WO2013045505A1 - Biomarqueurs pour traitement combiné par des agents sraa - Google Patents
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- WO2013045505A1 WO2013045505A1 PCT/EP2012/068985 EP2012068985W WO2013045505A1 WO 2013045505 A1 WO2013045505 A1 WO 2013045505A1 EP 2012068985 W EP2012068985 W EP 2012068985W WO 2013045505 A1 WO2013045505 A1 WO 2013045505A1
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
Definitions
- This invention relates generally to the analytical testing of biological samples in vitro, and more particularly to aspects of genotyping indicative of the efficacy of a RAAS combination therapy for treating particular disorders.
- renin aldosterone angiotensin system plays an important role in the regulation of blood pressure and volume homeostasis, and pivotal roles in the pathophysiology of cardiovascular, renal, and metabolic diseases. Renin is secreted by the kidney in response to a decrease in circulating volume and blood pressure, and cleaves the substrate angiotensinogen to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by angiotensin converting enzyme (ACE).
- ACE angiotensin converting enzyme
- Ang II interacts with cellular receptors, in particular ATI receptors, inducing vasoconstriction and release of catecholamines from the adrenal medulla and pre-junctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. In addition, Ang II inhibits renin release, thus providing a negative feedback to the system. Accordingly, Ang II acts at various levels (e.g. vasculature, sympathetic nervous system, cortex and medulla of the adrenal gland) to increase vascular resistance and blood pressure.
- various levels e.g. vasculature, sympathetic nervous system, cortex and medulla of the adrenal gland
- Renin inhibitors represent major drug classes that block the RAAS. Each individual drug class has a different mode of action and thus blocks the RAAS at a different level: Renin inhibitors block the first, rate-limiting step of RAAS cascade by competitively inhibiting the enzyme renin, thereby preventing the formation of Ang I from angiotensinogen.
- ACEi block the second step of the RAAS cascade by competitively inhibiting the enzyme ACE, thereby preventing the formation of Ang II.
- ARBs block the third and last step of the RAAS cascade by binding to and occupying the ATI receptors without activating them.
- ARBs prevent binding and activation of said ATI receptors by Ang II. It has been disclosed that certain gene polymorphisms reflecting on cardiovascular systems are useful as biomarkers for predicting disease susceptibility or progression, or as a guide for individualised therapy, including drug therapy.
- Renin has an important role in the regulation of electrolyte homeostasis and blood pressure (Corvol et al, Pathol. Biol., 45:229-239, 1997).
- an object of the present invention is to provide a method to predict which subjects will be more responsive to a combination treatment with RAAS agents.
- the invention relates to a method of predicting whether a subject having a cardiovascular, renal, and/or metabolic disease has an increased likelihood of benefiting from a particular treatment, comprising: analyzing a biological sample from the subject to determine the identity of the nucleotide pair at position -5312 of the renin gene, wherein the presence of a CC genotype at position -5312, or a GG genotype at its complement, indicates that the subject has an increased likelihood of benefiting from a combination treatment comprising therapeutically effective amounts of at least two RAAS agents selected from renin inhibitors, ACEi and ARBs.
- the invention relates to a method of selecting a subject having a cardiovascular, renal, and/or metabolic disease for a treatment with a combination of RAAS agents, comprising:
- the invention relates to a method of treating a subject having a cardiovascular, renal, and/or metabolic disease, or at risk of developing a cardiovascular, renal, and/or metabolic disease, comprising:
- the invention relates to an in vitro method for designing an individual therapy for a subject having a cardiovascular, renal, and/or metabolic disease, comprising: a) analyzing a biological sample from the subject to determine the identity of the nucleotide pair at position -5312 of the renin gene; and
- the invention relates to the use of a combination of at least two RAAS agents selected from renin inhibitors, ACEi and ARBs for the manufacture of a medicament for the treatment of a cardiovascular, renal, and/or metabolic disease in a subject that has a CC genotype at position -5312 of the renin gene.
