CA2255477A1 - Human vitreous and pharmaceutical compositions - Google Patents
Human vitreous and pharmaceutical compositions Download PDFInfo
- Publication number
- CA2255477A1 CA2255477A1 CA 2255477 CA2255477A CA2255477A1 CA 2255477 A1 CA2255477 A1 CA 2255477A1 CA 2255477 CA2255477 CA 2255477 CA 2255477 A CA2255477 A CA 2255477A CA 2255477 A1 CA2255477 A1 CA 2255477A1
- Authority
- CA
- Canada
- Prior art keywords
- val
- ser
- ala
- thr
- gly
- 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.)
- Abandoned
Links
- 239000008194 pharmaceutical composition Substances 0.000 title description 2
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 27
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 27
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 18
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 16
- 229920001184 polypeptide Polymers 0.000 claims description 12
- 210000002966 serum Anatomy 0.000 claims description 6
- 108010047303 von Willebrand Factor Proteins 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims 1
- 210000002808 connective tissue Anatomy 0.000 abstract description 9
- 230000035876 healing Effects 0.000 abstract description 4
- 230000006641 stabilisation Effects 0.000 abstract description 2
- 238000011105 stabilization Methods 0.000 abstract description 2
- 101710118873 Vitrin Proteins 0.000 description 27
- 102100035053 Vitrin Human genes 0.000 description 27
- 108010035532 Collagen Proteins 0.000 description 24
- 102000008186 Collagen Human genes 0.000 description 24
- 229960005188 collagen Drugs 0.000 description 24
- 235000018102 proteins Nutrition 0.000 description 24
- 229920001436 collagen Polymers 0.000 description 23
- 150000001413 amino acids Chemical class 0.000 description 12
- 210000001519 tissue Anatomy 0.000 description 10
- 235000001014 amino acid Nutrition 0.000 description 9
- 239000002299 complementary DNA Substances 0.000 description 9
- 101000803362 Homo sapiens Vitrin Proteins 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 102000055008 Matrilin Proteins Human genes 0.000 description 6
- 108010072582 Matrilin Proteins Proteins 0.000 description 6
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
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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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
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Abstract
This invention relates to a protein found in the ocular vitreous for use in facilitating the stabilization and healing of connective tissue matrices.
Description
HUMAN VITREOUS AND PHARMACEUTICAL COMPPOSITIONS
Field of the Invention:
This invention relates to a protein found in the ocular vitreous for use in facilitating the stabilization and healing of connective tissue matrices.
Background of the Invention:
Connective tissue proteins have been known. One such protein known as cartilage matrix protein (CMP) is a noncol-lagenous protein of the extracellular matrix of cartilage. It is a homotrimer of disulfide bonded subunits. A subunit or analog of cartilage matrix protein which is capable of binding collagen is disclosed and claimed in U.S. Patent 5,686,059.
Repeats of CMP (called CMP-1 and CMP-2) are homologous to regions within the von Willebrand factor A domain.
The vitreous chamber is the cavity inside the eyeball behind the lens. The vitreous humor or gel is the jelly-like substance contained in the chamber. Vitreous consists of two separate but interactive networks of collagen fibrils and hyaluronan molecules. Complete removal of the hyaluronan network with hyaluronidase or chondroitinase ABC results in the eventual collapse of the gel to form an insoluble aggre-gate of collagen fibrils. During aging or as a result of trauma or genetically inherited disease, changes occur due to the collapse of the collagen fibrillar network. As the vitre-ous gel becomes denser, it may contract from the surface of the retina. A similar protein identified as COCH is found in cochlea of ear. Mutations of the latter protein give rise to a form of deafness known as DNFA9.
Summary of the Invention:
Disclosed herein is the nucleotide and amino acid se-quence of human ocular vitreous protein, which has been se-quenced and to which polyclonal antibodies have been raised.
The vitreous protein, herein referred to as "vitrin", differs from many other connective tissue proteins in having two von Willebrand A domains. The vitrin has use as an agent to stabilize and facilitate repair of collagen tissues. It also has use as an additive to commercial preparations of hyaluron-an which are used for replacling the environment of the vitre-ous in patients during surgical procedures.
Brief Description of the Figures:
Fig. 1 is the cDNA sequence of human vitrin (SEQ ID
NOs:l-2).
Fig. 2 is a model of the vitrin molecule alone (1) show-ing the localization of the molecule on the collagen fibrils (2) and in addition interacting with the hyaluronan (3) net-work.
Fig. 3 compares the domains of vitrin with the domain structure of COCH.
Fig. 4 shows each domain of vitrin for which expression was achieved (SEQ ID NOs:3-8).
Fig. 5 is a photograph of gels showing the domains ex-pressed in bacteria.
Detailed Description of the Invention:
In the vitreous, collagen fibrils and hyaluronan mole-cules form independent networks that interact to maintain the transparency of the vitreous gel. A number of non-collagenous proteins and glycoproteins may contribute to this molecular organization. The new protein of about 70 - 72 kD was first identified on the surface of collagen fibrils of bovine vitre-ous. It is soluble in salt solutions, particularly NaCl solutions.
