WO2015172008A1 - Transglutaminadase 6 en tant que biomarqueur pour la sclérose en plaques - Google Patents

Transglutaminadase 6 en tant que biomarqueur pour la sclérose en plaques Download PDF

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Publication number
WO2015172008A1
WO2015172008A1 PCT/US2015/029865 US2015029865W WO2015172008A1 WO 2015172008 A1 WO2015172008 A1 WO 2015172008A1 US 2015029865 W US2015029865 W US 2015029865W WO 2015172008 A1 WO2015172008 A1 WO 2015172008A1
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tgm6
level
subject
sample
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PCT/US2015/029865
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Saud A. Sadiq
Massimiliano CRISTOFANILLI
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Multiple Sclerosis Research Center Of New York
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Publication of WO2015172008A1 publication Critical patent/WO2015172008A1/fr

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    • 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
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • 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
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/91045—Acyltransferases (2.3)
    • G01N2333/91074—Aminoacyltransferases (general) (2.3.2)
    • G01N2333/9108—Aminoacyltransferases (general) (2.3.2) with definite EC number (2.3.2.-)
    • G01N2333/91085—Transglutaminases; Factor XIIIq (2.3.2.13)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/285—Demyelinating diseases; Multipel sclerosis

Definitions

  • TRANSGLUTAMINADASE 6 AS A BIOMARKER FOR MULTIPLE SCLEROSIS
  • MS Multiple Sclerosis
  • CNS central nervous system
  • MS is associated with the development of discrete lesions in the CNS characterized by demyelination of neurons and infiltration of leucocytes.
  • Acute MS lesions are typified by areas of local demyelination, with CD3 + T-cells and CD68 + macrophages present throughout the lesion. In some cases inclusions containing myelin debris are seen in the interior of macrophages.
  • Acute lesions are further characterized by positive staining for amyloid precursor protein (APP), a marker for axonal damage, throughout the lesion.
  • APP amyloid precursor protein
  • Active chronic lesions are characterized by T-cells, macrophages, and APP staining present more around the border of the lesion than within.
  • Chronic lesions are characterized by few or no T-cells or macrophages in the lesion, no or low APP staining within or around the lesion, and reduced axon density.
  • MS and MS lesions are characterized by the presence of B cells, including CD 19+ B cells and CD 138+ plasma cells (Gilden et al., Mult. Scler. 2: 179-183 (1996); Ritchie et al., J. Immunol. 173:649-656 (2004)); and astrogliosis (activation of astrocytes; Gudi et al., Front. Cell. Neurosci. 8(73): 1-24 (2014)).
  • MS diagnosis is challenging because no single test with a high diagnostic accuracy is available (Rudick RA. et al., Neurology 78: 1904-1906 (2012)). Rather, diagnosis is made on the basis of patients' histories, physical exam findings, supporting evidence from a battery of tests and the exclusion of other neuroinflammatory disorders.
  • the two major diagnostic techniques used for MS diagnosis are magnetic resonance imaging (MRI) of the brain and spinal cord, and cerebrospinal fluid (CSF) analysis.
  • MRI uses gadolinium-based contrast to detect areas of demyelination and to distinguish old lesions from new, active lesions. It is currently routinely used for MS diagnosis.
  • Transglutaminase 6 is a member of the transglutaminase enzyme family found predominantly in the central nervous system (CNS), mainly expressed by neuronal cells under physiological conditions.
  • the main function of transglutaminase enzymes is to covalently cross-link or modify proteins by formation of an isopeptide bond between a peptide-bound glutamine residue and a primary amine.
  • Transglutaminase 2 also known as tissue transglutaminase, a relative of TGM6 found distributed in the endomysium of the human gut, is the primary auto-antigen in the T-cell mediated autoimmune mediated disorder celiac disease (CD).
  • TGM2 has been studied and proposed as a cerebrospinal fluid (CSF) biomarker in a few different neurodegenerative disorders, but not multiple sclerosis (MS).
  • CSF cerebrospinal fluid
  • Transglutaminase activity as measured by the levels of free gamma-glutamylamines has been studied in CSF of Huntington's disease (HD) patients (Jeitner TM et al., J
  • TGM6 has been proposed as the autoimmune target in gluten-sensitive patients with neurological symptoms such as cerebellar ataxia, independent of gastrointestinal involvement (Hadjivassiliou M et al., Ann Neurol. 64(3):332-43 (2008)). Since then, a few groups have investigated the levels of IgG and IgA antibodies against TGM6 in the sera of gluten-caused ataxic patients versus genetically ataxic patients, as well as in the sera of schizophrenic patients. However, TGM6 has not been studied in the context of MS.
  • the methods can further involve correlating TGM6 measurements with one or more additional methods for diagnosis or detection of MS selected from magnetic resonance imaging, neurological testing, and measurement of at least one additional biomarker for MS.
  • Additional biomarkers include from fetuin-A, chemokine (C-X-C motif) ligand 13, neurofilament, hepatocyte growth factor, osteopontin, isoprostane 8-iso-prostaglandin F 2a , Chitinase 3-like 1, and miR-29 miRNA.
  • the level of TGM6 can be measured by measuring the levels of TGM6 nucleic acid or TGM6 protein, such as by PCR, real-time PCR, RNA sequencing, microarray hybridization, Southern-blot, Northern-blot, Western-blot; immunoassay, ELISA, immunocytochemistry, or immunohistochemistry.
  • the methods can further involve correlating TGM6 measurements with one or more additional methods for diagnosis or detection of MS selected from magnetic resonance imaging, neurological testing, and measurement of at least one additional biomarker for MS.