- the invention relates to the combination of at least two RAAS agents selected from renin inhibitors, ACEi and ARBs for use in the treatment of a cardiovascular, renal, and/or metabolic disease in a subject that has CC genotype at position -5312 of the renin gene.
- the invention relates to the use of REN-5312C/T as marker for the selection of subjects having a cardiovascular, renal, and/or metabolic disease to be effectively treated with a combination treatment comprising therapeutically effective amounts of at least two RAAS agents selected from renin inhibitors, ACEi and ARBs.
- the invention in another aspect, relates to an assay kit comprising an agent for detecting the nucleotide pair at position -5312 of the renin gene of a subject having a cardiovascular, renal, and/or metabolic disease; and instructions for use, wherein the instructions specify that the presence of a C in both alleles at position -5312 of the renin gene, or a G in both alleles of its complement, indicates that the subject has an increased likelihood of benefiting from a combination treatment comprising therapeutically effective amounts of at least two RAAS agents selected from renin inhibitors, ACEi and ARBs.
- the invention relates to a method for producing a transmittable form of information on the genotype of a subject having a cardiovascular, renal, and/or metabolic disease comprising:
- LVMI left ventricular mass index
- the present invention is based, in part, on the finding that it is possible to select subjects having a cardiovascular, renal, and/or metabolic disease who, depending on their genotype, are likely to have clinical benefit following treatment with a particular combination of RAAS agents compared to subjects who do not have such a particular genotype. Specifically, it was found that subjects that are homozygous carriers of the C allele at position -5312 of the renin gene are likely to be more responsive to a combination treatment with at least two RAAS agents selected from renin inhibitors, ACEi, and ARBs, than subjects who carry at least one T allele at position -5312 of the renin gene.
- This unexpected finding provides a means of selecting subjects who are experiencing a cardiovascular, renal, and/or metabolic disease, or who are at risk of developing such a disease, and who are likely to benefit from a RAAS combination treatment, as described herein. Accordingly, the invention provides a powerful predictive tool for the treatment with a combination of RAAS agents.
- the invention relates to a method of predicting whether a subject having a cardiovascular, renal, and/or metabolic disease has an increased likelihood of benefiting from a particular treatment, comprising:
- the invention relates to a method of selecting a subject having a cardiovascular, renal, and/or metabolic disease for a treatment with a combination of RAAS agents, comprising:
- the term "effective amount” or “therapeutically effective amount” of a compound is a quantity of drug sufficient to achieve a desired therapeutic and/or prophylactic effect, for example, an amount which results in the prevention of or regression of left ventricular hypertrophy and/or the reduction in blood pressure.
- treating refers to both the therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder and the prophylactic or preventative measures that prevent and/or slow the development of a targeted pathologic condition or disorder.
- those in need of treatment include those already with the disorder, those prone to have the disorder, and those in whom the disorder is to be prevented.
- renin aldosterone angiotensin system includes any molecule that interacts with the RAAS providing an inhibitory or blocking effect. Such agents can have various biological effects including acting as an hypertension reducing agent. Examples of such RAAS agents include ACEi, ARBs and renin inhibitors.
- the RAAS agent can be a small molecule, polypeptide, carbohydrate, lipid, nucleotide, or combinations thereof.
- nucleotide pair means the nucleotides found at a polymorphic site on the two copies of a chromosome from a subject. Specifically, when the nucleotide pair is CC at position -5312 of the renin gene means that both alleles at this position of the renin gene are C, when the nucleotide pair is TT at position -5312 of the renin gene means that both alleles at this position of the renin gene are T, and when the nucleotide pair is CT at position - 5312 of the renin gene means that one allele is C and the other is T at this position of the renin gene.
- the term "subject" means that preferably the subject is a mammal, such as a human, but can also be an animal, e.g., domestic animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, pigs, horses and the like) and laboratory animals (e.g., monkey (e.g., cynmologous monkey), rats, mice, guinea pigs and the like).
- the subject is a human patient.
- the methods of the invention require the determination of the nucleotide pair at position - 5312 of the renin gene.
