >Benzene Ring Containing >Amino Nitrogen Attached To Aryl Ring Or Aryl Ring System By An Acyclic Carbon Or Acyclic Chain >The Chain Consists Of Two Or More Carbons Which Are Unsubtituted Or Have Acyclic Hydrocarbyl Substituents Only

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The Patent Description & Claims data below is from USPTO Patent Application 20120270948, Polymorphisims in the human cyp2d6 gene promoter region and their use in diagnostic and therapeutic applications.

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FIELD OF THE INVENTION

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 furthermore provides kits comprising oligonucleotides hybridizing to the CYP2D6 promoter and/or being capable of being extended into this region useful for diagnosing subjects that are for example ultrarapid or intermediate metabolizer of drugs.

Several documents are cited throughout the text of this specification. Each of the documents cited herein (including any manufacturer\'s specifications, instructions, etc.) are hereby incorporated herein by reference; however, there is no admission that any document cited is indeed prior art as to the present invention.

BACKGROUND OF THE INVENTION

Cytochrome P450 CYP2D6 belongs to the CYP2 family of P450s and is the only functionally active isozyme of the CYP2D subfamily in humans. It is involved in the metabolism of up to 25% of all therapeutically used drugs (Hardman et al, 1995). The gene encoding its synthesis is located in the CYP2D locus at q13.1 on the long arm of chromosome 22 (Eichelbaum et al., 1987). It is part of a gene cluster containing also two pseudogenes CYP2D7P and CYP2D8P (Kimura et al., 1989). Like other members of the human CYP2 gene family, the CYP2D genes consist of 9 exons and 8 introns. The enzyme exhibits a common genetic polymorphism (Meyer and Zanger, 1997). In fact it was the first cytochrome P450 enzyme for which a genetic polymorphism was demonstrated which was named the debrisoquine/sparteine polymorphism based on the two substrates involved in its discovery (Mahgoub et al., 1977; Eichelbaum et al., 1979). Depending on the metabolic handling of these two probe drugs, between 5 and 10% of subjects of European populations have a severely impaired capacity to form the major metabolites 4-hydroxydebrisoquine and 2-dehydrosparteine. These subjects were designated as poor metabolizers (PM), the remainder of the population being so-called extensive metabolizers (EM). The trait ‘poor metabolism’ is inherited in an autosomal recessive fashion, i.e. PMs are carriers of two non-functional alleles. The molecular basis of this polymorphism has been extensively investigated and more than 30 functional and non-functional alleles have been described which allow to predict the PM phenotype in Caucasians with an estimated 99% reliability. (Daly et al., 1996 and CYP Allele Nomenclature Web-Site: http://www.imm.ki.se/CYPalleles/cyp2d6.htm).

Over 50-fold variability in CYP2D6 activity exists among extensive metabolizers (genetically carriers of at least one functional allele) which has led to the designation of the most rapid “extensive” phenotype as “ultrarapid” (UM) and the slowest as “intermediate” metabolizer (IM). There is evidence in the literature that these sub-phenotypes are clinically relevant. 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.

A molecular explanation for the UM phenotype was provided by the discovery of the CYP2D6 gene duplication, which however only applies to a fraction of UMs (Johansson et al., 1993; Dahl et al., 1995). Two CYP2D6 alleles previously described result in lower enzyme activity and cause the IM phenotype in individuals not carrying a normal functional allele. However, both of these alleles (*9: Broly and Meyer, 1993; *10: Yokota et al., 1993) occur with a frequency of only 2% in the Caucasian population and only about 20% of the IMs have informative genotypes involving these two alleles (i.e *9/*0, *10/*0 and *10/*10; Sachse et al., 1997; Griese et al., 1998). 80% of the IMs have therefore “uninformative” genotypes, i.e. genotypes that are also associated with the normal extensive or the ultrarapid metabolizer phenotypes. It has therefore remained unclear whether the IM sub-phenotype has a genetic basis or whether it is an epigenetic phenomenon.

It is clear that naturally occurring mutations, if they exist can have effects on drug metabolization and efficacy of therapies with drugs. It is unknown, however, how many of such variations exist, and with what frequency and at what positions in the human CYP2D6 genes.

