WO1993010810A1 - Bone regeneration - Google Patents
Bone regeneration Download PDFInfo
- Publication number
- WO1993010810A1 WO1993010810A1 PCT/US1992/010214 US9210214W WO9310810A1 WO 1993010810 A1 WO1993010810 A1 WO 1993010810A1 US 9210214 W US9210214 W US 9210214W WO 9310810 A1 WO9310810 A1 WO 9310810A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- igf
- bone
- growth factor
- fgf
- acidic
- Prior art date
Links
- 230000010478 bone regeneration Effects 0.000 title description 5
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims abstract description 34
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 19
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 claims abstract description 18
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 claims abstract description 13
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 claims abstract description 5
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 claims abstract description 5
- 102000014429 Insulin-like growth factor Human genes 0.000 claims abstract 5
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 claims description 29
- 102100037852 Insulin-like growth factor I Human genes 0.000 claims description 14
- 230000002378 acidificating effect Effects 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- 239000003102 growth factor Substances 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 5
- 230000001172 regenerating effect Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 1
- 230000008929 regeneration Effects 0.000 abstract description 4
- 238000011069 regeneration method Methods 0.000 abstract description 4
- 230000003239 periodontal effect Effects 0.000 abstract description 3
- 102000018233 Fibroblast Growth Factor Human genes 0.000 abstract 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 abstract 1
- 229940126864 fibroblast growth factor Drugs 0.000 abstract 1
- 230000000638 stimulation Effects 0.000 abstract 1
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 13
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 7
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 7
- 108010081589 Becaplermin Proteins 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 210000002805 bone matrix Anatomy 0.000 description 5
- 230000001605 fetal effect Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 210000000963 osteoblast Anatomy 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 241000288906 Primates Species 0.000 description 3
- 241000244040 Terranova Species 0.000 description 3
- 210000002449 bone cell Anatomy 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 230000011164 ossification Effects 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 208000010392 Bone Fractures Diseases 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 102000048143 Insulin-Like Growth Factor II Human genes 0.000 description 2
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 2
- 241000906034 Orthops Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 102400001320 Transforming growth factor alpha Human genes 0.000 description 2
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000008468 bone growth Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 2
- NMWKYTGJWUAZPZ-WWHBDHEGSA-N (4S)-4-[[(4R,7S,10S,16S,19S,25S,28S,31R)-31-[[(2S)-2-[[(1R,6R,9S,12S,18S,21S,24S,27S,30S,33S,36S,39S,42R,47R,53S,56S,59S,62S,65S,68S,71S,76S,79S,85S)-47-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-4-oxobutanoyl]amino]-3-carboxypropanoyl]amino]-18-(4-aminobutyl)-27,68-bis(3-amino-3-oxopropyl)-36,71,76-tribenzyl-39-(3-carbamimidamidopropyl)-24-(2-carboxyethyl)-21,56-bis(carboxymethyl)-65,85-bis[(1R)-1-hydroxyethyl]-59-(hydroxymethyl)-62,79-bis(1H-imidazol-4-ylmethyl)-9-methyl-33-(2-methylpropyl)-8,11,17,20,23,26,29,32,35,38,41,48,54,57,60,63,66,69,72,74,77,80,83,86-tetracosaoxo-30-propan-2-yl-3,4,44,45-tetrathia-7,10,16,19,22,25,28,31,34,37,40,49,55,58,61,64,67,70,73,75,78,81,84,87-tetracosazatetracyclo[40.31.14.012,16.049,53]heptaoctacontane-6-carbonyl]amino]-3-methylbutanoyl]amino]-7-(3-carbamimidamidopropyl)-25-(hydroxymethyl)-19-[(4-hydroxyphenyl)methyl]-28-(1H-imidazol-4-ylmethyl)-10-methyl-6,9,12,15,18,21,24,27,30-nonaoxo-16-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29-nonazacyclodotriacontane-4-carbonyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid Chemical compound CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CSSC[C@H](NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](Cc4ccccc4)NC3=O)[C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N3CCC[C@H]3C(=O)N[C@@H](C)C(=O)N2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2c[nH]cn2)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)C(C)C)C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1)C(=O)N[C@@H](C)C(O)=O NMWKYTGJWUAZPZ-WWHBDHEGSA-N 0.000 description 1
- 238000010600 3H thymidine incorporation assay Methods 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241001574013 Collogenes Species 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- 102000015731 Peptide Hormones Human genes 0.000 description 1
- 108010038988 Peptide Hormones Proteins 0.000 description 1
- 108010050808 Procollagen Proteins 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 241000219492 Quercus Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 206010072170 Skin wound Diseases 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Natural products O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 101001076308 Xenopus laevis Insulin-like growth factor III Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000003277 amino acid sequence analysis Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 230000007321 biological mechanism Effects 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 230000004097 bone metabolism Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000011382 collagen catabolic process Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 210000004268 dentin Anatomy 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000004821 effect on bone Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000004349 growth plate Anatomy 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 210000004124 hock Anatomy 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 210000003455 parietal bone Anatomy 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 210000002379 periodontal ligament Anatomy 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 208000006860 root resorption Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 210000002303 tibia Anatomy 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
Classifications
-
- 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
- A61K38/22—Hormones
- A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to bone and periodontal regeneration.