- the single nucleotide polymorphism (SNP) present in the renin gene at C-5312T has been described previously. The location of this SNP is -5312 base pairs upstream from the transcription start site (+1) (Fuchs et al, Journal of Hypertension, 20(12):2391-2398, 2002).
- the methods of the invention can be performed on any suitable biological sample from a subject which contains genetic information, e.g., whole blood and components thereof such as serum, plasma, platelets, and subpopulations of blood cells such as leucocytes; semen, saliva, tears, mucus, urine, fecal material, sweat, buccal swab, skin and hair.
- suitable biological samples are saliva, blood, hair, and buccal swab, and even more suitable saliva and blood.
- SSCP single- strand conformation polymorphism
- DPLC denaturing high-performance liquid chromatography
- Other methods include hybridization, primer extension, and cleavage methods. Each of these methods must be connected to an appropriate detection system.
- Detection technologies include fluorescent polarization (Chan et al., Genome Res. 9:492-499, 1999), luminometric detection of pyrophosphate release (pyrosequencing) (Ahmadiian et al., Anal. Biochem.
- a specific upstream "invader” oligonucleotide and a partially overlapping downstream probe together form a specific structure when bound to complementary DNA template.
- This structure is recognized and cut at a specific site by the Cleavase enzyme, resulting in the release of the 5' flap of the probe oligonucleotide.
- This fragment then serves as the "invader” oligonucleotide with respect to synthetic secondary targets and secondary fluorescently labelled signal probes contained in the reaction mixture.
- Ryan D et al. Molecular Diagnosis 4(2): 135-144, 1999; Lyamichev V et al., Nature Biotechnology 17: 292-296, 1999; U.S. Pat. Nos. 5,846,717 and 6,001,567.
- the identity of the nucleotide pair at position -5312 in the renin gene may also be determined using a mismatch detection technique including, but not limited to, the RNase protection method using riboprobes (Winter et al., Proc. Natl. Acad. Sci. USA 82:7575, 1985; Meyers et al., Science 230:1242, 1985) and proteins that recognize nucleotide mismatches, such as the E. coli mutS protein (Modrich P, Ann Rev Genet. 25:229-253, 1991).
- variant alleles can be identified by SSCP analysis (Orita et al, Genomics 5:874-879, 1989; Humphries et al., in Molecular Diagnosis of Genetic Diseases, Elles R, ed., pp. 321-340, 1996) or denaturing gradient gel electrophoresis (DGGE) (Wartell et al., Nucl. Acids. Res. 18:2699-2706, 1990; Sheffield et al., Proc. Natl. Acad. Sci. USA 86:232-236, 1989).
- DGGE denaturing gradient gel electrophoresis
- a polymerase-mediated primer extension method may also be used to identify the polymorphisms.
- the invention provides methods and compositions for genotyping the renin gene in a subject.
- the terms "genotype" mean the genotype containing the nucleotide that is present at position -5312 in the renin gene as described above.
- compositions of the invention contain oligonucleotide probes and primers designed to specifically hybridize to the target regions containing, or that are adjacent to, position -5312 of the renin gene.
- Genotyping oligonucleotides of the invention may be immobilized on or synthesized on a solid surface such as a microchip, bead, or glass slide. See, e.g., WO 98/20020 and WO 98/20019.
- the method of the invention involves isolating from a subject a nucleic acid mixture comprising the two copies of the renin gene of interest, or fragment thereof, and determining the identity of the nucleotide pair at position -5312 in the two copies.
- the identity of a nucleotide (or nucleotide pair) at position -5312 may be determined by amplifying the target region containing the potential SNP in one or both copies of the gene, or fragments thereof, and sequencing the amplified regions by conventional methods.
- the genotype or haplotype for the gene of a subject may also be determined by hybridization of a nucleic sample containing one or both copies of the gene to nucleic acid arrays and subarrays such as described in WO 95/11995.
- the method of the invention provides probes which are useful in classifying subjects according to their types of genotype.
