WO2019092737A1 - Panel arnmi de prognostic en combinaison avec une charge virale pour l'évaluation du statut d'une maladie, de la réponse thérapeutique et d'une rechute chez des patients atteints de vhc - Google Patents

Panel arnmi de prognostic en combinaison avec une charge virale pour l'évaluation du statut d'une maladie, de la réponse thérapeutique et d'une rechute chez des patients atteints de vhc Download PDF

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WO2019092737A1
WO2019092737A1 PCT/IN2018/050184 IN2018050184W WO2019092737A1 WO 2019092737 A1 WO2019092737 A1 WO 2019092737A1 IN 2018050184 W IN2018050184 W IN 2018050184W WO 2019092737 A1 WO2019092737 A1 WO 2019092737A1
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mirna
hcv
treatment
patients
biological sample
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PCT/IN2018/050184
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English (en)
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Raju NAGARAPU
Sandeep Kumar Vishwakarma
Avinash Bardia
Md. Aejaz Habeeb
Syed Ameer Basha Paspala
Aleem Ahmed Khan
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Dr Habeebullah Life Sciences Limited
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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
    • 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
    • C12Q1/707—Specific hybridization probes for hepatitis non-A, non-B Hepatitis, excluding hepatitis D
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/50—Determining the risk of developing a disease

