WO2019012159A1 - Procédés et moyens de diagnostic et/ou traitement d'une maladie associée à une fatigue - Google Patents

Procédés et moyens de diagnostic et/ou traitement d'une maladie associée à une fatigue Download PDF

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WO2019012159A1
WO2019012159A1 PCT/EP2018/069305 EP2018069305W WO2019012159A1 WO 2019012159 A1 WO2019012159 A1 WO 2019012159A1 EP 2018069305 W EP2018069305 W EP 2018069305W WO 2019012159 A1 WO2019012159 A1 WO 2019012159A1
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human
level
activity
asparaginyl
inhibitor
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PCT/EP2018/069305
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Christiaan Hubert Simon Roelant
Kenny Leo De Meirleir
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Protea Biopharma N.V.
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Priority to EP18737937.5A priority Critical patent/EP3652542A1/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
    • 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
    • C12Q1/26—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving oxidoreductase
    • 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
    • G01N2333/902—Oxidoreductases (1.)
    • G01N2333/90241—Oxidoreductases (1.) acting on single donors with incorporation of molecular oxygen, i.e. oxygenases (1.13)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry
    • G01N2800/306—Chronic fatigue syndrome

Definitions

  • FIELD The invention relates to methods and means for diagnosing and/or treating a human suffering from a fatiguing illness. Said methods and means are directed to a newly discovered link between altered mitochondrial functioning and said fatiguing illness.
  • CFS Chronic Fatigue Syndrome
  • ME Systemic Exertion Intolerance Disease
  • CIDS Chronic Fatigue Immune Deficiency Syndrome
  • the present invention has established a relation between hypoxia, NADH metabolism and mitochondrial activity that may be causative to fatiguing illnesses such as CFS.
  • a central role is provided by a 2-oxoglutarate (20G)-dependent dioxygenase, in particular "Factor Inhibiting Hypoxia inducible factor” (FIH) and its interaction with Ankyrin Repeat Domain-containing proteins.
  • (20G)-dependent dioxygenase in particular "Factor Inhibiting Hypoxia inducible factor” (FIH) and its interaction with Ankyrin Repeat Domain-containing proteins.
  • the invention therefore provides a method of typing a human comprising determining a level of activity of a 2-oxoglutarate- dependent dioxygenase, preferably an asparaginyl ⁇ -hydroxylase such as FIH, in a cell of said human. Said level of activity may be determined directly or indirectly, as is known to a skilled person and is detailed herein below.
  • Said typing in a preferred method according to the invention provides an indication that the human is suffering from a fatiguing illness, preferably from chronic fatigue syndrome, fibromyalgia, multiple sclerosis, gulf war / veterans syndrome, amyotrophic lateral sclerosis, post-Lyme disease or related disorders.
  • a fatiguing illness preferably from chronic fatigue syndrome, fibromyalgia, multiple sclerosis, gulf war / veterans syndrome, amyotrophic lateral sclerosis, post-Lyme disease or related disorders.
  • a level of activity of 2-oxoglutarate-dependent dioxygenase may be determined by determining a ratio of intracellular nicotinamide adenine dinucleotide NADH/NAD + , preferably by imaging NADH auto-fluorescence, preferably by fluorescence lifetime imaging.
  • a level of activity of 2-oxoglutarate-dependent dioxygenase may be determined by determining a level of asparaginyl and/or histidinyl hydroxylation of at least one ankyrin repeat domain.
  • Said at least one ankyrin repeat domain may be present in a protein that is exogenous provided to a relevant cell of a human that is typed with a method according to the invention, preferably an isolated cell.
  • said ankyrin repeat domain is present in an endogenous protein, preferably in ankyrin.
  • a level of activity of 2-oxoglutarate-dependent dioxygenase may be determined by determining a level of activity of plasma membrane associated NADH oxidase.
  • a preferred method comprises isolating intact cells from the human; incubating the isolated cells with a chemiluminescent reagent and NADH; determining a level of chemiluminescence; comparing said determined level of chemiluminescence to a control level; and typing said human on the basis of the comparison.
  • the invention further provides a method of treating a human suffering from a fatiguing illness, comprising administering a therapeutically effective amount of an inhibitor of an asparaginyl ⁇ -hydroxylase to said human.
  • Said inhibitor preferably is a nucleic acid molecule, preferably a siRNA molecule or miRNA molecule, or a low molecular weight ( ⁇ 1 kdalton) molecule.
  • Said inhibitor preferably is or comprises a chromene derivative and/or a hydroxypyridone compound, or is or comprises a manganese superoxide dismutase, or a mimic thereof, preferably manganese(III) tetrakis(l-methyl-4- pyridyl)porphyrin, and/or a peroxide donor, preferably an alkali percarbonate such as sodium percarbonate and/or a peroxide such as magnesium peroxide or carbamide peroxide.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising an inhibitor of an asparaginyl ⁇ -hydroxylase, preferably of FIH, and a
  • Said pharmaceutical composition preferably is for use in a method of treating a human suffering from a fatiguing illness.