- the SNP probes according to the invention are oligonucleotides, that can identify if a SNP is present or absent. Oligonucleotides according to this embodiment of the invention can determine if a SNP is present or absent at position - 5312 of the renin gene in various ways. For example, under stringent hybridization conditions, an oligonucleotide of appropriate length will hybridize to the SNP, but not the wild type nucleotide. The oligonucleotide may be labelled using a radiolabel or a fluorescent molecular tag. Alternatively, an oligonucleotide of appropriate length can be used as a primer for PCR, wherein the 3' terminal nucleotide is complementary to one allele containing the SNP, but not to any other allele.
- the target regions may be amplified using any oligonucleotide-directed amplification method, including but not limited to polymerase chain reaction (PCR) (U.S. Pat. No. 4,965,188), ligase chain reaction (LCR) (Barany et al., Proc. Natl. Acad. Sci. USA 88:189-193, 1991; WO 90/01069), and oligonucleotide ligation assay (OLA) (Landegren et al., Science 241 : 1077-1080, 1988).
- PCR polymerase chain reaction
- LCR ligase chain reaction
- OLA oligonucleotide ligation assay
- Oligonucleotides useful as primers or probes in such methods should specifically hybridize to a region of the nucleic acid that contains or is adjacent to the SNP at position -5312 of the renin gene.
- the oligonucleotides are between 10 and 35 nucleotides in length and preferably, between 15 and 30 nucleotides in length. Most preferably, the oligonucleotides are 20 to 25 nucleotides long. The exact length of the oligonucleotide will depend on many factors that are routinely considered and practiced by the skilled artisan.
- nucleic acid amplification procedures may be used to amplify the target region including transcription-based amplification systems (U.S. Pat. No. 5,130,238, EP 329,822, U.S. Pat. No. 5,169,766, WO 89/06700) and isothermal methods (Walker et al., Proc. Natl. Acad. Sci. USA 89:392-396, 1992).
- the identity of the nucleotide pair at position -5321 in the renin gene can also be determined before or after amplification using one of several hybridization-based methods known in the art.
- allele-specific oligonucleotides are utilized in performing such methods.
- the allele-specific oligonucleotides may be used as differently labelled probe pairs, with one member of the pair showing a perfect match to one variant of a target sequence and the other member showing a perfect match to a different variant.
- more than one polymorphic sites may be detected at once using a set of allele-specific oligonucleotides or oligonucleotide pairs.
- the members of the set have melting temperatures within 5°C, and more preferably within 2°C, of each other when hybridizing to each of the polymorphic sites being detected.
- Hybridization of an allele-specific oligonucleotide to a target polynucleotide may be performed with both entities in solution, or such hybridization may be performed when either the oligonucleotide or the target polynucleotide is covalently or noncovalently affixed to a solid support. Attachment may be mediated, for example, by antibody-antigen interactions, poly-L-Lys, streptavidin or avidin-biotin, salt bridges, hydrophobic interactions, chemical linkages, UV cross-linking, baking, etc. Allele-specific oligonucleotide may be synthesized directly on the solid support or attached to the solid support subsequent to synthesis.
- Solid- supports suitable for use in detection methods of the invention include substrates made of silicon, glass, plastic, paper and the like, which may be formed, for example, into wells (as in 96-well plates), slides, sheets, membranes, fibres, chips, dishes, and beads.
- the solid support may be treated, coated or derivatised to facilitate the immobilization of the allele-specific oligonucleotide or target nucleic acid.
- An automatic analyzer can be used to detect whether or not a polymorphism exists at position -5312 of the renin gene as described above.
- PCR is used to detect the presence of the CC genotype at position -5312 of the renin gene and the autoanalyzer is a PCR machine.
- the result can be cast in a transmittable form that can be communicated or transmitted to other researchers or physicians or genetic counselors or patients.
- a transmittable form can vary and can be tangible or intangible.
- the result with respect to whether or not a polymorphism exists at position -5312 of the renin gene can be embodied in descriptive statements, diagrams, photographs, charts, images or any other visual forms. For example, images of gel electrophoresis of PCR products can be used in explaining the results.