The discovery of the full length cDNA sequence of human vitrin makes it possible to produce the protein and its sepa-rate domains by known biotechnological means. This discovery also makes it possible to study the mechanism of collapse of the vitreous gel, which can cause retinal detachment. The instant invention has also made it possible to study the nature of the tractional forces between collapsed collagen fibrils.
It was found that vitrin is released from the collagen fibrils at high salt concentrations. The unique band recog-nized on SDS-PAGE was subjected to amino acid sequencing of tryptic peptides. All sequences were unique. Cloning of both human and bovine vitrin was achieved using these sequences.
Northern blot analysis of vitrin showed that transcripts are present in the extracellular matrix of cardiac muscle, skele-tal muscle, kidney, lung and several other tissues. Northern analysis also showed that the transcript for vitrin is about 3.0 kb in size. An in vitro binding assay demonstrated that vitrin is able to bind to collagen fibrils. Hence, it is believed vitrin plays a role in regulating interactions be-tween collagen fibrils and other extra cellular matrix (ECM) components to maintain vitreous integrity. Vitrin also ap-pears to prevent collagen fibrils from aggregating, a process that leads to vitreous gel collapse and posterior vitreous detachment (PVD) with the potential for retinal detachment.
Analysis of the amino acid sequence of vitrin showed the presence of at least four recognizable domains (called DOM-1, vWAl, DOM-3 and vWA2), all of which share the location of cysteine residues with a protein of the cochlea of the ear called COCH (Fig. 3). Recently, the importance of the latter protein was clearly demonstrated by the identification of three mutations in the DOM-1 domain of LOCH that give rise to a nonsyndromic form of deafness called DNFA9. For expression of each domain of vitrin, a series of primers were prepared whose location is shown on Fig. 4, resulting in specific amplification by PCR of DOM-1, vWAl and vWA2. Each PCR prod-uct was ligated into PQE30 (Qiagen, Santa Clarita, CA) for bacterial expression. (See Fig. 5., which compares the molec-ular weights of the three domains expressed by bacteria on SDS-PAGE.) Purification of each his-tagged protein was achieved using the protocol provided by the manufacturer (Qiagen). The simplicity of the his-tag purification proce-dure is preferred, although expression of each domain can also be achieved with a variety of other commercial procedures (PGEX-SX, Pharmacia, Piscataway, New Jersey, pMAL-C2, New England Biolabs, Beverly, Maine).
The correct folding of the von Willebrand domains can be achieved by bacterial expression systems as is clearly shown by the X-ray crystallographic structure of four von Willebrand A-containing domains, including the I domains of integrins a,M, a2, and ~cl, plus the A3 domain of von Willebrand factor it self. For the latter domain, a his-tag expression system was utilized by both groups demonstrating that this short basic sequence will not interfere with crystallization. Other groups have also achieved expression of I-domains and demon-strated binding to collagen.
Expression of the full-length sequence of vitrin can also be successfully achieved using a baculovirus expression sys-tem, as has been successfully achieved for expression of laminin a, i3 and i-chains or type III and type I collagen. In addition, successful expression of type III collagen in the yeast Pichia pastoris has been reported. (See U.S. Patent 5,593,859, which is incorporated herein by reference in its entirety.) Several mammalian expression systems have also been utilized to successfully express connective tissue pro-teins, including type I and II collagen in HT1080 cells, type X procollagen in HEK293 cells, type VI collagen in NIH3T3 cells and type IV collagen in CHO cells. Expression of carti-lage matrix protein (CMP) has also been successfully achieved in COS-7 cells and binding of recombinant fragments to colla-gen shown.
Vitrin was found to consist partly of two von Willebrand A domains which may independently bind to collagen fibrils.
The invention makes it possible to study the relationship of vitrin to collagen fibrils and examine vitrin concentration at sites of vitreous collapse.