- composition which is known for this use is a combination of platelet derived growth factor (PDGF) and insulin-like growth factor I (IGF-l), described in U.S. Patent No. 4,861,757.
- Growth factors are polypeptide hormones which stimulate a defined population of target cells. As multifunctional hormone-like molecules, they may stimulate or inhibit cell proliferation as well as affect cell function, depending on the state of differentiation of the target cell and the combination of other signal peptides present.
- growth factors include PDGF, IGF's, transforming growth factor beta (TGF-/3) , transforming growth factor alpha (TGF- ⁇ ) , epidermal growth factor (EGF) and acidic or basic fibroblast growth factor (aFGF or bFGF) .
- IGF-l alone has also been studied for its effects on bone growth.
- IGF-I somatomedin C
- IGF-I platelet- derived growth factor-BB
- PDGF-BB platelet- derived growth factor-BB
- Hock et al (Endocrinology 1988; 122:254-60) found that IGF-I stimulates primarily pre-osteoblast replication in vitro and that collagen and bone matrix synthesis is stimulated independently of cell replication. Canalis et al (J. Cell. Phvsiol. 1989; 140:530-537) reported that PDGF-BB opposed the stimulatory effect of IGF-I on collagen synthesis, IGF-I prevented the PDGF effect on collagen degradation and that PDGF-BB and IGF-I had additive effects on calvarial DNA synthisis.
- FGF fiberblast growth factor
- bFGF did not significantly alter 3 Hy- thymidine incorporation in bone fracture calluses (Joyce et al 1991) .
- bFGF has been reported to enhance mitogenesis in fetal calvarial bone cultures but did not simulate differentiated function of osteoblasts directly (Canalis et al J. Clin. Invest. 1988; 81:1572).
- aFGF has the same reported biological effects on bone as bFGF but generally requires higher concentrations (Canalis J____ Clin. Invest. 1987; 79:52-58). Both aFGF and bFGF tend to decrease matrix synthesis in the fetal rat calvarial model (Canalis et al 1989) .
- bFGF has also been reported to enhance the capacity of bone marrow cells to form bone-like nodules in vitro (Noff et al F.E.B.S. Letters 1989; 250:619-21). Both aFGF and bFGF increased DNA synthesis in cells cultured from parietal bones while bFGF was a more potent stimulator of alpha 1 Type 1 procollagen mRNA (McCarthy et al Endocrinology 1989; 125:2118-26).
- the present invention provides novel methods for stimulating and enhancing bone and periodontal regeneration.
- the methods of the invention employ IGF's, preferably IGF-I, and acidic or basic (a or b respectively) FGF.
- IGF's preferably IGF-I, and acidic or basic (a or b respectively) FGF.
- the invention aids in regeneration, at least in part, by promoting the growth of bone, cementum, and ligament by stimulating protein and collagen synthesis. Bone regeneration using the invention is more effective than that achieved in the absence of treatment (i.e. without applying exogenous agents) or by treatment with similar levels of purified IGF-I or purified FGF's alone.
- a mammal e.g., a human patient
- a composition that includes purified acidic or basic FGF and purified IGF-I.
- the two factors can be applied sequentially, close enough in time to effect synergistic bone regeneration.
- the composition is prepared by combining, in a pharmaceutically acceptable carrier substance, e.g., commercially available inert gels, polymers or liquids (e.g., saline supplemented with albumin or methyl cellulose) , purified acidic or basic FGF and an IGF, e.g. IGF-I (which are commercially available) .
- a pharmaceutically acceptable carrier substance e.g., commercially available inert gels, polymers or liquids (e.g., saline supplemented with albumin or methyl cellulose)
- purified acidic or basic FGF and purified IGF-I are combined in a weight ratio of between 100:1 and 1:250. More preferably the purified FGF and IGF-I are combined in a weight ratio of between 50:1 and 1:100. Most preferably the FGF and IGF-I are combined in a weight ration of between 10:1 and 1:50.