Definitions

  • the invention relates to unique diagnostic and prognostic miRNA panel that acts as appropriate disease marker for proper diagnosis and disease progression in HCV infected patients and thereby helps in identifying suitable treatment options and also in determining the suitability of such treatment options. Further, the invention relates to methods of estimating the miRNA expression levels and viral load during different treatment regimens of patients infected with HCV genotype 1 and genotype 3 which have been identified as likely responders to HCV therapy with Direct Acting Antiviral (DAA's).
  • DAA's Direct Acting Antiviral
  • the primary HCV diagnosis is based on the HCV antibody detection followed by the HCV-RNA quantification. These approaches help to identify the HCV infection along with the liver function test (LFT).
  • LFT liver function test
  • the sub- population of HCV-antibody positive cases that are negative for viral copies can't be discriminated with normal individuals based on these methods which may lead to the chronic or cirrhosis disease progression.
  • identifying more appropriate disease marker for proper diagnosis and disease progression will give better information for monitoring the exact conditions of HCV-related diseases.
  • the unique panel of three selected miRNAs (miRNA-122, miRNA-21 and miRNA-181 a) identified in present invention deals with multi-level approach to give valuable information for such conditions and disease progression.
  • the present invention provides a unique panel of circulating miRNAs to facilitate the early diagnosis of HCV infection and disease pathogenesis which can overcome on earlier reported approaches (Jopling et al. 2005; Jopling et al. 2008; Zhang et al. 2015).
  • HCV related liver pathogenesis and progression depends on various aspects like, HCV viral load, genotype, host response to HCV with antivirals and host liver repair capacity.
  • Another aspect of HCV related pathogenesis includes the identification of treatment response and disease status. Failing to proper prognosis of HCV related pathogenesis leads to the increased mortality rate due to the progression of acute condition into chronic phase in very short time (Lee et al. 2014).
  • the miRNA panel selected in the present invention relates with the prediction of targeted molecules which are responsible for viral-host interaction and production of naive virions. Hence, this panel may provide significant information for identifying more specific and reliable disease prognosis and treatment response.
  • Another embodiment of the present invention relates with identification of relapse cases after treatment with different anti-HCV modalities which could be important to predict the disease persistence and designing more appropriate future treatment strategies.
  • Liver performs many diverse kinds of biochemical, synthetic and excretory functions.
  • Biochemical parameters offer only the status of global functions of liver. However, the major limitations of biochemical parameters are the lack of sensitivity and specificity.
  • the LFT levels may be normal in certain liver disease conditions such as cirrhosis, non-cirrhotic portal fibrosis and congenital hepatic fibrosis.
  • LFT parameters can also be elevated in certain pathologies which are processed outside of the liver. Other than this, after treatment of HCV related liver pathologies, biochemical parameters show normal values even before completing the treatment duration.
  • the progressive and relapse status of disease conditions can't be calculated based on only biochemical estimation.
  • Supportive diagnosis using tissue histology is an invasive procedure which is not advisable to all the patients during treatment.
  • Viral load estimation is quite sensitive approach which could support the miRNA reports.
  • the present invention also includes the HCV viral load quantification in combination with miRNA expression analysis in different category of HCV patients before and after treatment including the follow-up cases specifically in relapse identification.
  • the earlier inventions provide very limited applicability of miRNAs role in HCV related pathogenesis.
  • a such invention wherein a kit related with the detection of plasma miRNAs in HCC patients has been proposed as an option can't be applied for all HCV related pathogenic conditions and is more specific to HCC only (US 20130237456 A1 ).
  • such inventions tend to use a panel of eight miRNAs which can increase the cost and reliability for clinical testing.
  • Another invention wherein the use of three miRNA panel was proposed earlier to determine the response against anti-viral therapies in tissue samples provides very limited insights to claim the clinical diagnosis or prognosis for currently available anti-viral drugs and also as tissue biopsy in HCV infected patients is a very invasive procedure (US 201 10256534 A1 ).
  • a lot of work on miRNA panels related to HCV infection has been worked comprehensively by many investigators, but there is a need to develop standard panel which can give complete information for liver pathogenesis, host-virus interactions and treatment response.
  • an unique kit was developed using three miRNA panel in combination with viral load estimation to assess the disease status, treatment response and relapse in HCV patients.
  • the invention provides a microRNA (miRNA) panel for diagnosis and prognosis of HCV using expression analysis of three circulatory miRNAs in combination with the viral load which is estimated by identifying 5'UTR region in HCV genome.
  • the miRNA panel as described herein for the diagnosis and prognosis of HCV comprises of miRNA-21 , miRNA-122 and miRNA-181 a and deals with the circulating miRNAs in serum sample of HCV infected patients with genotype 1 and 3 (prevalent genotypes in India).