  • the invention further provides a use of an inhibitor of an asparaginyl ⁇ - hydroxylase, preferably of FIH, in a method for the preparation of a medicament for the treatment of a human suffering from a fatiguing illness
  • Fig. 1 Overall scheme of non-heme iron and heme iron-dependent
  • Fig. 2 Urine redox potential measured as tetrazolium-reduction after 10 minutes at pH 9.0. Range of O.D. values for controls and CFS samples are compared without and with ascorbate oxidase (100 U ).
  • E-demand is induced with ⁇ Verapamil (2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl- methylamino]-2-propan-2-ylpentanenitrile), a first generation calcium channel blocker.
  • Verapamil (2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl- methylamino]-2-propan-2-ylpentanenitrile
  • Fig. 4 Extracellular addition of NADH to mammalian cells (e.g. PBMC ) activates NADH-oxidase at the plasma membrane.
  • typing refers to assessing presence or absence of a fatiguing illness, preferably to discriminating between a human that is likely to suffer from a fatiguing illness and a human that is not likely to suffer from a fatiguing illness. Said typing provides an additional or alternative treatment decision-making factor.
  • the methods of the invention find particular use in choosing appropriate treatment for humans that are likely to suffer from a fatiguing illness.
  • 2-oxoglutarate-dependent dioxygenase refers to a protein that catalyzes hydroxylation of proteins by incorporating a dioxygen molecule, using ferrous iron as cofactor and 2-oxoglutarate as a co-substrate which is decarboxylated to succinate and CO2.
  • 2-Oxoglutarate-dependent dioxygenases are sensors of energy metabolism. A preferred 2-oxoglutarate-dependent
  • dioxygenase is an asparaginyl ⁇ -hydroxylase, most preferably Factor Inhibiting Hypoxia-inducible factor (FIH), also termed Hypoxia-inducible factor 1-alpha inhibitor (HIFAN) or Hypoxia-inducible factor asparagine hydroxylase.
  • FHIF Factor Inhibiting Hypoxia-inducible factor
  • HIFAN Hypoxia-inducible factor 1-alpha inhibitor
  • Hypoxia-inducible factor asparagine hydroxylase Hypoxia-inducible factor asparagine hydroxylase
  • HIF Hypoxia-Inducible transcription Factor
  • Hydroxylation of specific proline residues by HIF prolyl 4-hydroxylases targets the HIF-a subunit for proteasomal degradation. Hydroxylation of an asparagine in the C-terminal transactivation domain prevents its interaction with the transcriptional coactivators CBP/p300, thereby inhibiting transcriptional activation of downstream genes by HIF.
  • Factor Inhibiting Hypoxia-inducible factor refers to an Fe(II)/2-oxoglutarate-dependent dioxygenase that acts as a negative regulator of the hypoxia-inducible factor (HIF) by catalysing 6- hydroxylation of an asparaginyl residue in the C-terminal transcriptional activation domain of HIF.
  • FIH also catalyzes asparaginyl hydroxylation of ankyrin repeat domain-containing proteins, including Nuclear Factor ⁇ (NFKB1), NFKBIA, NOTCH 1, NOTCH2, NOTCH3, Tankyrase 2 (TNKS2) and Protein Phosphatase 1 Regulatory Subunit 12A, and hydroxylates histidinyl residues within the ankyrin repeat domain of, for example, Tankyrase-2 (Yang et al., 2011. FEBS J 278 1086-97).
  • NFKB1 Nuclear Factor ⁇
  • TNKS2 Tankyrase 2
  • fatiguing illnesses refers to diseases or disorders that are characterized by their complex, multi-organ chronic signs and symptoms, including muscle pain, chronic fatigue, headaches, memory loss, nausea, gastrointestinal problems, joint pain, lymph node pain, which last for at least 6 months.
  • diseases or disorders are chronic fatigue syndrome, fibromyalgia, multiple sclerosis, Parkinson's disease, gulf war / veterans syndrome, amyotrophic lateral sclerosis, cancer, post-Lyme disease and related disorders such as sick building syndrome and mercury/amalgam disease.
  • inhibitor of an asparaginyl ⁇ -hydroxylase refers to a therapeutic compound of any type, including small molecule-, peptide-, protein, antibody-, antisense-, small interfering RNA-, or microRNA-based compound, that inhibits, blocks or counteracts hydroxylation of an asparaginyl residue in at least one ankyrin-repeat domain-containing protein by an asparaginyl ⁇ -hydroxylase.
  • an inhibitor is an inhibitor of Factor Inhibiting Hypoxia-inducible factor (FIH).
  • FSH Factor Inhibiting Hypoxia-inducible factor
  • ankyrin repeat domain refers to a domain of about 33 amino acid residues in proteins that mediates protein— protein
  • An ankyrin repeat domain is defined by its structure rather than its function.
  • a consensus ankyrin repeat domain comprises the amino acid sequence:
  • a preferred consensus sequence is:
  • treatment refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and may be performed during the course of clinical pathology. Desirable effects of the treatment include preventing occurrence or recurrence of the illness, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the illness, and/or amelioration or palliation of the state of the illness.
