EP2394171A2 - Maladie polykystique rénale autosomique dominante (adpkd) - Google Patents

Maladie polykystique rénale autosomique dominante (adpkd)

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Publication number
EP2394171A2
EP2394171A2 EP09796710A EP09796710A EP2394171A2 EP 2394171 A2 EP2394171 A2 EP 2394171A2 EP 09796710 A EP09796710 A EP 09796710A EP 09796710 A EP09796710 A EP 09796710A EP 2394171 A2 EP2394171 A2 EP 2394171A2
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EP
European Patent Office
Prior art keywords
markers
polypeptide
absence
amplitude
adpkd
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP09796710A
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German (de)
English (en)
Inventor
Harald Mischak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mosaiques Diagnostics and Therapeutics AG
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Mosaiques Diagnostics and Therapeutics AG
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Priority to EP09796710A priority Critical patent/EP2394171A2/fr
Publication of EP2394171A2 publication Critical patent/EP2394171A2/fr
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/447—Systems using electrophoresis
    • G01N27/44756—Apparatus specially adapted therefor
    • G01N27/44791—Microapparatus
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/34—Genitourinary disorders
    • G01N2800/347—Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • ADPKD Autosomal dominant polycystic kidney disease
  • the present invention relates to a method and apparatus for diagnosing autosomal dominant polycystic kidney disease.
  • ADPKD Autosomal dominant Polycystic Kidney Disease
  • cysts are a complex process that is phenotypically similar to dedifferentiation, including high proliferation rates, increased apoptosis, altered protein sorting, altered secretory properties, and disorganization of the extracellular matrix.
  • kidney-type cysts are the most significant symptom
  • cyst formation also occurs outside the kidneys, especially in the liver (occasionally to the point of polycystic liver disease) and increased frequency of other disorders such as intercranial aneurysms. This shows that ADPKD is a systemic disease.
  • ADPKD is the most common life-threatening hereditary disease. The incidence of ADPKD is greater than that of HD, hemophilia, sickle cell anemia, cystic fibrosis, myotonic dystrophy, and Down syndrome combined.
  • ADPKD Alzheimer's disease
  • the gene for PKD-I has been located on chromosome 16 and is associated with polycystin-1 protein, which is mutated in approximately 85% of all patients with ADPKD.
  • the gene for PKD-2 located on chromosome 4 mutates in 15% of ADPKD cases and is associated with polycystin-2 protein.
  • Object of the present invention was to provide a way of diagnosing ADPKD available.
  • the problem is solved by a method for Diagnostic as claim 1 of an autosomal dominant polycystic kidney disease (ADPKD) comprising the step of determining the presence or absence or amplitude of at least three polypeptide markers in a urine sample, wherein the polypeptide markers are selected from the markers shown in Table 1 by values for molecular masses and the Mi rationszeit are characterized.
  • ADPKD autosomal dominant polycystic kidney disease
  • This method can also be used for early diagnosis and prognosis of further disease development.
  • At least five, at least six, at least eight, at least ten, at least 20 or at least 50 polypeptide markers be used, as defined in Table 1.
  • the urine sample is a midbeam urine sample.
  • the use of a human urine sample is preferred.
  • the measurement of the amplitudes and / or presence or absence can be done by a variety of methods. Suitable methods include capillary electrophoresis, HPLC, gas phase ion spectrometry and / or mass spectrometry.
  • capillary electrophoresis is performed prior to measuring the molecular mass of the polypeptide markers.
  • Mass spectrometry is particularly useful for measuring the amplitude or the presence or absence of the polypeptide marker (s).
  • the method preferably has a sensitivity of at least 60% and a specificity of at least 60%.
  • the sensitivity is at least 70% or at least 80% and the specificity is at least 70% or at least 80%.
  • the sample is initially separated into at least three, preferably at least 5 or 10 subsamples. Subsequently, an analysis of at least three, preferably at least 5 or 10 subsamples to determine a presence or absence or amplitude of at least one polypeptide marker in the sample, wherein the polypeptide marker is selected from the markers of Table 1, which by the molecular masses and migration time (CE Time) are characterized.
  • CE times given in the tables are based on a 90 cm long glass capillary with an internal diameter (ID) of 50 ⁇ m at an applied voltage of 25 kV, using as eluant 20% acetonitrile, 0.25% formic acid in water , Details are included in the experimental section.
