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WO2011073447A9 - Emd c-dépleté - Google Patents

Emd c-dépleté Download PDF

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Publication number
WO2011073447A9
WO2011073447A9 PCT/EP2010/070255 EP2010070255W WO2011073447A9 WO 2011073447 A9 WO2011073447 A9 WO 2011073447A9 EP 2010070255 W EP2010070255 W EP 2010070255W WO 2011073447 A9 WO2011073447 A9 WO 2011073447A9
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WO
WIPO (PCT)
Prior art keywords
proteins
emd
pharmaceutical
tissue
dental
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/EP2010/070255
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English (en)
Other versions
WO2011073447A1 (fr
Inventor
Aaldert Molenberg
Ruzica Ranevski
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Straumann Holding AG
Original Assignee
Straumann Holding AG
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Filing date
Publication date
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Publication of WO2011073447A1 publication Critical patent/WO2011073447A1/fr
Publication of WO2011073447A9 publication Critical patent/WO2011073447A9/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses

Definitions

  • Said improved composition is herein preferably intended to be used for treating and/or preventing periodontitis, promoting and/or inducing regeneration of hard tissue, tissue mineralization, bone growth and/or bone regrowth, regeneration of dentin, cementogenesis, and/or binding between parts of living mineralized tissue, for bonding of a piece of living mineralized tissue to a bonding site on a piece of other living tissue, for endorsing binding between hard tissues, and/or for filling a mineralized wound cavity and/or tissue defect following from a procedure and/or trauma.
  • the present invention in particular relates to the use of said improved pharmaceutical, dental and/or cosmetic composition of purified Enamel Matrix Derivative (EMD) proteins which have a molecular weight as determined by SDS PAGE electrophoresis substantially equal and/or above 6kDa for promoting, and/or inducing mineralized tissue healing and bone differentiation
  • EMD Enamel Matrix Derivative
  • osteogenesis through regulating osteoblast differentiation.
  • Enamel matrix proteins, present in the enamel matrix, are most well-known as precursors to enamel. Prior to cementum formation, enamel matrix proteins are deposited on the root surface at the apical end of the developing tooth-root. There is evidence that the deposited enamel matrix is the initiating factor for the formation of cementum. Again, the formation of cementum in itself is associated with the development of the periodontal ligament and the alveolar bone. Enamel matrix proteins can therefore promote periodontal regeneration through mimicking the natural attachment development in the tooth (Gestrelius S, Lyngstadaas SP, Hammarstrom L. Emdogain - periodontal regeneration based on biomimicry. Clin Oral Invest 4: 120-125 (2000).
  • EMD Enamel Matrix Derivative
  • HPLC High Pressure Liquid Chromatography
  • EMD is composed of a number of proteins, such as amelogenins, enamelin, tuft protein, proteases, and albumin.
  • Amelogenins a major constituent of EMD, are a family of hydrophobic proteins derivable from a single gene by alternative splicing and controlled post secretory processing. They are highly conserved throughout vertebrate evolution and demonstrate a high overall level of sequence homology among all higher vertebrates examined (80%). In fact, the sequences of porcine and human amelogenin gene transcript differ only in 4% of the bases. Thus, enamel matrix proteins, although of porcine origin, are considered "self when encountered in the human body and can promote dental regeneration in humans without triggering allergic responses or other undesirable reactions.
  • enamel contains a complex of amelogenin proteins which includes components ranging in size from 3.5-25 kDa. This is due to the expression and secretion of a family of amelogenins derivable from multiple mRNAs generated by differential splicing from one or two copies of the amelogenin gene, located on the X and Y chromosome. What is more, subsequent to secretion, these proteins appear further to undergo extensive proteolytic processing.
  • LRAP leucine-rich amelogenin polypeptide
  • TRIP tyrosine-rich amelogenin polypeptide
  • TRIPs Two human tyrosine-rich amelogenin polypeptides (TRAPs) of approximately 5 kDa in size have prior been identified (see Fincham et al., 1989). These polypeptides were found to be of 42
