Polymorphisms in the human MDR-1 gene and their use in diagnostic and therapeutic applications
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Abstract
Described are general 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 Multi Drug Resistance-1 (MDR-1) gene. In particular, polynucleotides of molecular variant MDR-1 genes which, for example, are associated with unsufficient and/or altered uptake of drugs by a target cell, and vectors comprising such polynucleotides are provided. Furthermore, host cells comprising such polynucleotides or vectors and their use for the production of variant MDR-1 proteins are described. In addition, variant MDR-1 proteins and antibodies specifically recognizing such proteins as well as concerns transgenic non-human animals comprising the above-described polynucleotide or vectors are provided. Described are also methods for identifying and obtaining inhibitors for therapy of disorders related to the malfunction of the MDR-1 gene as well as methods of diagnosing the status of such disorders. Pharmaceutical and diagnostic compositions comprising the above-described polynucleotides, vectors, proteins, antibodies and inhibitors by the above-described method are provided. Said compositions are particularly useful for diagnosing and treating various diseases with drugs that are substrates, inhibitors or modulators of the MDR-1 gene product.
9 Citations
61 Claims
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1-45. -45. (canceled)
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46. A method of diagnosing acquired multidrug resistance or sensitivity related to the presence of a molecular variant of the MDR-1 gene comprising determining in a sample from a subject the presence of a polynucleotide selected from the group consisting of:
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(a) a polynucleotide having the nucleic acid sequence of SEQ ID NO 122;
(b) a polynucleotide encoding a molecular variant Multi Drug Resistance (MDR)-1 polypeptide, wherein said polynucleotide is having at a position corresponding to position 176 of the MDR-1 gene (Accession No;
M29445 or J05168) a nucleotide exchange;
(c) a polynucleotide encoding a molecular variant MDR-1 polypeptide, wherein said polynucleotide is having at a position corresponding to position 176 of the MDR-1 gene (Accession No;
M29445 or J05168) a T; and
(d) a nucleic acid molecule complementary to the polynucleotide of (a) to (c);
wherein the presence of said polynucleotide is considered indicative of said acquired multidrug resistance or sensitivity in said method. - View Dependent Claims (47, 48, 49, 52, 53, 54, 55, 56, 60, 61)
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50. A method of diagnosing a disorder related to the presence of a molecular variant of the MDR-1 gene or susceptibility to such a disorder, comprising determining in a sample from a subject the presence of a polynucleotide selected from the group consisting of:
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(a) a polynucleotide having the nucleic acid sequence of SEQ ID NO 122;
(b) a polynucleotide encoding a molecular variant Multi Drug Resistance (MDR)-1 polypeptide, wherein said polynucleotide is having at a position corresponding to position 176 of the MDR-1 gene (Accession No;
M29445 or J05168) a nucleotide exchange;
(c) a polynucleotide encoding a molecular variant MDR-1 polypeptide, wherein said polynucleotide is having at a position corresponding to position 176 of the MDR-1 gene (Accession No;
M29445 or J05168) a T; and
(d) a nucleic acid molecule complementary to the polynucleotide of (a) to (c);
wherein the presence of said polynucleotide is considered indicative of said acquired multidrug resistance or sensitivity in said method. - View Dependent Claims (51)
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- 57. A method for the prediction of blood levels of a MDR-1 substrate and/or inducer for improvement of drug safety and efficacy, to predict and prevent side effects and drug interactions and/or to increase patient compliance comprising using a MDR-1 gene single nucleotide polymorphism (SNP) MDR-1 in exon 26 (C3435T) as a pharmacogenetic factor.
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59. A diagnostic composition comprising a polynucleotide selected from the group consisting of:
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(a) a polynucleotide having the nucleic acid sequence of SEQ ID NO 122;
(b) a polynucleotide encoding a molecular variant Multi Drug Resistance (MDR)-1 polypeptide, wherein said polynucleotide is having at a position corresponding to position 176 of the MDR-1 gene (Accession No;
M29445 or J05168) a nucleotide exchange;
(c) a polynucleotide encoding a molecular variant MDR-1 polypeptide, wherein said polynucleotide is having at a position corresponding to position 176 of the MDR-1 gene (Accession No;
M29445 or J05168) a T; and
(d) a nucleic acid molecule complementary to the polynucleotide of (a) to (c).
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Specification