- FGF or IGF acidic or basic FGF or IGF which, prior to mixing with the other growth factor, is 90% or greater, by weight, FGF or IGF, i.e., is substantially free of other proteins, lipids, and carbohydrates with which it is naturally associated.
- a purified protein preparation will generally yield a single major band on a polyacrylamide gel for each subunit of IGF or acidic or basic FGF.
- the purified a or b FGF or IGF used in the compositions of the invention is pure as judged by amino- ter inal amino acid sequence analysis.
- the purified a or b FGF and IGF may be obtained by purifying them from natural sources e.g. brain or plasma, respectively, by recombinant DNA technology, or by chemical synthesis.
- - ⁇ IGF and FGF we mean naturally derived, recombinant, and synthesized materials of mammalian, preferably primate, origin; most preferably, the primate is a human, but can also be a chimpanzee or other primate.
- a method of making recombinant a and b FGF and analogues thereof is dislcosed in EP 88311099.1.
- IGF's are commercially available from Amgen Corporation' (Thousand Oaks, California) and Kabi (Sweden) .
- a and b FGF are commercially available from R & D Systems (Minneapolis, MN) and AmGen Corporation.
- FGF and IGF include active fragments and analogs thereof which mediate biological activity through their respective receptors. Analogs which are presently unknown may be made and tested for this purpose. Testing of these analogs for efficacy is routine, and may be easily accomplished by conventional methods, e.g. radioreceptor assays. Suitable analogs are disclosed in EP 88311099.1. While IGF-I is preferred, IGF-II or IGF-III may also be used in the invention.
- compositions of the invention are formed by combining an IGF with a or b FGF using known mixing methods or by attaching these proteins to polymers.
- the composition is prepared by combining the two growth factors in a pharmaceutically acceptable carrier substance, e.g., commercially available inert gels, polymers or liquids (e.g., saline polymers supplemented with albumin or methyl cellulose) .
- a pharmaceutically acceptable carrier substance e.g., commercially available inert gels, polymers or liquids (e.g., saline polymers supplemented with albumin or methyl cellulose) .
- the purified growth factors are combined in a weight ratio of between 100:1 and 1:250 more preferably from 50:1 to 1:100, and most preferably from 10:1 to 1:50 aFGF or bFGF to IGF.
- regenerating bone of a mammal is accomplished by administering to the patient, preferably by local administration to the area of injured or depleted bone, an effective amount of a composition of the invention.
- Systemic administration can also be used.
- a preferred dosage of the composition is about 0.1-1000 ⁇ g, more preferably l-100 ⁇ g, of biologically active growth factors/cm 2 of the area of injured or depleted bone.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Molecular Biology (AREA)
- Endocrinology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5510253A JPH07504160A (ja) | 1991-11-27 | 1992-11-24 | 骨の再生 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US799,375 | 1977-05-23 | ||
US79937591A | 1991-11-27 | 1991-11-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993010810A1 true WO1993010810A1 (en) | 1993-06-10 |
Family
ID=25175741
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1992/010214 WO1993010810A1 (en) | 1991-11-27 | 1992-11-24 | Bone regeneration |
Country Status (3)
Country | Link |
---|---|
JP (1) | JPH07504160A (ja) |
CA (1) | CA2123803A1 (ja) |
WO (1) | WO1993010810A1 (ja) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0677294A1 (en) * | 1993-08-25 | 1995-10-18 | Kaken Pharmaceutical Co., Ltd. | Periodontal disease remedy |
WO1998019700A1 (en) * | 1996-11-01 | 1998-05-14 | Genentech, Inc. | Treatment of inner ear hair cells |
US6046164A (en) * | 1993-08-25 | 2000-04-04 | Kaken Pharmaceutical Co., Ltd. | Therapeutic agent for diseases of periodontal tissue |
US6156728A (en) * | 1996-11-01 | 2000-12-05 | Genentech, Inc. | Treatment of inner ear hair cells |
EP1284748A1 (en) * | 2000-05-03 | 2003-02-26 | GroPep Limited | Treatment of damaged connective tissue |
US10071182B2 (en) | 2014-10-14 | 2018-09-11 | Samuel E. Lynch | Methods for treating wounds |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0298723A1 (en) * | 1987-07-07 | 1989-01-11 | California Biotechnology, Inc. | Recombinant fibroblast growth factors |
-
1992
