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

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
apoe
glutl
mice
hspcs
cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2017/051418
Other languages
English (en)
Inventor
Laurent YVAN-CHARVET
Manon VIAUD
Rodolphe GUINAMARD
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institut National de la Santé et de la Recherche Médicale
Université Côte d'Azur
Original Assignee
Institut National de la Santé et de la Recherche Médicale
Université Côte d'Azur
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institut National de la Santé et de la Recherche Médicale, Université Côte d'Azur filed Critical Institut National de la Santé et de la Recherche Médicale
Publication of WO2017129558A1 publication Critical patent/WO2017129558A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • Emergency Medicine (AREA)
  • Communicable Diseases (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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 Ceased WO2017129558A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP16305067.7 2016-01-25
EP16305067 2016-01-25

Publications (1)

Publication Number Publication Date
WO2017129558A1 true WO2017129558A1 (fr) 2017-08-03

Family

ID=55237616

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/051418 Ceased WO2017129558A1 (fr) 2016-01-25 2017-01-24 Méthodes permettant de prévoir ou de traiter la septicémie et les maladies cardiométaboliques induites par la myélopoïèse

Country Status (1)

Country Link
WO (1) WO2017129558A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
EP0368684A1 (fr) 1988-11-11 1990-05-16 Medical Research Council Clonage de séquences d'immunoglobulines de domaines variables.
EP0404097A2 (fr) 1989-06-22 1990-12-27 BEHRINGWERKE Aktiengesellschaft Récepteurs mono- et oligovalents, bispécifiques et oligospécifiques, ainsi que leur production et application
WO1993011161A1 (fr) 1991-11-25 1993-06-10 Enzon, Inc. Proteines multivalentes de fixation aux antigenes
WO1999032619A1 (fr) 1997-12-23 1999-07-01 The Carnegie Institution Of Washington Inhibition genetique par de l'arn double brin
US5981732A (en) 1998-12-04 1999-11-09 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-13 expression
US6046321A (en) 1999-04-09 2000-04-04 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-i1 expression
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6107091A (en) 1998-12-03 2000-08-22 Isis Pharmaceuticals Inc. Antisense inhibition of G-alpha-16 expression
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO2001036646A1 (fr) 1999-11-19 2001-05-25 Cancer Research Ventures Limited Inhibition d"expression genique a l"aide d"arn bicatenaire
WO2001068836A2 (fr) 2000-03-16 2001-09-20 Genetica, Inc. Procedes et compositions d'interference d'arn
US6365354B1 (en) 2000-07-31 2002-04-02 Isis Pharmaceuticals, Inc. Antisense modulation of lysophospholipase I expression
US6410323B1 (en) 1999-08-31 2002-06-25 Isis Pharmaceuticals, Inc. Antisense modulation of human Rho family gene expression
US6566131B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of Smad6 expression
US6566135B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of caspase 6 expression
US6573099B2 (en) 1998-03-20 2003-06-03 Benitec Australia, Ltd. Genetic constructs for delaying or repressing the expression of a target gene
US6982321B2 (en) 1986-03-27 2006-01-03 Medical Research Council Altered antibodies
WO2006003388A2 (fr) 2004-06-30 2006-01-12 Domantis Limited Compositions et procedes pour le traitement de troubles inflammatoires
WO2006030220A1 (fr) 2004-09-17 2006-03-23 Domantis Limited Compositions monovalentes pour la liaison au cd40l et procedes d'utilisation
US7087409B2 (en) 1997-12-05 2006-08-08 The Scripps Research Institute Humanization of murine antibody
WO2011119866A1 (fr) 2010-03-24 2011-09-29 Ohio University Compositions et procédés pour l'inhibition du transport du glucose
WO2013182612A1 (fr) 2012-06-07 2013-12-12 Bayer Pharma Aktiengesellschaft Inhibiteurs de transport du glucose
US20140314740A1 (en) * 2011-12-09 2014-10-23 The Johns Hopkins University Compositions and methods for the prevention or treatment of diabetic complications
WO2015112581A1 (fr) 2014-01-21 2015-07-30 The Medical College Of Wisconsin, Inc. Procédés d'inhibition sélective de cellules souches pluripotentes

