WO2017129558A1 - Méthodes permettant de prévoir ou de traiter la septicémie et les maladies cardiométaboliques induites par la myélopoïèse - Google Patents

Méthodes permettant de prévoir ou de traiter la septicémie et les maladies cardiométaboliques induites par la myélopoïèse Download PDF

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WO2017129558A1
WO2017129558A1 PCT/EP2017/051418 EP2017051418W WO2017129558A1 WO 2017129558 A1 WO2017129558 A1 WO 2017129558A1 EP 2017051418 W EP2017051418 W EP 2017051418W WO 2017129558 A1 WO2017129558 A1 WO 2017129558A1
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apoe
glutl
mice
hspcs
cells
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PCT/EP2017/051418
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Laurent YVAN-CHARVET
Manon VIAUD
Rodolphe GUINAMARD
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Universite Nice Sophia Antipolis
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention is in the field of coronary or vascular disorders, more particularly to myelopoiesis-driven cardio metabolic diseases and sepsis.
  • the present invention also relates to a pharmaceutical composition for the treatment of myelopoiesis-driven cardio metabolic diseases and sepsis.
  • Atherosclerosis is a chronic, hypercholesterolemia-driven inflammatory disease that is initiated by the deposition of cholesterol-rich lipoproteins in the artery wall, leading to monocyte-macrophage recruitment.
  • Hypercholesterolemia and/or defective cholesterol efflux have also been documented to induce myelopoiesis, which contributes to atherosclerotic lesion formation by fueling plaques with monocytes and neutrophils.
  • the monocyte count in particular, independently predicts risk for coronary artery disease after adjustment for conventional risk factors. 3 ' 4
  • Hematopoietic stem cells are quiescent in the bone marrow (BM) niche and are the source of all hematopoietic stem and multi-potential progenitors (HSPCs) and differentiated cells that are critical for the maintenance and replenishment of peripheral leukocytes in adult life, particularly during emergency hematopoiesis.
  • HSPCs multi-potential progenitors
  • inventors and others have recently shown that chronic cholesterol accumulation in HSPCs due to hypercholesterolemia and/or defective apo lipoprotein (Apo)-mediated cholesterol efflux promotes pathogenic HSPC expansion and proliferation leading to uncontrolled myelopoiesis.
  • the present invention relates to a method of treating myelopoiesis-driven cardio metabolic diseases and sepsis in a subject in need thereof comprising the step of administrating the subject with a therapeutically effective amount of an agent selected from the group consisting of GLUT1 inhibitors and GOTs inhibitors.
  • an agent selected from the group consisting of GLUT1 inhibitors and GOTs inhibitors.
  • the present invention relates to a method of treating myelopoiesis-driven cardio metabolic diseases and sepsis in a subject in need thereof comprising the step of inhibiting Glutl and GOTs in said subject.
  • the present invention relates to a method of treating myelopoiesis- driven cardio metabolic diseases and sepsis in a subject in need thereof comprising the step of administrating the subject with a therapeutically effective amount of an agent selected from the group consisting of GLUT1 inhibitors and GOTs inhibitors.
  • treating refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subject at risk of contracting the disease or suspected to have contracted the disease as well as subject who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).
  • myelopoiesis-driven cardio metabolic diseases refers to myocardium infarction or chronic atherosclerosis.
  • Myelopoiesis refers to a formation of myeloid cells, including eosinophilic granulocytes, basophilic granulocytes, neutrophilic granulocytes, and monocytes.
  • Hypercholesterolemia and/or defective cholesterol efflux have also been documented to induce myelopoiesis, which contributes to atherosclerotic lesion formation by fueling plaques with monocytes and neutrophils.
  • MI Myocardium infarction
  • Atherosclerosis is a chronic, hypercholesterolemia-driven inflammatory disease that is initiated by the deposition of cholesterol-rich lipoproteins in the artery wall, leading to monocyte-macrophage recruitment.