  • TRAP-2 and 44 (TRAP-1 ) amino acid residues in length; two forms of TRAP molecules, differing only by cleavage of a carboxy-terminal dipeptide, which were described to be a general feature of human and other mammalian enamel proteins, probably being derived by postsecretory cleavage from the primary extracellular amelogenin.
  • the present invention for the first time presents an improved pharmaceutical, dental and/or cosmetic composition
  • an improved pharmaceutical, dental and/or cosmetic composition comprising purified Enamel Matrix Derivative (EMD) proteins, which is substantially depleted of any Enamel Matrix Derivative (EMD) proteins below 6kDa.
  • EMD Enamel Matrix Derivative
  • DISCLOSURE OF THE INVENTION The porcine Enamel Matrix Derivative (EMD) is used widely in clinical dentistry because of its ability to promote regeneration of soft and hard tissues and to reduce inflammation and infections. Previous studies have used indirect methods to explain its angiogenic and proliferative effect on cells associated with wound healing.
  • Emdogain® a product composed of an alginate carrier (Propylene Glycol Alginate) and porcine Enamel Matrix Derivative (EMD) is widely used in the treatment of periodontal diseases and has been shown to promote hard and soft tissue regeneration and decrease inflammation following periodontal surgery. Not surprisingly, it has been shown to contain a number of low molecular weight proteins (mainly amelogenins) which have been associated with cementogenesis and osteogenesis during tooth development.
  • EMD Enamel Matrix Derivative
  • amelogenin due to alternative splicing of the primary transcript and the following proteolytic processing of the secreted proteins, degrades into smaller pieces (fragments and polypeptide fragments), and these pieces are hypothesized to interact differentially with the surrounding tissue and promote serial steps in the development of the periodontal system.
  • fraction C is the component in EMD that acts on preosteoblasts and which has both osteogenic and cementogenic potential, thus suggesting that it is one of the active components of EMD and amelogenin with respect to bone and cementum regeneration.
  • the inventors have recently found that fraction C were upregulating activity of periodontal cells, and/or upregulating very early osteoblast differentiation and/or proliferation markers, as well as upregulating mesenchymal stem cell proliferation and/or reducing and/or inhibiting differentiation of mesenchymal stem cells.
  • fraction C was more strongly detected as a strong inducer or facilitator of proliferation of osteoblast or mesenchymal cells, whereas the effect on early differentiation, measured by the expression of marker genes in these cells, was rather negative.
  • Fraction C is thus found to be the earliest active fraction of EMD, comprising an assertion of components of EMD that will induce instant proliferating stimuli into the surrounding tissue, at an early stage prioritising the amassment of undifferentiated cells over the specification of them.
  • Fraction C clearly demonstrated a strong biological effect on the induction of proliferation in osteoblast like precursor cells as well as in PDL cells, and could even be shown to reduce the level of later differentiation markers.
  • the present invention for the first time presents an improved pharmaceutical, dental and/or cosmetic composition
  • an improved pharmaceutical, dental and/or cosmetic composition comprising purified Enamel Matrix Derivative (EMD) proteins, which is substantially substantially depleted of any Enamel Matrix Derivative (EMD) proteins below 6kDa.
  • EMD Enamel Matrix Derivative
  • fraction A typically has a molecular weight of approximately 20kDa, as determined by SDS PAGE electrophoresis
  • fraction B typically has a molecular weight of between approximately 6kDa and 15kDa, such as approximately 15kDa, 12kDa, 10kDa and 6kDa, as determined by SDS PAGE electrophoresis.
  • the present invention relates to a pharmaceutical, dental and/or cosmetic composition
  • a pharmaceutical, dental and/or cosmetic composition comprising purified Enamel Matrix Derivative (EMD) proteins, wherein the weight ratio of the main protein peaks at 20/14/5 kDa of the enamel matrix proteins as determined by SDS PAGE electrophoresis is about x/y/z and wherein:
  • EMD Enamel Matrix Derivative
  • Another, equally preferred aspect relates to a pharmaceutical, dental and/or cosmetic composition consisting of a suitable pharmaceutical carrier and purified Enamel Matrix Derivative (EMD) proteins, wherein the weight ratio of the main protein peaks at 20/14/5 kDa of the enamel matrix proteins as determined by SDS PAGE electrophoresis is about x/y/z and wherein:
  • EMD Enamel Matrix Derivative
  • a pharmaceutical, dental and/or cosmetic composition according to the present invention is typically purified from porcine, rat, human, or mouse Enamel Matrix Derivative (EMD) proteins.