- the statements and visual forms can be recorded on a tangible media such as papers, computer readable media such as floppy disks, compact disks, etc., or on an intangible media, e.g., an electronic media in the form of email or website on internet or intranet.
- a tangible media such as papers, computer readable media such as floppy disks, compact disks, etc.
- an intangible media e.g., an electronic media in the form of email or website on internet or intranet.
- the result with regard to the presence or absence of the SNP in the subject tested can also be recorded in a sound form and transmitted through any suitable media, e.g., analog or digital cable lines, fiber optic cables, etc., via telephone, facsimile, wireless mobile phone, internet phone and the like.
- the information and data on a test result can be produced anywhere in the world and transmitted to a different location.
- the information and data on a test result may be generated and cast in a transmittable form as described above.
- the test result in a transmittable form thus can be imported into the U.S.
- the present invention also encompasses a method for producing a transmittable form of information on the genotype of a subject.
- the method comprises the steps of (a) analyzing a biological sample from the subject to determine the identity of the nucleotide pair at position -5312 of the renin gene according to the present invention; and (b) embodying the result of the determining step (a) in a transmittable form.
- the transmittable form is the product of the production method.
- the present invention is directed to determining the identity of the nucleotide pair at position -5312 of the renin gene in a biological sample from a subject having a cardiovascular, renal, and/or metabolic disease, wherein the presence of a CC genotype at position -5312 indicates that the subject has an increased likelihood of benefiting from a combination treatment comprising therapeutically effective amounts of at least two RAAS agents selected from renin inhibitors, ACEi and ARBs.
- the combination treatment comprises a renin inhibitor and an ARB.
- the combination treatment comprises a renin inhibitor and an ACEi.
- Renin inhibitors to which the present invention applies are any of those having renin inhibitory activity in vivo.
- Renin inhibitors for use herein include, but are not limited to, those disclosed in EP 678.503, WO 00/64887, WO 00/064873, WO 2005/051895, WO 2006/095020, US 2009/0076062, WO 2011/056126, Yokokawa et al. (Expert Opin. Ther. Patents 18(6):581-602, 2008), and Maibaum et al. (Expert Opin. Ther. Patents 13(5):589-603, 2003), the entire contents of which are incorporated herein by reference.
- suitable renin inhibitors include compounds having different structural features.
- the renin inhibitor is preferably selected from aliskiren, ditekiren, terlakiren, zankiren, RO 66- 1132, RO 66-1168, VTP27999, ACT-280778, and TAK-272, and pharmaceutically acceptable salts, prodrugs, derivatives and isomers thereof.
- the preferred renin inhibitor is aliskiren or a pharmaceutically acceptable salt thereof. Aliskiren is specifically disclosed in EP 678.503 and it is especially preferred the hemi-fumarate salt thereof.
- An ARB according to the invention is any molecule that can specifically antagonize or block the action of angiotensin II type 1 receptors (ATI receptors).
- ARBs suitable for use herein include, but are not limited to, losartan, valsartan, irbesartan, candesartan, telmisartan, eprosartan, tasosartan, zolarsartan, azilsartan, olmesartan, saprisartan, forasartan, E-4177, and ZD-8731, and pharmaceutically acceptable salts, prodrugs, derivatives and isomers thereof.
- the preferred ARB is selected from valsartan, losartan, and olmesartan, and pharmaceutically acceptable salts thereof, and even more preferably it is selected from valsartan and losartan, and pharmaceutically acceptable salts thereof.
- An ACEi according to the invention is any molecule that can specifically inhibit the enzymatic activity of angiotensin converting enzyme.
- ACEi suitable for use herein include, but are not limited to, benazepril, benazeprilat, captopril, zofenopril, enalapril, enaprilat, fosinopril, ceronapril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, alacepril, cilazapril, delapril, imidapril, rentiapril, spirapril, temocapril, and moveltipril, and pharmaceutically acceptable salts, prodrugs, derivatives and isomers thereof.