- 1992-11-24 CA CA002123803A patent/CA2123803A1/en not_active Abandoned
- 1992-11-24 JP JP5510253A patent/JPH07504160A/ja not_active Ceased
- 1992-11-24 WO PCT/US1992/010214 patent/WO1993010810A1/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0298723A1 (en) * | 1987-07-07 | 1989-01-11 | California Biotechnology, Inc. | Recombinant fibroblast growth factors |
Non-Patent Citations (2)
Title |
---|
J. CLIN. INVEST., Volume 84, Number 2, issued August 1989, pp. 640-646, LYNCH et al., "Growth Factors in Wound Healing". * |
J. ENDOCRINOL. INVEST., Volume 12, issued 1989, CANALIS et al., "Growth Factors and the Skeletal System", pages 577-584. * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0677294A1 (en) * | 1993-08-25 | 1995-10-18 | Kaken Pharmaceutical Co., Ltd. | Periodontal disease remedy |
EP0677294A4 (en) * | 1993-08-25 | 1998-02-04 | Kaken Pharma Co Ltd | AGAINST PERIODONTAL DISEASES. |
US6046164A (en) * | 1993-08-25 | 2000-04-04 | Kaken Pharmaceutical Co., Ltd. | Therapeutic agent for diseases of periodontal tissue |
WO1998019700A1 (en) * | 1996-11-01 | 1998-05-14 | Genentech, Inc. | Treatment of inner ear hair cells |
US6156728A (en) * | 1996-11-01 | 2000-12-05 | Genentech, Inc. | Treatment of inner ear hair cells |
US6653279B1 (en) | 1996-11-01 | 2003-11-25 | Genentech, Inc. | Treatment of inner ear hair cells |
US6927204B2 (en) | 1996-11-01 | 2005-08-09 | Genentech, Inc. | Treatment of inner ear hair cells |
EP1284748A1 (en) * | 2000-05-03 | 2003-02-26 | GroPep Limited | Treatment of damaged connective tissue |
EP1284748A4 (en) * | 2000-05-03 | 2005-02-16 | Gropep Ltd | TREATMENT OF CONJUNCTIVE TISSUES DAMAGED |
US10071182B2 (en) | 2014-10-14 | 2018-09-11 | Samuel E. Lynch | Methods for treating wounds |
Also Published As
Publication number | Publication date |
---|---|
JPH07504160A (ja) | 1995-05-11 |
CA2123803A1 (en) | 1993-06-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU656372B2 (en) | Composition for promoting tissue repair and regeneration | |
Tozum et al. | Platelet-rich plasma: a promising innovation in dentistry | |
Inui et al. | Local application of basic fibroblast growth factor minipellet induces the healing of segmental bony defects in rabbits | |
US5470829A (en) | Pharmaceutical preparation | |
Steenfos | Growth factors and wound healing | |
Rutherford et al. | Induction of reparative dentine formation in monkeys by recombinant human osteogenic protein-1 | |
US5118667A (en) | Bone growth factors and inhibitors of bone resorption for promoting bone formation | |
Kimoto et al. | Continuous administration of basic fibroblast growth factor (FGF-2) accelerates bone induction on rat calvaria—an application of a new drug delivery system | |
JP2557779B2 (ja) | 2成分型骨粗鬆症用薬剤 | |
EP0289314B1 (en) | Use of IGF-II in the treatment of bone disorders | |
JPH09510209A (ja) | 骨の成長を刺激するための繊維芽細胞成長因子の用途 | |
US6083912A (en) | Method for soft tissue augmentation | |
CA2589930C (en) | Activating extraction of demineralized bone matrix | |
Hedner et al. | Systemically and locally administered growth hormone stimulates bone healing in combination with osteopromotive membranes: an experimental study in rats | |
CA2105997A1 (en) | Method of inhibiting padgem-mediated interactions using an inhibitor comprising a 2,6 sialic acid component | |
Lynch et al. | The combination of platelet‐derived growth factor‐BB and insulin‐like growth factor‐I stimulates bone repair in adult Yucatan miniature pigs | |
SK136693A3 (en) | Therapeutic compositions for osteoinduction | |
WO1993010810A1 (en) | Bone regeneration | |
WO1995028950A1 (en) | Administration of platelet-derived growth factor and bone seeking drugs for osteoporosis and bone regeneration | |
EP0531425B1 (en) | Combination of IGF-I and TGF-beta for bone regeneration | |
Thaller et al. | Effect of insulin-like growth factor type 1 on critical-size defects in diabetic rats | |
JPH06157339A (ja) | 骨形成組成物及びその使用方法 | |
Ren et al. | Effects of rhBMP-2/7 heterodimer and RADA16 hydrogel scaffold on bone formation during rabbit mandibular distraction | |
Schiltz et al. | Growth hormone stimulates cortical bone formation in immature hypophysectomized rats | |
Steinbrech et al. | Gene expression of insulin-like growth factors I and II in rat membranous osteotomy healing |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): CA JP |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2123803 Country of ref document: CA |
|
122 | Ep: pct application non-entry in european phase |