  • Atherosclerosis contributes to the development of atherosclerotic vascular diseases (AVD) which may affect the coronary arteries (causing ischaemic heart disease), the cerebral circulation (causing cerebrovascular disease), the aorta (producing aneurysms that are prone to thrombosis and rupture) and peripheral blood vessels, typically the legs (causing peripheral vascular disease and intermittent claudication).
  • Ischaemic heart disease (IHD) includes angina (chest pain caused by insufficient blood supply to cardiac muscle) and myocardial infarction (death of cardiac muscle) and cerebrovascular disease includes stroke and transient ischaemic attacks.
  • Sepsis is a systemic reaction characterized by arterial hypotension, metabolic acidosis, decreased systemic vascular resistance, tachypnea and organ dysfunction. Sepsis (including septic shock) is characterized by a systemic inflammatory response which results from the activation of a number of host defense mechanisms including the release of cytokines, the activation of immune cells, the complement system and the coagulation pathway.
  • the method according to the present invention can be supplied to a subject, who has been diagnosed as presenting one of the following myelopoiesis-driven cardio metabolic driven diseases: myocardium infarction or chronic atherosclerosis.
  • the method according to the present invention wherein the myelopoiesis-driven cardio metabolic disease is atherosclerosis.
  • the method of the present invention can also be supplied to a subject who has been diagnosed for sepsis.
  • subject refers to any mammals, such as a rodent, a feline, a canine, and a primate.
  • the subject is a human afflicted with or susceptible to be afflicted with myelopoiesis-driven diseases.
  • the subject is a human afflicted or susceptible to be afflicted with atherosclerosis.
  • agent selected from the group consisting of GLUT1 inhibitors and GOTs inhibitors refers to the capacity of any compound to reduce or inhibit Glutl cell surface expression or GOTs, particularly Glutl expression or GOTs in HSPCs and myeloid cells. Inhibition includes reduction of function and full blockade.
  • Glucose transporter 1 also known as solute carrier family 2 or facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the SLC2A1 gene.
  • GLUT1 facilitates the transport of glucose across the plasma membranes of mammalian cells, particularly facilitates the entry of D-glucose across the blood-barrier brain.
  • Glutamate oxaloacetate transaminases are pyridoxal phosphate-dependent enzymes which exist in cytoplasmic and mitochondrial forms, GOT1 and GOT2, respectively. GOTs play a role in amino acid metabolism and the urea and tricarboxylic acid cycles. The two enzymes are homodimeric and show close homology.
  • the inhibitors of GLUT1 could be an antibody, synthetic or native sequence peptides, small molecules or aptamers.
  • the inhibitor of Glutl is a small organic molecule.
  • small organic molecule refers to a molecule of a size comparable to those organic molecules generally used in pharmaceuticals.
  • small organic molecules range in size up to about 5000 Da, more preferably up to 2000 Da, and most preferably up to about 1000 Da.
  • the inhibitor of Glutl is a small organic molecule such as described in WO2011119866, WO2013182612, WO2015112581, Wood et al 2008, Amann et al 2009, Liu et al 2012, Qian et al 2014 and Shibuya et al 2014.
  • the inhibitor of Glutl is WZB117, also called 3-Fluoro- 1 ,2-phenylene bis(3-hydroxybenzoate), 3-Hydroxy-benzoic acid 1,1 ' -(3-fluoro-l,2- phenylene) ester and has the following formula in the art:
  • the inhibitor of Glutl is Fasentin, also called N-[4-Chloro- 3-(trifluoromethyl)phenyl]-3-oxobutanamide and has the followin formula in the art:
  • the inhibitor of Glutl is a plant carbohydrate product such as Astragalin-6-glucoside such as described in Thom son et al 2015.
  • the inhibitor of Glutl is genistein, also called 5,7- dihydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one and has the following formula in the art:
  • the inhibitor of GLUT1 is an antibody.
  • antibody is used in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g. bispecific antibodies) formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.
  • two heavy chains are linked to each other by disulfide bonds and each heavy chain is linked to a light chain by a disulfide bond.
  • light chain There are two types of light chain, lambda (1) and kappa (k).
