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WO2014076270A1 - Collagène soluble vi destiné à être utilisé dans le traitement de maladies liées à l'hyperglycémie et de troubles de transport du glucose. composition pharmaceutique, procédé et utilisation d'un milieu liquide extracellulaire de cellule pour accroître l'absorption de glucose - Google Patents

Collagène soluble vi destiné à être utilisé dans le traitement de maladies liées à l'hyperglycémie et de troubles de transport du glucose. composition pharmaceutique, procédé et utilisation d'un milieu liquide extracellulaire de cellule pour accroître l'absorption de glucose Download PDF

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Publication number
WO2014076270A1
WO2014076270A1 PCT/EP2013/074038 EP2013074038W WO2014076270A1 WO 2014076270 A1 WO2014076270 A1 WO 2014076270A1 EP 2013074038 W EP2013074038 W EP 2013074038W WO 2014076270 A1 WO2014076270 A1 WO 2014076270A1
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WO
WIPO (PCT)
Prior art keywords
collagen
soluble collagen
cells
glucose
treatment
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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/EP2013/074038
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English (en)
Inventor
Cecilia JIMÉNEZ MALLEBRERA
Ana Maria GÓMEZ FOIX
Óscar OSORIO CONLES
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Hospital Sant Joan de Deu
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Hospital Sant Joan de Deu
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Publication date
Application filed by Hospital Sant Joan de Deu filed Critical Hospital Sant Joan de Deu
Publication of WO2014076270A1 publication Critical patent/WO2014076270A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention is related to the use of soluble collagen VI for the preparation of a medicament for the treatment of hyperglycemia linked diseases and glucose transport disorders. It is also related to a cell extracellular medium comprising the protein collagen VI as a method for increasing glucose uptake in mammalian cells.
  • Collagen VI is a protein found in many extracellular matrices including that of (striated) muscle, tendon, skin, blood vessels and adipose tissue.
  • Collagen VI is encoded by three separate genes, COL6A1 , COL6A2 and COL6A3. Mutations in any of the three collagen VI genes give raise to a spectrum of neuromuscular phenotypes including Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM), intermediate collagen Vl-related myopathy and myosclerosis myopathy.
  • Ullrich Congenital Muscular Dystrophy (UCMD) is the second most common form of congenital muscular dystrophy.
  • UCMD patients with UCMD present typically at birth or within the first year of life with hypotonia, delayed motor milestones, proximal muscle weakness, distal joint hyperlaxity and proximal joint contractures. The most severe cases never achieve ambulation. Those patients with UCMD who walk independently typically loose ambulation by the age of 12 years. Respiratory insufficiency invariably develops in UCMD and intermediate collagen VI patients who require night-time noninvasive ventilatory support during the teenage years.
  • Skeletal muscle and adipose tissue are two of the key tissues responsible for the regulation of glucose and lipid metabolism.
  • Collagen VI is the most abundant collagen type in the extracellular matrix of adipose tissue. It has been shown that expression of collagen VI genes increases during adipogenesis and once the protein is secreted surrounds the fat cell. At the transcriptional level, collagen VI genes expression is regulated by glucose levels and diet. Hyperglycemic glucose concentrations and a diet rich in fatty acids increases COL6 mARN levels whilst PPPAR Y agonists have the opposite effect (Berria, R. et al., 2006, Increased collagen content in insulin-resistant skeletal muscle.
  • One aspect of the invention is the use of soluble collagen VI, herewith use of soluble collagen VI of the invention, for the preparation of a medicament for the treatment of hyperglycemia linked diseases.
  • Collagen VI consists of three a chains, namely a1 (VI), a2 (VI) and ⁇ 3 (VI), encoded by genes COL6A1 , (database accession number OMIM 120220), COL6A2 (database accession number OMIM 120240) and COL6A3 (database accession number OMIM 120250), respectively.
