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WO2018182346A1 - Composition de diagnostic ou de prédiction du syndrome du qt long induit par un médicament, kit, et procédé de diagnostic ou de prédiction de syndrome du qt long induit par un médicament l'utilisant - Google Patents

Composition de diagnostic ou de prédiction du syndrome du qt long induit par un médicament, kit, et procédé de diagnostic ou de prédiction de syndrome du qt long induit par un médicament l'utilisant Download PDF

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WO2018182346A1
WO2018182346A1 PCT/KR2018/003752 KR2018003752W WO2018182346A1 WO 2018182346 A1 WO2018182346 A1 WO 2018182346A1 KR 2018003752 W KR2018003752 W KR 2018003752W WO 2018182346 A1 WO2018182346 A1 WO 2018182346A1
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snta1
seq
arrhythmia
syndrome
diagnosing
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최종일
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Korea University Research and Business Foundation
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Korea University Research and Business Foundation
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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
    • 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
    • G01N33/483—Physical analysis of biological material

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  • the present invention relates to compositions, kits for diagnosing or predicting drug-induced QT prolongation syndrome, and methods for diagnosing or predicting drug-induced QT prolongation syndrome using the same.
  • Drug-induced QT prolongation syndrome is an acquired disease, mostly caused by drug block of I Kr , such as antiarrhythmic agents.
  • I Kr drug block of I Kr
  • KCNH2 or KCNQ1 that encode K + channels.
  • Addition of I Kr blocking drugs to this population may increase late cardiac sodium current (I Na-L ), thereby increasing the action potential (AP), thus increasing the QT interval associated with fatal deep vein tachycardia.
  • AP action potential
  • I Na-L due to drug-induced phosphoinositide 3-kinase (PI3K) signaling may also contribute to QT prolongation.
  • the cardiac Na + channel Na V 1.5 is encoded and the third most common variant of the cLQT locus SCN5A is less relevant to diLQTS.
  • SNTA1 Coded by the SNTA1 gene 1-syntrophin (SNTA1) is a dystrophin-associated protein and a potent regulator of voltage-gated Na + channels. SNTA1 forms pores Interaction with the C terminus of the subunit forms a Na V 1.5 channel macromolecular complex. SNTA1 comprises a postsynaptic density protein-95 / disc large / zona occludens-1 (PDZ) domain, two pleckstrin homology (PH1 and PH2) domains, and a syntrophin (SU) domain. The PDZ domain of SNTA1 interacts with a PDZ binding motif consisting of the last three amino acids (serine-isoleucine-valine) at the Na V 1.5 COOH terminus.
  • PDZ postsynaptic density protein-95 / disc large / zona occludens-1
  • PH1 and PH2 two pleckstrin homology
  • SU syntrophin
  • SNTA1 also interacts with plasma membrane Ca-ATPase (PMCA) 4b to form a complex of three proteins. These complexes can inhibit NOS mediated NO production by inhibiting neuronal nitric oxide synthase (nNOS).
  • nNOS neuronal nitric oxide synthase
  • the physiological and clinical relevance of this interaction is highlighted by previous identifications that disrupted the binding between SNTA1 and PMCA4b in LQTS patients of the variant (A390V) within the PH2 domain of SNTA1, thereby relieving the inhibition of nNOS and , S-nitrosylation of Na V 1.5 mediated by locally highlighted NO production resulted in increased pathogenic I Na-L . Increased I Na-L causes cardiac arrhythmias by prolonging AP duration and reducing repolarization maintenance.
  • compositions for diagnosing or predicting arrhythmia consisting of the nucleotide sequence of SEQ ID NO: 1 and SEQ ID NO: 2, comprising a first primer set for specifically detecting the SNTA1 gene mutation, there is provided a composition for diagnosing or predicting arrhythmia.
  • the arrhythmia may occur in a drug-induced Long QT Syndrome (diLQTS) patients.
  • diLQTS drug-induced Long QT Syndrome
  • it may further comprise a second primer set to specifically detect the SNTA1 gene mutation.
  • the SNTA1 gene mutation may increase late sodium current (I Na-L ).
  • the SNTA1 gene mutation may be the 1168th base of SEQ ID NO: 5 is substituted from G to T, the 1225th base is substituted from G to C.
  • kits for diagnosing or predicting arrhythmia comprising a composition according to an embodiment of the present invention.
  • the method comprises: extracting a biological sample; Amplifying the sample using a first primer set consisting of the nucleotide sequences of SEQ ID NO: 1 and SEQ ID NO: 2; And identifying whether the SNTA1 gene is mutated; Including, an arrhythmia diagnosis or prediction method is provided.
