WO2012031412A1 - Profil plasmatique des arnmi pour anticiper l'effet thérapeutique de l'interféron dans le traitement de l'hépatite b chronique, et kits de détection - Google Patents

Profil plasmatique des arnmi pour anticiper l'effet thérapeutique de l'interféron dans le traitement de l'hépatite b chronique, et kits de détection Download PDF

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WO2012031412A1
WO2012031412A1 PCT/CN2010/077506 CN2010077506W WO2012031412A1 WO 2012031412 A1 WO2012031412 A1 WO 2012031412A1 CN 2010077506 W CN2010077506 W CN 2010077506W WO 2012031412 A1 WO2012031412 A1 WO 2012031412A1
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mirna
interferon
seq
mirnas
chronic hepatitis
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Chinese (zh)
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袁正宏
张小楠
邬敏
陈良
张继明
张欣欣
张占卿
吴景迪
王介非
陈晓蓉
黄涛
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上海市公共卫生临床中心
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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
    • C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
    • C12Q1/701—Specific hybridization probes
    • C12Q1/706—Specific hybridization probes for hepatitis
    • 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
    • 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
    • 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
    • C12Q2600/158—Expression markers
    • 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
    • C12Q2600/178—Oligonucleotides characterized by their use miRNA, siRNA or ncRNA