  • a pharmaceutical composition according to the present invention is envisioned to be usable as a medicament.
  • a pharmaceutical, dental and/or cosmetic composition according to the present invention provides an improved formulation for treating and/or preventing periodontitis, for promoting mineralized tissue healing and osteogenesis and/or for regulating osteoblast differentiation.
  • a pharmaceutical, dental and/or cosmetic composition provides an improved formulation for promoting and/or inducing regeneration of hard tissue, tissue mineralization, bone growth and/or bone regrowth, regeneration of dentin, cementogenesis, and/or binding between parts of living mineralized tissue, for bonding of a piece of living mineralized tissue to a bonding site on a piece of other living tissue, for endorsing binding between hard tissues, and/or for filling a mineralized wound cavity and/or tissue defect following from a procedure and/or trauma.
  • the present invention in one aspect also relates to the use of purified Enamel Matrix Derivative (EMD) proteins which have a molecular weight as determined by SDS PAGE electrophoresis substantially substantially equal and/or above 6kDa for the manufacture of a pharmaceutical, dental and/or cosmetic composition, for treating and/or preventing periodontitis, for promoting regeneration of hard tissues, for promoting and/or inducing regeneration of hard tissue, tissue mineralization, bone growth and/or bone regrowth, regeneration of dentin, cementogenesis, and/or binding between parts of living mineralized tissue, for bonding of a piece of living mineralized tissue to a bonding site on a piece of other living tissue, for endorsing binding between hard tissues, and/or for filling a mineralized wound cavity and/or tissue defect following from a procedure and/or trauma.
  • EMD Enamel Matrix Derivative
  • the invention in another aspect, relates to a method of promoting the formation and/or regeneration of dentin following dental procedures involving exposure of vital dental pulp tissue, the method comprising applying an effective amount of a pharmaceutical, dental and/or cosmetic composition according to the present invention.
  • a pharmaceutical, dental and/or cosmetic composition comprising purified Enamel Matrix Derivative (EMD) proteins, being consequently depleted of fraction C.
  • EMD Enamel Matrix Derivative
  • the implant or device may be used for fixation of complicated fractures, e.g. of the neck, legs or arms, or skull fractures, thus the implant or device may be a pin or screw conventionally used to immobilize (fix) fragments of fractured bone.
  • Such pins or screws typically comprise a portion that penetrates the skin of the patient at or near the site of the fracture.
  • Pins and screws for this purpose may conventionally be prepared from a metal such as titanium or steel, and may optionally be coated with a polymeric material which may typically be biodegradable or stabilized to facilitate soft tissue closure and sealing.
  • an implant may be an electrical conductor such as one used in, e.g., pacemakers, brain implants or biosensors.
  • the implant may also be an artificial tooth or a dental prosthesis, such as a screw and/or an abutment.
  • Whether a pharmaceutically acceptable excipient is suitable for use in a pharmaceutical composition is generally dependent on which kind of dosage form is chosen for use for a particular kind of wound, and/or any other type of disorder and/or damage to a body.
  • humectants examples include glycerin, propylene glycol, sorbitol, lactic acid, urea, and mixtures thereof.
  • hydroxypropylmethylcellulose hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, pectin, xanthan gum, locust bean gum, acacia gum, gelatin, carbomer, emulsifiers like vitamin E, glyceryl stearate, cetanyl glycoside, collagen, carrageenan, hyaluronates and alginates and chitosan.
  • Defect areas in dental pulp in humans typically have a size of about 5-10 x 2-4 x 5-10 mm corresponding to about 200 pi and normally at the most about 0.5-1 ml such as about 0.2-0.3 ml per tooth is applied of a composition having a concentration of about 1 -40 mg total protein/ml such as, e.g., 5-30 mg/ml is applied.
  • 0.2-0.3 mg/ml corresponds to about 6 mg protein per 25-100 mm 2 or about 0.1 mg/mm 2 if calculated only on root surface. Normally an excessive volume is applied to cover the affected surfaces adequately. Even a multilayer would only require a small fraction of the above-mentioned amounts.
  • FIG. 1 Size exclusion (SEC) method description.
  • Schema 1 Fraction C, size exclusion chromatography (SEC), TOSOH 3000SW column.