  • Specificity is defined as the number of actual negative samples divided by the sum of the number of actual negatives and the number of false positives. A specificity of 100% means that a test identifies all healthy persons as healthy, ie no healthy person is identified as ill. This does not say anything about how well the test detects sick patients. Sensitivity is defined as the number of actual positive samples divided by the sum of the number of actual positives and the number of false negatives. A sensitivity of 100% means that the test detects all patients. He does not say how well the test detects healthy people.
  • the markers according to the invention make it possible to achieve a specificity of at least 60, preferably at least 70, more preferably 80, even more preferably at least 90 and most preferably at least 95%, for the indicated disease for which a diagnosis is desired.
  • the markers of the invention make it possible to achieve a sensitivity of at least 60, preferably at least 70, more preferably 80, even more preferably at least 90 and most preferably at least 95% for the indicated disease for which a diagnosis is desired.
  • the migration time is determined by capillary electrophoresis (CE) - e.g. in example under point 2 - determined.
  • CE capillary electrophoresis
  • a 90 cm long glass capillary with an inner diameter (ID) of 50 ⁇ m and an outer diameter (OD) of 360 ⁇ m is operated at an applied voltage of 30 kV.
  • eluent for example, 30% methanol, 0.5% formic acid in water can be used.
  • CE migration time can vary. Nevertheless, the order in which the polypeptide labels elute is typically the same for each CE system used under the conditions indicated. To even out any differences in migration time, the system can be normalized using standards for which migration times are known. These standards may e.g. the polypeptides given in the examples (see examples).
  • CE-MS capillary electrophoresis mass spectrometry
  • polypeptide markers according to the invention are proteins or peptides or degradation products of proteins or peptides. They may be chemically modified, eg by post-translational modifications such as glycolization, phosphorylation, alkylation or disulfide bridging, or altered by other reactions, eg in the context of degradation. In addition, the Polypeptide marker also chemically modified during the purification of the samples, for example, oxidized, be.
  • polypeptide markers molecular mass and migration time
  • polypeptides of the invention are used to diagnose ADPKD.
  • Diagnosis is the process of gaining knowledge by assigning symptoms or phenomena to a disease or injury.
  • the presence or absence of certain polypeptide markers is also used differential diagnosis.
  • the presence or absence of a polypeptide marker can be measured by any method known in the art. Methods that can be used are exemplified below.
  • a polypeptide marker is present when its reading is at least as high as the threshold. If its reading is below that, the polypeptide marker is absent.
  • the threshold value can either be determined by the sensitivity of the measurement method (detection limit) or defined based on experience.
  • the threshold is preferably exceeded when the sample reading for a given molecular mass is at least twice that of a blank (e.g., only buffer or solvent).
  • the polypeptide marker (s) is / are used to measure its presence or absence, the presence or absence being indicative of ADPKD.
  • polypeptide markers which are typically present in individuals with ADPKD, but are less common or non-existent in individuals without ADPKD.
  • polypeptide markers that are present in patients with ADPKD but are not or only rarely present in patients without ADPKD.
  • amplitude markers can also be used for diagnosis.
  • Amplitude markers are used in a manner that does not determine the presence or absence, but decides the magnitude of the signal (amplitude) in the presence of the signal in both groups.
  • the tables show the mean amplitudes of the corresponding signals (characterized by mass and migration time) over all measured samples. Two nomination procedures are possible to achieve comparability between differently concentrated samples or different measurement methods. In the first approach, all peptide signals of a sample are normalized to a total amplitude of 1 million counts. The respective mean amplitudes of the single markers are therefore given as parts per million (ppm).
  • All groups used consist of at least 20 individual patients or control samples to obtain a reliable mean amplitude.
  • the decision to make a diagnosis depends on how high the amplitude of the respective polypeptide markers in the patient sample is compared to the mean amplitudes in the control group or the "sick" group. If the value is close to the mean amplitude of the "sick" group, it can be assumed that the presence of ADPKD is more in line with the mean amplitudes of the control group and is not based on ADPKD.
  • the distance to the mean amplitude can be interpreted as a probability of belonging to a group.
  • the distance between the measured value and the mean amplitude may be considered as a probability of belonging to a group.
  • a frequency marker is a variant of the amplitude marker, in which the amplitude is low in some samples. It is possible to convert such frequency markers into amplitude markers in which, in the calculation of the amplitude, the corresponding samples in which the marker is not found, with a very small amplitude - in the range of the detection limit - are included in the calculation.