Patent Citations (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US6982321B2 (en) 1986-03-27 2006-01-03 Medical Research Council Altered antibodies
EP0368684A1 (fr) 1988-11-11 1990-05-16 Medical Research Council Clonage de séquences d'immunoglobulines de domaines variables.
EP0404097A2 (fr) 1989-06-22 1990-12-27 BEHRINGWERKE Aktiengesellschaft Récepteurs mono- et oligovalents, bispécifiques et oligospécifiques, ainsi que leur production et application
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1993011161A1 (fr) 1991-11-25 1993-06-10 Enzon, Inc. Proteines multivalentes de fixation aux antigenes
US7087409B2 (en) 1997-12-05 2006-08-08 The Scripps Research Institute Humanization of murine antibody
WO1999032619A1 (fr) 1997-12-23 1999-07-01 The Carnegie Institution Of Washington Inhibition genetique par de l'arn double brin
US6506559B1 (en) 1997-12-23 2003-01-14 Carnegie Institute Of Washington Genetic inhibition by double-stranded RNA
US6573099B2 (en) 1998-03-20 2003-06-03 Benitec Australia, Ltd. Genetic constructs for delaying or repressing the expression of a target gene
US6107091A (en) 1998-12-03 2000-08-22 Isis Pharmaceuticals Inc. Antisense inhibition of G-alpha-16 expression
US5981732A (en) 1998-12-04 1999-11-09 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-13 expression
US6046321A (en) 1999-04-09 2000-04-04 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-i1 expression
US6410323B1 (en) 1999-08-31 2002-06-25 Isis Pharmaceuticals, Inc. Antisense modulation of human Rho family gene expression
WO2001036646A1 (fr) 1999-11-19 2001-05-25 Cancer Research Ventures Limited Inhibition d"expression genique a l"aide d"arn bicatenaire
WO2001068836A2 (fr) 2000-03-16 2001-09-20 Genetica, Inc. Procedes et compositions d'interference d'arn
US6365354B1 (en) 2000-07-31 2002-04-02 Isis Pharmaceuticals, Inc. Antisense modulation of lysophospholipase I expression
US6566131B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of Smad6 expression
US6566135B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of caspase 6 expression
WO2006003388A2 (fr) 2004-06-30 2006-01-12 Domantis Limited Compositions et procedes pour le traitement de troubles inflammatoires
WO2006030220A1 (fr) 2004-09-17 2006-03-23 Domantis Limited Compositions monovalentes pour la liaison au cd40l et procedes d'utilisation
WO2011119866A1 (fr) 2010-03-24 2011-09-29 Ohio University Compositions et procédés pour l'inhibition du transport du glucose
US20140314740A1 (en) * 2011-12-09 2014-10-23 The Johns Hopkins University Compositions and methods for the prevention or treatment of diabetic complications
WO2013182612A1 (fr) 2012-06-07 2013-12-12 Bayer Pharma Aktiengesellschaft Inhibiteurs de transport du glucose
WO2015112581A1 (fr) 2014-01-21 2015-07-30 The Medical College Of Wisconsin, Inc. Procédés d'inhibition sélective de cellules souches pluripotentes

Non-Patent Citations (58)