  • the amplifying the sample amplifying using a second primer set consisting of the nucleotide sequence of SEQ ID NO: 3 and SEQ ID NO: 4; may further comprise a.
  • the arrhythmia may occur in a drug-induced Long QT Syndrome (diLQTS) patients.
  • diLQTS drug-induced Long QT Syndrome
  • composition for diagnosing or predicting the prolonged syndrome of drug-induced QT of the present invention can be diagnosed in advance by examining whether the ATAV or E409Q mutation of the SNTA1 gene in the subject is diagnosed, and thus whether or not a specific drug is taken, and thus the sudden death that can be caused by the drug The risk can be prevented.
  • FIG. 1 shows the results of analysis for patients with drug-induced QT prolongation syndrome including E409Q mutation in SNTA1.
  • 1A shows the electrocardiogram (ECG) of a subject during the post cardiac arrest period.
  • FIG. 1B shows the electrocardiogram (ECG) of the subject for 2 months after discontinuation of heart attack.
  • Figure 1c shows a family tree of the initiator. Arrows indicate the start of the p.E490Q mutation.
  • 1D shows interspecies sequence conservation for normal versus A390V and E409Q in SNTA1.
  • FIG. 2 shows electrophysiological data of Na V 1.5 in HEK293T cells expressing WT or SNTA1 mutations simultaneously with PMCA4b, nNOS.
  • FIG. 2A shows representative traces of inward Na + currents for the three groups under test.
  • 2B shows the IV curve.
  • 2c shows activation (G / Gmax) values.
  • 2d shows the deactivation (I / Imax) values.
  • 2E shows the recovery (P2 / P1) value.
  • 3 shows late Na + currents in HEK293T cells.
  • 3A shows representative late Na + currents with WT and SNTA1 mutations.
  • Figure 3b A390V - shows the result of both SNTA1 and E409Q-SNTA1 increase I Na-L significantly in HEK293T cells as compared to WT-SNTA1.
  • FIG. 4 shows electrophysiological data of Na + currents in adult rat cardiomyocytes infected with WT or SNTA1 mutations.
  • FIG. 4A shows representative traces of inward Na + currents for the three groups under test.
  • 4B shows the IV curve.
  • 4c shows the activation (G / Gmax) values.
  • 4D shows the deactivation (I / Imax) values.
  • 4E shows the recovery (P2 / P1) value.
  • FIG. 5 shows late Na + currents in adult rat cardiomyocytes infected with adenovirus expressing wild type (WT) or one of two SNTA1 mutations.
  • 5A shows representative late Na + currents with WT and SNTA1 mutations.
  • Figure 5b shows the result of E409Q-SNTA1 significantly increased I Na-L compared to WT-SNTA1.
  • FIG. 6 schematically shows the mechanism of Syntrophin mutations and late sodium currents.
  • the variant of SNTA1 causes a breakdown of binding to PMCA4b and exhibits an inhibitory action of nNOS, thereby increasing I Na-L through S-nitrolation of Na V 1.5.
  • the present inventors have made diligent efforts to establish a reliable genetic diagnosis method for the disease by searching for mutations specific to arrhythmias in patients with drug-induced QT prolongation syndrome.
  • late sodium currents in E409Q a novel mutation of the SNTA1 gene, were identified.
  • Sodium Current, I Na-L was confirmed to increase. This has led to the discovery of novel pathogenic mutations on the SNTA1 gene, which are conventionally unknown as mutations over sodium channels.
  • a composition for diagnosing or predicting arrhythmia comprising the nucleotide sequence of SEQ ID NO: 1 and SEQ ID NO: 2, comprising a first primer set for specifically detecting the SNTA1 gene mutation, there is provided a composition for diagnosing or predicting arrhythmia.
  • the first set of primers can detect the E409Q mutation of SNTA1.
  • the arrhythmia may occur in a drug-induced Long QT Syndrome (diLQTS) patients.
  • diLQTS drug-induced Long QT Syndrome
  • the term "QT prolongation syndrome” is a congenital due to genetic abnormality, which is a serious disease that has an unexplained prolonged QT time on ECG and can cause fainting and sudden cardiac death by ventricular fibrillation. , Depending on the electrolyte and the drug can be distinguished.
  • the heart's electrical system recharges itself for the next heartbeat, which requires longer time than a normal person with a cardiac interval syndrome, which causes an abnormally fast arrhythmia called torsade de points ( arrhythmia) comes.
  • arrhythmia torsade de points
  • it may further comprise a second primer set to specifically detect the SNTA1 gene mutation.
  • the second set of primers can detect the A390V mutation of SNTA1.
  • the SNTA1 gene mutation may increase late sodium current (I Na-L ).
  • the SNTA1 gene mutation may be the 1168th base of SEQ ID NO: 5 is substituted from G to T, the 1225th base is substituted from G to C.