  • the discrimination among the na ⁇ ve HCV infected patients with healthy individuals, responders and non-responders is based on the involvement of different mechanisms of selected miRNAs which signifies their role in viral-host interaction.
  • This investigation involved five categories of patients (anti-HCV positive and HCV-RNA negative, patients with acute and chronic HCV, HCV related cirrhosis and hepatocellular carcinoma) which are differentiated based on the HCV-antibody detection, HCV-RNA quantification and liver related pathogenesis using available clinical parameters.
  • the miRNA panel for diagnosis, prognosis and determining the suitability of the treatment of HCV in a subject comprises of miRNA-21 , miRNA-122 and miRNA- 181 a, using expression analysis of the said miRNAs and their correlation with the HCV viral load in a biological sample, for example blood plasma.
  • the biomarker miRNA-122 shows the value to determine the liver function status and is the biomarker for responsiveness to HCV treatment. Further, the biomarker miRNA- 122 with viral load can be used as diagnostic and prognostic panel to identify the viral replication, disease status and liver condition.
  • the biomarker miRNA-21 levels predict the HCV disease progression from acute to HCC and the biomarker miRNA-181 a reveals the immune responses.
  • the miRNA-181 a can be used to predict the immunological response of HCV patients before and after treatment and can predict the viral-host interactions.
  • the invention further discloses a diagnostic kit for diagnosis, prognosis and determining the suitability of the treatment of HCV in a subject comprising of at least one forward amplification primer, at least one reverse amplification primer, probe for the detection of microRNA or immobilized probe for the detection of microRNA or the resources for sample analysis used for analysis of short RNS's, wherein the primers are designed to enable specific amplification of nucleotide sequences of miRNA-21 , miRNA-122 and miRNA-181 a, in a biological sample, for example blood plasma.
  • the diagnostic kit as described herein enables specific amplification and measurement of all microRNA's selected from the group of miRNA-21 , miRNA- 122 and miRNAI 81 a.
  • the method of diagnosis, prognosis and/or determining of the treatment of HCV in a subject as described herein comprises of (a) determining the risk of developing HCV, (b) diagnosing the presence of HCV, (c) determining the progression, in particular the worsening or response to treatment of HCV, and/or identifying relapse cases.
  • Fig.2 [12] [fig.2] illustrates the miRNA expression levels in chronic HCV infected patients before and during the treatment with PEG IFN-a 2a combination with Ribavirin.
  • miRNA-21 was showed normal expression levels in HCV Genotype-1 and HCV Genotype-3 patients.
  • [13] illustrates the miRNA expression levels in chronic HCV infected patients before and during the treatment with Sofosbuvir combination with Ribavirin.
  • miRNA-21 was showed normal expression levels in HCV Genotype-1 and HCV Genotype-3 patients.
  • [14] [fig.4] illustrates the miRNA expression levels in chronic HCV infected with genotype-3 patients before and during the treatment with Sofosbuvir combination with Daclatasvir.
  • miRNA-21 was showed normal expression levels
  • [15] illustrates the miRNA expression levels in chronic HCV infected with genotype-3 patients before and during the treatment with Sofosbuvir combination with Ledipasvir.
  • miRNA-21 was showed normal expression levels
  • miRNA- 122 was showed significant expression levels
  • [fig-6] illustrates the miRNA expression levels in 6 months follow-up of chronic HCV infected patients with genotype 1 and 3 after treatment (a-f).
  • FIG.7 illustrates the functional analysis of endocrine nature of repopulated DSM under hyperglycaemic stimulation.
  • A Representative quantification of dynamics for insulin secretion under sequential hyperglycaemic challenge showing increased levels at each challenge
  • B Fluorescence images of un- induced and hyperglycemia induced cells within the DSM at different time points
  • C-D Comparison of released insulin by repopulated DSM and 2D-cultured cells on collagen under continuous hyperglycaemic challenge. The insulin level was comparatively higher in DSM than 2D-cultured cells.
  • HCV RNA ND hepatitis C virus RNA not detected
  • Acute acute HCV infection
  • Chronic chronic HCV infection
  • Cirrhosis HCV related cirrhosis
  • HCC HCV related hepatocellular carcinoma
  • BT before treatment
  • 3MT after 3 months treatment
  • 6MT after 6 months treatment
  • 9MT after 9 months treatment
  • 12MT after 12MT months treatment
  • HCV G-1 HCV genotype 1
  • HCV G-3 HCV genotype 3
  • ***p ⁇ 0.001 statastically significant.
  • a miRNA panel for diagnosis, prognosis and determining the suitability of the treatment of HCV in a subject the miRNA panel comprising of miRNA-21 , miRNA-122 and miRNA-181 a, using expression analysis of the said miRNAs and their correlation with the HCV viral load in a biological sample.
  • the biological sample is blood plasma.
  • the miRNA-122 shows the value to determine the liver function status and is the biomarker for responsiveness to HCV treatment; and the miRNA-122 with viral load can be used as diagnostic and prognostic panel to identify the viral replication, disease status and liver condition.
  • the miRNA-21 levels predict the HCV disease progression from acute to HCC and the miRNA-181 a reveal the immune responses. Further, the miRNA-181 a can be used to predict the immunological response of HCV patients before and after treatment and can predict the viral-host interactions.
  • a diagnostic kit for diagnosis, prognosis and determining the suitability of the treatment of HCV in a subject comprising of at least one forward amplification primer; at least one reverse amplification primer; probe for the detection of microRNA or immobilized probe for the detection of microRNA or the resources for sample analysis used for analysis of short RNA's; wherein the primers are designed to enable specific amplification of nucleotide sequences of miRNA-21 , miRNA-122 and miRNA-181 a, in a biological sample.