* Cited by examiner, † Cited by third party
Title
ANUP SRIVASTAVA ET AL: "PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis", FRONTIERS IN PHYSIOLOGY, vol. 5, 9 March 2015 (2015-03-09), CH, pages 4436, XP055276187, ISSN: 1664-042X, DOI: 10.1038/ncomms5436 *
CHEN C; LIU Y; LIU R; IKENOUE T; GUAN KL; LIU Y; ZHENG P.: "TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species", J EXP MED., vol. 205, 2008, pages 2397 - 2408
CHIONG MARIO ET AL: "Influence of glucose metabolism on vascular smooth muscle cell proliferation", VASA, BERN, CH, vol. 42, no. 1, 1 January 2013 (2013-01-01), pages 8 - 16, XP009190260, ISSN: 0301-1526 *
COLLER BS: "Leukocytosis and ischemic vascular disease morbidity and mortality", ARTERIOSCLER THROMB VASC BIOL., vol. 25, 2005, pages 658 - 670
DAWSON AG: "Oxidation of cytosolic NADH formed during aerobic metabolism in mammalian cells", TRENDS BIOCHEM SCI., vol. 4, 1979, pages 171 - 176, XP023571749, DOI: doi:10.1016/0968-0004(79)90417-1
DEBERARDINIS RJ; LUM JJ; HATZIVASSILIOU G; THOMPSON CG: "The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation", CELL METAB., vol. 7, 2008, pages 11 - 20
DRECHSLER M; MEGENS RTA; VAN ZANDVOORT M; WEBER C; SOEHNLEIN O: "Hyperlipidemai-triggered neutrophilia promotes early atherosclerosis/clinical perspectives", CIRCULATION, vol. 122, 2010, pages 1837 - 1845
DUTTA P; SAGER HB; STENGEL KR; NAXEROVA K; COURTIES G; SAEZ B; SILBERSTEIN L; HEIDT T; SEBAS M; SUN Y: "Myocardial infarction activates CCR2+ hematopoietic stem and progenitor cells", CELL STEM CELL, vol. 16, 2015, pages 477 - 487
EBERT BL; FIRTH JD; RATCLIFFE PJ: "Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct Cis-acting sequences", J BIOL CHEM., vol. 49, 1995, pages 29083 - 29089
ENAMI H ET AL.: "Splenic metabolic activity predicts risk of future cardiovascular events: demonstration of a cardiosplenic axis in humans", JACC CARDIOVASC IMAGING., vol. 8, 2015, pages 121 - 30, XP029197578, DOI: doi:10.1016/j.jcmg.2014.10.009
FLIER JS; MUECKLER MM; USHER P; LODISH HF: "Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes", SCIENCE, vol. 235, 1987, pages 1492 - 1495
GAN B; HU J; JIANG S; LIU Y; SAHIN E; ZHUANG L; FLETCHER-SANANIKONE E; COLLA S; WANG YA; CHIN L: "LKB1 regulates quiescence and metabolic homeostasis of hematopoietic stem cells", NATURE, vol. 468, 2010, pages 701 - 704
GAO M; ZHAO D; SCHOUTEDEN S; SORCI-THOMAS MG; VAN VELDHOVEN PP; EGGERMONT K; LIU G; VERFAILLIE CM; FENG Y: "Regulation of high-density lipoprotein on hematopoietic stem/progenitor cells in atherosclerosis requires scavenger receptor type BI expression", ARTERIOSCLER THROMB VASC BIOL., vol. 34, 2014, pages 1900 - 9
GARCIA-GARCIA HM; JANG IK; SERRUYS PW; KOVACIC JC; NARULA J; FAYAD, Z.: "Imaging plaques to predict and better manage patients with acute coronary events", CIRC. RES., vol. 114, 2014, pages 1904 - 1917
GAUTIER EL; WESTERTERP M; BHAGWAT N; CREMERS S; SHIH A; ABDEL-WAHAB O; LUTJOHANN D; RANDOLPH GJ; LEVINE RL; TALL AR: "HDL and Glutl inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders", J EXP MED., vol. 210, 2013, pages 339 - 353
GURUMURTHY S; XIE SZ; ALAGESAN B; KIM J; YUSUF RZ; SAEZ B; TZATSOS A; OZSOLAK F; MILOS, P; FERRARI F: "The Lkbl metabolic sensor maintains haematopoietic stem cell survival", NATURE, vol. 486, 2010, pages 659 - 663, XP055280045, DOI: doi:10.1038/nature09572