  • Each chain contains distinct sequence domains.
  • the light chain includes two domains, a variable domain (VL) and a constant domain (CL).
  • the heavy chain includes four domains, a variable domain (VH) and three constant domains (CHI, CH2 and CH3, collectively referred to as CH).
  • the variable regions of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen.
  • the constant region domains of the light (CL) and heavy (CH) chains confer important biological properties such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fc receptors (FcR).
  • the term includes antibody fragments that comprise an antigen binding domain such as Fab', Fab, F(ab')2, single domain antibodies (DABs), TandAbs dimer, Fv, scFv (single chain Fv), dsFv, ds-scFv, Fd, linear antibodies, minibodies, diabodies, bispecific antibody fragments, bibody, tribody (scFv-Fab fusions, bispecific or trispecific, respectively); sc-diabody; kappa(lamda) bodies (scFv-CL fusions); BiTE (Bispecific T-cell Engager, scFv-scFv tandems to attract T cells); DVD-Ig (dual variable domain antibody, bispecific format); SIP (small immunoprotein, a kind of minibody); SMIP ("small modular immunopharmaceutical” scFv-Fc dimer; DART (ds-stabilized diabody "Dual Affinity ReTargeting"
  • Antibodies can be fragmented using conventional techniques. For example, F(ab')2 fragments can be generated by treating the antibody with pepsin. The resulting F(ab')2 fragment can be treated to reduce disulfide bridges to produce Fab' fragments. Papain digestion can lead to the formation of Fab fragments.
  • Fab, Fab' and F(ab')2, scFv, Fv, dsFv, Fd, dAbs, TandAbs, ds-scFv, dimers, minibodies, diabodies, bispecific antibody fragments and other fragments can also be synthesized by recombinant techniques or can be chemically synthesized. Techniques for producing antibody fragments are well known and described in the art. For example, each of Beckman et al, 2006; Holliger & Hudson, 2005; Le Gall et al, 2004; Reff & Heard, 2001 ; Reiter et al, 1996; and Young et al, 1995 further describe and enable the production of effective antibody fragments.
  • the antibody is a "chimeric" antibody as described in U.S. Pat. No. 4,816,567.
  • the antibody is a humanized antibody, such as described U.S. Pat. Nos. 6,982,321 and 7,087,409.
  • the antibody is a human antibody.
  • a "human antibody” such as described in US 6,075,181 and 6,150,584.
  • the antibody is a single domain antibody such as described in EP 0 368 684, WO 06/030220 and WO 06/003388.
  • the inhibitor of Glutl is a monoclonal antibody.
  • Monoclonal antibodies can be prepared and isolated using any technique that provides for the production of antibody molecules by continuous cell lines in culture.
  • Techniques for production and isolation include but are not limited to the hybridoma technique, the human B-cell hybridoma technique and the EBV- hybridoma technique.
  • the inhibitor of GOTs belongs to the aminooxyacetic acid
  • AO A 2-(aminooxy) acetic acid
  • the inhibitor of Glutl or GOTs is an inhibitor of GLUT1 or GOTs expression.
  • an “inhibitor of GLUT1 or GOTs expression” refers to a natural or synthetic compound that has a biological effect to inhibit or significantly reduce the expression of the gene encoding for GLUT1 or GOTs.
  • the inhibitor of GLUT1 or GOTs expression has a biological effect on one or more of the following events: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, 5' cap formation, and/or 3' end formation); (3) translation of an RNA into a polypeptide or protein; and/or (4) post-translational modification of a polypeptide or protein.
  • the inhibitor of GLUT1 or GOTs expression is an antisense oligonucleotide.
  • Anti-sense oligonucleotides including anti-sense RNA molecules and anti- sense DNA molecules, would act to directly block the translation of GLUT1 mRNA or GOTs mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of GLUT1 or GOTs proteins, and thus activity, in a cell.
  • antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding GLUT1 or GOTs can be synthesized, e.g., by conventional phosphodiester techniques and administered by e.g., intravenous injection or infusion.