- the preferred ACEi is selected from ramipril and enalapril, and pharmaceutically acceptable salts thereof, and even more preferably it is
- the RAAS combination therapy described herein can also optionally include other agents such as calcium channel blockers (CCB), beta blockers and diuretics.
- CB calcium channel blockers
- beta blockers and diuretics.
- CCB block voltage-gated calcium channels in cardiac muscle and blood vessels, leading to a reduction in muscle contraction.
- CCB suitable for use herein include, but are not limited to, amlodipine, felodipine, nicardipine, nifedipine, nimodipine, isradipine, nitrendipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, ryodipine, lacidipine, lercanidipine, manidipine, nilvadipine, niguldipine, niludipine, nisoldipine, diltiazem, anipamil, verapamil, bepridil, clentiazem, fendilme, fendiline, tiapamil, gallopamil, mibefradil, prenylamine, semotiadil,
- Beta blockers are agents which block beta-adrenergic substances in the body.
- a beta blocker may block the beta-adrenergic substance adrenaline (epinephrine), a key agent in the "sympathetic" portion of the autonomic (involuntary) nervous system and activation of heart muscle.
- adrenaline epinephrine
- Beta blockers suitable for use herein include, but are not limited to, acebutolol, atenolol, alprenolol, amosulalol, arotmolol, befunolol, betaxolol, bisoprolol, bucindolol, bevantolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrine, butofilolol, carteolol, carvedilol, carazolol, celiprolol, cetamolol, cloranololdilevalol, epanolol, esmolol, indenolol, levobunolol, labetalol, metoprolol, mepindolol, metipranolol, moprolol, nado
- Diuretics are a class of drugs that elevate the rate of urination and thus provides a means of forced dieresis.
- Any diuretic that is known in the art can be used and include, but are not limited to, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, spironolactone, triamterene, chlorthalidone, chlorothiazide, epitizide, hydrochlorothiazide, hydroflumthiazide, trichlormethiazide, cyclopenthiazide, methylchlothiazide, mebutizide, bendroflumethiazide, metolazone, indapamide, dichlorphenamide, quinethazone, clopamide, mefruside, clofenamide, meticrane, xipamide, clorexolone, fenquizone, eplerenone, benzamil, potassium canrenoate,
- the structure of the active agents identified by generic names may be taken from the actual edition of the standard compendium "The Merck Index” or from databases, e.g. LifeCycle Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.
- the invention relates to a method of treating a subject having a cardiovascular, renal, and/or metabolic disease, or at risk of developing a cardiovascular, renal, and/or metabolic disease, comprising:
- the invention relates to the use of a combination of at least two RAAS agents selected from renin inhibitors, ACEi and ARBs for the manufacture of a medicament for the treatment of a cardiovascular, renal, and/or metabolic disease in a subject that has a CC genotype at position -5312 of the renin gene.
- the invention relates to the combination of at least two RAAS agents selected from renin inhibitors, ACEi and ARBs for use in the treatment of a cardiovascular, renal, and/or metabolic disease in a subject that has CC genotype at position -5312 of the renin gene.
- Cardiovascular diseases as the term is used herein include, but is not limited to, hypertension (whether of the malignant, essential, renovascular, diabetic, isolated systolic, resistant, or other secondary type), heart failure such as diastolic and congestive heart failure (acute and chronic), left ventricular dysfunction such as left ventricular hypertrophy, endothelial dysfunction, diastolic dysfunction, ischemic cardiomyopathy, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, cardiac fibrosis, atrial flutter, detrimental vascular remodeling such as hypertrophic medial thickening in arteries and/or in large vessels, heart target organ damage, plaque stabilization, myocardial infarction and its sequelae, atherosclerosis including coronary arterial disease, angina pectoris (whether unstable or stable), thrombosis, vascular aneurysm, vascular stenosis and infarction, vascular dementia, secondary aldosteronism,
- Renal diseases include, but are not limited to, chronic kidney disease (diabetic and non- diabetic), renal fibrosis, polycystic kidney disease, renal failure conditions such as nephrotic syndrome, nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, renal vascular hypertension, and end-stage renal disease.