  • treatment or “treating” is preferably understood to mean improving at least the physical capacity of a human suffering from a fatiguing illness by administering a pharmaceutical composition comprising an inhibitor of an asparaginyl ⁇ -hydroxylase.
  • terapéuticaally effective amount refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, a therapeutically effective amount of an agent is an amount sufficient to inhibit or treat the disease or condition without causing a substantial cytotoxic effect in the subject. The therapeutically effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic agent.
  • the term refers to (i) an amount sufficient to inhibit, block or counteract hydroxylating activity of an asparaginyl ⁇ -hydroxylase, preferably of Factor Inhibiting Hypoxia-inducible factor (FIH), and/or (ii) an amount sufficient to treat a human suffering from a fatiguing illness. It is within the knowledge and capabilities of the skilled practitioner to determine therapeutically effective dosage regimens.
  • an asparaginyl ⁇ -hydroxylase preferably of Factor Inhibiting Hypoxia-inducible factor (FIH)
  • FSH Factor Inhibiting Hypoxia-inducible factor
  • administering refers to the physical introduction of an agent or therapeutic compound that inhibits, blocks or counteracts
  • Administration of small molecules described herein can be performed by non-parenteral administration such as by oral and enteral administration.
  • Preferred routes of administration for protein-based agents such as antibodies is by parenteral administration, including intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, executed inter alia by injection or infusion in the form of a solution.
  • Administering can be performed, for example, once, a plurality of times, and/or over one or more extended periods of time.
  • mitochondrial disfunctioning results in activation of "hypoxia inducing factor inhibitor” (FIH), leading to aberrant hydroxylation of ankyrin repeat domains (ARD) in intracellular structural and metabolic proteins.
  • FHI hyperoxia inducing factor inhibitor
  • ARD ankyrin repeat domains
  • This aberrant hydroxylation is an important factor in fatiguing illnesses such as chronic fatigue syndrome, fibromyalgia, multiple sclerosis, gulf war / veterans syndrome, amyotrophic lateral sclerosis, post-Lyme disease and related disorders.
  • said mitochondrial disfunctioning might be triggered by diverse factors such as, e.g. hypoxia, bacterial-, viral- or mycoplasma infections, or interactions with metals, which cause changes in intracellular calcium-fluxes, thereby influencing mitochondrial functioning.
  • triggering might result, in some individuals, to mitochondrial disfunctioning, resulting in decreased efflux of hydrogen peroxide from the mitochondria and activation of FIH.
  • the efflux of hydrogen peroxide that is produced by superoxide dismutase 2 (SOD2)-catalyzed dismutation of O 2" is proportional to the
  • FIH is a dioxygenase, which is a group of enzymes requiring oxygen as a substrate. As such, they are oxygen sensors and play a key role in health and disease.
  • 2-Oxoglutarate (20G)-dependent dioxygenases (20G) such as FIH have been found to play a central role in processes by which cells sense and respond to hypoxia by hydroxylation of hypoxia inducible factor HIFl-oc (Franke et al., 2013. Blood 122: 1122-1128; Tian et al., 2011. J Biol Chem 286: 13041-13051).
  • FIH controls hypoxia inducible factor (HIFl-oc) association with the key activators p300 and CREB Binding Protein (CBP) and regulates the transcriptional activity of HIF1.
  • FIH targets a conserved asparaginyl residue in the C-terminal
  • Ankyrin repeat Domains are common interaction motifs of proteins that have been shown to be efficiently hydroxylated by FIH.
  • An ankyrin repeat is a structural motif in proteins forming an elongated stacked structure build of 4-6 copies with a continuous hydrophobic core and a large solvent-accessible surface (Wilkins et al., 2016. Chem Med Chem 11: 773-786). It is a protein-protein interaction unit involved in a diverse set of cellular activities such as cell-cycle regulation, cytoskeletal integrity, ion transport through ion channels, signal transduction and other.
  • the first reported ARD substrates for FIH were pl05 and IkBa, components of the NF-kB signaling system which palsy a key role in immune responses.
  • FIH may also hydroxylate histidinyl and aspartyl residues making FIH a highly promiscuous oxygenase, a property it shares with other 2 OG- oxygenases acting on proteins including JmjC histone demethylases (Markolovic et al., 2015. J Biol Chem 290: 20712-20722). The interaction of all these factors are summarized in Fig. 1.
  • a method of typing a human according to the invention comprises determining a level of activity of a 2- oxoglutarate-dependent dioxygenase, preferably an asparaginyl ⁇ -hydroxylase such as FIH, in a cell of said human.
  • a level of activity of a 2-oxoglutarate-dependent dioxygenase may be determined directly, by determining a catalytic activity of 2-oxoglutarate- dependent dioxygenase and/or indirectly by determining a ratio of intracellular nicotinamide adenine dinucleotide NADH/NAD+, by determining a level of asparaginyl and/or histidinyl hydroxylation of at least one ankyrin repeat domain, and or by determining a level of activity of plasma membrane associated NADH oxidase.