  • Additional biomarkers include from fetuin-A, chemokine (C-X-C motif) ligand 13, neurofilament, hepatocyte growth factor, osteopontin, isoprostane 8-iso-prostaglandin F 2a , Chitinase 3-like 1, and miR-29 miRNA.
  • Also contemplated are methods to determine the MS subtype of a subject with MS comprising measuring the level of TGM6 in a biological sample from the subject, comparing the level of TGM6 in the sample with a range representing the levels of TGM6 in subjects with identified MS subtypes, and determining the MS subtype of the subject by determining the range within which the TGM6 level of the sample falls.
  • the MS subtype can be primary progressive MS, secondary progressive MS, or relapsing remitting MS.
  • the biological sample can be a sample of cerebrospinal fluid, brain, or spinal cord.
  • the level of TGM6 can be measured by measuring the levels of TGM6 nucleic acid or TGM6 protein, such as by PCR, real-time PCR, RNA sequencing, microarray hybridization, Southern-blot, Northern- blot, Western-blot; immunoassay, ELISA, immunocytochemistry, or immunohistochemistry.
  • the methods can further involve correlating TGM6 measurements with one or more additional methods for diagnosis or detection of MS selected from magnetic resonance imaging, neurological testing, and measurement of at least one additional biomarker for MS.
  • Additional biomarkers include from fetuin-A, chemokine (C-X-C motif) ligand 13, neurofilament, hepatocyte growth factor, osteopontin, isoprostane 8-iso-prostaglandin F 2a , Chitinase 3-like 1, and miR-29 miRNA.
  • FIGS. 1A-1E ELISA for TGM6-IgG on CSF samples.
  • B PP group had the highest TGM6-IgG level, followed by the SP and the RR groups.
  • FIGS. 2A-2X Immunohistochemical staining (IHC) for TGM6 on a series of adjacent paraffin embedded brain sections containing areas of MS plaques (lesion) as well as normal appearing white matter (NAWM) identified by luxol fast blue (LFB) and PLP staining.
  • A-D lesioned areas lacking LFB.
  • E-H lesioned areas lacking PLP.
  • I-L lesioned areas lacking LFB and PLP signal contain TGM6 expressing cells which are particularly abundant around blood vessels (marked by red or blue arrows).
  • M-P TGM6 expressing cells have astrocyte morphology and express GFAP.
  • Q-R and U-V GFAP + cells.
  • T, X GFAP + cells are present around perivascular areas of the NAWM.
  • S, W GFAP + cells do not express TGM6.
  • FIGS. 3A-3T EAE induction in C57/BL6 mice and TGM6 expression.
  • A EAE induced in C57/BL6 mice using the MOG-35-55 peptide.
  • the black line indicates disability score of 1-5 using Stromnes-Goverman scale for al mice in the study; the red line indicates disability score for animals sacrificed to measure TGM6 protein levels in the brain and spinal cord by ELISA and western blot.
  • the blue line represents mice sacrificed to analyze the distribution of TGM6 and GFAP protein in the spinal cord by immunohistochemistry and by immunofluorescence.
  • IHC Immunohistochemistry
  • I-L TGM6 IHC in naive mice.
  • M-P Immunofluorescent
  • IF Immunofluorescent
  • Myelin is stained by MBP in red.
  • Q-T IF colocalization (yellow) of TGM6 (green) and GFAP (red) signals.
  • TGM6 transglutaminase 6
  • MS multiple sclerosis
  • MS Multiple sclerosis
  • CNS central nervous system
  • myelin the fatty substance that surrounds and insulates axons
  • the damaged myelin forms lesions which result in scar tissue (sclerosis) formation, which distorts or interrupts neuronal signaling, leading to a variety of neurological symptoms.
  • MS can be categorized as progressive MS (PMS, in which symptoms and disease course steadily worsen over time with little or no remission) or relapsing-remitting MS (RRMS).
  • RRMS is characterized by defined attacks of worsening neurologic function, also called relapses, flare-ups or exacerbations, followed by partial or complete recovery periods (remissions), during which symptoms improve partially or completely and there is no apparent progression of disease.
  • PMS Progressive MS encompasses secondary progressive MS (SPMS) and primary progressive MS (PPMS).
  • SPMS secondary progressive MS
  • PPMS primary progressive MS
  • a subject is defined as a person diagnosed with MS, a person suspected of having MS, or a person having at least one neurological symptom.
  • the subject is a person with "active" MS disease as defined by the presence of at least one of the following criteria in the 6 months preceding sample collection: (1) one or more relapses documented by a neurologist's examination; (2) a change in 0.5 points or greater in the EDSS score; and (3) change in MRI, such as a change in the number or size of lesions or the presence of gadolinium-enhancing lesions.
  • the subject has not been treated for MS; in other embodiments, the subject has been treated for MS.
  • the disclosed methods can be used to diagnose multiple sclerosis in a subject with at least one neurological symptom.
  • a "neurological symptom" as encompassed herein includes: numbness or weakness in one or more limbs; partial or complete loss of central vision in one eye; partial or complete loss of central vision in both eyes; pain during eye movement (optic neuritis); double vision or blurring of vision; tingling or pain in parts of the body; electric- shock sensations occurring with certain head movements; tremors; walking (gait), balance, or coordination problems; slurred speech; fatigue; dizziness; bladder or bowel dysfunction; cognitive dysfunction; emotional changes; sexual dysfunction; depression; spasticity; speech or swallowing problems; hearing loss; seizures; respiration or breathing problems; and itching.
  • the subject has at least two, at least three, at least four, or at least five neurological symptoms.
  • the levels of TGM6 can be measured by measuring the level or levels of TGM6 nucleic acid or the level or levels of TGM6 protein product.