- the renal disease is preferably chronic kidney disease.
- Metabolic diseases include, but are not limited to, insulin resistance and metabolic syndrome, type 2 diabetes, diabetic nephropathy, diabetic retinopathy, and obesity.
- the metabolic disease is preferably selected from type 2 diabetes and diabetic nephropathy.
- a therapeutically effective amount of each of the RAAS agents of the present invention may be administered separately, simultaneously or sequentially and in any order.
- the RAAS agents may form part of the same dosage form or be provided as separate dosage forms for administration at the same time or at a different time.
- the RAAS agent combinations described herein can be prepared in a manner known in the art suitable for enteral administration, such as oral or rectal administration, and parenteral administration to mammals (warmblooded animals), including man.
- Typical oral formulations include tablets, capsules, syrups, elixirs and suspensions.
- Typical parenteral formulations include solutions and suspensions.
- the corresponding active ingredient or a pharmaceutically acceptable salt of the RAAS agents described herein may be used in any form such as a hydrate, a polymorph or a solvate.
- the administration of the RAAS agent combinations to a subject includes self- administration or the administration by another.
- each of the RAAS agents described herein can depend on a variety of factors, such as particular formulation, mode of administration, homeothermic species, age, body weight, sex, diet, and/or individual condition.
- Preferred dosages for the active ingredients of the combinations according to the present invention are therapeutically effective dosages, especially those which are commercially available.
- the dosage of the renin inhibitors is preferably from about 1 mg/day to about 2 g/day, and more preferably from about 5 mg/day to about 1 g/day.
- the dosage amount is from about 1 mg/day to about 1 g/day, preferably from about 75 mg/day to about 600 mg/day, even more preferably about 150 mg/day and about 300 mg/day, being once daily administration the most preferred.
- the dosage of the ARBs is preferably from about 1 mg/day to about 2 g/day, and more preferably from about 5 mg/day to about 1 g/day.
- the dosage amount is from about 10 mg/day to about 200 mg/day, preferably from about 20 mg/day to about 150 mg/day, even more preferably about 25 mg/day, about 50 mg/day and about 100 mg/day, being once daily administration the most preferred.
- the dosage amount is from about 10 mg/day to about 500 mg/day, preferably from about 30 mg/day to about 350 mg/day, even more preferably about 40 mg/day, about 80 mg/day, about 160 mg/day, and about 320 mg/day, being once daily administration the most preferred.
- the dosage of ACEi is preferably from about 0.1 mg/day to about 100 mg/day, and more preferably from about 1 mg/day to about 80 mg/day.
- the dosage amount is from about 0.75 mg/day to about 30 mg/day, preferably from about 1 mg/day to about 25 mg/day, even more preferably about 1.25 mg/day, about 2.5 mg/day, 5 mg/day, 10 mg/day, and 20 mg/day, being once daily administration the most preferred.
- kits useful for haplotyping and/or genotyping the gene in a subject are useful for classifying subjects as likely to benefit from the treatment as described herein or as subjects unlikely to benefit from the treatment described herein.
- the invention encompasses kits for detecting the presence of a nucleic acid corresponding to a marker of the invention in a biological sample.
- the kit can comprise a labelled oligonucleotide probe that can bind to DNA to detect the genotype of the invention in a biological sample and means for identifying the relevant nucleotide pair in the sample, and also instructions for interpreting the results obtained using the kit.
- the kit may also contain other components such as hybridization buffer (where the oligonucleotides are to be used as a probe) packaged in a separate container.
- the kit may contain, packaged in separate containers, a polymerase and a reaction buffer optimized for primer extension mediated by the polymerase, such as in the case of PCR.
- such kit may further comprise a DNA sample collecting means.
- the kit can comprise, e.g., (1) an oligonucleotide, e.g., a detectably-labelled oligonucleotide, which hybridizes to a nucleic acid sequence which detects the absence of the SNP in the renin gene; or (2) a pair of primers useful for amplifying a nucleic acid molecule corresponding to a marker of the invention.