  • Methods for using antisense techniques for specifically alleviating gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Pat. Nos. 6,566,135; 6,566,131; 6,365,354; 6,410,323; 6,107,091; 6,046,321; and 5,981,732).
  • the inhibitor of GLUT1 or GOTs expression is a small inhibitory RNAs (siRNAs).
  • GLUT1 or GOTs expression can be reduced by contacting the subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that GLUT1 or GOTs expression is specifically inhibited (i.e. RNA interference or RNAi).
  • dsRNA small double stranded RNA
  • RNAi RNA interference
  • Methods for selecting an appropriate dsRNA or dsRNA-encoding vector are well known in the art for genes whose sequence is known (e.g. see Tuschl, T. et al. (1999); Elbashir, S. M. et al. (2001); Hannon, GJ.
  • inhibitor of GLUT1 or GOTs expression is ribozyme.
  • Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA.
  • the mechanism of ribozyme action involves sequence specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleo lytic cleavage.
  • Engineered hairpin or hammerhead motif ribozyme molecules that specifically and efficiently catalyze endonucleo lytic cleavage of GLUT1 or GOTs mRNA sequences are thereby useful within the scope of the present invention.
  • Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, which typically include the following sequences, GUA, GUU, and GUC.
  • RNA sequences of between about 15 and 20 ribonucleotides corresponding to the region of the target gene containing the cleavage site can be evaluated for predicted structural features, such as secondary structure, that can render the oligonucleotide sequence unsuitable.
  • the suitability of candidate targets can also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using, e.g., ribonuclease protection assays.
  • a "therapeutically effective amount" is intended for a minimal amount of active agent which is necessary to impart therapeutic benefit to a subject.
  • a "therapeutically effective amount" to a subject is such an amount which induces, ameliorates or otherwise causes an improvement in the pathological symptoms, disease progression or physiological conditions associated with or resistance to succumbing to a disorder. It will be understood that the total daily usage of the compounds of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific compound employed; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • GLUT1 inhibitors and GOTs inhibitors as described above may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions.
  • pharmaceutically acceptable excipients such as a carboxylate, a carboxylate, a carboxylate, a carboxylate, a carboxylate, a carboxylate, a carboxylate, a carboxylate, a pharmaceutically acceptable.
  • pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • Suitable unit administration forms comprise oral- route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the polypeptide (or nucleic acid encoding thereof) can be formulated into a composition in a neutral or salt form.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active polypeptides in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • sterile powders for the preparation of sterile injectable solutions
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
  • solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • parenteral administration in an aqueous solution for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
  • one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • FIGURES
  • FIG. 1 Enhanced glucose utilization in the aortic arch, splenocytes, BM and HSPCs of ApoE' ' BM chimeras.
  • A 2-deoxy-[ 14 C] -glucose uptake in aortic arch, bone marrow and spleen of ApoE ' '' ' recipients transplanted with WT or ApoE '1' BM at 12 weeks after the transplantation procedure.
  • MMP mitochondrial membrane potential
  • TMRE fluorescent tetramethylrhodamine ethyl ester
  • Lin Lineage marker
  • Lin + and CD34 CD34 + HSPCs isolated from the BM of these mice.
  • E NBD-glucose binding and/or uptake and
  • F cell surface expression of Glutl was also quantified in these cells. All results are the means ⁇ SEM and are representative of at least one experiment performed with 6-10 animals per group. *P ⁇ 0.05 vs. WT. ⁇ ⁇ 0.05 vs. the untreated condition.
  • FIG. 1 HIFla-independent regulation of Glutl expression and ApoE-/- HSPC expansion and myeloid lineage fate.
  • A Experimental overview. Bone marrow from Mxl- Cre (controls), Mxl-cre HIFl D fi/fi, ApoE-/- Mxl-Cre, ApoE-/- Mxl-cre HIFl D fi/fl mice were transplanted into ApoE-/- recipient mice and, after a 5 week recovery period, the mice were injected with PolyTC and fed a high fat diet for 12 weeks to induce the expansion of HSPCs.