HAG AM; PEDERSEN SF; CHRISTOFFERSEN C; BINDERUP T; JENSEN MM; JORGENSEN JT; SKOVGAARD D; RIPA RS; KJAER A.: "18)F-FDG PET imaging of murine atherosclerosis: association with gene expresion of key molecular markers", PLOS ONE, vol. 7, 2012, pages E50908
JANG YY; SHARKIS SJ: "A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche", BLOOD, vol. 110, 2007, pages 3056 - 3063
KAUPPINEN RA; SIHRA TS; NICHOLLS DG: "Aminooxyacetic acid inhibits the malate-aspartate shuttle in isolated nerve terminals and prevents the mitochondria from utilizing glycolytic substrates", BIOCHIM BIOPHYS ACTA, vol. 930, 1987, pages 173 - 8, XP025210880, DOI: doi:10.1016/0167-4889(87)90029-2
KIM EJ; KIM S; KANG DO; SEO HS: "Metabolic activity of the spleen and bone marrow in patients with acute myocardial infarction evaluated by 18f-fluorodeoxyglucose positron emission tomographic imaging", CIRC CARDIOVASC IMAGING., vol. 7, 2014, pages 454 - 60
LEE SJ; THIEN QUACH CH; JUNG KH; PAIK JY; LEE JH; PARK JW; LEE KH: "Oxidized low-density lipoprotein stimulates macrophage 18F-FDG uptake via hypoxia-inducible factor-la activation through Nox2-dependent reactive oxygen species generation", J NUCL MED., vol. 55, 2014, pages 1699 - 705, XP055276190, DOI: doi:10.2967/jnumed.114.139428
LIU J; CAO L; CHEN J; SONG S; LEE IH; QUIJANO C; LIU H; KEYVANFAR K; CHEN H; CAO LY: "Bmil regulates mitochondrial function and DNA damage response pathway", NATURE, vol. 459, 2009, pages 387 - 393
LUM JJ; BAUER DE; KONG M; HARRIS MH; LI C; LINDSTEN T; THOMPSON CB: "Growth factor regulation of autophagy and cell survival in the absence of apoptosis", CELL, vol. 120, 2005, pages 237 - 48
LUNT SY; VANDER HEIDEN MG: "Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation", ANNU. REV. CELL DEV. BIOL., vol. 27, 2011, pages 441 - 64
MACINTYRE AN; GERRIETS VA; NICHOLS AG; MICHALEK RD; RUDOLPH MC; DEOLIVEIRA D; ANDERSON SM; ABEL ED; CHEN BJ; HALE LP: "The glucose transporter Glutl is selectively essential for CD4 T cell activation and effectyor function", CELL METAB, vol. 20, 2014, pages 1 - 12
MIHARADA K; KARLSSON G; REHN M; RORBY E; SIVA K; CAMMENGA J; KARLSSON S: "Cripto regulates hematopoietic stem cells as hypoxic-niche-related factor through cell surface receptor GRP78", CELL STEM CELL, vol. 9, 2011, pages 330 - 344, XP028310027, DOI: doi:10.1016/j.stem.2011.07.016
MIYAMOTO K; ARAKI KY; NAKA K, ARAI F; TAKUBO K; YAMAZAKI S; MATSUOKA S; MIYAMOTO T; ITO K; OHMURA M; CHEN C: "Foxo3a is essential for maintenance of the hematopoietic stem cell pool", CELL STEM CELL, vol. 1, 2007, pages 101 - 112
MORTENSEN M; SOILLEUX EJ; DJORDJEVIC G; TRIPP R; LUTTEROPP M; SADIGHI-AKHA E; STRANKS AJ; GLANVILLE J; KNIGHT S; JACOBSEN SE: "The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance", J EXP MED., vol. 208, 2011, pages 455 - 67
MURAKAMI T; NISHIYAMA T; SHIROTANI T; SHINOHARA Y; KAN M; ISHII K; KANAI F; NAKAZURU S; EBINA Y: "Identification of two enhancer elements in the gene encoding the type 1 glucose transporter from the mouse which are responsive to serum, growth factor, and oncogenes", J BIOL CHEM., vol. 267, 1992, pages 9300 - 6