  • the A309V mutant is replaced with amino acid No. 390 from Alanine to Valine, and the E409Q mutation is substituted with amino acid 409 from Glutamic Acid to Glutamine. .
  • kits for diagnosing or predicting arrhythmia comprising a composition according to an embodiment of the present invention.
  • the method comprises: extracting a biological sample; Amplifying the sample using a first primer set consisting of the nucleotide sequences of SEQ ID NO: 1 and SEQ ID NO: 2; And identifying whether the SNTA1 gene is mutated; Including, an arrhythmia diagnosis or prediction method is provided.
  • the amplifying the sample may further include amplifying the second primer set including the nucleotide sequences of SEQ ID NO: 3 and SEQ ID NO: 4.
  • Gene amplification using the first and second primers of the present invention can be carried out through various amplification reactions known in the art, such as polymerase chain reaction (PCR), reverse transcriptase-polymerase chain reaction (RT-PCR), Ligase chain reaction, repair chain reaction, transcription-mediated amplification, self-sustaining sequence replication, nucleic acid sequence based amplification, etc. Including but not limited to.
  • PCR polymerase chain reaction
  • RT-PCR reverse transcriptase-polymerase chain reaction
  • Ligase chain reaction Ligase chain reaction
  • repair chain reaction transcription-mediated amplification
  • self-sustaining sequence replication nucleic acid sequence based amplification
  • Human SNTA1 plasmid vectors were mutated using Quickchange II Site-Directed Mutagenesis (Agilent Technologies, Santa Clara, Calif.) And the following primers. The underlined portions in the following primers indicate variations.
  • each of these constructs was subcloned into a pAdRFP adenovirus shuttle vector, followed by polymerase chain reaction and bacterial transformation.
  • the AdEasy system (Agilent Technologies, Santa Clara, Calif.) was used to generate WT- SNTA1 and mutant viruses, and adenovirus plasmids were packaged in HEK293 cells. After several freeze / thaw cycles, the recombinant virus was isolated, further amplified, and purified and concentrated using Vivapure AdenoPACK 20 (Sartorius Stedim Biotech, Goettinggen, Germany). Virus titers were determined and used at 50-200 infectivity (MOI). All structures were confirmed by sequence analysis.
  • HEK293T cells at a 4: 4: 4: 1 ratio of pIRES2EGFP plasmid vector expressing tetrodotoxin (TTX) sensitive Na V 1.5, nNOS, PMCA4b and human wild type (WT) or SNTA1 mutations (A390V and E409Q).
  • TTX tetrodotoxin
  • WT human wild type
  • SNTA1 mutations A390V and E409Q
  • the resistance of the electrode is 2-4M It was.
  • Standard step-pulse voltages were generated using pClamp 9.0 software (Axon Instruments) with an Axopatch 200B amplifier.
  • the current was filtered at 5kHz and digitized using an analog-digital interface (Digidata 1322A, Axon Instruments).
  • Digidata 1322A Axon Instruments
  • Current density (pA / pF) was calculated by normalization to cell capacitance.
  • G Conductance
  • V 1/2 is the voltage corresponding to half of the Na v 1.5 channel activation
  • Is the slope coefficient
  • V m the membrane potential.
  • a standard two-pulse protocol was used to generate a steady state deactivation curve: cells were processed stepwise at a holding potential of -120 mV up to a 500-ms preconditioning potential that varied between -140 mV and -20 mV, and then A 20 ms test pulse was performed up to -40 mV.
  • the heart was then removed and inserted into the aorta using the Langendorff device (Radnoti Glass Technology) to perfusion the heart back into the line for about 10 minutes.
  • BDM 2,3-butanedione monoxime
  • Culture medium is Earle's Salts, L-Glutamine, BSA 0.1 mg / ml, BDM 10 mM, 1X insulin-selenium-transferrin supplement (Gibco), creatine 5 mM, taurine 5 mM, L-carnitine 2 mM, and blebbistatin 25 MEM medium containing M (Toronto Research Chemicals) was used. Oxygen was supplied to all solutions for at least 30 minutes at 95% O 2 /5% CO 2 . Cells were identified by RFP fluorescence 36-48 hours after infection. Sticky striped cells were observed through electrophysiology.
  • Pulse protocol period was maintained at 3 seconds for complete Na + channel recovery.
  • Current amplitude data of each cell was normalized to cell capacity (current density, pA / pF).
  • the current was extracted by a 50 ms pulse at a holding potential of -120 mV and tested for potentials between -100 mV and +60 mV in 5 mV increments.
  • Sodium conductance (G) was calculated by dividing the peak current for each voltage step by driving force (Vm-Vr) and normalizing the peak conductance (Gmax). The data is It was calculated using the Boltzmann function represented by.