  • the level of expression of the TGM6 gene or TGM6 RNA expression can be measured by any technique known in the art, including but not limited to PCR, real-time PCR, RNA sequencing, microarray hybridization, Southern-blot, and Northern-blot.
  • TGM6 protein can be measured by any technique known in the art, including but not limited to Western-Blot; immunoassays, such as ELISA;
  • immunocytochemistry and immunohistochemistry.
  • Each of these formats utilizes a binding agent, such as an antibody, that recognizes TGM6.
  • Blotting techniques are known to those of ordinary skill in the art, and may be performed as, for example electro -blots, semidry-blots, vacuum-blots or dot-blots.
  • Immunocyto/histochemical staining procedures are known to those of skill in the art, and may comprise binding agent-mediated detection of polypeptides as well as in situ hybridisation techniques.
  • the level of TGM6 in a sample is compared with a control representing the level of TGM6 in a subject without MS.
  • the control level represents the average expression of TGM6 in a healthy person without MS.
  • "Elevated” or “increased” levels of TGM6, compared to control levels can be an increase of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% or greater relative to control levels.
  • chemokine (C-X-C motif) ligand 13 CXCL13
  • CXCL13 chemokine (C-X-C motif) ligand 13
  • neurofilament hepatocyte growth factor (HGF); osteopontin; isoprostane 8-iso-prostaglandin F 2a (8-iso-PGF 2a ); Chitinase 3-like 1 (CHI3L1); and miRNAs, such as miR-29 miRNA (for review, see Harris, VH, and Sadiq, SA, Mol Diagn Ther. 18(6): 605-617 (2014), the contents of which are incorporated by reference).
  • miRNAs such as miR-29 miRNA
  • Levels of these additional biomarkers also increase between primary progressive MS, secondary progressive MS, and relapsing remitting MS.
  • correlation of elevated levels of MS with elevated levels of one or more additional biomarkers can confirm a diagnosis of MS, confirm that MS is progressing, and/or confirm that the subject has primary progressive MS, secondary progressive MS, or relapsing remitting MS subtype.
  • the activity and/or progression of MS is monitored by measuring the level of TGM6 in a biological sample from the subject and comparing the measured level of TGM6 in the sample with the level of TGM6 in a biological sample taken from the subject at an earlier time point.
  • An increase in the level of TGM6 at a later time point, relative to the level of TGM6 at an earlier time point, indicates that MS in the subject is increasing in severity.
  • Such increase can also indicate the need for the start of therapy, if the subject was not previously undergoing therapy; or can indicate the need for additional, or different, therapeutic methods, if the subject was already undergoing therapeutic treatment.
  • CSF Patient Selection and CSF Collection.
  • CSF was collected with IRB approval and informed consent from 181 patients (138 with clinically definite MS (McDonald WI et al., Ann Neurol. 50(1): 121-7 (2001)) and 43 non-MS controls) seen at the International Multiple Sclerosis Management Practice, the clinical affiliate of the Tisch MS Research Center of New York.
  • 41 were primary progressive, 51 secondary progressive, and 46 relapsing remitting.
  • 43 controls 22 samples were obtained for diagnostic purpose from untreated patients with other neurological diseases and 21 from healthy donor. In the MS group 86 patients had active disease, and 52 had inactive disease.
  • ELISA and Western blot Fresh mouse brain and spinal cord were placed in RIPA buffer (Cell Signaling Technologies, Danvers, MA) with Halt Protease and Phosphatase Inhibitor Single-Use Cocktail (Thermo Scientific, Rockford, IL) and then sonicated for protein extraction. The other half was processed for RNA extraction using QIAzol Lysis Reagent and RNeasy Lipid Tissue Midi Kit (Qiagen, Venlo, Netherlands).
  • CSF levels of IgG against TGM6 are higher in MS vs. Controls and in Active vs. Inactive MS.
  • CSF samples were collected from 138 MS patients and 43 controls as described in Methods and their cell count, total protein content, and albumin levels were determined.
  • the control group included 21 healthy subjects, 11 with autoimmune diseases other than MS, 8 with non-autoimmune diseases, and 3 with non-specified neurological conditions.
  • TGM6 IgG To confirm the presence of TGM6 IgG in our patient' s CSF cohort the inventors performed a western blot using CSF as source of primary antibody to bind a recombinant humanTGM6 protein (Fig. IE). Compare to CSF samples with low levels of TGM6-IgG (measured by ELISA), CSF samples with high levels of TGM6-IgG showed a stronger binding to recombinant TGM6 protein.
  • TGM6 is upregulated in the mouse CNS during EAE and its expression by reactive astrocytes in the spinal cord correlates with disease course.
  • the inventors induced EAE in C57/BL6 mice using the MOG-35-55 peptide (black line in Fig. 3A) and analyzed TGM6 expression during disease course.
  • ELISA analysis for spinal cord proteins extracted at different time point during EAE revealed a striking correlation between TGM6 expression (Fig. 3B) and disease score of sacrificed animals (red line in Fig. 3A). Such correlation was further confirmed by Western blot (Fig. 3C).
  • TGM6 expression in the brain was lower than in the spinal cord for each time point examined. It peaked at 14 days post immunization and then plateau to lower level for the remaining of the disease duration (Fig. 3B-C).
  • TGM6 signal in the spinal cord of mice with EAE was localized primarily in reactive astrocytes as showed by the colocalization with the GFAP IF signal (Fig. 3Q-T) and the correlation between the two signals during EAE (Fig 3D). Similar to the IHC data, TGM6 IF signal in the white matter of naive animal was virtually absent (data not shown).