MURPHY AJ; AKHTARI M; TOLANI S; PAGLER T; BIJL N; KUO CL; WANG M; SANSON M; ABRAMOWICZ S; WELCH C: "ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice", J CLIN INVEST., vol. 121, 2011, pages 4138 - 4149
NAKADA D; SAUNDERS TL; MORRISON S: "Lkbl regulates cell cycle and energy metabolism in haematopoietic stem cells", NATURE, vol. 468, 2010, pages 653 - 658
NISHIZAWA T; KANTER JE; KRAMER F; BARNHART S; SHEN X; VIVEKANANDAN-GIRI A; WALL VZ; KOWITZ J; DEVARAJ S; O'BRIEN KD: "An in vivo test of the hypothesis that glucose in myeloid cells stimulates inflammation and atherosclerosis", CELL REPORT, vol. 7, 2014, pages 356 - 65
NORDDAHL GL; PRONK CJ; WAHLESTEDT M; STEN G; NYGREN JM; UGALE A; SIGVARDSSON M; BRYDER D: "Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging", CELL STEM CELL, vol. 8, 2011, pages 499 - 510, XP028349998, DOI: doi:10.1016/j.stem.2011.03.009
OBUROGLU L; TARDITO S; FRITZ V; DE BARROS SC; MERIDA P; CRAVEIRO M; MAMEDE J; CRETENET G; MONGELLAZ C; AN X: "Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification", CELL STEM CELL, vol. 15, 2014, pages 169 - 184
OLIVARES R; DUCIMETIERE P; CLAUDE JR: "Monocyte count: a risk factor for coronary heart disease?", AM J EPIDEMIOL., vol. 137, 1993, pages 49 - 53
PARATHATH S; YANG Y; MICK S; FISHER EA: "Hypoxia in murine atherosclerotic plaques and its adverse effects on macrophages", TRENDS CARDIOVASC MED, vol. 23, 2013, pages 80 - 4, XP028990740, DOI: doi:10.1016/j.tcm.2012.09.004
PIETRAS EM; REYNAUD D; KANG YA; CARLIN D; CALERO-NIETO FJ; LEAVITT AD; STUART JM; GOTTGENS B; PASSEGUE E: "Functionally distinct subsets of lineage-biased multipotent progenitors control blood production in normal and regenerative conditions", CELL STEM CELL, vol. 17, 2015, pages 35 - 46
ROBBINS CS; CHUDNOVSKIY A; RAUCH PJ; FIGUEIREDO JL; IWAMOTO Y; GORBATOV R; ETZRODT M; WEBER GF; UENO T; VAN ROOIJEN N: "Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrates atherosclerotic lesions", CIRCULATION, vol. 125, 2012, pages 364 - 74
ROGERS IS; TAWAKOL A: "Imaging of coronary inflammation with FDG-PET: feasibility and clinical hurdles", CURR CARDIOL REP., vol. 13, 2011, pages 138 - 144
ROZMAN S; YOUSEFI S; OBERSON K; KAUFMANN T; BENARAFA C; SIMON HU: "The generation of neutrophils in the bone marrow is controlled by autophagy", CELL DEATH DIFFER., vol. 22, 2015, pages 445 - 56
S. J. LEE ET AL: "Oxidized Low-Density Lipoprotein Stimulates Macrophage 18F-FDG Uptake via Hypoxia-Inducible Factor-1 Activation Through Nox2-Dependent Reactive Oxygen Species Generation", THE JOURNAL OF NUCLEAR MEDICINE, vol. 55, no. 10, 1 October 2014 (2014-10-01), US, pages 1699 - 1705, XP055276190, ISSN: 0161-5505, DOI: 10.2967/jnumed.114.139428 *
SEIJKENS T; HOEKSEMA MA; BECKERS L; SMEETS E; MEILER S; LEVELS J; TJWA M; DE WINTHER MPJ; LUTGENS E: "Hypercholesterolemia-induced priming of hematopoietic stem and progenitor cells aggravate atherosclerosis", THE FASEB J., vol. 28, 2014, pages 2202 - 2213
SELAK MA; ARMOUR SM; MACKENZIE ED; BOULAHBEL H; WATSON DG; MANSFIELD KD; PAN Y; SIMON MC; THOMPSON CB; GOTTLIEB E: "Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase", CANCER CELL, vol. 7, 2005, pages 77 - 85
SIMSEK T; KOCABAS F; ZHENG J; DEBERARDINIS RJ; MAHMOUD AI; OLSON EN; SCHNEIDER, JW; ZHANG CC; SADEK HA: "The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche", CELL STEM CELL, vol. 7, 2010, pages 380 - 390