  • Molecules 20: 20551-20568 describe several assays, including radioactive isotope-based assays, fluorescence-based assays and mass spectrometry-based assays that can be used for directly measuring activity of a 2-oxoglutarate-dependent dioxygenase, as is used herein, preferably a level of activity of an asparaginyl ⁇ -hydroxylase such as FIH.
  • radioactive isotope-based assays fluorescence-based assays
  • mass spectrometry-based assays that can be used for directly measuring activity of a 2-oxoglutarate-dependent dioxygenase, as is used herein, preferably a level of activity of an asparaginyl ⁇ -hydroxylase such as FIH.
  • a level of activity of 2-oxoglutarate-dependent dioxygenase preferably of preferably an asparaginyl ⁇ -hydroxylase such as FIH, may be indirectly
  • a ratio of intracellular nicotinamide adenine dinucleotide NADH/NAD+ may be determined by imaging NADH auto-fluorescence. It is known to a person skilled in the art that live tissues illuminated with ultraviolet light emit blue fluorescence, arising primarily from mitochondrial NADH. The nicotinamide moiety of NADH absorbs light of wavelength 340 ⁇ 30 nm and emits fluorescence at 460 ⁇ 50 nm
  • a ratio of intracellular nicotinamide adenine dinucleotide NADH/NAD+ preferably is determined by fluorescence lifetime imaging, allowing to differentiate between NADH and NADPH at the level of a single cell (Blacker et al., 2014.
  • a level of activity of 2-oxoglutarate-dependent dioxygenase may further be determined by determining a level of asparaginyl and/or histidinyl hydroxylation of at least one ankyrin repeat domain. Any method known in the art to determine a level of asparaginyl and/or histidinyl hydroxylation of at least one ankyrin repeat domain may be used. For example, a hydroxylation status of an ankyrin repeat domain (ARD) may be analyzed using, for example, mass spectrometry (MS) or, preferably, tandem MS (MS/MS).
  • MS mass spectrometry
  • MS/MS tandem MS
  • a preferred method for determining a hydroxylation status of an ARD comprises high performance liquid chromatography (HPLC), preferably coupled to tandem mass spectrometry (LC-MS/MS).
  • HPLC high performance liquid chromatography
  • LC-MS/MS tandem mass spectrometry
  • the LC-MS/MS analysis may be performed, for example by using a HPLC chromatographic system coupled to a triple- quadrupole mass-spectrometer.
  • Said ankyrin repeat domain may be exogenously present in a cell of a human.
  • a peptide or protein comprising said ankyrin repeat domain may be introduced into said cell.
  • said ARD may be introduced by infection or transfection of a vector encoding the peptide or protein comprising said ankyrin repeat domain.
  • said peptide or protein comprising said ankyrin repeat domain may be introduced, for example by providing said peptide of protein with a cell-penetrating domain.
  • a cell-penetrating domain refers to peptides that facilitate cellular intake/uptake of various molecules.
  • suitable cell-penetrating domains are penetratin or Antenapedia (N- terminus RQIKWFQNRRMKWKK), TAT (N-terminus YGRKKRRQRRR), SynBl (N- terminus RGGRLSYSRRRFSTSTGR), SynB3 (N-terminus RRLSYSRRRF), PTD-4 (N-terminus PIRRRKKLRRLK), and PTD-5 (N-terminus RRQRRTSKLMKR).
  • a level of asparaginyl and/or histidinyl hydroxylation of at least one ankyrin repeat domain may further be determined by analysis of an ankyrin repeat domain that is present in an endogenous protein, preferably in ankyrin.
  • Suitable downstream targets of 2-oxoglutarate-dependent dioxygenase, preferably of an asparaginyl ⁇ -hydroxylase such as FIH include the myosin binding subunit of Myosin Phosphatase D, termed MYPT1, RNase L, IkB-a, Notch, TRPV, Ankyrin, Ankyrin G and Tankyrase 2, all of which can be implicated in clinical symptoms as being described in humans suffering from a fatiguing illness such as chronic fatigue syndrome.
  • MYPT1 comprises an ARD that is a target of FIH hydroxylation (Webb et al., 2009. Biochem J 420: 327-333). Altered hydroxylation of MYPT1 may compromise relaxation of smooth muscles. Smooth muscles are involved in blood circulation in particular "arterioles”. Altered contraction and relaxation of smooth muscles surrounding arterioles may result in "painful" ischemic conditions (Selvaraju et al., 2014. Antioxid Redox Signal 20: 2631-2665), as frequently experienced by CFS patients and a majority of women suffering from fibromyalgia. In particular, women are more sensitive because of the fact that muscle contraction is under control of oestradiol.
  • Heart function may be affected by altered Ankyrin repeat domain hydroxylation of smooth muscle types involved in pumping blood "into the heart” (diastolic). It is known but remains unexplained that CFS patients have a lower throughput of blood in their heart, described as CFS associated cardiomyopathy, displaying a pattern of blood flow through the heart called "pseudonormalization" which is indicative of an intermediate case of diastolic dysfunction. This would indicate that the left ventricle has stiffened sufficiently to prevent it from filling during the second (a) phase of the diastolic pulse which is also merely a problem observed with female patients.