  • B Representative Western blots showing HIFl ⁇ levels in BM cells freshly isolated from these mice at the end of the study period.
  • Quantification (normalized to ⁇ -actin) is expressed as arbitrary unit and indicated by numbers below (C) mRNA expression of HIFl ⁇ and HIF1 D target genes Ldha and Glutl in BM cells freshly isolated from these mice at the end of the study period. (D) Histograms showing Glutl cell surface expression (expressed as the mean fluorescence intensity (MFI)) in CD34- and CD34+ HSPCs. (E) Quantification of the CD34- or CD34+ HSPCs by flow cytometry was expressed as the percentage of total BM. (F) peripheral blood neutrophils, monocytes and eosinophils were also quantified in these mice at the end of the study period. The results are the means ⁇ SEM of 6-10 animals per group. *P ⁇ 0.05 vs. Mxl-Cre. ⁇ P ⁇ 0.05 vs. ApoE-/- Mxl-Cre.
  • FIG. 3 The ApoE A HSPC expansion and myeloid lineage fate and Glutl upregulation are driven by the IL3R signaling pathway.
  • A Twenty- week-old WT and ApoE ' '' ' mice were injected with IgG control or 100 ⁇ g of the IL-3RP blocking antibody for 24 h and analyzed for peripheral blood myeloid cells by flow cytometry.
  • B The CD34 " or CD34 + HSPCs were quantified in the BM of these mice and was expressed as the percentage of total BM.
  • C The percentage of these cells in S/G2M phase was determined by Hoechst staining, and
  • D Glutl cell surface expression was expressed as the mean fluorescence intensity (MFI). The results are the means ⁇ SEM of 5 to 6 animals per group. *P ⁇ 0.05 vs. WT IgG control. ⁇ ⁇ 0.05 vs. ApoE '1' IgG control.
  • FIG. 4 Mitochondrial glycolytic substrate utilization is required for ApoE-/- HSPC proliferation and myelomonyctic fate in vitro.
  • Bone marrow cells from fluorouracil-treated WT and ApoE-/- mice were grown for 72h in liquid culture containing 10% FBS IMDM in the presence of the indicated chemical compounds and 6ng/mL IL-3 or 2ng/mL GM-CSF.
  • Glutl is required in vitro for the IL3R -dependent ApoE' ' HSPC expansion and myeloid lineage fate. Bone marrow cells from WT, Glutl +/ ⁇ , ApoE '11' , and
  • ApoE ⁇ / ⁇ Glutl +/ ⁇ mice were sorted for Lin " cells (i.e, enriched in HSPCs) and cultured for 72h in liquid culture in presence or absence of 6ng/mL IL-3 or 2ng/mL GM-CSF.
  • A Representative dot plots and (B) quantification of HSPCs after in vitro culture.
  • C Representative dot plots and (D) quantification of CDl lb + Gr-l + myeloid cells after in vitro culture.
  • E Quantification of ROS generation and (F) mitochondrial membrane potential (MMP) by flow cytometry using fluorescent carboxy-H 2 DCFDA and tetramethylrhodamine ethyl ester (TMRE) dyes, respectively in HSPCs after in vitro culture.
  • TMRE mitochondrial membrane potential
  • FIG. 6 Glutl-dependence of ApoE-/- HSPC expansion and myelopoiesis in vivo.
  • A Experimental overview. Bone marrow from WT, Glutl +/-, ApoE-/-, and ApoE-/- Glutl +/- mice were transplanted into ApoE-/- recipient mice and, after a 5 week recovery period, the mice were fed a high fat diet for 12 weeks to induce the expansion of HSPCs.
  • Histograms show (B) the Glutl cell surface expression and (C) NBD-glucose binding and/or uptake in HSPC subpopulations from the most quiescent (long-term LT-HSCs) to the most cycling multipotential progenitors (CD34-CD150+Flt3->CD34+CD150+Flt3- >CD34+CD150-Flt3->CD34+CD150-Flt3+) and are expressed as the mean fluorescence intensity (MFI).