SWIRSKI FK; LIBBY P; AIKAWA E; ALCAIDE P; LUSCINSKAS FW; WEISSLEDER R; PITTET MJ: "Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata", J CLIN INVEST, vol. 117, 2007, pages 195 - 205, XP002526385, DOI: doi:10.1172/JCI29950
SWIRSKI FK; NAHRENDORF M: "Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure", SCIENCE, 2013, pages 161 - 166
TACKE F; ALVAREZ D; KAPLAN TJ; JAKUBZICK C; SPANBROEK R; LLODRA J; GARIN A; LIU J; MACK M; VAN ROOIJEN N: "Monocyte subsets differentially employ CCR2, CCR5, and CX3CRl to accumulate within atherosclerotic plaques", J CLIN INVEST., vol. 117, 2007, pages 185 - 194, XP002526386, DOI: doi:10.1172/JCI28549
TAKUBO K; GODA N; YAMADA W; IRIUCHISHIMA H; IKEDA E; KUBOTA Y; SHIMA H; JOHNSON RS; HIRAO A; SUEMATSU M: "Regulation of the HIF-1Q level is essential for hematopoietic stem cells", CELL STEM CELL, vol. 7, 2010, pages 391 - 402
TAKUBO K; NAGAMATSU G; KOBAYASHI CI; NAKAMURA-ISHIZU A; KOBAYASHI H; IKEDA, E; GODA N; RAHIMI Y; JOHNSON RS; SOGA T: "Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells", CELL STEM CELL, vol. 12, 2013, pages 49 - 61
TALL AR; YVAN-CHARVET L: "Cholesterol in inflammation and immune function", NAT IMMUNOL REV., vol. 15, 2015, pages 104 - 16
TOMOHIRO NISHIZAWA ET AL: "Testing the Role of Myeloid Cell Glucose Flux in Inflammation and Atherosclerosis", CELL REPORTS, vol. 7, no. 2, 1 April 2014 (2014-04-01), US, pages 356 - 365, XP055276493, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2014.03.028 *
TOTHOVA Z; KOLLIPARA R; HUNTLY BJ; LEE BH; CASTRILLON DH; CULLEN DE; MCDOWELL EP; LAZO-KALLANIAN S; WILLIAMS IR; SEARS C: "FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress", CELL, vol. 128, 2007, pages 325 - 339, XP055203673, DOI: doi:10.1016/j.cell.2007.01.003
VANDER HEIDEN MG; CANTLEY LC; THOMPSON CB: "Understanding the Warburg effect: the metabolic requirements of cell proliferation", SCIENCE, vol. 324, 2009, pages 1029 - 1033
WANG M; SUBRAMANIAN M; ABRAMOWICZ S; MURPHY AJ; GONEN A; WITZTUM J; WELCH C; TABAS I; WESTERTERP M; TALL AR: "Interleukin-3/Granulocyte macrophage colony-stimulating factor receptor promotes stem cell expansion, monocytosis, and atheroma macrophage burden in mice with hematopoietic ApoE deficiency", ARTERIOSCLER THROMB VASC BIOL., vol. 34, 2014, pages 976 - 984
WEBER GF; CHOUSTERMAN BG; HE S; FENN AM; NAIRZ M; ANZAI A; BRENNER T; UHLE F; IWAMOTO Y; ROBBINS CS: "Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis", SCIENCE, vol. 347, 2015, pages 1260 - 5, XP055229899, DOI: doi:10.1126/science.aaa4268
WEISSMAN IL; SHIZURU JA: "The origins of the identification and isolation of hematopoietic stem cells, and their capability to induce donor-specific transplantation tolerance and treat autoimmune diseases", BLOOD, vol. 112, 2008, pages 3543 - 53
YU WM; LIU X; SHEN J; JOVANOVIC 0; POHL EE; GERSON SL; FINKEL T; BROXMEYER HE; QU CK: "Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation", CELL STEM CELL, vol. 12, 2013, pages 62 - 74
YVAN-CHARVET L; PAGLER TA; GAUTIER EL; AVAGYAN S; SIRY RL; HAN S; WELCH CL; WANG N; RANDOLPH GJ; SNOECK HW: "ATP binding cassette transporters and HDL suppress hematopoietic stem cell proliferation", SCIENCE, vol. 328, 2010, pages 1689 - 1693