  • V 1/2 is the voltage corresponding to half of the Nav1.5 channel activation
  • Is the slope coefficient
  • V m is the membrane potential.
  • a standard two-pulse protocol was used to generate a steady state deactivation curve: cells were processed stepwise at a holding potential of -120 mV up to a 500-ms preconditioning potential that varied between -140 mV and -20 mV, and then A 20 ms test pulse was performed up to -40 mV. Current I is normalized to I max, The Boltzmann function of the form was calculated.
  • V1 / 2 is half the voltage at the Nav1.5 channel activation
  • Is the slope coefficient and Vm is the membrane potential.
  • I NA-L is the average between 190 and 200 ms after the initiation of depolarization, determined as 200 ms depolarization from -120 mV to -40 mV, 30
  • the peak current after digital subtraction of the recorded current in the presence and absence of Abtx Biochemicals (TTX) was recorded.
  • TTX Abtx Biochemicals
  • Results are expressed as mean ⁇ standard error (SEM). The statistical significance of the differences between the groups was assessed by Student's t- test. For parametric tests for normality, nonparametric Mann-Whitney The test was compared using. Values of P ⁇ 0.05 were considered statistically significant. Statistical analysis was performed using SPSS Statistics software version 17.0 (IBM, Armonk, NY).
  • ICD implantable cardiac defibrillator
  • I Na-L was measured using a long depolarization pulse (200 ms at -10 mV from a holding potential of -120 mV) and TTX (1 The background was removed by the administration of M).
  • FIGS. 4C and 4D The dynamics of activation and steady state inactivation of wild type and mutations. There was no significant difference in the dynamics of activation and steady-state inactivation between wild-type and SNTA1 mutations. Compared to WT-SNTA1, the recovery rate from inactivation appeared to be slightly delayed in E409Q-SNTA, but there was no statistical significance (FIG. 4E).
  • Na V 1.5 channel interaction protein (NaChIP) complexed with nNOS and PMCA4b has been established. Mutations induce the function acquisition regulation of NaV1.5 (increased I Na-L ) and cLQTS.
  • Ueda et al. Reported that mutations in the PH2 domain of SNTA1 (A390V) disrupted binding to PMCA4b, inhibiting nNOS, leading to S-nitrosylation of NaV1.5 and an increase in I Na-L . Novel mutants are disclosed herein and E409Q is outside the PH2 region.
  • E409Q affects Na V 1.5 currents similarly to A390V in both cardiomyocytes and E409Q affects PMCA4b interactions similar to A390V in heterogeneous systems where all major components of the macromolecular complex are present. You can check it. Thus, we concluded that the binding site for PMCA4b should extend further towards the C-terminus of PMCA4b than the PH2 domain or that the E409Q variant allosterically affects the PH2 binding domain. 6 schematically shows the resulting mechanism for the aforementioned interactions and increased I Na-L .
  • I Na-L due to SNTA1 mutations is part of the pathogenesis of cLQTS and channel pathogenic infantile death syndrome (SIDS), and mutations are indicative of the acquisition of I Na .
  • E409Q and A309V SNTA1 variants are wild type SNTA1. Compared with, increase I Na-L without showing significant difference in peak I Na .
  • E409Q mutations in HEK293T cells showed a reduced k inactivation, and adenovirus expression was used to confirm the electrophysiological characteristics of SNTA1 mutations in adult rat cardiomyocytes, indicating that recovery from inactivation was observed in HEK293T cells and cardiomyocytes. It was found to be different when comparing.
  • Voltage-gated cardiac sodium channels are known to be responsible for a subgroup of LQTSs (LQT3).
  • LQT9, LQT10 and LQT12 are also found in Na V 1.5.
  • I Na-L increases because it affects subunits or NaChIPs such as caveolin-3 and SNTA1.
  • Patients in this study were diagnosed with diLQTS, congenital or clinic disease, most commonly explained by repolarization abnormalities due to potassium channel blockade.
  • the notched T wave shown in FIG. 1A is consistent with the pattern observed after the I Kr block.
  • I Kr (hERG channel) blockers, prokinetics or antiarrhythmic may reduce the "repolarization" of the patient and prolong the QT interval.
  • diLQTS may be due to genetic susceptibility due to mutations in the cLQTS locus (SNTA1), which are exacerbated by a decrease in the repolarization maintenance by amitriptyline and pseudoephedrine.
  • SNTA1 cLQTS locus
  • the identification of variants in the cLQTS locus in patients suffering from diLQTS can provide advice on cascade screening and outcomes to affected family members to avoid known QT prolongation drugs.
  • a drug targeting I Na-L such as ranolazine is recommended. Treatment may be a reasonable strategy.