Definitions

  • the present invention relates to the fields of molecular biology and medicine. More specifically, it relates to plasma miRNA expression levels predicting the efficacy of interferon in the treatment of chronic hepatitis B. The invention also relates to methods and kits for detecting miRNA levels.
  • Hepatitis B virus (HBV) infection can cause chronic liver disease and significantly increase the risk of developing hepatocellular carcinoma.
  • HBV infection remains an important health problem in countries all over the world.
  • Interferon alpha and nucleoside analogs such as lamivudine, adefovir, entecavir, telbivudine, etc., are the main therapeutic agents for HBV infection.
  • Interferon therapy usually only achieves a complete response in a limited number of patients, and is prone to recurrence after discontinuation of treatment.
  • pegylated interferon also known as long-acting interferon, mainly PEG-IFNa2a, PEG-IFNa2b
  • PEG-IFNa2a mainly PEG-IFNa2a
  • PEG-IFNa2b mainly PEG-IFNa2a
  • PEG-IFNa2b mainly PEG-IFNa2a
  • PEG-IFNa2b e antigen seroconversion
  • long-acting interferons are prone to cause side effects such as flu-like symptoms, depression, and personality changes.
  • Nucleoside analogs such as lamivudine, adefovir, entecavir, telbivudine, etc., are potent inhibitors of hepatitis B reverse transcriptase polymerase and block viral genome replication.
  • such drug treatments do not achieve a high seroconversion rate, and a large proportion of patients relapse after discontinuation of medication.
  • long-term use is likely to cause the formation of drug resistance mutations.
  • the technical problem to be solved by the present invention is to determine a molecular marker which can be detected in blood and which has a high prediction accuracy.
  • miRNA small non-coding RNA
  • Drosha nuclease
  • miRNAs small RNA
  • DICER DICER enzyme
  • Small RNAs are a class of short nucleotides present in plasma that have been reported to be very sensitive molecular markers of liver damage and pregnancy.
  • the present invention has been extensively studied to determine a plasma miRNA profile predicting the efficacy of interferon in the treatment of chronic hepatitis B, which includes one or more of the miRNAs of SEQ ID NO.
  • a kit for predicting the therapeutic effect of interferon for treating chronic hepatitis B comprising one or more miRNA-specific probe nucleotides for SEQ ID NO.
  • a chip for predicting the efficacy of interferon in the treatment of chronic hepatitis B which contains one or more miRNA-specific probe nucleotides in SEQ ID NO 1-10. Most preferably, the chip contains a miRNA-specific probe nucleotide for SEQ ID NO 1-10.
  • the present invention also provides a method for predicting the therapeutic effect of interferon in the treatment of chronic hepatitis B, which is to detect the expression level of one or more miRNAs in SEQ ID NO 1-10 before use of interferon plasma and serum samples, and express the expression in the sample.
  • the difference between the level and the standard level was analyzed by statistical methods to predict the efficacy of interferon.
  • Expression levels of at least one of the miRNAs are above or below a known standard level.
  • the method comprises the steps of: (1) extraction of plasma, serum sample small RNA, (2) nucleic acid sample hybridization with a chip having one or more miRNA-specific probes as in SEQ ID NO. (3) Compare the hybridization signal with the hybridization sample.
  • the statistical method described is the analysis of the significance of the difference between the expression level and the standard level in the sample.
  • the statistical methods include: miRNA expression profiling scores each miRNA by maximum correlation degree minimum redundancy analysis; using neighborhood classification algorithm as a prediction engine for category judgment; eigenvalue increment analysis method and leave one method cross validation to optimize selected miRNAs quantity.
  • the expression profile of a part of miRNA before treatment of hepatitis B patients can predict the therapeutic effect of interferon alpha, and accordingly, a method for detecting miRNA, a method for establishing a predictive model, and a detection kit are disclosed.
  • the present invention provides a unique miRNA expression profile that is capable of distinguishing whether a patient with HBV has a response to long-acting interferon or a common interferon treatment (initial virological response, 12 weeks greater than 21 og HBV DNA reduction).
  • This expression profile consists of hsa-miR-1268 (SEQ ID NO. 1), has-miR-150* (SEQ ID NO. 2), has-miR-22 (SEQ ID NO. 3), has-miR-197 (SEQ ID NO. 4), hsa-miR- 26a (SEQ ID NO. 5), has- miR-188- 5p (SEQ ID NO. 6), has- miR-1471 (SEQ ID NO.
  • the present invention provides a method for detecting a serum miRNA expression profile. Specifically, the method includes the steps of: (1) extracting total plasma RNA, and (2) detecting the expression profile of a specific miRNA in the total RNA by using a microarray. It can be operated in accordance with conventional methods in the art.
  • the statistical method includes one or more of the following: (1) miRNA expression profiles are scored for each miRNA by maximum relevance minimum redundancy analysis (mRMR), (2) using a neighbor classification algorithm (NN) As a predictive engine for class judgment, (3) Eigenvalue Incremental Analysis (IFS) and leave-one-out cross-validation optimize the number of selected miRNAs.
  • miRNA expression profiles are scored for each miRNA by maximum relevance minimum redundancy analysis (mRMR), (2) using a neighbor classification algorithm (NN) As a predictive engine for class judgment, (3) Eigenvalue Incremental Analysis (IFS) and leave-one-out cross-validation optimize the number of selected miRNAs.
  • mRMR maximum relevance minimum redundancy analysis
  • NN neighbor classification algorithm
  • IFS Eigenvalue Incremental Analysis
  • leave-one-out cross-validation optimize the number of selected miRNAs.
  • miRNA expression profile of the present invention 66 samples of HBV patients receiving long-acting interferon therapy were analyzed with a sensitivity of 63.33% and a specificity of 69.44%.
  • This miRNA profile consisted of 10 specific nucleotide sequences, and its expression was significantly different in the non-response and fast response groups.
  • the present invention further validated this predictive model in 28 patients with HBV who received general interferon therapy and achieved an accuracy of 60.7%.
  • the present invention provides a miRNA expression profile capable of predicting the efficacy of interferon in the treatment of chronic hepatitis B with higher accuracy.
  • This expression profile is an independent predictor compared to other known efficacy-related factors.
  • This expression profile combined with HBV-resistant mutation analysis will facilitate the development of individualized treatment regimens, ultimately reducing treatment costs and increasing the proportion of complete responses.
  • the corresponding detection method is convenient, fast, and low in cost.
  • the invention also provides an efficient and inexpensive corresponding detection kit and chip.
  • FIG. 1 Ten miRNA expression profiles are shown in the heat map of the fast response and non-response groups. Green: Less than mean - standard deviation, black: between mean - standard deviation and mean + standard deviation, red: greater than average + standard deviation.
  • the ten miRNAs are: hsa- miR- 1268 (SEQ ID NO. 1), has- miR- 150* (SEQ ID NO. 2), has- miR- 22 (SEQ ID NO. 3), has- miR- 197 (SEQ ID NO. 4), hsa-miR-26a (SEQ ID NO. 5), has- miR-188-5p (SEQ ID NO. 6), has- miR-1471 (SEQ ID NO. 7), Has- miR-484 (SEQ ID NO. 8), has-miR-1181 (SEQ ID NO. 9), has-miR-194 (SEQ ID NO. 10).