  • Each ⁇ (VI) chain is made up of two large globular domains connected by a short triple-helical domain of Gly-Xaa-Yaa amino acid repeat sequences.
  • Heterotrimeric monomers align to form antiparallel dimers, which in turn associate to form tetramers (dimers and tetramers are stabilised by disulfide bonds occurring between cysteine residues in the triple-helical domains). These tetramers are secreted from the cell and associate in an end-to-end fashion to give rise to the final microfilamentous network.
  • hyperglycemia linked diseases refers to a group of diseases and conditions characterised by a common fact, an impairment of glucose uptake.
  • the impairment of glucose uptake causes hyperglycemia, a prolonged excessive concentration of glucose circulating in the blood plasma (above 140 mg/dL according to the American Diabetes Association).
  • Hyperglycemia is most commonly caused by diabetes mellitus.
  • Type 1 diabetes mellitus is due to a deficient production of insulin subsequent to autoimmune destruction of the pancreatic beta-cells and type 2 diabetes mellitus (T2DM) is triggered by an impaired response to insulin action (or insulin resistance) and beta-cell dysfunction.
  • T2DM is the most common form of diabetes (accounting for 90% of the 346 million people with diabetes across the world according to the world health organization) and its incidence is especially very high in the aged and obese population.
  • lipodystrophy The expert committee on the diagnosis and classification of diabetes mellitus, 2002, Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes care 25, suppl 1 ; Fiorenza CG, Chou SH, Mantzoros CS. (201 1 ) Lipodystrophy: pathophysiology and advances in treatment. Nature Reviews Endocrinology 7(3):137-50.).
  • GLUT1 hereditary diseases that are caused by a defect in the glucose uptake by tissues. This is the case of the deffect of GLUT1 , which is a congenital error of glucose transport to the brain causing cerebral glucose deficiency.
  • the brain for its high level of cellular activity, is a major consumer of energy that is obtained, mainly, from glucose. The arrival of glucose to the brain should therefore be regularly maintained and controlled. This is especially important in the case of children, in which the brain is immature and needs glucose to develop normally.
  • GLUT-1 is the main glucose transporter in the blood-brain barrier. GLUT-1 transporter deficiency occurs due to mutations (mostly de novo dominants) in the SLC2A1 gene encoding this protein.
  • CSF cerebrospinal fluid
  • soluble collagen VI of the invention is the use of soluble collagen VI of the invention, wherein said disease is selected from the group composed by diabetes mellitus, metabolic syndrome, dysfunction of the thyroid gland, dysfunction of the adrenal gland, dysfunction of the pituitary gland, exocrine pancreatic diseases, acute stress, sepsis, infection with hepatitis C. Particularly, said acute stress is stroke or myocardial infarction.
  • soluble collagen VI of the invention is diabetes mellitus type 2.
  • One embodiment is soluble collagen VI for use in the treatment of glucose transport disorders.
  • said glucose transport disorder is caused by a defficiency in the brain of the glucose transporter GLUT 1 .
  • hyperglycemia linked disease is hyperglycemia originated by corticosteroid treatment or anti-HIV treatment with protease inhibitors.
  • Another aspect of the invention is a pharmaceutical composition, herewith pharmaceutical composition of the invention, comprising soluble collagen VI, together with pharmaceutically acceptable excipients.
  • One embodiment is the pharmaceutical composition of the invention, wherein the administration of said composition is selected from the group composed by parenteral, digestive, respiratory and topical administration.
  • Another aspect of the invention is the use of a cell extracellular liquid medium, herewith use of a cell extracellular liquid medium of the invention, comprising soluble collagen VI for increasing glucose uptake in mammalian cells.
  • One embodiment is the use of a cell extracellularlar liquid medium of the invention, wherein said mammalian cells are human cells.