  • RNase L is a mediator of type 1 interferon-induced anti-viral activity playing diverse and critical cellular roles including the regulation of cell proliferation, differentiation, senescence, apoptosis, tumorigenesis and the control of the immune response (De Meirleir et al., 2000. Am J Med 108: 99-105).
  • RNase L monomers binding to 2'-5' linked oligoadenylates (2-5A) induces dimerization and activation of RNase L. 2-5A binding occurs in the ARD domains 2-4 that are located in the N- terminal portion of RNase L.
  • RNase L is inhibited by the RNase L inhibitor (Englebienne and De Meirleir (EDs). 2002. "Chronic Fatigue Syndrome: A
  • RNase L activity may become activated because excess hydroxylation by FIH of its ARD prevents RNase L to dimerize optimally because of steric hindrance and therefore may escape full control of the RNase L Inhibitor (RLI). Uncontrolled RNase L activity may result in mRNA destruction and cell apoptosis (Nys and De Meirleir, 2005. In Vivo 19: 1013- 1021); Brennan-Laun et al., 2014. J Interferon & Cytokine Res 34: 275-288).
  • IkB-a an inhibitor of Nuclear Factor- ⁇ (NF-kB)
  • NF-kB Nuclear Factor- ⁇
  • ARDs that are hydroxylated by FIH. Hydroxylated ARDs render IkB-a unstable and prone to degradation, resulting in translocation of NF-kB to the nucleus where it associates with various activators and initiates the transcription of many genes involved in the inflammatory response (Brennan-Laun et al., 2014. J Interferon & Cytokine Res 34: 275-288).
  • NF-kB pathway Since the NF-kB pathway is known to be important in the inflammatory response, modulation of the activity of the Ankyrin proteins in the pathway by inhibition of 2 OG oxygenases that modify Ankyrin proteins, so that their stability is altered, is useful for treatments of diseases associated with the inflammatory response. Desirable medicinal effects include the regulation of inflammation and immunity such as is achieved by reducing or increasing the interaction between NF-kB proteins such as pl05 and IkB-a and the p50/p65 transcripitional process ( D'Ignazio and Rocha, 2016. Cells 5: 10; Wilkins et al., 2016. ChemMedChem 11: 773-786).
  • Notch is another substrate for FIH hydroxylation of its ARD (Coleman et al., 2007. J Biol Chem 282: 24027-24038; Myllymaki et al., 2017. Mol Cell Biol 37: e00529-16; Zheng et al.. 2008. Proc Natl Acad Sci USA 105: 3368-3373). Altered
  • Notch activity has serious consequences for cell signaling, cytoskeleton movement, control through tyrosine kinase, apoptosis, actin control, bone generation and osteoporosis, gut ligands, pancreatic differentiation, cardiac valve homeostasis and neuronal functions, of which deregulations are frequently observed in fatiguing illnesses such as CFS (Englebienne and De Meirleir (EDs), 2002. "Chronic Fatigue Syndrome: A Biological Approach. CRC Press, ISBN:0849 31046 6).
  • Ionic channel activity in particular Vanilloid (TRPV) activity
  • TRPV4 Vanilloid
  • a calcium-permeable cation channel plays important physiological roles in osmosensation, mechanosensation, cell barrier formation and bone homeostasis.
  • mutations in TRPV4 including mutation in some in its ankyrin repeat domain, are associated with human inherited diseases, including neuropathies and skeletal dysplasias, probably because of the increased constitutive activity of the channel.
  • Ion channelopathy is a presumed dysfunction in CFS (Englebienne and De Meirleir (EDs), 2002. "Chronic Fatigue Syndrome: A Biological Approach. CRC Press, ISBN:0849 31046 6).
  • Altered hydroxylation of ARD may result in impaired interaction of ankyrin 1 protein with spectrin in reticulocytes before mitochondrial extrusion, creating symptoms of hereditary spherocytosis (Zhang et al., 2009. Blood 114: 157-164; White et al., 1990. Proc Natl Acad USA 87: 3117-3121). This may explain the altered deformability of red blood cells and abnormal sedimentation rates observed with CFS.
  • AnkG Altered hydroxylation of Ankyrin G (AnkG) also plays an important role in the course of a fatiguing illness such as CFS.
  • AnkG regulates neuronal plasticity, maintenance of axons, possibly through interaction with NF-kB (Konig et al., 2017. Sci Rep 7: 42006; doi: 10.1038/srep42006), and interacts with membrane-bound Na+ ion channel Epithelial Sodium Channel (ENaC) (Christine A. Klemens, 2017. PhD thesis. University of Pittsburgh) .
  • ENaC Epithelial Sodium Channel
  • Altered AnkG hydroxylation may explain a chronic failure of the aldosterone-renin- angiotensin system (the so called aldosterone-renin paradox in CFS/ME), altered Na+/K+ fluxes and Mg2+ reuptake leading to disturbed electrolyte balances and fatigue, as is observed in patients suffering from a fatiguing illness such as CFS and in patients with Adison's disease.