The cDNA was shown to have the following sequence:
TAGAATAATTTGGATGGGATTTGTGATGCAGGAAAGCCTAAGGGAAAA.AGAATATTCATTCT
GTGTGGTGAAAATTTTTTGAA.A.A.A.AAAATTGCCTTCTTCAAACAAGGGTGTCATTCTGATAT
TTATGAGGACTGTTGTTCTCACTATGAAGGCATCTGTTATTGAAATGTTCCTTGTTTTGCTG
GTGACTGGAGTACATTCAAACAAAGAAACGGCAAAGAAGATTAAAAGGCCCAAGTTCACTGT
GCCTCAGATCAACTGCGATGTCAAAGCCGGAAAGATCATCGATCCTGAGTTCATTGTGAAAT
GTCCAGCAGGATGCCAAGACCCCAAATACCATGTTTATGGCACTGACGTGTATACATCCTAC
TCCAGTGTGTGTGGCGCTGCCGTACACAGTAGTGTGCTTGATGATTCAGGAGGGAAAATACT
TGTTCGGAAGGTTGCTGGACAGTCTGGTTACAAAGGGAGTTATTCCAACGGTGTCCAATCGT
TATCCCTACCACGATGGAGAGAATCCTTTATCGTCTTAGAAAGTAAACCCAAA.A.AGGGTGTA
ACCTACCCATCAGCTCTTACATACTCATCATCGAAAAGTCCAGCTGCCCAAGCAGGTGAGAC
CACAAAAGCCTATCAGAGGCCACCTATTCCAGGGACAACTGCACAGCCGGTCACTCTGATGC
AGCTTCTGGCTGTCACTGTAGCTGTGGCCACCCCCACCACCTTGCCAAGGCCATCCCCTTCT
GCTGCTTCTACCACCAGCATCCCCAGACCACAATCAGTGGGCCACAGGAGCCAGGAGATGGA
TCTCTGGTCCACTGCCACCTACACAAGCAGCCAA.AACAGGCCCAGAGCTGATCCAGGACTTG
TTCCAAAAGAAGAATTGAGCACACAGTCTTTGGAGCCAGTATCCCTGGGAGATCCAAACTGC
AAA.ATTGACTTGTCGTTTTTAATTGATGGGAGCACCAGCATTGGCAAACGGCGATTCCGAAT
CCAGAAGCAGCTCCTGGCTGATGTTGCCCAAGCTCTTGACATTGGCCCTGCCGGTCCACTGA
TGGGTGTTGTCCAGTATGGAGACAACCCTGCTACTCACTTTAACCTCAAGACACACACGAAT
TCTCGAGATCTGAAGACAGCCATAGAGAAAATTACTCAGAGAGGAGGACTTTCTAATGTAGG
TCGGACCATCTCCTTTGTGACCAAGAACTTCTTTTCCAAAGCCAATGGAAACAGAAGCGGGG
CTCCCAATGTGGTGGTGGTGATGGTGGATGGCTGGCCCACGGACAAAGTGGAGGAGGCTTCA
AGACTTGCGAGAGTGTCAGGAATCAACATTTTCTTCATCACCATTGAAGGTGCTGCTGAAAA
TGAGAAGCAGTATGTGGTGGAGCCCAACTTTGCAAACAAGGCCGTGTGCAGAACAAACGGCT
TCTACTCGCTCCACGTGCAGAGCTGGTTTGGCCTCCACAAGACCCTGCAGCCTCTGGTGAAG
CGGGTCTGCGACACTGACCGCCTGGCCTGCAGCAAGACCTGCTTGAACTCGGCTGACATTGG
CTTCGTCATCGACGGCTCCAGCAGTGTGGGGACGGGCAACTTCCGCACCGTCCTCCAGTTTG
TGACCAACCTCACCAAAGAGTTTGAGATTTCCGACACGGACACGCGCATCGGGGCCGTGCAG
TACACCTACGAACAGCGGCTGGAGTTTGGGTTCGACAAGTACAGCAGCAAGCCTGACATCCT
CAACGCCATCAAGAGGGTGGGCTACTGGAGTGGTGGCACCAGCACGGGGGCTGCCATCAACT
TCGCCCTGGAGCAGCTCTTCAAGAAGTCCAAGCCCAACAAGAGGAAGTTAATGATCCTCATC
ACCGACGGGAGGTCCTACGACGACGTCCGGATCCCAGCCATGGCTGCCCATCTGAAGGGAGT
GATCACCTATGCGATAGGCGTTGCCTGGGCTGCCCAAGAGGAGCTAGAAGTCATTGCCACTC
ACCCCGCCAGAGACCACTCCTTCTTTGTGGACGAGTTTGACAACCTCCATCAGTATGTCCCC
AGGATCATCCAGAACATTTGTACAGAGTTCAACTCACAGCCTCGGAACTGAATTCAGAGCAG
GCAGAGCACCAGCAAGTGCTGCTTTACTAACTGACGTGTTGGACCACCCCACCGCTTAATGG
GGCACGCACGGTGCATCAAGTCTTGGGCAGGGCATGGAGAAACAAATGTCTTGTTATTATTC
TTTGCCATCATGCTTTTTCATATTCCAAAACTTGGAGTTACAAAGATGATCACAAACGTATA
GAATGAGCCAAAAGGCTACATCATGTTGAGGGTGCTGGAGATTTTACATTTTGACAATTGTT
TTCAAAATAAATGTTCGGAATACAGTGCAGCCCTTACGACAGGCTTACGTAGAGCTTTTGTG
AGATTTTTAAGTTGTTATTTCTGATTAGAACTCTGTAACCCTCAGCAAGTTTCATTTTTGTC
ATGACAATGTAGGAATTGCTGAATTAAATGTTTAGAAGGATGAC
(SEQ ID NO:1) The amino acid sequence of the human vitrin was shown to be:
M R T V V L T M K A S V I E M F L V L L V
T G V H S N K E T A K K I K R P K F T V P
Q I N C D V K A G K I I D P E F I V K C P
A G C Q D P K Y H V Y G T D V Y T S Y S S
V C G A A V H S S V L D D S G G K I L V R
-K V A G Q S G Y K G S Y S N G V Q S L S L
S A L T Y S S S K S P A A Q A G E T T K A
Y Q R P P I P G T T A Q P V T L M Q L L A
V T V A V A T P T T L P R P S P S A A S T
T S I P R P Q S V G H R S Q E M D L W S T
L S T Q S L E P V S L G D P N C A I D L S
K
F L I D G S T S I G K R R F R I Q K Q L L
A D V A Q A L D I G P A G P L M G V V Q Y
G D N P A T H F N L K T H T N S R D L K T
T K N F F S K A N G N R S G A P N V V V V
M V D G W P T D K V E E A S R L A R V S G
I N I F F I T I E G A A E N E K Q Y V V E
P N F A N K A V TC R T N G F Y S L H V Q S
A C S K T C A N S A D I G F V I D G S S S
L
V G T G N F R T V L Q F V T N L T K E F E
I S D T D T R I G A V Q Y T Y E Q R L E F
G F D K Y S S K P D I L N A I K R V G Y W
K P N K R K L M I L I T D G R S Y D D V R
I P A M A A H L K G V I T Y A I G V A W A
A Q E E L E V I A T H P A R D H S F F V D
E F D N L H Q Y V P R I I Q N I TC T E F N
(SEQ ID N0:2) In the sequence listing above, A designates the start of the von Willebrand domains and T designates the end of the do-mains.
