WO2020239623A1 - Utilisation d'inhibiteurs de ngal pour le traitement d'une plaie chronique - Google Patents

Utilisation d'inhibiteurs de ngal pour le traitement d'une plaie chronique Download PDF

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WO2020239623A1
WO2020239623A1 PCT/EP2020/064260 EP2020064260W WO2020239623A1 WO 2020239623 A1 WO2020239623 A1 WO 2020239623A1 EP 2020064260 W EP2020064260 W EP 2020064260W WO 2020239623 A1 WO2020239623 A1 WO 2020239623A1
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ngal
wounds
diabetic
wound
macrophages
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Frédéric JAISSER
Van Tuan NGUYEN
Nicolette Farman
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Sorbonne Université
Université de Paris
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • the present invention is in the field of medicine, in particular in dermatology.
  • a chronic inflammatory environment is also a common feature observed in unhealed wounds and is mainly associated with the uncontrolled recruitment and activation of inflammatory cells, in particular monocytes/macrophages (Boniakowski et al., 2017, Leal et al., 2015, Okizaki et ak, 2015).
  • macrophages present various phenotypes and functions, depending on the stage of the healing response and how they are activated.
  • Ml macrophages classically activated macrophages, known as Ml macrophages, are recruited and secrete pro-inflammatory cytokines to kill pathogens and clear away the damaged tissue.
  • M2 macrophages secrete anti- inflammatory factors to resolve inflammation and produce factors required for later regenerative phases.
  • the balance between these macrophage subpopulations is pivotal for maintaining a physiological healing process (Gordon, 2003, Mahdavian Delavary et al, 2011, Mantovani et al, 2004).
  • macrophages are chronically activated and restrained to the Ml phenotype, heavily contributing to the chronic inflammatory microenvironment observed in these wounds. Moreover, such prolonged inflammation delays the process of tissue regeneration, including re-epithelialization, granulation tissue formation, and vascularization (Boniakowski et al., 2017, He et al., 2017, Maruyama et al, 2007, Okizaki et al, 2015). Enhancing macrophage polarization towards M2 phenotype may help to promote cellular proliferation and angiogenesis and to accelerate diabetic wound closure (He et al., 2017, Leal et al., 2015, Okizaki et al., 2015).
  • NGAL is a primary target of aldosterone/mineralocorticoid receptor signaling in many organs and that NGAL plays a key role in the action of mineralocorticoids in the cardiovascular system (Buonafme et al, 2018). However, its role in chronic wounds has never been investigated.
  • the present invention relates to the use of NGAL inhibitor for the treatment of chronic wound.
  • MR mineralocorticoid receptor
  • canrenoate or MR siRNA can resolve inflammation to improve delayed skin wound healing in diabetic mouse models; importantly, wounds from normal mice are unaffected.
  • MR blockade leads to downregulation of the MR target, lipocalin 2 (Lcn or NGAL), which may facilitate macrophage polarization towards the M2 phenotype and improve impaired angiogenesis in diabetic wounds.
  • mice showed improved wound healing, associated with macrophage M2 polarization and angiogenesis.
  • recombinant Lcn2 protein prevented IL4-induced macrophages switch from Ml to M2 phenotype.
  • inhibiting the activity or expression of NGAL would very suitable for the treatment of chronic wound.
  • the present invention relates to a method of treating chronic wound in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a NGAL inhibitor.
  • the method herein disclosed is particularly suitable for the treatment of chronic wound.
  • the term“chronic wound” or“delayed wound closure” refers to those wounds that do not heal in an orderly set of stages and in a predictable amount of time. Typically, wounds that do not heal within three months are considered chronic.
  • Chronic wounds include, but are not limited to, venous stasis ulcers, diabetic foot ulcers, and the like. Chronic, wounds may also include those relating to trauma (or repeated trauma), thermal injury (e.g., burns) and radiation damage. In some embodiments, treatment of chronic wound in subject suffering from sickle-cell disease is also encompassed. In some embodiments, treatment of chronic wound in elderly is also encompassed.
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients 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 patient 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 patient during treatment of an illness, e.g., to keep the patient 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., disease manifestation, etc.]).
  • NGAL Neutrophil Gelatinase- Associated Lipocalin as described in Schmidt-Ott KM. et al. (2007) (Schmidt-Ott KM, Mori K, Li JY, Kalandadze A, Cohen DJ, Devarajan P, Barasch J. Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol. 2007 Feb; 18(2):407-13. Epub 2007 Jan 17. Review.).