  • a poly-ADP-ribosyltransferase termed tankyrase-2, uses NAD+ as a cosubstrate to link ADP-ribose polymers to target proteins, resulting in a post- translational modification referred to as PARsylation (Hsiao and Smith, 2008.
  • Tankyrase-2 is also known to be involved in vesicle trafficking and in telomere length regulation (Hsiao and Smith, 2008. Biochimie 90: 83- 92). Multiple FIH-dependent Asn hydroxylation sites have been identified in tankyrase-2 ARD (Cockman et al., 2009. Mol Cell Proteomics 8:535-546) and two histidinyl residues in the tankyrase-2 ARD are also substrates for FIH- catalysed 6-hydroxylation (Yang et al., 2011. FEBS J 278: 1086-1097).
  • hypoxia has been implicated in telomere regulation
  • telomere shortening has been observed in persons suffering from a fatiguing illness such as chronic fatigue syndrome (Unger et al., 2016. FASEB J 30: Supplement Ib459).
  • a level of activity of 2-oxoglutarate-dependent dioxygenase may further be determined by determining a level of activity of plasma membrane associated NADH oxidase.
  • NADH oxidase The activity of a NADH oxidase at the cell surface is regulated by a coenzyme Q/QH2 oxidoreductase-mediated plasma membrane electron transport accepting electrons from cytosolic [NADH/NAD+] cy tosoi controlled by the aspartate/malate shuttle-mediated electron flux which itself is proportional to the mitochondrial matrix [NAD H/NAD +] mito .
  • a method of typing a human comprising determining a level of activity of a 2- oxoglutarate-dependent dioxygenase, preferably an asparaginyl ⁇ -hydroxylase, in a cell of said human by determining an activity of a plasma membrane associated NADH oxidase is preferably performed by a method comprising isolating intact cells from the human; incubating the isolated cells with a chemiluminescent reagent and NADH; determining a level of chemiluminescence; comparing said determined level of chemiluminescence to a control level; and typing said human on the basis of the comparison.
  • Cationic chemiluminescent reagent including but not limited to chemiluminogenic probe (CLP 2+ ) will bind to the negatively charged cell surface and becomes univalently reduced.
  • the resulting CLP + reacts with oxygen to produce superoxide anion radicals that may react back with CLP+ to produce excited methylacrida (MA) and long lived luminescence (hv). Free unbound CLP remains in the CLP2+ state and does not participate in the reaction process further.
  • chemiluminescent reagents are imidazopyrazinone derivatives, lophine derivatives and acridinium esters such as phenoxy-substituted acridinium ester (di-ortho-bromophenyl- acridinium ester), oxalate esters, as is known to a skilled person.
  • Said cells preferably are isolated from a liquid sample, such as blood, urine, stool, or bodily fluids.
  • said cells are or comprise mononuclear peripheral blood cells. Methods to isolate mononuclear peripheral blood cells from blood are known to a skilled person, and include ficoll isopaque density gradient
  • a coefficient or stimulation index is determined that is a measure of a similarity or dissimilarity of a sample with a previously established reference level that is specific to a certain cell type, tissue, disease state or any other interesting biological or clinical interesting sample group.
  • Typing of a sample can be based on its (dis) similarity to a reference, or based on multiple references such as, for example, a reference from at least one person suffering from a fatiguing illness such as chronic fatigue syndrome, and a reference from at least one person not suffering from a fatiguing illness.
  • the references are representative of samples from humans that are known to suffer from a fatiguing illness, and/or that are known not to suffer from a fatiguing illness.
  • Said reference preferable refers to the average level obtained in a mixture of samples from humans that are known to suffer from a fatiguing illness, and/or that are known not to suffer from a fatiguing illness.
  • a threshold may be provided that demarcates a sample of a person suffering from a fatiguing illness such as chronic fatigue syndrome, and a sample a person not suffering from a fatiguing illness.
  • Said threshold may be a value of a level of activity of a 2-oxoglutarate-dependent dioxygenase, as is used herein, preferably a level of activity of an asparaginyl ⁇ -hydroxylase such as FIH, or a value of a coefficient or stimulation index, as is known to a person skilled in the art.
  • the invention further provides a method of treating a human suffering from a fatiguing illness, comprising administering a therapeutically effective amount of an inhibitor of an asparaginyl ⁇ -hydroxylase, preferably of FIH, to said human.
  • Said human preferably is typed as suffering from a fatiguing illness by a method of the invention.
  • Said inhibitor preferably is a nucleic acid molecule, preferably a siRNA molecule or miRNA molecule, or a low molecular weight ( ⁇ 1 kdalton) molecule.
  • RNAi RNA interference
  • siRNA small interfering RNA
  • RNAi small interfering RNA
  • RNAi allows silencing of a gene on the basis of its sequence.
  • a heterologous expression cassettes encoding the two strands of the dsRNA duplex molecule may be constructed.
  • Said heterologous expression cassettes preferably comprise a polymerase III enhancer/promoter.
  • a preferred polymerase III enhancer/promoter is selected from the U6 and HI promoter.