  • the individual from whom the sample is derived, in which the presence or absence of one or more polypeptide markers is determined can be any individual who may suffer from ADPKD.
  • the subject is a mammal, most preferably a human.
  • not only three polypeptide markers but a larger combination of markers are used to facilitate differential diagnostics.
  • the falsification of the overall result can be reduced or avoided by individual individual deviations from the typical probability of presence in the individual.
  • the sample measuring the presence or absence of the polypeptide marker (s) of the invention may be any sample recovered from the subject's body.
  • the sample is a sample having a polypeptide composition suitable for making statements about the condition of the individual.
  • it may be blood, urine, synovial fluid, tissue fluid, body secretions, sweat, cerebrospinal fluid, lymph, intestinal, gastric, pancreatic, bile, tears, tissue, sperm, vaginal fluid, or a stool sample.
  • it is a liquid sample.
  • the sample is a urine sample.
  • Urine samples may be known as known in the art.
  • a mid-jet urine sample is used.
  • the urine sample may e.g. by means of a catheter or also with the aid of a urination apparatus, as described in WO 01/74275.
  • the presence or absence of a polypeptide marker in the sample can be determined by any method known in the art suitable for measuring polypeptide markers. Those skilled in such methods are known. In principle, the presence or absence of a polypeptide marker can be determined by direct methods such as e.g. Mass spectrometry, or indirect methods, e.g. by ligands.
  • the sample of the individual e.g. the urine sample
  • pretreated prior to measuring the presence or absence of the polypeptide marker (s) by any suitable means e.g. be cleaned or separated.
  • the treatment may e.g. a purification, separation, dilution or concentration.
  • the methods may be, for example, centrifugation, filtration, ultrafiltration, dialysis, precipitation or chromatographic methods such as affinity separation or separation by means of ion exchange chromatography, or an electrophoretic separation.
  • the sample is separated by electrophoresis prior to its measurement, purified by ultracentrifugation and / or separated by ultrafiltration into fractions containing polypeptide labels of a specific molecular size.
  • a mass spectrometric method is used to determine the presence or absence of a polypeptide marker, which method may precede purification or separation of the sample.
  • the mass spectrometric analysis has the advantage over current methods that the concentration of many (> 100) polypeptides of a sample can be determined by a single analysis. Any type of mass spectrometer can be used. With mass spectrometry, it is possible to routinely measure 10 fmoles of a polypeptide marker, that is, 0.1 ng of a 10 kDa protein with a measurement accuracy of approximately ⁇ 0.01% from a complex mixture. For mass spectrometers, an ionic forming unit coupled with a suitable analyzer.
  • electrospray ionization (ESI) interfaces are most commonly used to measure ions from liquid samples, whereas the matrix assisted laser desorption / ionization (MALDI) technique is used to measure ions from sample crystallized with a matrix.
  • MALDI matrix assisted laser desorption / ionization
  • quadrupoles, ion traps or time-of-flight (TOF) analyzers can be used to analyze the resulting ions.
  • electrospray ionization the molecules present in solution i.a. under the influence of high voltage (e.g., 1-8 kV) to form charged droplets which become smaller by evaporation of the solvent.
  • high voltage e.g. 1-8 kV
  • Coulomb explosions lead to the formation of free ions, which can then be analyzed and detected.
  • TOF analyzers have a very high scanning speed and achieve a very high resolution.
  • Preferred methods for determining the presence or absence of polypeptide markers include gas phase ion spectrometry, such as laser desorption / ionization mass spectrometry, MALDI-TOF-MS, SELDI-TOF-MS (surface enhanced laser desorption ionization), LC-MS (liquid chromatography mass spectrometry), 2D-PAGE-MS and capillary electrophoresis mass spectrometry (CE-MS). All of the methods mentioned are known to the person skilled in the art.
  • gas phase ion spectrometry such as laser desorption / ionization mass spectrometry, MALDI-TOF-MS, SELDI-TOF-MS (surface enhanced laser desorption ionization), LC-MS (liquid chromatography mass spectrometry), 2D-PAGE-MS and capillary electrophoresis mass spectrometry (CE-MS). All of the methods mentioned are known to the person skilled in the art.
  • CE-MS in which capillary electrophoresis is coupled with mass spectrometry. This process is described in detail, for example, in German patent application DE 10021737, in Kaiser et al. (J. Chromatogr. A 1 2003, Vol. 1013: 157-171, and Electrophoresis, 2004, 25: 2044-2055) and in Wittke et al. (J. Chromatogr. A 1 2003, 1013: 173-181).