Referring to Fig. 1, the cDNA sequence of human vitrin, T
identifies signal peptide cleavage sites. (Hence, T has different meanings in Fig. 1 and in the listing above.) The shaded peptides show the peptides for which amino acid se-quence is available.
The ability to raise antibodies to peptide sequences of human vitrin makes it possible to evaluate changes in amount of vitrin in the adult versus the amount in children, to study effects of such changes in disease conditions such as diabetic retinopathy, and to evaluate the amount of vitrin in any given patient tissue. As discussed below, vitrin may also be admin-istered for therapeutic purposes.
Vitrin differs from most other connective tissue proteins in having two von Willebrand A domains which appear to func-tion to crosslink collagen fibrils. The invention, therefore, includes the protein and polypeptides of the protein which are capable of binding collagen. Each von Willebrand domain appears to be primarily involved in the binding of the protein to collagen.
The protein and expressed domains of the invention may be used to facilitate healing of weakened or injured connective tissue. The collagen-binding polypeptides and proteins may be administered to the appropriate sites in need of healing in several ways. It may be applied to the tissue in or on sup-ports such as absorbable supports, including sutures. When the damaged tissue is exposed as, for example, during surgery, the vitrin protein or polypeptides may be applied topically to the tis-sue. Compositions containing vitrin or collagen-binding polypeptide sequences of human vitrin may be used in high salt solutions. Supports having the inventive proteins or peptides may be placed in the operative area.
Field of the Invention:
This invention relates to a protein found in the ocular vitreous for use in facilitating the stabilization and healing of connective tissue matrices.
Background of the Invention:
Connective tissue proteins have been known. One such protein known as cartilage matrix protein (CMP) is a noncol-lagenous protein of the extracellular matrix of cartilage. It is a homotrimer of disulfide bonded subunits. A subunit or analog of cartilage matrix protein which is capable of binding collagen is disclosed and claimed in U.S. Patent 5,686,059.
Repeats of CMP (called CMP-1 and CMP-2) are homologous to regions within the von Willebrand factor A domain.
The vitreous chamber is the cavity inside the eyeball behind the lens. The vitreous humor or gel is the jelly-like substance contained in the chamber. Vitreous consists of two separate but interactive networks of collagen fibrils and hyaluronan molecules. Complete removal of the hyaluronan network with hyaluronidase or chondroitinase ABC results in the eventual collapse of the gel to form an insoluble aggre-gate of collagen fibrils. During aging or as a result of trauma or genetically inherited disease, changes occur due to the collapse of the collagen fibrillar network. As the vitre-ous gel becomes denser, it may contract from the surface of the retina. A similar protein identified as COCH is found in cochlea of ear. Mutations of the latter protein give rise to a form of deafness known as DNFA9.
Summary of the Invention:
Disclosed herein is the nucleotide and amino acid se-quence of human ocular vitreous protein, which has been se-quenced and to which polyclonal antibodies have been raised.
The vitreous protein, herein referred to as "vitrin", differs from many other connective tissue proteins in having two von Willebrand A domains. The vitrin has use as an agent to stabilize and facilitate repair of collagen tissues. It also has use as an additive to commercial preparations of hyaluron-an which are used for replacling the environment of the vitre-ous in patients during surgical procedures.
Brief Description of the Figures:
Fig. 1 is the cDNA sequence of human vitrin (SEQ ID
NOs:l-2).
Fig. 2 is a model of the vitrin molecule alone (1) show-ing the localization of the molecule on the collagen fibrils (2) and in addition interacting with the hyaluronan (3) net-work.
Fig. 3 compares the domains of vitrin with the domain structure of COCH.
Fig. 4 shows each domain of vitrin for which expression was achieved (SEQ ID NOs:3-8).
Fig. 5 is a photograph of gels showing the domains ex-pressed in bacteria.
Detailed Description of the Invention:
In the vitreous, collagen fibrils and hyaluronan mole-cules form independent networks that interact to maintain the transparency of the vitreous gel. A number of non-collagenous proteins and glycoproteins may contribute to this molecular organization. The new protein of about 70 - 72 kD was first identified on the surface of collagen fibrils of bovine vitre-ous. It is soluble in salt solutions, particularly NaCl solutions.
The discovery of the full length cDNA sequence of human vitrin makes it possible to produce the protein and its sepa-rate domains by known biotechnological means. This discovery also makes it possible to study the mechanism of collapse of the vitreous gel, which can cause retinal detachment. The instant invention has also made it possible to study the nature of the tractional forces between collapsed collagen fibrils.