Accordingly, means and methods for diagnosing and treating a variety of forms of individual drug intolerability and inefficacy of drug therapy which result from CYP2D6 gene polymorphisms that interfere e.g., with chemotherapeutic treatment of diseases was hitherto not sufficiently available but are nevertheless highly desirable.

Thus, the technical problem of the present invention is to comply with the needs described above.

The solution to this technical problem is achieved by providing the embodiments characterized in the claims.

SUMMARY

OF THE INVENTION

The present invention is based on the finding of novel, so far unknown variations in the nucleotide sequences of the CYP2D6 gene promoter and the population distribution of these alleles. Based upon the knowledge of these novel sequences diagnostic tests and reagents for such tests were designed for the specific detection and genotyping of CYP2D6 promoter alleles in humans, including homozygous as well as heterozygous, frequent as well as rare alleles of the CYP2D6 promoter. The determination of the CYP2D6 promoter allele status of humans with such tests is useful for the optimization of therapies with the numerous substrates of CYP2D6.

In a first embodiment, the invention provides polynucleotides of molecular variant CYP2D6 gene promoter and embodiments related thereto such as vectors and host cells transferred therewith.

In yet another embodiment, the invention provides methods for therapy of disorders related to acquired drug hypo- or hypersensitivity as well as methods of diagnosing the status of such disorders.

In a further embodiment, the invention provides kits comprising the above-described polynucleotides or vectors containing the same.

The novel variant forms of CYP2D6 gene according to the invention provide the potential for the development of a pharmacodynamic profile of drugs for a given patient.

DESCRIPTION OF THE INVENTION

The finding and characterization of variations in the CYP2D6 genes, and diagnostic tests for the discrimination of different CYP2D6 alleles in human individuals provide a very potent tool for improving the therapy of diseases with drugs that are targets of the CYP2D6 gene product, and whose metabolization is therefore dependent on CYP2D6 activity. The diagnosis of the individual allelic CYP2D6 status permits a more focused therapy, e.g., by opening the possibility to apply individual dose regimens of drugs. It may also be useful as prognostic tool for therapy outcome. Furthermore, diagnostic tests to genotype CYP2D6 will improve therapy with established drugs and help to correlate genotypes with drug activity or side effects.

Thus, the present invention provides a way to exploit molecular biology and pharmacological research for drug therapy while bypassing their potential detrimental effects which are due to expression of variant expression of the CYP2D6 gene.

Accordingly, the invention relates to a polynucleotide selected from the group consisting of: (a) a molecular variant polynucleotide having the nucleic acid sequence of SEQ ID NO: 1, wherein at nucleotide position corresponding to nucleotide position −1584 of the CYP2D6 promotor as shown in FIG. 1, is a G; (b) a molecular variant polynucleotide capable of hybridizing to the CYP2D6 promotor as shown in FIG. 1, wherein said polynucleotide is having at a position corresponding to position -1584 of the CYP2D6 promoter as shown in FIG. 1 at least one nucleotide deletion, addition and/or substitution; and (c) a molecular variant polynucleotide capable of hybridizing to the CYP2D6 promoter as shown in FIG. 1, wherein said polynucleotide is having at a position corresponding to position −1584 of the CYP2D6 promotor as shown in FIG. 1, a G.

In the context of the present invention the term “molecular variant” CYP2D6 promoter, gene or protein as used herein means that said CYP2D6 promoter, gene or protein differs from the wild type CYP2D6 promoter, gene or protein by way of nucleotide substitution(s), addition(s) and/or deletion(s) (Genomic sequences of the CYP2D6 gene including the promoter are described, for example in Genbank, http://www.ncbi.nlm.nih.gov/Genbank/GenbankOverview.html [accession number M33388]).



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stats Patent Info
Application #
US 20120270948 A1
Publish Date
10/25/2012
Document #
13350635
File Date
01/13/2012
USPTO Class
514654
Other USPTO Classes
435/611, 435/612, 435/618, 435243, 4353201, 536 243, 536 2433, 564381
International Class
/
Drawings
5



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