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Abstract

L'invention concerne des procédés pour diagnostiquer la sclérose en plaques (SEP) chez un sujet, par la mesure du taux de transglutaminadase 6 (TGM6) dans un échantillon biologique provenant du sujet. L'invention concerne en outre des procédés qui permettent de surveiller l'activité et/ou la progression de la SEP chez un sujet atteint de SEP, par la mesure du taux de TGM6 au cours du temps chez le sujet. L'invention concerne également des procédés qui permettent de déterminer le sous-type de SEP d'un sujet atteint de SEP, par la comparaison du taux de TGM6 dans un échantillon provenant du sujet à des taux de référence, la corrélation des taux de TGM6 avec des sous-types de SEP et la détermination du sous-type de SEP du sujet par détermination de la plage dans laquelle le taux de TGM6 de l'échantillon s'inscrit.
PCT/US2015/029865 2014-05-09 2015-05-08 Transglutaminadase 6 en tant que biomarqueur pour la sclérose en plaques WO2015172008A1 (fr)

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US61/991,120 2014-05-09

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6794414B1 (en) * 1998-06-17 2004-09-21 Yeda Research And Development Co. Ltd. Method and compositions for treating diseases mediated by transglutaminase activity
US20120077686A1 (en) * 2008-11-12 2012-03-29 The Brigham And Women's Hospital, Inc. Diagnosis of multiple sclerosis

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6794414B1 (en) * 1998-06-17 2004-09-21 Yeda Research And Development Co. Ltd. Method and compositions for treating diseases mediated by transglutaminase activity
US20120077686A1 (en) * 2008-11-12 2012-03-29 The Brigham And Women's Hospital, Inc. Diagnosis of multiple sclerosis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GUAN ET AL.: "Transglutaminase 6 interacts with polyQ proteins and promotes the formation of polyQ aggregates", BIOCHEM BIOPHYS RES COMMUN, vol. 437, no. 1, 19 July 2013 (2013-07-19), pages 94 - 100, XP028679476, ISSN: 0006-291x *

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