  • the CE-MS technique allows to determine the presence of several hundreds of polypeptide markers of a sample simultaneously in a short time, a small volume and high sensitivity. After a sample has been measured, a pattern of the measured polypeptide markers is prepared. This can be compared with reference patterns of ill or healthy individuals. In most cases it is sufficient to use a limited number of polypeptide markers for the diagnosis of UAS. More preferred is a CE-MS method which includes CE coupled online to an ESI-TOF-MS.
  • the use of volatile solvents is preferred, and it is best to work under essentially salt-free conditions.
  • suitable solvents include acetonitrile, methanol and the like.
  • the solvents may be diluted with water and an acid (eg 0.1% to 1% formic acid) added to protonate the analyte, preferably the polypeptides.
  • an acid eg 0.1% to 1% formic acid
  • Capillary electrophoresis makes it possible to separate molecules according to their charge and size. Neutral particles migrate at the rate of electroosmotic flow upon application of a current, cations are accelerated to the cathode and anions are retarded.
  • capillaries in electrophoresis is the favorable ratio of surface area to volume, which enables a good removal of the Joule heat arising during the current flow. This in turn allows the application of high voltages (usually up to 30 kV) and thus a high separation efficiency and short analysis times.
  • quartz glass capillaries with internal diameters of typically 50 to 75 ⁇ m are normally used. The used lengths are 30-100 cm.
  • the capillaries usually consist of plastic-coated quartz glass.
  • the capillaries may be both untreated, i. on the inside show their hydrophilic groups, as well as be coated on the inside. A hydrophobic coating can be used to improve the resolution.
  • a pressure which is typically in the range of 0-1 psi may also be applied. The pressure can also be created during the separation or changed during the process.
  • the markers of the sample are separated by capillary electrophoresis, then directly ionized and transferred online to a mass spectrometer coupled thereto for detection.
  • polypeptide markers can advantageously be used for diagnostics.
  • Figure 1 shows the summed data from urine samples from control patients and ADPKD patients.
  • FIG. 2 shows the receiver operating characteristic curves for the training and the test set.
  • Urine was used to detect polypeptide markers for diagnosis. Urine was given by healthy donors (peer group), patients undergoing chronic kidney disease or renal or bladder carcinoma ("disease control") as well as patients suffering from ADPKD.
  • proteins such as albumin and immunoglobulins, which are also present in urine of patients in higher concentrations, had to be separated by ultrafiltration.
  • 700 .mu.l of urine were removed and treated with 700 .mu.l filtration buffer (2M urea, 1OmM ammonia, 0.02% SDS).
  • 700 .mu.l filtration buffer (2M urea, 1OmM ammonia, 0.02% SDS).
  • sample volumes were ultrafiltered (20 kDa, Sartorius, Gottingen, DE).
  • the UF was carried out at 3000 rpm in a centrifuge until 1.1 ml ultrafiltrate was obtained.
  • CE-MS measurements were performed using a Beckman Coulter capillary electrophoresis system (P / ACE MDQ System, Beckman Coulter Ine, Fullerton, USA) and Bruker ESI-TOF mass spectrometer (micro-TOF MS, Bruker Daltonik, Bremen, D).
  • the CE capillaries were purchased from Beckman Coulter, having an ID / OD of 50/360 ⁇ m and a length of 90 cm.
  • the mobile phase for the CE separation consisted of 20% acetonitrile and 0.25% formic acid in water. 30% isopropanol with 0.5% formic acid was used for the "sheath flow" on the MS, here with a flow rate of 2 ⁇ l / min.
  • the coupling of CE and MS was performed by a CE-ESI-MS sprayer kit (Agilent Technologies , Waldbronn, DE).
  • the duration of the injection was 99 seconds. With these parameters about 150 nl of the sample were injected into the capillary, this corresponds to about 10% of the capillary volume.
  • a "stacking" technique was used, injecting an IM NH 3 solution for 7 sec (at 1 psi) before injecting the sample and injecting a 2M formic acid solution for 5 sec after sample injection the separation voltage (30 kV), the analytes are automatically concentrated between these solutions.
  • the following CE separation was performed with a pressure method: 0 psi for 40 minutes, 0.1 psi for 2 minutes, 0.2 psi for 2 minutes, 0.3 psi for 2 minutes, 0.4 psi for 2 minutes, finally 17 min at 0.5 psi.
  • the total duration of a separation run was thus 65 minutes.
  • the "Nebulizer gas" was set to the lowest possible value.
  • the voltage applied to the spray needle to generate the electrospray was 3700 - 4100 V.
  • the remaining settings on the mass spectrometer were optimized according to the manufacturer's instructions for peptide detection.
  • the spectra were recorded over a mass range of m / z 400 to m / z 3000 and accumulated every 3 seconds. 3.
  • ELM sequence: ELMTGELPYSHINNRDQIIFMVGR 23.49 min
  • the proteins / polypeptides are each used in a concentration of 10 pmol / ⁇ l in water.
  • REV "REV”, "ELM”, “KINCON” and “GIVLY” represent synthetic peptides.
  • the most probable assignment is that in which there is a substantially linear relationship between the shift for the peptide 1 and for the peptide 2.
  • the 75 biomarkers already showed an AUC of 0.89, so they are excellently suited.