  • FIG. 1 IFS (incremental eigenvalue) plot of interferon efficacy prediction.
  • X-axis, number of eigenvalues, Y-axis, go to an interactive test accuracy. The arrival accuracy is highest when 10 eigenvalues are selected.
  • the present invention obtains plasma and serum samples from 94 chronic hepatitis B patients receiving long-acting interferon and common interferon.
  • the study was reviewed by an ethics committee and all patients signed informed consent.
  • the training set included 66 patients with HBV who received EG-IFN a2a (180 ⁇ / week) or PEG-IFN a2b (100 ⁇ / week).
  • the test set included 28 patients receiving normal interferon.
  • HBV patients IFN-a2b or IFN-alb, 3-5 MU/qod.
  • the basic clinical data of the enrolled patients are shown in Table 1, in which 81.9% are e antigen positive, and the average viral load is 7. 05 log 10 copies/ml.
  • Enrollment exclusion criteria HBV patients enrolled were not treated with nucleoside analogues or interferon 6 months prior to initiation of treatment, viral load was above 5 X 10 4 copies/ml, and liver alanine aminotransferase was abnormal 1. 0 ULN) .
  • Exclusion criteria include HIV or HCV co-infection. All patients were tested for HBV surface antigen, e antigen (Abbott AXSYM HBsAg (normal: 0 - 2S/N) and HBe 2. 0 ME IA Kit (normal: 0
  • the Qiagen RNAeasy FFPE kit was used to extract RNA from formalin fixed paraffin-embedded specimens (FFPE). Briefly, the procedure is as follows: Scrape the FFPE specimen from the slide with a scalpel, dewax it with xylene, remove xylene by centrifugation, and add 100% ethanol to remove residual xylene.
  • the protease K passed through the FFPE specimen was digested at 55 ° C for 15 minutes and at 80 ° C for 15 minutes.
  • the sample was passed through an RNeasy column, washed twice, and eluted with nuclease-free water. miRNA chip detection
  • the present invention compared 94 plasma samples and 13 FFPE specimens using a human miRNA chip (Agilent Technologies, Santa Clara, CA).
  • This chip contains the Sanger database V12. 0 851 human miRNAs.
  • the sample total RNA was labeled with Cy3 and hybridized with the chip.
  • the chip was scanned by G2505C (Agilent Technologies, Santa Clara, CA) scanner.
  • the labeling and hybridization procedures were performed according to the standard operation of the agilent miRNA chip system.
  • the information was analyzed by the scanning software Rev. 5. 0 (Agilent Technologies, Santa Clara, CA) and converted into intensity information. Through background removal, the chip signals were exported to GeneSpring GX10 software (Agilent Technologies, Standardization was carried out by Santa Clara, CA).
  • RNA was obtained from 100_200 ⁇ 1 plasma samples using the mirVANA miRNA extraction kit, as described in the product manual.
  • the eluted RNA was concentrated by the Labconco freeze-drying system, and the RNA was reverse transcribed and amplified using a megaplex RT primer library and an amplification primer library (ABI).
  • the obtained cDNA was quantified using a Taqman miRNA detection kit. III. Experimental results
  • miRNA expression profiling was performed on 94 patients with HBV who received interferon therapy.
  • the training group was validated in 28 test cases by training the miRNA expression profile.
  • the basic clinical levels of the two groups were similar (Table 1), and the initial response rates were 45.5% and 35.7%, respectively (p value 0. 4948, Fi sher' s exact test)
  • a neighbor classification algorithm is used in the present invention as a prediction algorithm.
  • the NN algorithm is a simple but very effective machine learning method that is widely used for various classification problems. It makes a decision by calculating the distance between the vector to be detected and each vector in the training set. The interrogation vector will be grouped into one class that is closest to the vector distance.
  • the present invention uses the leave-one-cross test to evaluate the performance of the predictive model.
  • each data is sequentially removed as test data of other data, and the prediction engine is trained by multiple detections.
  • the final total prediction accuracy is calculated as follows:
  • TP is true positive
  • TN is true negative
  • FP false positive is true negative
  • the score of each eigenvalue for the predicted relevance is obtained after the mRMR analysis.
  • the leave-one-out cross test further tests and evaluates different predictive models.
  • Correlation analysis uses the lowess and lm functions of the R software. We used univariate and multivariate logistic regression analysis to evaluate the known efficacy-related factors and the odds ratios of the miRNA prediction models.
  • the prediction of miRNA target genes uses miRanda, RNAhybrid and TargetScan online prediction services. Result
  • the present invention first pre-treats the miRNA expression profile of 66 HBV patients before treatment, and removes miRNAs which are not detected in more than 50% of the samples, so that genes with relatively high expression levels can be enriched for further analysis.
  • the invention uses mRMR
  • the analytic method evaluated the scores most relevant to the efficacy (Maxrel score, Table 2), and the grading miRNAs further compared the distribution of the three miRNA expression levels in the fast response and non-responder patients by Fisher test. (1) less than the mean - standard deviation, (2) between the mean - standard deviation and the mean + standard deviation, (3) greater than the mean + standard deviation.
  • Figure 2 shows the expression patterns of these miRNAs.
  • the present invention uses the Nearest Neighbor Classification Algorithm (NN) for prediction, and the leave-one-out cross-validation further verifies the prediction performance.
  • NN Nearest Neighbor Classification Algorithm
  • IFS curve analysis evaluated the prediction accuracy of the number of different features (Figure 3). The highest prediction accuracy was highest in the calculation of 10 miRNAs (Table 2). miR-1268, miR_150*, miR-22 and miR-197 are the most significant efficacy-related genes (p ⁇ 0.01, Table 2). The overall prediction accuracy of the model consisting of ten miRNAs was 66.7%.
  • PIK3CG PIK3CG, ABHD12., ACCN4, FZD8, CACNA2D1,
  • PIK3CG PIK3CG
  • ACCN4 FZD8 CACNA2D
  • PIK3CG PIK3CG, ABHD12, ACCN4, FZD8, CACNA2D1
  • the present invention further tests whether the predicted models of the ten miRNAs can effectively distinguish the initial virological response in a test set consisting of 28 patients.
  • Table 1 the basic clinical data of the test set and the training set are similar, except that the test set patients received general interferon therapy. Since different interferon preparations cause differences in the concentration of effective drugs in the body, this may affect the predicted performance. Despite this, we still get an overall forecast accuracy of 60.7% in the training set.
  • the present invention further performs univariate and multivariate logistic regression analysis to assess whether the miRNA model is an independent predictor associated with efficacy.
  • miRNA prediction model 3.27 1.39 7.69 0.007 Age-year 0.99 0.94 1.05 0.84 Female 1.94 0.83 4.57 0.127 Serum ALT, XULN 1.47 1.15 1.88 0.002
  • the miRNA present in plasma is considered to be a product secreted by various organs.
  • the liver is an important organ responsible for metabolism in the human body. It has been reported that miRNA can be released into peripheral blood in acute drug-induced liver injury.
  • FFPE formalin-fixed formaldehyde-encapsulated liver biopsy specimens