  • the last step was intended to remove ACN from the samples by using a Hl-Trap desalting column (HR 16/20). To determine concentrations of the fractions, a size exclusion HPLC column was utilized (same as in step 1 )) with PBS).
  • Affymetrix gene array Primary osteoblasts were cultured in T75 culture flasks and cultured after treatment for 24h, 72h or 7d respectively and lysed in 7ml Trizol solution (Gibco, USA). Trizol lysates were kept at -70°C until RNA isolation according to the manufacturer's protocols and further processing (Dep. of Medical Biochemistry, Oslo University, Norway). Double stranded cDNA and biotin labeled cRNA probes were made from 5ug total RNA using the Superscript Choice system (Invitrogen) and the Enzo Bioarray respectively. Procedures were according to recommendations from Affymetrix.
  • This cRNA was hybridized to Hu-133A chips (Affymetrix) containing cDNA oligonucleotides representing more than 22 ⁇ 00 transcripts followed by washing and staining on the Gene Chips Fluidics Station 450 (Affymetrix) according to manufacturer's instructions. The chips were scanned on the Affymetrix Gene Array® 2500 scanner. The quality of the RNA and probe was controlled by an Affymetrix based test measuring the ratio between 5' and 3' mRNAs for n-actin and GAPDH and found to be highly satisfactory. The datasets were processed by the Affymetrix Mas5.0 software, and signal values representing the expression level of each transcript were generated. Each procedure has been done in twice in parallel and the resulting values indicate the mean of at least two donor's cells in duplicate experiments.
  • Cells were seeded in 48 wells plates at a density of 5000 cells / well/ ml medium.
  • n 3.
  • As controls served medium cells with medium and peptides in medium without cells (in case of background values).
  • the peptides were added immediately after cell seeding at a final concentration of 10pg/ml medium.
  • the medium from each well was transferred to Eppendorf tubes, centrifuged at 1 ⁇ 00 rpm for 5 min. Supernatants were kept at -20C until the assays were performed.
  • Cell layers were washed with 2 x 1 ml PBS. After addition of 0.5 ml of milliQwater to the different cell layers bended pipette tips were used to scrape of the cells.
  • Cell suspensions were transferred to Eppendorf tubes and lysed by the use of an ultrasonic water bath for 10 min and centrifuged at 1000 rpm for 5 min. The cell lysates were kept at -20C until the assays were performed. Changes of medium (with peptides included as for the initial seeding of cells) were made after 3 days.
  • FIG. 1 RT-PCR of cultured osteoblasts (one donor, NHO-3). A1 stimulates expression of the following gene products to a greater extend than A2, most prominently after 7 days: osteocalcin and leptin. Values represent the relative concentrations of each protein relative to tubulin and are shown as the means of the single results from duplicate experiments.
  • A1 and A2 have different effects on cultured osteosarcoma cells
  • A1 stimulates bone formation by up-regulation of ALP and osteocalcin
  • A2 reduced the expression of CD44, an osteocyte marker Protein analysis by ELISA
  • TOSOH 300 SW length: 25 cm, diameter: 1 cm.
  • SEC size exclusion column
  • GPC gel-filtration or gel-permeation chromatography
  • the SEC gel has to be swollen over night with the degassed. After 12 h it has to be degassed again and cast in the air lever straighten XK column. If the gel is dropped the column bed will be perched with eluent for around 30 mL (2 CV).
  • the liquid sample is separated and monitored. Monitoring is taken place with the JASCO HPLC and a TOSOH column.
  • EMD-C has retention time between 3.6 to 6 min. The characterization was done with ESI MS and sequencing procedures.
  • Spectrophotometer Spectra Max plus
  • EMD 31 13 (7x 30mg) and 31 15 (1 g) total: 1 ,2g, non-heat treated.
  • HPLC High performance liquid chromatography
  • JASCO HPLC 2 pumps (PU 1580), one detector (UV 1575) and one column oven (CO-2065Puls)).
  • SEC gel-filtration or gel-permeation chromatography
  • GPC gel-permeation chromatography
  • the SEC gel has to be swollen over night with the degassed. After 12 h it has to be degassed again and cast in the air lever straighten XK column. If the gel is dropped the column bed will be perched with eluent for around 2 CV.
  • the lyophilized EMD was redissolve in 3 mL 0.05 M formic acid.
  • the dissolved EMD was collected in a 50ml tube, the vials rinsed with some more formic acid.
  • the liquid sample was separated (flow rate: 60 mL/h, fraction size: 10 mL (10 Min) and monitored. Monitoring is taken place with the JASCO HPLC and a TOSOH column.
  • Frac A has retention time between 5 to 6 min. The characterization was done with 1 D-SDS page 10-20%.