  • a polymerase III enhancer/promoter preferably drives expression of small interfering RNA (siRNA) strands that, upon duplex formation by base-pairing, comprise 18-23 (typically 19) nucleotide-long double-stranded siRNA molecules with 2 nucleotide-long 3' overhangs with one of the strands exhibiting extensive homology to a part of a mRNA transcript from a gene encoding an asparaginyl ⁇ -hydroxylase, preferably FIH.
  • siRNA activates the RNA interference (RNAi) pathway and interferes with the expression of said gene.
  • a further preferred heterologous expression cassette preferably comprises a polymerase II or polymerase III promoter that drives expression of a short hairpin RNA (shRNA) or a miRNA.
  • shRNA short hairpin RNA
  • a short hairpin RNA (shRNA) comprises a 50-100 nucleotide long RNA molecule comprising two stretches of 20-25 nucleotides that are complementary and can base-pair, whereby the two stretches are
  • shRNA hairpin structure is cleaved by the cellular machinery into double stranded siRNA, which silences gene expression via RNA interference.
  • miRNA molecules are transcribed by polymerase II as pri- miRNA with a cap and poly-A tail and processed to short, 70-nucleotide stem-loop structures known as pre-miRNA in the cell nucleus. These pre-miRNAs are then processed to mature double stranded miRNAs of about 18-23 nucleotides in the cytoplasm which silence gene expression via RNA interference, primarily by suppressing translation.
  • Said heterologous expression cassette is provided to a relevant cell with the aid of a vector comprising said expression cassette.
  • Said vector preferably is a viral vector.
  • a variety of viral vector systems may be utilized to express a nucleic acid molecule in cells according to the methods of the invention. Suitable vectors include vectors based on gammaretrovirus, lentivirus, adenovirus (AdV), adeno-associated virus (AAV) and herpes simplex virus (HSV). Methods for targeting cells are known in the art, including pseudotyping of retroviral vectors with a viral glycoprotein that binds to a specific membrane receptor of a specific cell type.
  • a viral glycoprotein can be fused with a ligand protein or antibody that recognizes cell type-specific surface molecules, providing a versatile way of cell type-specific gene delivery (Vannucci et al., 2013. New Microbiol 36, 1-22).
  • a low molecular weight ( ⁇ 1 kdalton) molecule for use in methods of the invention preferably is a low molecular weight molecule of 500 Dalton or less. Said molecule preferably shows good absorption and permeation in biological systems and is consequently more likely to be a successful drug candidate than a molecule with a molecular weight above 1 kdalton or even above 500 Dalton (Lipinski et al., 1997. Advanced Drug Delivery Reviews 23: 3-25).
  • Synthetic compound libraries e.g. LOP ACTM, Sigma Aldrich
  • natural compound libraries Specs, TimTec
  • a preferred inhibitor is or comprises a chromene derivative and/or a hydroxypyridone compound.
  • Suitable chromene derivatives have been described in US20100331400, which is hereby incorporated by reference. Said chromene derivatives inhibit hydroxylation by FIH, and are thereby suitable for use in the methods of the present invention.
  • Suitable hydroxypyridone compounds have been described in US Appl. No.2 08/991,913, which is hereby incorporated by reference.
  • a further preferred inhibitor is or comprises a manganese superoxide dismutase, or a mimic thereof, preferably manganese(III) tetrakis(l-methyl-4- pyridyl)porphyrin, and/or a peroxide donor, preferably an alkali percarbonate such as sodium percarbonate and/or a peroxide such as magnesium peroxide or carbamide peroxide.
  • a manganese superoxide dismutase or a mimic thereof, preferably manganese(III) tetrakis(l-methyl-4- pyridyl)porphyrin, and/or a peroxide donor, preferably an alkali percarbonate such as sodium percarbonate and/or a peroxide such as magnesium peroxide or carbamide peroxide.
  • Manganese(III) tetrakis(l-methyl-4-pyridyl)porphyrin is a manganese- porphyrin which acts as a superoxide dismutase (SOD) mimetic with increased stability to pH and hydrogen peroxide.
  • SOD superoxide dismutase
  • the invention further provides a method of treating a human suffering from a fatiguing illness, comprising administering a therapeutically effective amount of a compound that reduces or increases interaction between, for example, pl05 and IkB-a and the p50/p65 transcriptional complex (Rius et al., 2008. Nature 453: 807- 11; Cockman et al., 2006. Proc Natl Acad Sci USA 103: 14767-14772) to said human. Since the NF-kB pathway is known to be important in the inflammatory response, desirable medicinal effects can be obtained by administering a
  • the invention further provides a method of treating a human suffering from a fatiguing illness, comprising administering a therapeutically effective amount of a compound that stimulates hydrogen peroxide emission of mitochondria by interference with oxidation of free fatty acids, preferably of palmitoyl-carnitine and mildronate.
  • a compound that stimulates hydrogen peroxide emission of mitochondria include carnitine, malate, palmitoyl carnitine, and combinations thereof such as malate and carnitine, palmitoyl carnitine and carnitine, and malate and palmitoyl carnitine.