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Abstract

Cette invention concerne le profil plasmatique des ARNmi utilisé pour anticiper l'effet thérapeutique de l'interféron dans le traitement de l'hépatite B chronique, ledit profil contenant un ou plusieurs ARNmi de SEQ ID N°: 1 à 10. Le kit, la puce de détection et le procédé utilisés pour analyser le niveau d'expression du profil correspondant des ARNmi sont également décrits. Les produits et le procédé offrent une efficacité élevée à bas coût, et sont destinés à évaluer l'effet thérapeutique de l'interféron en milieu clinique. Le profil des ARNmi selon l'invention est un facteur d'anticipation indépendant. Combiné à une analyse des mutations de la résistance du HBV aux médicaments, le profil des ARNmi contribue à l'élaboration d'un projet thérapeutique individuel, qui réduit le coût thérapeutique et améliore la proportion de réponse complète.
PCT/CN2010/077506 2010-09-08 2010-09-30 Profil plasmatique des arnmi pour anticiper l'effet thérapeutique de l'interféron dans le traitement de l'hépatite b chronique, et kits de détection WO2012031412A1 (fr)

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CN2010102755614A CN102399852A (zh) 2010-09-08 2010-09-08 用于预测干扰素治疗慢性乙型肝炎疗效的血浆miRNA谱及检测试剂盒

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CN107557464B (zh) * 2016-07-02 2021-06-04 上海市公共卫生临床中心 用于干扰素治疗慢性乙型肝炎早期病毒学反应的预测模型及检测试剂盒

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