- an oligonucleotide e.g., a detectably-labelled oligonucleotide, which hybridizes to a nucleic acid sequence which detects the absence of the SNP in the renin gene
- a pair of primers useful for amplifying a nucleic acid molecule corresponding to a marker of the invention.
- the kit can also contain a control sample or a series of control samples, which can be assayed and compared to the biological sample.
- Each component of the kit can be enclosed within an individual container and all of the various containers can be within a single package, along with instructions for interpreting the results of the assays performed using the kit.
- the invention relates to an assay kit comprising an agent for detecting the nucleotide pair at position -5312 of the renin gene of a subject having a cardiovascular, renal, and/or metabolic disease; and instructions for use, wherein the instructions specify that the presence of a C in both alleles at position -5312 of the renin gene indicates that the subject has an increased likelihood of benefiting from a combination treatment comprising therapeutically effective amounts of at least two RAAS agents selected from renin inhibitors, ACEi and ARBs.
- the invention relates to an in vitro method for designing an individual therapy for a subject having a cardiovascular, renal, and/or metabolic disease, comprising: a) analyzing a biological sample from the subject to determine the identity of the nucleotide pair at position -5312 of the renin gene; and
- a treatment based on a combination treatment comprising therapeutically effective amounts of at least two RAAS agents selected from renin inhibitors, ACEi and ARBs when the identity of this nucleotide pair is CC.
- the invention relates to the use of REN-5312C/T as marker for the selection of subjects having a cardiovascular, renal, and/or metabolic disease to be effectively treated with a combination treatment comprising therapeutically effective amounts of at least two RAAS agents selected from renin inhibitors, ACEi and ARBs.
- Example 1 Association of renin gene polymorphisms with responsiveness to the treatment with aliskiren, losartan, or both.
- a 36-weeks, randomized, double-bind clinical trial was conducted in order to compare the efficacy of the combination of aliskiren and losartan on the regression of left ventricular hypertrophy in overweight patients with essential hypertension and left ventricular hypertrophy when compared to losartan monotherapy.
- Primary analysis was directed to determine the change from baseline in the left ventricular mass index (LVMI) as measured by magnetic resonance imaging at the end of the study, and secondary analysis was focus on the change from baseline in BP (mean sitting diastolic BP (msDBP) and mean sitting systolic BP (msSBP) at the end of the study. The change of some other biomarkers at the end of the study was also evaluated, such as plasma aldosterone.
- LVMI left ventricular mass index
- Genomic DNA was extracted from blood samples (EDTA Whole Blood) using an Qiagen Autopure Extraction Robot. Genotyping for REN -5312C/T variants was completed with TaqMan ® assays. Specifically, TaqMan® genotyping was performed using TaqMan Assays- by-Design and Assays-on-Demand (Applied Biosystems, Foster City, CA) on an ABI 7900 sequencer. Up to 20 ng of genomic DNA was used in the experiment according to the manufacturer's instructions.
- Table 1 shows the change from baseline in LVMI, msDBP, and msSBP at the end of the study depending on the REN -5312 genotype of the patients.
- Table 2 shows the change from baseline in plasma aldosterone at the end of the study depending on the REN -5312 genotype of the patients.
- patients with hypertension and left ventricular hypertrophy carrying the REN -5312 CC genotype are more responsive to the effect of a combination of RAAS agents than the T allele carriers.
Abstract
La présente invention concerne une méthode permettant de prédire si un sujet souffrant d'une maladie cardiovasculaire, rénale et/ou métabolique présente une probabilité accrue de se trouver bien d'un traitement combiné impliquant au moins deux agents SRAA choisis parmi les inhibiteurs de la rénine, les ECAi et les ARA. Ledit procédé comprend les étapes consistant à analyser un échantillon biologique prélevé chez le sujet pour identifier la paire de nucléotides en position -5312 du gène de la rénine, la présence d'un génotype CC en position -5312 indiquant que le sujet présente une probabilité accrue de se trouver bien d'un tel traitement combiné.
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