  • One embodiment is the use of a cell extracellular liquid medium of the invention, wherein said human cells are selected from the group composed by skeletal muscle cells, adipose cells and liver cells.
  • One embodiment is the use of a cell extracellular liquid medium of the invention, wherein said collagen VI concentration is in the range of 0.1 to 30 mg/L.
  • One embodiment is the use of a cell extracellular liquid medium of the invention, wherein said concentration is in the range of 0.5 to 10 mg/L.
  • kit of the invention comprising collagen VI and other appropriate reagents.
  • Another aspect of the invention is a method for increasing glucose uptake in mammalian cells, herewith method of the invention, which comprises:
  • step (b) culturing mammalian cells in the cell extracellularlar liquid medium comprising collagen VI obtained from step (a).
  • One embodiment is the method of the invention, characterised in that collagen VI concentration is in the range of 0.1 to 30 mg/L.
  • One embodiment is the method of the invention, wherein said concentration is in the range of 0.5 to 10 mg/L.
  • the therapeutical use of the invention can also be formulated as soluble collagen VI for use in the treatment of hyperglycemia linked diseases.
  • This aspect can also be formulated as a method of treating hyperglycemia linked diseases, herewith method of treatment of the invention, comprising administering a therapeutically effective amount of soluble collagen VI to a human subject
  • the preferred embodiment of the invention is a pharmaceutical composition comprising soluble collagen VI, together with pharmaceutically acceptable excipients.
  • Figure 1 Stimulation of 2-deoxyglucose uptake in LHCN-M2 skeletal muscle cells treated during different times with soluble collagen VI.
  • Value data are mean ⁇ SEM of at least 2 experiments performed in triplicate and are presented as a percentage of the mean value in control cells. The significance of the differences is with respect to control cells # p ⁇ 0.001 .
  • FIG. 1 Stimulation of 2-deoxyglucose uptake in LHCN-M2 skeletal muscle cells treated with increasing concentrations of soluble collagen VI.
  • Value data are mean ⁇ SEM of at least 2 experiments performed in triplicate and are presented as a percentage of the mean value in control cells without insulin.
  • Figures 4a and 4b Effect of soluble collagen I and V on 2-deoxyglucose uptake in LHCN-M2 skeletal muscle cells. Differentiated LHCN-M2 cells, 5 days post- differentiation, were pre-incubated without collagen, control cells (crol), or with the indicated concentrations of collagen I ( Figure 4a) or V ( Figure 4b) for 16 h. Then, cells were further incubated without insulin (white bar) or with 0.1 ⁇ insulin (INS) for 20 min (black bars).
  • Value data are mean ⁇ SEM of 2 experiments performed in quadruplicate and are presented as a percentage of the mean value in control cells without insulin. The significance of the differences are: with respect to control cells -INS * p ⁇ 0.001 and with respect to control cells +INS #p ⁇ 0.001 .
  • FIG. 8 Effect of soluble collagen VI in the phosphorylation of PKB/Akt.
  • the amount of phosphorylated PKB/Akt in each of the conditions was analyzed by immunoblot using monoclonal antibodies that detects the phosphorylated form of PKB/Akt in Ser743.
  • the band intensity was adjusted in relation to the intensity of the correspondent bands of a control protein, which concentration is not altered (alpha-tubulin).
  • the band intensity was measured by densitometry with the software ImageJ and it is expressed as intensity units.
  • Collagen I (ref 354265), Collagen V (ref 354246) and Collagen VI (ref 354261 ).
  • Collagen VI used consists of a chains crt (VI), ⁇ 2 (VI) and ⁇ 3 (VI), encoded by genes COL6A1 , COL6A2 and COL6A3, respectively.
  • Cells (LHCN-M2, C2C12, L6 or 3T3-L1 ) were grown in 24-well tissue culture plates (16 mm each) under the conditions mentioned above.
  • Collagen VI was diluted in 1 M NaCI, 1 .25 mM Tris (pH 8.0) solution and eventually the same volume of this solution was added to control cells.
  • Collagen I and V were diluted in distilled water.
  • Collagens were added to cell culture medium at a dilution ratio 1 :50.
  • Cell monolayers were incubated in PBS, 0.1 mmol/l CaCI(2), and 0.1 % BSA. Insulin was included when stated, and the mixture was incubated for 20 min at 37 °C.