It was found that vitrin is released from the collagen fibrils at high salt concentrations. The unique band recog-nized on SDS-PAGE was subjected to amino acid sequencing of tryptic peptides. All sequences were unique. Cloning of both human and bovine vitrin was achieved using these sequences.
Northern blot analysis of vitrin showed that transcripts are present in the extracellular matrix of cardiac muscle, skele-tal muscle, kidney, lung and several other tissues. Northern analysis also showed that the transcript for vitrin is about 3.0 kb in size. An in vitro binding assay demonstrated that vitrin is able to bind to collagen fibrils. Hence, it is believed vitrin plays a role in regulating interactions be-tween collagen fibrils and other extra cellular matrix (ECM) components to maintain vitreous integrity. Vitrin also ap-pears to prevent collagen fibrils from aggregating, a process that leads to vitreous gel collapse and posterior vitreous detachment (PVD) with the potential for retinal detachment.
Analysis of the amino acid sequence of vitrin showed the presence of at least four recognizable domains (called DOM-1, vWAl, DOM-3 and vWA2), all of which share the location of cysteine residues with a protein of the cochlea of the ear called COCH (Fig. 3). Recently, the importance of the latter protein was clearly demonstrated by the identification of three mutations in the DOM-1 domain of LOCH that give rise to a nonsyndromic form of deafness called DNFA9. For expression of each domain of vitrin, a series of primers were prepared whose location is shown on Fig. 4, resulting in specific amplification by PCR of DOM-1, vWAl and vWA2. Each PCR prod-uct was ligated into PQE30 (Qiagen, Santa Clarita, CA) for bacterial expression. (See Fig. 5., which compares the molec-ular weights of the three domains expressed by bacteria on SDS-PAGE.) Purification of each his-tagged protein was achieved using the protocol provided by the manufacturer (Qiagen). The simplicity of the his-tag purification proce-dure is preferred, although expression of each domain can also be achieved with a variety of other commercial procedures (PGEX-SX, Pharmacia, Piscataway, New Jersey, pMAL-C2, New England Biolabs, Beverly, Maine).
The correct folding of the von Willebrand domains can be achieved by bacterial expression systems as is clearly shown by the X-ray crystallographic structure of four von Willebrand A-containing domains, including the I domains of integrins a,M, a2, and ~cl, plus the A3 domain of von Willebrand factor it self. For the latter domain, a his-tag expression system was utilized by both groups demonstrating that this short basic sequence will not interfere with crystallization. Other groups have also achieved expression of I-domains and demon-strated binding to collagen.
Expression of the full-length sequence of vitrin can also be successfully achieved using a baculovirus expression sys-tem, as has been successfully achieved for expression of laminin a, i3 and i-chains or type III and type I collagen. In addition, successful expression of type III collagen in the yeast Pichia pastoris has been reported. (See U.S. Patent 5,593,859, which is incorporated herein by reference in its entirety.) Several mammalian expression systems have also been utilized to successfully express connective tissue pro-teins, including type I and II collagen in HT1080 cells, type X procollagen in HEK293 cells, type VI collagen in NIH3T3 cells and type IV collagen in CHO cells. Expression of carti-lage matrix protein (CMP) has also been successfully achieved in COS-7 cells and binding of recombinant fragments to colla-gen shown.
Vitrin was found to consist partly of two von Willebrand A domains which may independently bind to collagen fibrils.
The invention makes it possible to study the relationship of vitrin to collagen fibrils and examine vitrin concentration at sites of vitreous collapse.