  • An exemplary human amino acid sequence is represented by SEQ ID NO: 1.
  • NGAL inhibitor refers to a molecule that partially or fully blocks, inhibits, or neutralizes a biological activity or expression of NGAL. Suitable inhibitor molecules specifically include antagonist antibodies or antibody fragments, fragments or amino acid sequence variants of native polypeptides, peptides, antisense oligonucleotides, small organic molecules, recombinant proteins or peptides, etc.
  • a NGAL inhibitor can be a molecule of any type that interferes with the signaling associated with NGAL, for example, either by decreasing transcription or translation of NGAL encoding nucleic acid, or by inhibiting or blocking NGAL activity, or both.
  • a NGAL inhibitor is an agent that interferes with the signaling associated with NGAL.
  • NGAL inhibitors include, but are not limited to, antisense polynucleotides, interfering RNAs, catalytic RNAs, RNA-DNA chimeras, NGAL -specific aptamers, anti-NGAL antibodies, NGAL-binding fragments of anti- NGAL antibodies, NGAL-binding small molecules, NGAL-binding peptides, and other polypeptides that specifically bind NGAL (including, but not limited to, NGAL-binding fragments of one or more NGAL ligands, optionally fused to one or more additional domains), such that the interaction between the NGAL inhibitor and NGAL results in a reduction or cessation ofNGAL activity or expression.
  • NGAL inhibitors described herein may be strong inhibitors ofNGAL.
  • the NGAL inhibitor is a small molecule, such as a small organic molecule, which typically has a molecular weight less than 5,000 kDa.
  • the NGAL inhibitor is an anti-NGAL antibody.
  • antibody as includes but is not limited to polyclonal, monoclonal, humanized, chimeric, Fab fragments, Fv fragments, F(ab’) fragments and F(ab’)2 fragments, as well as single chain antibodies (scFv), fusion proteins and other synthetic proteins which comprise the antigen-binding site of the antibody.
  • Antibodies can be made by the skilled person using methods and commercially available services and kits known in the art. Methods of preparation of monoclonal antibodies are well known in the art and include hybridoma technology and phage display technology.
  • the NGAL inhibitor is an inhibitor of NGAL expression.
  • An “inhibitor of expression” refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene.
  • said inhibitor of gene expression is a siRNA, an antisense oligonucleotide or a ribozyme.
  • anti-sense oligonucleotides including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of NGAL mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of NGAL, 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 NGAL can be synthesized, e.g., by conventional phosphodiester techniques.
  • Methods for using antisense techniques for specifically inhibiting 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).
  • Small inhibitory RNAs siRNAs
  • siRNAs can also function as inhibitors of expression for use in the present invention.
  • NGAL gene expression can be reduced by contacting a patient 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 NGAL gene expression is specifically inhibited (i.e. RNA interference or RNAi).
  • dsRNA small double stranded RNA
  • RNAi RNA interference or RNAi
  • Antisense oligonucleotides, siRNAs, shRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector.
  • a "vector" is any vehicle capable of facilitating the transfer of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid to the cells and typically cells expressing NGAL.
  • the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector.
  • the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid sequences.
  • Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus; adenovirus, adeno-associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus.
  • retrovirus such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus
  • adenovirus adeno-associated virus
  • SV40-type viruses polyoma viruses
  • Epstein-Barr viruses Epstein-Barr viruses
  • papilloma viruses herpes virus
  • vaccinia virus
  • the endonuclease is CRISPR-cas.
  • the endonuclease is CRISPR-cas9, which is from Streptococcus pyogenes.
  • the CRISPR/Cas9 system has been described in US 8697359 B1 and US 2014/0068797.
  • the endonuclease is CRISPR-Cpfl, which is the more recently characterized CRISPR from Provotella and Francisella 1 (Cpfl) in Zetsche et al. (“Cpfl is a Single RNA- guided Endonuclease of a Class 2 CRISPR-Cas System (2015); Cell; 163, 1-13).
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.
  • a therapeutically effective amount of drug may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of drug to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the active ingredient (i.e. the NGAL inhibitor) are outweighed by the therapeutically beneficial effects.