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Abstract

L'invention concerne un procédé de diagnostic d'une maladie polykystique rénale autosomique dominante (ADPKD) comportant l'étape de détermination de la présence, de l'absence ou de l'amplitude d'au moins trois polypeptides marqueurs dans un échantillon d'urine, les polypeptides marqueurs étant sélectionnés parmi les marqueurs du tableau 1 caractérisés par des valeurs de masses moléculaires et de temps de migration.
EP09796710A 2008-12-17 2009-12-17 Maladie polykystique rénale autosomique dominante (adpkd) Ceased EP2394171A2 (fr)

Priority Applications (1)

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EP09796710A EP2394171A2 (fr) 2008-12-17 2009-12-17 Maladie polykystique rénale autosomique dominante (adpkd)

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EP08171983 2008-12-17
EP09796710A EP2394171A2 (fr) 2008-12-17 2009-12-17 Maladie polykystique rénale autosomique dominante (adpkd)
PCT/EP2009/067430 WO2010079076A2 (fr) 2008-12-17 2009-12-17 Maladie polykystique rénale autosomique dominante (adpkd)

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EP2338054A1 (fr) * 2008-09-17 2011-06-29 Mosaiques Diagnostics And Therapeutics AG Carcinome à cellules rénales
US20220050113A1 (en) * 2018-09-14 2022-02-17 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of amniotic fluid peptides for predicting postnatal renal function in congenital anomalies of the kidney and the urinary tract

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EP1808694A1 (fr) * 2006-01-17 2007-07-18 Universitätsklinikum Freiburg Procédé de diagnostic d'une maladie polykystique des reins

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