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Similar Documents

Publication Publication Date Title
Bakhtiyari et al. The role of bone marrow microenvironment (BMM) cells in acute myeloid leukemia (AML) progression: immune checkpoints, metabolic checkpoints, and signaling pathways
Thapa et al. Metabolic influence on macrophage polarization and pathogenesis
Frydrych et al. Diabetes and sepsis: risk, recurrence, and ruination
Sager et al. Targeting interleukin-1β reduces leukocyte production after acute myocardial infarction
Ziegler et al. The bispecific SDF1-GPVI fusion protein preserves myocardial function after transient ischemia in mice
DeBerge et al. Immunometabolism at the heart of cardiovascular disease
Huang et al. M2 macrophages secrete glutamate-containing extracellular vesicles to alleviate osteoporosis by reshaping osteoclast precursor fate
Gonzalez et al. Inflammation resolution in the cardiovascular system: arterial hypertension, atherosclerosis, and ischemic heart disease
Cataisson et al. CXCR2 ligands and G-CSF mediate PKCα-induced intraepidermal inflammation
Hardaway et al. IL-1β, RAGE and FABP4: targeting the dynamic trio in metabolic inflammation and related pathologies
Ohshima et al. Intraperitoneal and intravenous deliveries are not comparable in terms of drug efficacy and cell distribution in neonatal mice with hypoxia–ischemia
US20220257755A1 (en) Combination therapy for the treatment of autoimmune diseases
Paquet et al. Effect of N-acetylcysteine combined with infliximab on toxic epidermal necrolysis. A proof-of-concept study
BR112012017150B1 (pt) Formulação farmacêutica, recipiente farmacêutico, e kit
Gao et al. Endothelial‐specific telomerase inactivation causes telomere‐independent cell senescence and multi‐organ dysfunction characteristic of aging
Tan et al. Dynamic aging: channeled through microenvironment
Hoque et al. Cardiac fibrogenesis: an immuno-metabolic perspective
CN103648531A (zh) 用于预防或治疗代谢综合症的方法
Hałucha et al. Protective role of platelets in myocardial infarction and ischemia/reperfusion injury
Iqbal et al. Inducible nitric oxide synthase (NOS-2) in subarachnoid hemorrhage: Regulatory mechanisms and therapeutic implications
Ciortan et al. Cross-talk between neutrophils and macrophages post-myocardial infarction: from inflammatory drivers to therapeutic targets
AU2015270925A1 (en) Methods and compositions for immunomodulation
Kanuri et al. Macrophage heterogeneity in myocardial infarction: Evolution and implications for diverse therapeutic approaches
Huang et al. IL-1 signaling pathway, an important target for inflammation surrounding in myocardial infarction
Li et al. Eicosapentaenoic acid induces macrophage Mox polarization to prevent diabetic cardiomyopathy

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17701146

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17701146

Country of ref document: EP

Kind code of ref document: A1