  • the efficient dosages and dosage regimens for drug depend on the disease or condition to be treated and may be determined by the persons skilled in the art. A physician having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • a suitable dose of a composition of the present invention will be that amount of the compound, which is the lowest dose effective to produce a therapeutic effect according to a particular dosage regimen.
  • One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.
  • An exemplary, non-limiting range for a therapeutically effective amount of drug is about 0.1-100 mg/kg, such as about 0.1-50 mg/kg, for example about 0.1-20 mg/kg, such as about 0.1-10 mg/kg, for instance about 0.5, about such as 0.3, about 1, about 3 mg/kg, about 5 mg/kg or about 8 mg/kg.
  • An exemplary, non-limiting range for a therapeutically effective amount of an antibody of the present invention is 0.02-100 mg/kg, such as about 0.02-30 mg/kg, such as about 0.05-10 mg/kg or 0.1-3 mg/kg, for example about 0.5-2 mg/kg.
  • Administration may e.g. be intravenous, intramuscular, intraperitoneal, or subcutaneous, and for instance administered proximal to the site of the target.
  • the drug of the present invention is administered to the subject in the form of a pharmaceutical composition, which comprises a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, di sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, polyethylene glycol and wool fat.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • the topical pharmaceutically acceptable carrier is any substantially nontoxic carrier conventionally usable for topical administration of pharmaceuticals in which the active ingredient of the invention (i.e. the NGAL inhibitor) will remain stable and bioavailable when applied directly to skin or corneal surfaces.
  • carriers such as those known in the art effective for penetrating the keratin layer of the skin into the stratum comeum may be useful in delivering the active ingredient of the invention (i.e. the NGAL inhibitor) to the area of interest.
  • Such carriers include liposomes wherein the active ingredient of the invention (i.e.
  • the NGAL inhibitor can be dispersed or emulsified in a medium in a conventional manner to form a liquid preparation or mixed with a semi-solid (gel) or solid carrier to form a paste, powder, ointment, cream, lotion or the like.
  • Suitable topical pharmaceutically acceptable carriers include water, buffered saline, petroleum jelly (vaseline), petrolatum, mineral oil, vegetable oil, animal oil, organic and inorganic waxes, such as microcrystalline, paraffin and ozocerite wax, natural polymers, such as xanthanes, gelatin, cellulose, collagen, starch, or gum arabic, synthetic polymers, alcohols, polyols, and the like.
  • the carrier can be a water miscible carrier composition.
  • Such water miscible, topical pharmaceutically acceptable carrier composition can include those made with one or more appropriate ingredients outset of therapy.
  • the topical carrier can also be a topical cosmetically acceptable carrier.
  • the topical cosmetically acceptable carrier will be any substantially non-toxic carrier conventionally usable for topical administration of cosmetics in which active ingredient of the invention (i.e. the NGAL inhibitor) will remain stable and bioavailable when applied directly to the skin surface.
  • Suitable cosmetically acceptable carriers are known to those of skill in the art and include, but are not limited to, cosmetically acceptable liquids, creams, oils, lotions, ointments, gels, or solids, such as conventional cosmetic night creams, foundation creams, suntan lotions, sunscreens, hand lotions, make-up and make-up bases, masks and the like.
  • Topical cosmetically acceptable carriers may be similar or identical in nature to the above described topical pharmaceutically acceptable carriers.
  • the compositions can contain other ingredients conventional in cosmetics including perfumes, estrogen, vitamins A, C or E, alpha-hydroxy or alpha-keto acids such as pyruvic, lactic or glycolic acids, lanolin, vaseline, aloe vera, methyl or propyl paraben, pigments and the like.
  • a delivery system that controls the release of active ingredient of the invention (i.e. the NGAL inhibitor) to the wound and adheres to or maintains itself on the wound for an extended period of time to increase the contact time of the active ingredient of the invention (i.e. the NGAL inhibitor) on the wound.
  • Sustained or delayed release of active ingredient of the invention i.e. the NGAL inhibitor
  • suitable carriers for sustained or delayed release in a moist environment include gelatin, gum arabic, xanthane polymers.
  • Pharmaceutical carriers capable of releasing the active ingredient of the invention i.e.
  • thermoplastic or flexible thermoset resin or elastomer including thermoplastic resins such as polyvinyl halides, polyvinyl esters, polyvinylidene halides and halogenated polyolefins, elastomers such as brasiliensis, polydienes, and halogenated natural and synthetic rubbers, and flexible thermoset resins such as polyurethanes, epoxy resins and the like.