  • 2-Deoxy-d-fH] glucose uptake was then measured by the addition of 0.5 Ci/well and unlabeled 2- deoxyglucose at the concentration of 0.1 mmol/l, followed by three washes in ice-cold PBS after 6 min of exposure. Cells were subsequently lysed with 1 % SDS, and aliquots were measured for radioactivity in 5 ml of the cocktail (Optiphase, LKB).
  • Example 2 Glucose intolerance and insulin resistance in Ullrich Congenital Muscular Dystrophy (UCMD) patients.
  • Soluble collagen VI increases glucose uptake in cultured human skeletal muscle cells.
  • LHCN-M2 myotubes human immortalized skeletal muscle cell line, kind gift of Woodring Wright, UT Southwestern, US
  • soluble collagen VI purified from placenta, BD
  • glucose uptake increased very significantly (p ⁇ 0.001 )
  • Fig. 1 Treating LHCN-M2 myotubes with increasing concentrations of soluble collagen VI (0.5 mg/L, 1 mg/L, 5 mg/L and 10mg/L) for 16 h resulted in a dose dependent increase in glucose uptake by LHCN-M2 cells (Fig. 2) with and without insulin pre- treatment.
  • Example 4 (comparative example). Collagen I and collagen V are not able to stimulate glucose uptake in skeletal muscle cells.
  • Example 6 Collagen VI also induces glucose uptake in murine skeletal muscle cells lines. Similar experiments in C2C12 (mouse skeletal muscle cell line, Fig. 5) and in L6 cells (rat skeletal muscle cell line, Fig. 6) show that human collagen VI does significantly increase glucose transport (with and without insulin pre-treatment) whereas collagen I and V do not (Fig. 6 and 7).
  • Collagen VI can induce glucose uptake in several skeletal muscle cell lines which lends evidence for its role on regulation of glucose utilisation.
  • Example 7 Collagen VI induces glucose uptake in adipocytes
  • Collagen VI does significantly increase glucose uptake in adipocytes.
  • Example 8 The collagen VI treatment reduces the phosphorylation of PKB/Akt molecule in human muscle cells.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne du collagène soluble VI destiné à être utilisé dans le traitement de maladies liées à l'hyperglycémie, ladite maladie étant choisie dans le groupe composé du diabète sucré, du syndrome métabolique, du dysfonctionnement de la glande thyroïde, du dysfonctionnement de la glande surrénale, du dysfonctionnement de la glande pituitaire, des maladies pancréatiques exocrines, du stress aigu, de la septicémie et de l'infection par le virus de l'hépatite C. La présente invention concerne également du collagène soluble VI destiné à être utilisé dans le traitement de troubles de transport du glucose. La présente invention concerne également une composition pharmaceutique comprenant du collagène soluble VI, l'utilisation d'un milieu liquide extracellulaire de cellule comprenant du collagène soluble VI pour accroître l'absorption de glucose dans des cellules de mammifère, ainsi qu'un coffret et un procédé pour accroître l'absorption de glucose dans des cellules de mammifère.
PCT/EP2013/074038 2012-11-19 2013-11-18 Collagène soluble vi destiné à être utilisé dans le traitement de maladies liées à l'hyperglycémie et de troubles de transport du glucose. composition pharmaceutique, procédé et utilisation d'un milieu liquide extracellulaire de cellule pour accroître l'absorption de glucose Ceased WO2014076270A1 (fr)

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Application Number Priority Date Filing Date Title
ES201231787 2012-11-19
ES201231787 2012-11-19

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WO2014076270A1 true WO2014076270A1 (fr) 2014-05-22

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6946440B1 (en) * 1999-09-15 2005-09-20 Dewoolfson Bruce H Composition for stabilizing corneal tissue during or after orthokeratology lens wear
WO2007044668A2 (fr) * 2005-10-08 2007-04-19 Potentia Pharmaceuticals, Inc. Compstatine et analogues de celle-ci pour des troubles de la vue

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6946440B1 (en) * 1999-09-15 2005-09-20 Dewoolfson Bruce H Composition for stabilizing corneal tissue during or after orthokeratology lens wear
WO2007044668A2 (fr) * 2005-10-08 2007-04-19 Potentia Pharmaceuticals, Inc. Compstatine et analogues de celle-ci pour des troubles de la vue

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