The cDNA was shown to have the following sequence:
TAGAATAATTTGGATGGGATTTGTGATGCAGGAAAGCCTAAGGGAAAA.AGAATATTCATTCT
GTGTGGTGAAAATTTTTTGAA.A.A.A.AAAATTGCCTTCTTCAAACAAGGGTGTCATTCTGATAT
TTATGAGGACTGTTGTTCTCACTATGAAGGCATCTGTTATTGAAATGTTCCTTGTTTTGCTG
GTGACTGGAGTACATTCAAACAAAGAAACGGCAAAGAAGATTAAAAGGCCCAAGTTCACTGT
GCCTCAGATCAACTGCGATGTCAAAGCCGGAAAGATCATCGATCCTGAGTTCATTGTGAAAT
GTCCAGCAGGATGCCAAGACCCCAAATACCATGTTTATGGCACTGACGTGTATACATCCTAC
TCCAGTGTGTGTGGCGCTGCCGTACACAGTAGTGTGCTTGATGATTCAGGAGGGAAAATACT
TGTTCGGAAGGTTGCTGGACAGTCTGGTTACAAAGGGAGTTATTCCAACGGTGTCCAATCGT
TATCCCTACCACGATGGAGAGAATCCTTTATCGTCTTAGAAAGTAAACCCAAA.A.AGGGTGTA
ACCTACCCATCAGCTCTTACATACTCATCATCGAAAAGTCCAGCTGCCCAAGCAGGTGAGAC
CACAAAAGCCTATCAGAGGCCACCTATTCCAGGGACAACTGCACAGCCGGTCACTCTGATGC
AGCTTCTGGCTGTCACTGTAGCTGTGGCCACCCCCACCACCTTGCCAAGGCCATCCCCTTCT
GCTGCTTCTACCACCAGCATCCCCAGACCACAATCAGTGGGCCACAGGAGCCAGGAGATGGA
TCTCTGGTCCACTGCCACCTACACAAGCAGCCAA.AACAGGCCCAGAGCTGATCCAGGACTTG
TTCCAAAAGAAGAATTGAGCACACAGTCTTTGGAGCCAGTATCCCTGGGAGATCCAAACTGC
AAA.ATTGACTTGTCGTTTTTAATTGATGGGAGCACCAGCATTGGCAAACGGCGATTCCGAAT
CCAGAAGCAGCTCCTGGCTGATGTTGCCCAAGCTCTTGACATTGGCCCTGCCGGTCCACTGA
TGGGTGTTGTCCAGTATGGAGACAACCCTGCTACTCACTTTAACCTCAAGACACACACGAAT
TCTCGAGATCTGAAGACAGCCATAGAGAAAATTACTCAGAGAGGAGGACTTTCTAATGTAGG
TCGGACCATCTCCTTTGTGACCAAGAACTTCTTTTCCAAAGCCAATGGAAACAGAAGCGGGG
CTCCCAATGTGGTGGTGGTGATGGTGGATGGCTGGCCCACGGACAAAGTGGAGGAGGCTTCA
AGACTTGCGAGAGTGTCAGGAATCAACATTTTCTTCATCACCATTGAAGGTGCTGCTGAAAA
TGAGAAGCAGTATGTGGTGGAGCCCAACTTTGCAAACAAGGCCGTGTGCAGAACAAACGGCT
TCTACTCGCTCCACGTGCAGAGCTGGTTTGGCCTCCACAAGACCCTGCAGCCTCTGGTGAAG
CGGGTCTGCGACACTGACCGCCTGGCCTGCAGCAAGACCTGCTTGAACTCGGCTGACATTGG
CTTCGTCATCGACGGCTCCAGCAGTGTGGGGACGGGCAACTTCCGCACCGTCCTCCAGTTTG
TGACCAACCTCACCAAAGAGTTTGAGATTTCCGACACGGACACGCGCATCGGGGCCGTGCAG
TACACCTACGAACAGCGGCTGGAGTTTGGGTTCGACAAGTACAGCAGCAAGCCTGACATCCT
CAACGCCATCAAGAGGGTGGGCTACTGGAGTGGTGGCACCAGCACGGGGGCTGCCATCAACT
TCGCCCTGGAGCAGCTCTTCAAGAAGTCCAAGCCCAACAAGAGGAAGTTAATGATCCTCATC
ACCGACGGGAGGTCCTACGACGACGTCCGGATCCCAGCCATGGCTGCCCATCTGAAGGGAGT
GATCACCTATGCGATAGGCGTTGCCTGGGCTGCCCAAGAGGAGCTAGAAGTCATTGCCACTC
ACCCCGCCAGAGACCACTCCTTCTTTGTGGACGAGTTTGACAACCTCCATCAGTATGTCCCC
AGGATCATCCAGAACATTTGTACAGAGTTCAACTCACAGCCTCGGAACTGAATTCAGAGCAG
GCAGAGCACCAGCAAGTGCTGCTTTACTAACTGACGTGTTGGACCACCCCACCGCTTAATGG
GGCACGCACGGTGCATCAAGTCTTGGGCAGGGCATGGAGAAACAAATGTCTTGTTATTATTC
TTTGCCATCATGCTTTTTCATATTCCAAAACTTGGAGTTACAAAGATGATCACAAACGTATA
GAATGAGCCAAAAGGCTACATCATGTTGAGGGTGCTGGAGATTTTACATTTTGACAATTGTT
TTCAAAATAAATGTTCGGAATACAGTGCAGCCCTTACGACAGGCTTACGTAGAGCTTTTGTG
AGATTTTTAAGTTGTTATTTCTGATTAGAACTCTGTAACCCTCAGCAAGTTTCATTTTTGTC
ATGACAATGTAGGAATTGCTGAATTAAATGTTTAGAAGGATGAC
(SEQ ID NO:1) The amino acid sequence of the human vitrin was shown to be:
M R T V V L T M K A S V I E M F L V L L V
T G V H S N K E T A K K I K R P K F T V P
Q I N C D V K A G K I I D P E F I V K C P
A G C Q D P K Y H V Y G T D V Y T S Y S S
V C G A A V H S S V L D D S G G K I L V R
-K V A G Q S G Y K G S Y S N G V Q S L S L
S A L T Y S S S K S P A A Q A G E T T K A
Y Q R P P I P G T T A Q P V T L M Q L L A
V T V A V A T P T T L P R P S P S A A S T
T S I P R P Q S V G H R S Q E M D L W S T
L S T Q S L E P V S L G D P N C A I D L S
K
F L I D G S T S I G K R R F R I Q K Q L L
A D V A Q A L D I G P A G P L M G V V Q Y
G D N P A T H F N L K T H T N S R D L K T
T K N F F S K A N G N R S G A P N V V V V
M V D G W P T D K V E E A S R L A R V S G
I N I F F I T I E G A A E N E K Q Y V V E
P N F A N K A V TC R T N G F Y S L H V Q S
A C S K T C A N S A D I G F V I D G S S S
L
V G T G N F R T V L Q F V T N L T K E F E
I S D T D T R I G A V Q Y T Y E Q R L E F
G F D K Y S S K P D I L N A I K R V G Y W
K P N K R K L M I L I T D G R S Y D D V R
I P A M A A H L K G V I T Y A I G V A W A
A Q E E L E V I A T H P A R D H S F F V D
E F D N L H Q Y V P R I I Q N I TC T E F N
(SEQ ID N0:2) In the sequence listing above, A designates the start of the von Willebrand domains and T designates the end of the do-mains.