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Abstract

La présente invention concerne : une composition grâce à laquelle le syndrome du QT long induit par un médicament (diLQTS) peut être diagnostiqué ou prédit par E409Q, qui est une nouvelle mutation SNTA1 par rapport à l'arrhythmie, plus particulièrement l'arrhythmie survenant chez les patients présentant un syndrome du QT long induit par un médicament ; un kit ; et un procédé de diagnostic/prédiction.
PCT/KR2018/003752 2017-03-30 2018-03-30 Composition de diagnostic ou de prédiction du syndrome du qt long induit par un médicament, kit, et procédé de diagnostic ou de prédiction de syndrome du qt long induit par un médicament l'utilisant Ceased WO2018182346A1 (fr)

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KR20170040908 2017-03-30
KR10-2017-0040908 2017-03-30
KR1020180030834A KR20180111533A (ko) 2017-03-30 2018-03-16 약물 유발 qt 연장 증후군 진단 또는 예측용 조성물, 키트 및 이를 이용한 약물 유발 qt 연장 증후군 진단 또는 예측 방법
KR10-2018-0030834 2018-03-16

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009516691A (ja) * 2005-11-21 2009-04-23 タツプ・フアーマシユーテイカル・プロダクツ・インコーポレイテツド Ｑｔ間隔延長およびこれに伴う疾病の治療
US20150307941A1 (en) * 2009-04-21 2015-10-29 Transgenomic, Inc. Mutations associated with long qt syndrome

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009516691A (ja) * 2005-11-21 2009-04-23 タツプ・フアーマシユーテイカル・プロダクツ・インコーポレイテツド Ｑｔ間隔延長およびこれに伴う疾病の治療
US20150307941A1 (en) * 2009-04-21 2015-10-29 Transgenomic, Inc. Mutations associated with long qt syndrome

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHOI, JONG- IL ET AL.: "Abstract 11781 alpha1-syntrophin mutation identified in drug-induced long-QT syndrome increases late sodium current", CIRCULATION, vol. 132, 6 November 2015 (2015-11-06), XP055612501, Retrieved from the Internet <URL:https://www.ahajournals.org/doi/abs/10.1161/circ.132.suppl_3.11781> *
CHOI, JONG- IL: "al-syntrophin variant identified in drug-induced long QT syndrome increases late sodium current", PLOS ONE, vol. 11, no. 3, 30 March 2016 (2016-03-30), pages 1 - 17, XP055612502 *
UEDA, KAZUO ET AL.: "Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex", PNAS- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 105, no. 27, 8 July 2008 (2008-07-08), pages 9355 - 9360, XP055612504 *
WU, GERU ET AL.: "alpha-1-syntrophin mutation and the long-QT syndrome : a disease of sodium channel disruption", CIRCULATION: ARRHYTHMIA AND ELECTROPHYSIOLOGY, vol. 1, no. 3, August 2008 (2008-08-01), pages 193 - 201, XP055612505 *

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