  • the diagnostic kit as described herein enables specific amplification and measurement of all microRNA's selected from the group of miRNA-21 , miRNA- 122 and miRNA181 a.
  • the biological sample is blood plasma.
  • the said method for the diagnosis, prognosis and/or determining of the treatment of HCV in a subject comprises - determining the risk of developing HCV; diagnosing the presence of HCV; determining the progression, in particular the worsening or response to treatment of HCV, and/or identifying the relapse cases.
  • HCV infection was diagnosed in all patients by the presence of anti-HCV antibodies and HCV-RNA in the serum. All patients were negative for hepatitis B surface antigen (HBsAg). Patients were diagnosed and followed during treatment with weekly intra-muscular injections of PEG-IFNa2a and daily oral doses of RBV. Whereas quarterly follow-up was done during treatment with direct acting antiviral's (DAA's) (Sofosbuvir, Daclatasvir and Ledipasvir). Age and gender matched healthy controls were enrolled in this study.
  • DAA's direct acting antiviral's
  • peripheral blood samples of 25 healthy controls and 184 HCV patients were collected after taking the informed consents of each subject after taking approval from the Institutional Review Board (IRB) of Deccan College of Medical Sciences (DCMS), India. Pregnant women's, patients with alcoholic liver disease, patients on any corticosteroids or laser therapy and injection drug users were excluded from the study.
  • IRS Institutional Review Board
  • DCMS Deccan College of Medical Sciences
  • Group 6 Chronic HCV infected patients with HCV genotype 1 before and during treatment with Sofosbuvir and Ledipasvir
  • Serum samples were processed on the same day and within few hours after collection. Serum was separated from blood samples of each subject by centrifugation at 1 ,500 x g for 10 min and used for miRNA analysis, viral load estimation, genotyping and liver function tests. The blood samples were taken before starting treatment and after 3 months, 6 months, 9 months, 12 months treatment and 6 months follow-up after treatment.
  • miRNA from the serum sample of each subject was extracted immediately (within 4h of sample collection) using miRNeasy Serum/Plasma Kit (Qiagen).
  • Complementary DNA was prepared using reverse transcriptase enzyme using universal stem loop (USLP) and U6 primer (Yang et al. 2014). Constructed cDNAs were stored at -80°C for further experimental purposes.
  • Viral RNA was extracted from all infected samples using High Pure Viral RNA Kit (Roche) and quantified HCV viral load by amplifying 5'UTR using Real time primers and Taqman probes (Kumar et al. 201 1 ). HCV genotyping was performed by PCR and sequencing of 5'UTR of HCV genome (Simmonds et al. 1993). The amplified PCR products were sequenced by using both forward and reverse primers in ABI sequencer. The chromatographic reads of nucleotide sequence were extracted and compared with NCBI database to confirm the particular genotype. Based on the nucleotide change they were categorized into their respective sub-genotypes.
  • Sample size was determined by open Ep1 strategies at 95% confidence level with >90% of sample power.
  • Gene expression was analyzed using relative quantification as per Livak method (Livak et al. 2001 ) and further validated by Pfaffl method (Pfaffl et al. 2001 ). Results were expressed as mean ⁇ standard error of the mean (SEM). Data was analyzed by using Graph Pad Prism software (version V; SanDiego, CA). Mann-Whitney U test was used to draw comparisons between groups. Spearman test was used for correlation studies, p values ⁇ 0.05 were considered statistically significant for all the variables.
  • ALT, AST and ALP levels in untreated HCV infected patients were significantly increased as compared to healthy volunteers (ALT: 69.23 ⁇ 25.68 IU/L vs 26.65 ⁇ 13.24 IU/L; AST: 56.81 ⁇ 38.91 IU/L vs 22.31 ⁇ 10.83 IU/L; ALP: 218.31 ⁇ 76.31 IU/L vs 201 .67 ⁇ 82.35 IU/L).
  • BT before treatment
  • 3MT after 3 months treatment
  • 6MT after 6 months treatment
  • 9MT after 9 months treatment
  • 12MT after 12MT months treatment.
  • PTL1 Jia Fan et al. Marker consisting of plasma microrna and a new method for diagnosis of hepatocellular carcinoma. 201 1 , US 20130237456 A1
  • PTL2 Witold filipowicz et al. Prediction of antiviral therapy response. 201 1 , US 201 10256534 A1 .
  • NPL1 Bertino G, Ardiri A, Proiti M et al. Chronic hepatitis c: this and the new era of treatment. World J Hepatol 2016; 8: 2: 92-106.
  • NPL2 Inui M, Martello G and Piccolo S. MicroRNA control of signal transduction. Nat Rev Mol Cell Biol 2010; 1 1 : 252-263.
  • NPL3 Jopling CL, Yi M, Lancaster AM, Lemon SM and Sarnow P.
  • NPL4 Jopling CL. Regulation of hepatitis c virus by microrna-122.
  • NPL5 Kumar YN, Rahmathulla S, Madhavi C, Ramachandra VV, Vishnupriya S, Habeeb MA, Khaja MN. Simultaneous detection of Hepatitis B virus and Hepatitis C virus in human plasma using Taq-man chemistry. J Med Allied Sci. 201 1 ; 2: 69-73.
  • NPL6 Lee MH, Yang HI, Yuan Y et al. Epidemiology and natural history of hepatitis c virus infection. World J Gast. 2014; 20: 9270-9280.
  • NPL7 Livak KJ, and Schmittgen TD. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the Method. Methods. 2001 ; 25: 402 ⁇ 108.
  • NPL8 Pfaffl MW.
  • NPL9 Simmonds P, McOmish F, Yap PL. Sequence variability in the 5 ' non- coding region of hepatitis C virus: Identification of new virus type and restriction sequence diversity. J Gen Virol. 1993; 74: 661-68.
  • NPL10 Yang L, Wang S, Tang L, Liu B, Ye W. Universal Stem-Loop Primer Method for Screening and Quantification of MicroRNA. Plos One. 2014; 12: e1 15293.
  • NPL1 1 Zhang S, Ouyang X, Jiang X, Gu D, Lin Y, Kong S.K, Xie W.