  • Controlled delivery systems are described, for example, in U.S. Pat. No. 5,427,778 which provides gel formulations and viscous solutions for delivery of the active ingredient of the invention (i.e.
  • the sustained or delayed release carrier is a gel, liposome, microsponge or microsphere.
  • the active ingredient of the invention i.e. the NGAL inhibitor
  • can also be administered in combination with other pharmaceutically effective agents including, but not limited to, antibiotics, other wound healing agents, and antioxidants.
  • the route of administration of the active ingredient of the invention will depend on the site of the wound and the type and extent of the injury. Any suitable application method can be used as long as an effective amount of the active ingredient of the invention (i.e. the NGAL inhibitor) is able to reach the areas which require reepithelialisation to occur.
  • Routes of administration include, but are not limited to, topical, transdermal and parenteral. Typically, the ingredient of the invention will be administered by topical or transdermal application.
  • Topical administration for cutaneous treatment is accomplished via a topically applied solution, cream, ointment, gel or other suitable formulation healing bandage which can then be applied to the wound such that the active ingredient of the invention (i.e. the NGAL inhibitor) composition contacts the wound.
  • suitable transdermal devices are described, for instance, in U.S. Pat. No. 4,818,540.
  • the active ingredient of the invention i.e. the NGAL inhibitor
  • the wound area can be irrigated or soaked with a solution of the active ingredient of the invention (i.e. the NGAL inhibitor). The solution will be applied two to twelve times per day.
  • the active ingredient of the invention i.e. the NGAL inhibitor
  • a composition capable of allowing the active ingredient of the invention (i.e. the NGAL inhibitor) to penetrate the skin and site of the wound Such compositions are applied directly to the skin or incorporated into a protective carrier such as a transdermal or "patch" device.
  • the active ingredient of the invention (i.e. the NGAL inhibitor) formulations for transdermal administration can be used to coat the fibers of an absorbent gauze dressing.
  • FIGURES are a diagrammatic representation of FIGURES.
  • Lcn2mRNA (A) and protein (B) levels in wounds at day 5 were analyzed by real-time PCR and ELISA.
  • C-G Diabetes was induced in wildtype (CT) and Lcn2 KO mice by STZ injections before wounding. Quantification of the wound area (C) from CT and Lcn2 KO mice with or without STZ treatment at the indicated times post-wounding.
  • Ml (D) and M2 (E) macrophages and endothelial cells (F) of wounds at day 5 were quantified by FACS analysis. Total macrophages were sorted from wounded skin at day 5 and angiogenic factors mRNA levels were analyzed by real-time PCR (G).
  • mice streptozotocin-induced type I diabetes ad type II diabetes
  • db-db mice streptozotocin-induced type I diabetes ad type II diabetes
  • Wounds were generated with 6 mm biopsy punch.
  • wounds were done at 10 weeks of age. At that time all the dorsum skin displayed a homogenous pink color.
  • streptozotocin groups diabetes was induced at 10 weeks and we performed wounds at 15 weeks of age. We have given a special attention to select dorsum areas at a telogen stage, featured by pink skin color after hair clipping.
  • Mouse MR Stealth siRNAs (Set of 3, MSS201383, MSS201384, MSS272869) were purchased from ThermoFisher Scientific (Renfrew, UK). Stock solution was made by adding lml H20 to 20 nMol MR siRNA set. The siRNA working solution was prepared by 1 : 10 dilution of siRNA stock solution with Mirus transfection reagent. After wounding, 100 pi of siRNA solution (0.2 nMol) was locally injected with needle into each wound at day 0 and day 2. The scrambled siRNA (StealthTM RNAi negative control, medium GC duplex, ThermoFischer Scientific) was prepared according to manufacturer’s instruction and used as negative control. Photographs of wounds at day 3 and day 5 were used to evaluate the degree of wound closure. Mice were sacrificed at day 5, and wounded skin samples were collected for histological and molecular analysis.
  • keratin- 14 staining showed that impaired re-epithelialization of db-db wounds was rescued by local Canre treatment, as illustrated by the longer neo-epidermis at the edges of the wound sections (data not shown) and the shorter residual wound length (the distance between two edges) in Canre- treated db-db mice than in PBS-treated db-db mice (data not shown). This reduction in wound surface is indicative of re-epithelialization rather than wound contraction.