  • MFI mean fluorescence intensity
  • D The percentage of cells in S/G2M phase was determined by DAPI staining and flow cytometry, and (E) quantified as the percentage of total BM.
  • GMP granulocyte macrophage progenitor
  • CMP common myeloid progenitor
  • MEP megakaryocyte-erythroid progenitor
  • FIG. 7 Cell autonomous role of Glutl on ApoE ⁇ A HSPC expansion and myeloid lineage commitment.
  • Schematic diagram showing the protocol for the competitive repopulation assay. Equally mixed portions of BM from the respective genotypes were transplanted into WT recipients. Chow- fed recipient mice were analyzed at 10 weeks after reconstitution by flow cytometry for the contribution of the donor (CD45.1 + /CD45.2 + ) to the HSPC subpopulations from the most quiescent (long-term LT-HSCs) to the most cycling multipotential progenitors (CD34 CD150 + >CD34 + CD150 + > CD34 + CD150 " ) in the bone marrow.
  • FIG. 8 Glutl deficiency reduces the accelerated atherosclerosis of ApoE ⁇ A BM chimeras.
  • the values for individual mice are shown as open circles, representing an average of 6 sections per mouse.
  • the horizontal bars represent the group medians.
  • the macrophages were detected by F4/80 immuno fluorescent staining in the proximal aorta and quantified as the mean intensity (magnification, X200). Aortic arch and spleen uptake of 2-deoxy-[ 14 C] -glucose in these mice at the end of the study period. All results are the means ⁇ SEM and are representative of 10 to 12 animals per group. ⁇ ⁇ 0.05 vs. ApoE '1' mice receiving ApoE '1' BM.
  • the enhanced glucose uptake in atheromatous plaques under hypercholesterolemic conditions correlates with higher metabolic activity of hematopoietic cells and is associated with higher Glutl expression in HSPCs.
  • To monitor the metabolic activity of hematopoietic cells we first investigated the uptake of the radiolabeled D-glucose analogue 2-deoxy [14C] glucose in organs isolated from irradiated ApoE-/- recipient mice transplanted with either WT or ApoE-/- bone marrow (BM).
  • HIFla is neither involved in the up-regulation of Glutl in ApoE-/- HSPCs nor the enhanced myelopoiesis of ApoE-/- mice.
  • HIFla is neither involved in the up-regulation of Glutl in ApoE-/- HSPCs nor the enhanced myelopoiesis of ApoE-/- mice.
  • hypoxia inducible factor 1 ⁇ up-regulates Glut 1,37 and HIF1 ⁇ contributes to HSPC homeostasis.18,20
  • FITC fluorescein-conjugated anti-Pimonidazole
  • HIF I D protein was also barely detectable in WT and ApoE-/- BM cell lysates under normoxic culture conditions and cell lysates from ApoE-/- BM cells showed amounts of HIF I D protein similar to those of WT cells under hypoxia (Supplemental Fig. 1A).
  • HFD high fat diet
  • PIpC polykpolylC
  • HIF1 ⁇ deficiency also did not alter the cell surface expression of Glutl in CD34+ HSPCs and CD34- LT-HSCs (Fig. 2D) or the frequency of these cells (Fig. 2E). Furthermore, quantification of the blood myeloid cells in these mice revealed that HIF1 ⁇ deficiency further increased the neutrophil, monocyte and eosinophil counts in these mice (Fig. 2F). Together, these findings suggest that HIF1 ⁇ does not mediate the upregulation of Glutl in ApoE-/- HSPC or their expansion and minimally contributed to myelopoiesis under hypercholesterolemic conditions.
  • the IL-3RJ5 signaling pathway concomitantly controls the cycling and the upregulation of Glutl in ApoE-/- HSPCs.
  • Glutl can be up-regulated by growth hormone-dependent activation of oncogenes, such as Ras or Src.38,39 Therefore, we investigated the expression of Glutl in WT and ApoE-/- BM cultures in response to various growth hormones.