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Abstract

La présente invention concerne un panel ARNmi de diagnostic, prognostic et de détermination de l'aptitude du traitement contre le VHC chez un sujet, le panel ARNmi comprenant de l'ARNmi-21, ARNmi-122 et ARNmi-181a, en à l'aide de l'analyse d'expression desdits ARNmi et leur corrélation avec la charge virale VHC dans un prélèvement biologique. Le prélèvement biologique est du plasma sanguin.
PCT/IN2018/050184 2017-11-13 2018-03-31 Panel arnmi de prognostic en combinaison avec une charge virale pour l'évaluation du statut d'une maladie, de la réponse thérapeutique et d'une rechute chez des patients atteints de vhc WO2019092737A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110111976A1 (en) * 2008-04-25 2011-05-12 Merck Sharp & Dohme Corp. Microrna biomarkers of tissue injury
US20170233801A1 (en) * 2014-08-19 2017-08-17 Roche Molecular Systems, Inc. Methods and Compositions for Nucleic Acid Detection

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110111976A1 (en) * 2008-04-25 2011-05-12 Merck Sharp & Dohme Corp. Microrna biomarkers of tissue injury
US20170233801A1 (en) * 2014-08-19 2017-08-17 Roche Molecular Systems, Inc. Methods and Compositions for Nucleic Acid Detection

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ELHELW ET AL.: "Predictive Prognostic Role of MiR-181a with Discrepancy in the Liver and Serum of Genotype 4 Hepatitis C Virus Patients", BIOMEDICAL REPORTS, vol. 2, no. 6, 2014, pages 843 - 848, XP055607842, DOI: 10.3892/br.2014.343 *
SHRIVASTAVA ET AL.: "MicroRNAs: Role in Hepatitis C Virus Pathogenesis", GENES & DISEASES, vol. 2, no. 1, 2015, pages 35 - 45, XP055607841, DOI: 10.1016/j.gendis.2015.01.001 *
SIRIO FIORINO, ET AL: "MicroRNAs as possible biomarkers for diagnosis and prognosis of hepatitis B- and C-related-hepatocellular-carcinoma", WORLD JOURNAL OF GASTROENTEROLOGY, vol. 22, no. 15, 21 April 2016 (2016-04-21), pages 3907 - 3936, XP055607850, DOI: 10.3748/wjg.v22.i15.3907 *

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