  • Impaired dermal wound angiogenesis is a key contributor to the wound healing defect of diabetes.
  • MR magnetic resonance resonator
  • the density of CD31 + blood vessels was lower in the wounds of STZ-induced (data not shown) and db-db diabetic mice than those of control mice (data not shown), consistent with previous reports.
  • Decreased vessel density of diabetic wounds was partly rescued by topical treatment of these wounds with Canre (data not shown).
  • MR inactivation by local MR siRNA treatment of STZ wounds also showed an beneficial effect on wound angiogenesis (data not shown).
  • MR blockade ameliorates inflammation of diabetic wounds
  • MR blockade blunted the inflammation observed in diabetic wounds and resulted in an anti-inflammatory status that could improve the impaired cellular proliferation and poor angiogenesis.
  • MR antagonism induces the switch of unrestrained Ml towards M2 macrophages in diabetic wounds
  • MR blockade rescues the impaired macrophage expression of angiogenic factors in diabetic wounds
  • macrophages in wounds also promote cellular proliferation and tissue regeneration, including re-epithelialization and dermal vascularization (Gordon, 2003, Lucas et al, 2010).
  • canrenoate treatment improves delayed diabetic wound angiogenesis through the modulation of macrophage polarization by assessing a panel of pro-angiogenic factors in wound tissue.
  • gene expression of pro-angiogenic factors was impaired in STZ wounds with a significant decrease of FGF-2, PLGF, Tie-2, and angiopoietin-2 mRNA levels (data not shown).
  • topical canrenoate application restored the expression of these factors in diabetic wounds (data not shown).
  • VEGF-a, FGF-2, PLGF, and Tie2 mRNA levels were significantly lower in macrophages isolated from STZ wounds than those from control wounds, whereas topical application of Canre restored the inadequate expression of these angiogenic factors (data not shown).
  • the MR target Lcn2 promotes macrophage phenotypic polarization/switching and angiogenesis in diabetic wounds
  • Lcn2 is a primary target of aldosterone/mineralocorticoid receptor signaling in many organs and that Lcn2 plays a key role in the action of mineralocorticoids in the cardiovascular system (Buonafme et al., 2018).
  • Lcn2 mRNA and protein expression was much higher in diabetic wounds than in control, non-diabetic wounds ( Figures 1A-1B).
  • Local canre or MR siRNA treatment lowered the upregulated expression of Lcn2 in diabetic wounds to near the level found in control wounds, indicating that Lcn2 is also an MR target in diabetic skin ( Figures 1A-1B).
  • Lcn2 protein induces an unrestrained pro-inflammatory Ml macrophage phenotype in vitro
  • MR blockade controls the phenotypic polarization of macrophages towards a repair M2 phenotype and promotes dermal angiogenesis through modulation of the expression and activity of Lcn2, thereby improving the delayed wound healing in diabetes (data not shown).
  • I ⁇ b-Hydroxysteroid dehydrogenase type 1 may interfere with MR/GR signaling balance in skin diseases (Sevilla and Perez, 2018, Slominski et ah, 2014, 2015, Tiganescu et ah, 2013). Efforts towards better integrations of these factors should help to propose novel therapeutic improvements of delayed wound healing.
  • macrophages are significantly involved in the repair process (Brancato and Albina, 2011, Lucas et ah, 2010, Rahmani et ah, 2018). Importantly, they show heterogeneous phenotypes and functions and can switch/polarize between phenotypes to adapt to the wound stage (Boniakowski et al, 2017, Novak and Koh, 2013). The balance of such macrophage populations is pivotal for the progression of wound healing. However, most diabetic wounds do not progress, but remain in a chronic state of inflammation.
  • MR antagonism up-regulated the expression of some anti-inflammatory factors, while downregulating the expression of pro-inflammatory cytokines in wound tissues.
  • This is consistent with previous findings that showed the role of MR activation in various diseases involving chronic inflammation, including diabetes (Guo et al., 2008, Jaisser and Farman, 2016, Marzolla et al., 2014).
  • Previous studies reported a central role of MR over-activation in sustained macrophage polarization after renal injury induced by ischemia reperfusion (Barrera-Chimal et al, 2018).
  • MR antagonism also promoted the polarization of activated Ml macrophages toward an anti inflammatory M2 phenotype, suggesting that this may be a common mode of action of MR antagonists in wound healing in cardiovascular, renal, or metabolic injury (Barrera-Chimal et al, 2018).