  • the Glutl mRNA levels in WT BM cells were increased upon stimulation with GM-CSF and IL-3, but not Flt3L or TPO, and this response was further increased in the ApoE-/- BM cells and blunted by a farnesyl transferase inhibitor that blocks Ras activation (Supplemental Fig.
  • Glutl deficiency prevented the reduced Cyto-ID staining induced by IL-3 in HSPCs isolated from WT Lin- cultures and restored the autophagic flux of ApoE-/- HSPCs to the level of control cells (Supplemental Fig. 2E and 2F).
  • the Glutl cell surface expression was decreased by an approximately 1.4-fold in the MMP2 of mice receiving either Glutl+/- or ApoE-/-Glutl+/- BM (Fig. 6B and Supplemental Fig. 3D). This confirmed the efficiency of the transplantation procedure.
  • the 2-NBDG staining quantified by flow cytometry suggested Glutl - independent glucose utilization in different populations within the HSPCs, but confirmed an approximately 1.35-fold decrease in 2-NBDG staining in the CD34+CD150+Flt3- MMP2 of mice receiving either Glutl+/- or ApoE-/-Glutl+/- BM compared to their respective controls (Fig. 6C and Supplemental Fig.
  • CMP common myeloid progenitor
  • GMP granulocyte macrophage progenitor
  • MEP megakaryocyte-erythroid progenitor
  • Glutl acts in a cell-autonomous fashion to regulate ApoE-/- HSPC proliferation and myelopoiesis.
  • this phenotype was caused by cell autonomous effects of Glutl within the my elo id-biased HSPCs or involved a cell extrinsic effect.
  • we performed a competitive BM transplantation experiment with equally mixed BM cells from CD45.1 ApoE-/- mice and either CD45.2 ApoE-/- BM or CD45.2 ApoE-/-Glutl+/ BM into irradiated WT recipients.
  • Glutl deficiency prevents the progression of atherosclerosis in ApoE-/- BM- transplanted mice.
  • the body weight, plasma LDL and HDL cholesterol or plasma glucose were not significantly different with regard to Glutl deficiency.
  • the metabolic phenotype of ApoE '1' HSPCs outlined here could be relevant to the adaptability of HSPCs to cholesterol overload and may indicate that the glycolytic phenotype of HSPCs is not merely a product of their hypoxic environment.
  • the existence of different molecular mechanisms underlying the different glycolytic phenotypes in HSPCs may suggest strategies for specifically modulating the pool of HSPCs that are committed to the myeloid lineage under stressed conditions, such as in myeloproliferative disorders, 36 sepsis, 53 myocardium infarction, 54 or chronic atherosclerosis, as shown in the present study.
  • Inhibition of glucose uptake by a Glutl inhibitor that does not cross the blood-brain barrier could ultimately provide a novel therapeutic approach to prevent myelopoiesis-driven diseases such as atherosclerosis.
  • Drechsler M Megens RTA, van Zandvoort M, Weber C, Soehnlein O. Hyperlipidemai-triggered neutrophilia promotes early atherosclerosis/clinical perspectives.

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Abstract

La présente invention concerne une méthode permettant de traiter la septicémie et les maladies induites par la myélopoïèse chez un sujet en ayant besoin, comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un agent sélectionné dans le groupe constitué d'inhibiteurs de GLUT1 et d'inhibiteurs de GOTs.
PCT/EP2017/051418 2016-01-25 2017-01-24 Méthodes permettant de prévoir ou de traiter la septicémie et les maladies cardiométaboliques induites par la myélopoïèse WO2017129558A1 (fr)

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CN114751854A (zh) * 2022-03-23 2022-07-15 中国科学院自动化研究所 近红外荧光探针及其制备方法和应用

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CN114751854A (zh) * 2022-03-23 2022-07-15 中国科学院自动化研究所 近红外荧光探针及其制备方法和应用
CN114751854B (zh) * 2022-03-23 2023-09-15 中国科学院自动化研究所 近红外荧光探针及其制备方法和应用

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