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Abstract

La présente invention concerne une composition pharmaceutique, dentaire et/ou cosmétique comprenant des protéines dérivées de matrice d'émail (EMD) purifiées, qui sont sensiblement séparées de protéines dérivées de matrice d'émail (EMD) au-dessous de 6 kDa. Dans un mode de réalisation, l'invention concerne une composition pharmaceutique, dentaire et/ou cosmétique constituée de protéines dérivées de matrice d'émail (EMD) purifiées qui ont un poids moléculaire tel que déterminé par électrophorèse sur SDS PAGE sensiblement égal et/ou supérieur à 6 kDa, formulée dans un véhicule pharmaceutique adapté. Ladite composition améliorée est présentement de préférence destinée à être utilisée pour traiter et/ou prévenir la parodontite, stimuler et/ou induire la régénération de tissu dur, la minéralisation tissulaire, la croissance osseuse et/ou la recroissance osseuse, la régénération de dentine, la cémentogénèse, et/ou fixation entre des parties de tissu minéralisé vivant, pour fixer une pièce de tissu minéralisé vivant à un site de fixation sur une pièce d'autre tissu vivant, pour favoriser la fixation entre des tissus durs, et/ou pour remplir une cavité de plaie minéralisée et/ou un défaut tissulaire consécutif à une procédure et/ou un traumatisme.
PCT/EP2010/070255 2009-12-18 2010-12-20 Emd c-dépleté Ceased WO2011073447A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0950992-8 2009-12-18
SE0950992 2009-12-18

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Publication Number Publication Date
WO2011073447A1 WO2011073447A1 (fr) 2011-06-23
WO2011073447A9 true WO2011073447A9 (fr) 2012-03-29

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012166626A1 (fr) * 2011-05-27 2012-12-06 University Of Washington Through Its Center For Commercialization Réactifs et procédés pour traiter une maladie dentaire
US10730918B2 (en) 2013-04-30 2020-08-04 Straumann Holding Ag Trap 63

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2496273B1 (fr) 2009-11-02 2016-11-30 Straumann Holding AG Composition de protéine emd purifiée
GB0922438D0 (en) * 2009-12-22 2010-02-03 Ucl Business Plc Agents having tissue generative activity
CN115074358A (zh) * 2021-02-24 2022-09-20 中国人民解放军军事科学院军事医学研究院 一种检测il-6的实时荧光定量pcr检测方法

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012166626A1 (fr) * 2011-05-27 2012-12-06 University Of Washington Through Its Center For Commercialization Réactifs et procédés pour traiter une maladie dentaire
US9809633B2 (en) 2011-05-27 2017-11-07 University Of Washington Through Its Center For Commercialization Reagents and methods for treating dental disease
US10730918B2 (en) 2013-04-30 2020-08-04 Straumann Holding Ag Trap 63

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