  • Defective angiogenesis often occurs in diabetic wounds.
  • the defect of wound angiogenesis may be due to inadequate mobilization and abnormal activation of endothelial progenitor cells (Loomans et al., 2004).
  • Several therapies based on promoting the functional activity of endothelial cells and their progenitors have been proposed to improve healing (Liu et al, 2014, Marrotte et al, 2010, Nishimura et al, 2012).
  • Impaired angiogenesis may also be associated with chronic inflammation, inhibiting the production of pro-angiogenic factors and limiting endothelial cell activity. Macrophages are important sources of pro-angiogenic factors.
  • M2 polarized macrophages induced by the inhibition of MR signaling, expressed higher levels of pro-angiogenic factors than those from non-treated diabetic wounds, contributing to angiogenesis and wound healing improvement.
  • Topical cutaneous treatment with MR antagonists provided significant benefits, limiting atrophy and improving wound healing (Maubec et al., 2015, Nguyen et al., 2016).
  • MR overexpression in keratinocyte was shown to induce epidermal atrophy in mice (Sainte Marie et al., 2007).
  • Boix et al. demonstrated that epidermal deletion of MRs leads to increased keratinocyte proliferation and differentiation (Boix et al., 2016).
  • Other studies proposed that epidermal MR cooperates with glucocorticoid receptor acting as an anti-inflammatory factor to counteract skin inflammation and regulate epidermal development in inflamed skin (Bigas et al, 2018, Sevilla and Perez, 2018).
  • lipocalin 2 a primary target of aldosterone/mineralocorticoid receptor signaling (Buonafme et al., 2018), as a promising candidate in diabetes-associated delayed wound healing.
  • Lipocalin 2 secretion is increased in the wound lysates of diabetic foot ulcers due to the release of neutrophil extracellular traps (Fadini et al., 2019).
  • Lcn2 activation is also considered to be a biomarker for chronic inflammatory diseases of skin, such as psoriasis and venous ulcers (Serra et al, 2013, Shao et al, 2016).
  • this study indicates the efficacy of NGAL blockade to restore impaired reepithelialization, angiogenesis and to reduce inflammation after an acute wound in diabetic mice; whether these benefits extend to human chronic diabetic wounds as leg ulcers remain to be demonstrated.
  • TNF-alpha Tumor necrosis factor-alpha
  • Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells.
  • Lipocalin 2 is a regulator of macrophage polarization and NF- kappaB/STAT3 pathway activation. Mol Endocrinol 2014;28(10): 1616-28.
  • Hydrogen sulfide improves wound healing via restoration of endothelial progenitor cell functions and activation of angiopoietin-1 in type 2 diabetes. Diabetes 2014;63(5): 1763-78.

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Abstract

Les plaies chroniques et en particulier les ulcères diabétiques sont une complication grave du diabète. Une inflammation non résolue, associée à la dérégulation à la fois du phénotype et de la fonction des macrophages, est impliquée dans la mauvaise cicatrisation des plaies diabétiques. Ici, l'inventeur rapporte que l'inhibition pharmacologique topique du récepteur minéralocorticoïde (MR) par canrenoate ou MR siRNA peut résoudre une inflammation pour améliorer la cicatrisation retardée de la peau chez des modèles de souris diabétiques ; il est important de relever que celui-ci n'affecte pas les plaies de souris normales. En outre, il montre que le blocage MR conduit à la régulation à la baisse de la cible MR, de la lipocaline 2 (Lcn ou NGAL), ce qui pourrait faciliter la polarisation des macrophages vers le phénotype M2 et améliorer l'angiogenèse altérée dans des plaies diabétiques. En effet, les souris diabétiques déficientes en Lcn2 présentent une cicatrisation améliorée, associée à la polarisation M2 du macrophage et à l'angiogenèse. De plus, la protéine Lcn2 de recombinaison empêche les macrophages induits par IL4 de passer du phénotype M1 au phénotype M2. En conclusion, l'inhibition de l'activité ou de l'expression de NGAL se prêterait parfaitement au traitement de plaies chroniques.
PCT/EP2020/064260 2019-05-24 2020-05-22 Utilisation d'inhibiteurs de ngal pour le traitement d'une plaie chronique WO2020239623A1 (fr)

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