  • the invention further provides a method of treating a human suffering from a fatiguing illness, comprising administering a therapeutically effective amount of a compound that regulates peroxisomal catalase activity.
  • a compound that regulates peroxisomal catalase activity include flavonoids such as genistein, luteolin, kaempferol, and quercetin, and a phytoestrogen such as bioclanin A which also acts as a peroxisome proliferator- activated receptor gamma agonist.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising an inhibitor of an asparaginyl ⁇ -hydroxylase, preferably of FIH, and a
  • Said inhibitor of an asparaginyl ⁇ -hydroxylase preferably of FIH, preferably is selected from baicalein (5,6,7-trihydroxyflavone), 3,4- dihydroxybenzoate, N-oxalylglycine, oxaloacetate, citrate, and combinations thereof.
  • Said pharmaceutically acceptable excipient preferably is selected from diluents, binders or granulating ingredients, a carbohydrate such as starch, a starch derivative such as starch acetate and/or maltodextrin, a polyol such as xylitol, sorbitol and/or mannitol, lactose such as a-lactose monohydrate, anhydrous a-lactose, anhydrous 6-lactose, spray-dried lactose, and/or agglomerated lactose, sugars such as dextrose, maltose, dextrate and/or inulin, glidants (flow aids) and lubricants, and combinations thereof.
  • a carbohydrate such as starch
  • a starch derivative such as starch acetate and/or maltodextrin
  • a polyol such as xylitol, sorbitol and/or mannito
  • a pharmaceutical composition according to the invention preferably is for use in a method of treating a human suffering from a fatiguing illness.
  • the invention further provides a use of an inhibitor of an asparaginyl ⁇ - hydroxylase, preferably of FIH, as described herein above in a method for the preparation of a medicament for the treatment of a human suffering from a fatiguing illness.
  • MTT (3-(4,5'-dimethylthiazol-2- yl)-2,5-dipehenyl tetrazolium), Lucigenin (9,9'-bis(N-methylacridinium) di-nitrate), NADH ( beta- nicotinamide adenine dinucleotide, reduced form), ascorbic acid, ascorbate oxidase (from Cucurbita sp.) and Verapamil ((RS)-2-(3,4- dimethoxyphenyl) - 5- [2- (3, 4- dimethoxyphenyl) ethyl- methyl- amino] - 2- ( 1 - methylethyl)pentanenitrile) were obtained from Sigma-Aldrich.
  • PBS/Tris buffer pH 9.00 was prepared by mixing of equal volumes of PBS ( phosphate buffered saline solution ) and 100 mM Tris buffer, pH 9.
  • PBMC isolation tubes 50 ml were purchased from Greiner Bio One. O.D. readings were performed using a BioRad (i- Mark) plate reader and chemiluminescence was observed using a Beckman LSC6500 scintillation counter operated in in-coincidence Tritium window setting.
  • Controls 82 healthy people referred to the laboratory for general check-up were tested. They had a normal white blood cell count, no inflammation, CRPC ⁇ 1 mg/1, no clinical history of immune disease nor diabetes mellitus. Overnight fasting first morning urine samples and venous blood for isolation of PBMC were used in our study.
  • PBMC peripheral blood mononuclear cells
  • CLP2+ preferentially reacts with superoxide anion radicals (O2-) to produce an excited dioxetane (CLP*) and light (hv)(Afanas'ev, 2001. Circulation Res 89: e46).
  • O2- superoxide anion radicals
  • CLP* excited dioxetane
  • hv light
  • CLP 2+ -dependent chemiluminescence based on NADH-induced O2-, reflecting intra-cellular energy requirements.
  • Univalently reduced CLP (CLP+) is produced by plasma membrane-associated NADH-oxidase:
  • the chemiluminescence observed is a measure of cellular energetic demand.
  • Freshly isolated PBMC do hardly produce any chemiluminescence, whereas cells that are depleted of ATP produce significant luminescence upon addition of NADH.
  • the NADH consumption by the plasma- membrane quantified by the chemiluminescence (hv) response is proportional to the proton motive force or the redox state of the NADH pool of the mitochondria and their efflux of hydrogen peroxide acting as a retrograde signal to the cell to enable the activity, transcription, translation, import or degradation of

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Abstract

La présente invention concerne des procédés de typage d'un humain comprenant la détermination d'un niveau d'activité d'une dioxygénase 2-oxoglutarate-dépendante, de préférence une asparaginyl-β-hydroxylase, dans une cellule dudit humain. Ledit typage donne de préférence une indication que l'humain souffre d'une maladie associée à une fatigue. L'invention concerne des procédés de traitement d'un humain qui est typé comme souffrant d'une maladie associée à une fatigue.
PCT/EP2018/069305 2017-07-14 2018-07-16 Procédés et moyens de diagnostic et/ou traitement d'une maladie associée à une fatigue WO2019012159A1 (fr)

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WO2022155349A1 (fr) * 2021-01-14 2022-07-21 Cash Alan B Traitement de la fatigue pathologique à l'aide d'oxaloacétate

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