Referring to Fig. 1, the cDNA sequence of human vitrin, T
identifies signal peptide cleavage sites. (Hence, T has different meanings in Fig. 1 and in the listing above.) The shaded peptides show the peptides for which amino acid se-quence is available.
The ability to raise antibodies to peptide sequences of human vitrin makes it possible to evaluate changes in amount of vitrin in the adult versus the amount in children, to study effects of such changes in disease conditions such as diabetic retinopathy, and to evaluate the amount of vitrin in any given patient tissue. As discussed below, vitrin may also be admin-istered for therapeutic purposes.
Vitrin differs from most other connective tissue proteins in having two von Willebrand A domains which appear to func-tion to crosslink collagen fibrils. The invention, therefore, includes the protein and polypeptides of the protein which are capable of binding collagen. Each von Willebrand domain appears to be primarily involved in the binding of the protein to collagen.
The protein and expressed domains of the invention may be used to facilitate healing of weakened or injured connective tissue. The collagen-binding polypeptides and proteins may be administered to the appropriate sites in need of healing in several ways. It may be applied to the tissue in or on sup-ports such as absorbable supports, including sutures. When the damaged tissue is exposed as, for example, during surgery, the vitrin protein or polypeptides may be applied topically to the tis-sue. Compositions containing vitrin or collagen-binding polypeptide sequences of human vitrin may be used in high salt solutions. Supports having the inventive proteins or peptides may be placed in the operative area.
Frequently a problem arises when bone or other materials are placed in the patient following breakage or disintegration of bone and connective tissue. The collagen-binding polypeptides and proteins may be applied to prosthetic devices or placed in the region of bone or muscle grafts to enhance growth and development of the connective tissue in the region.
The patient's serum may be used as a carrier for the polypeptides and proteins, since it would be a compatible carrier for use in the patient. A concentration of about O.OOlo to 5% vitrin is suggested. Whole blood can be drawn from the patient before surgery and the serum collected for use as a carrier for the vitrin. For example, 50 ml of blood is drawn from a patient for purposes of obtaining serum. To the serum obtained from the above sample is added 1 mg of vitrin. The serum containing the vitrin is then applied to a hip prosthesis and the surgical site during surgical implanta-tion.
The partial sequence of the bovine cDNA has been deposit-ed in Genbank and given the number AF063832. The full length human cDNA sequence has been deposited and assigned the number AF 063833.
8a SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) APPLICANT: UAB RESEARCH FOUNDATION
(ii) TITLE OF INVENTION: Human Vitreous and Pharmaceutical Compositions (iii) NUMBER OF SEQUENCES: 4 (iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: Glenna Hendricks (B) STREET: P.O. Box 2509 (C) CITY: Fairfax (D) STATE: VA
(E) COUNTRY: U.S.A.
(F) ZIP: 22031 (v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: PatentIn Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER: 2,255,477 (B) FILING DATE: 11-DEC-1998 (C) CLASSIFICATION:
(viii) ATTORNEY/AGENT INFORMATION:
(A) NAME: COTE, France (B) REGISTRATION NUMBER: 4166 (C) REFERENCE/DOCKET NUMBER: 12452-24 FC/gC
(ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: 514-845-7126 (B) TELEFAX: 514-288-8389 (C) TELEX:
(2) INFORMATION FOR SEQ ID NO:1:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2547 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: cDNA to mRNA
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(vi) ORIGINAL SOURCE:
(F) TISSUE TYPE: Sequence encoding vitreous humor (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:
8b CTGTGTGGTGAAAATTTTTTGP~1~A TTGCCTTCTTCAAACAAGGGTGTCATTCTG 120 8c TGACAAAAAAP,~~AAAAAAAAAAAAAAA 2547 (2) INFORMATION FOR SEQ ID N0:2:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 656 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(v) FRAGMENT TYPE: N-terminal (vi) ORIGINAL SOURCE:
(F) TISSUE TYPE: amino acid sequence of human vitreous humor (xi) SEQUENCE DESCRIPTION:'SEQ ID N0:2:
Met Arg Thr Val Val Leu Thr Met Lys Ala Ser Val Ile Glu Met Phe 8d Leu Val Leu Leu Val Thr Gly Val His Ser Asn Lys Glu Thr Ala Lys Lys Ile Lys Arg Pro Lys Phe Thr Val Pro Gln Ile Asn Cys Asp Val Lys Ala Gly Lys Ile Ile Asp Pro Glu Phe Ile Val Lys Cys Pro Ala Gly Cys Gln Asp Pro Lys Tyr His Val Tyr Gly Thr Asp Val Tyr Thr Ser Tyr Ser Ser Val Cys Gly Ala Ala Val His Ser Ser Val Leu Asp Asp Ser Gly Gly Lys Ile Leu Val Arg Lys Val Ala Gly Gln Ser Gly Tyr Lys Gly Ser Tyr Ser Asn Gly Val Gln Ser Leu Ser Leu Pro Arg Trp Arg Glu Ser Phe Ile Val Leu Glu Ser Lys Pro Lys Lys Gly Val Thr Tyr Pro Ser Ala Leu Thr Tyr Ser Ser Ser Lys Ser Pro Ala Ala Gln Ala Gly Glu Thr Thr Lys Ala Tyr Gln Arg Pro Pro Ile Pro Gly Thr Thr Ala Gln Pro Val Thr Leu Met Gln Leu Leu Ala Val Thr Val Ala Val Ala Thr Pro Thr Thr Leu Pro Arg Pro Ser Pro Ser Ala Ala Ser Thr Thr Ser Ile Pro Arg Pro Gln Ser Val Gly His Arg Ser Gln Glu Met Asp Leu Trp Ser Thr Ala Thr Tyr Thr Ser Ser Gln Asn Arg Pro Arg Ala Asp Pro Gly Leu Val Pro Lys Glu Glu Leu Ser Thr Gln Ser Leu Glu Pro Val Ser Leu Gly Asp Pro Asn Cys Lys Ile Asp Leu Ser Phe Leu Ile Asp Gly Ser Thr Ser Ile Gly Lys Arg Arg Phe Arg Ile Gln Lys Gln Leu Leu Ala Asp Val Ala Gln Ala Leu Asp Ile Gly Pro Ala Gly Pro Leu Met Gly Val Val Gln Tyr Gly Asp Asn Pro Ala 8e Thr His Phe Asn Leu Lys Thr His Thr Asn Ser Arg Asp Leu Lys Thr Ala Ile Glu Lys Ile Thr Gln Arg Gly Gly Leu Ser Asn Val Gly Arg Thr Ile Ser Phe Val Thr Lys Asn Phe Phe Ser Lys Ala Asn Gly Asn Arg Ser Gly Ala Pro Asn Val Val Val Val Met Val Asp Gly Trp Pro Thr Asp Lys Val Glu Glu Ala Ser Arg Leu Ala Arg Val Ser Gly Ile Asn Ile Phe Phe Ile Thr Ile Glu Gly Ala Ala Glu Asn Glu Lys Gln Tyr Val Val Glu Pro Asn Phe Ala Asn Lys Ala Val Cys Arg Thr Asn Gly Phe Tyr Ser Leu His Val Gln Ser Trp Phe Gly Leu His Lys Thr Leu Gln Pro Leu Val Lys Arg Val Cys Asp Thr Asp Arg Leu Ala Cys Ser Lys Thr Cys Leu Asn Ser Ala Asp Ile Gly Phe Val Ile Asp Gly Ser Ser Ser Val Gly Thr Gly Asn Phe Arg Thr Val Leu Gln Phe Val Thr Asn Leu Thr Lys Glu Phe Glu Ile Ser Asp Thr Asp Thr Arg Ile Gly Ala Val Gln Tyr Thr Tyr Glu Gln Arg Leu Glu Phe Gly Phe Asp Lys Tyr Ser Ser Lys Pro Asp Ile Leu Asn Ala Ile Lys Arg Val Gly Tyr Trp Ser Gly Gly Thr Ser Thr Gly Ala Ala Ile Asn Phe Ala Leu Glu Gln Leu Phe Lys Lys Ser Lys Pro Asn Lys Arg Lys Leu Met Ile Leu Ile Thr Asp Gly Arg Ser Tyr Asp Asp Val Arg Ile Pro Ala Met Ala Ala His Leu Lys Gly Val Ile Thr Tyr Ala Ile Gly Val Ala Trp Ala Ala Gln Glu Glu Leu Glu Val Ile Ala Thr His Pro Ala Arg Asp 8f His Ser Phe Phe Val Asp Glu Phe Asp Asn Leu His Gln Tyr Val Pro Arg Ile Ile Gln Asn Ile Cys Thr Glu Phe Asn Ser Gln Pro Arg Asn (2) INFORMATION FOR SEQ ID N0:3:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 160 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: cDNA to mRNA
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(vi) ORIGINAL SOURCE:
(F) TISSUE TYPE: Sequence encoding vitreous humor (xi) SEQUENCE DESCRIPTION: SEQ ID N0:3:
Lys Ile Asp Leu Ser Phe Leu Ile Asp Gly Ser Thr Ser Ile Gly Lys Arg Arg Phe Arg Ile Gln Lys Gln Leu Leu Ala Asp Val Ala Gln Ala Leu Asp Ile Gly Pro Ala Gly Pro Leu Met Gly Val Val Gln Tyr Gly Asp Asn Pro Ala Thr His Phe Asn Leu Lys Thr His Thr Asn Ser Arg Asp Leu Lys Thr Ala Ile Glu Lys Ile Thr Gln Arg Gly Gly Leu Ser Asn Val Gly Arg Thr Ile Ser Phe Val Thr Lys Asn Phe Phe Ser Lys Ala Asn Gly Asn Arg Ser Gly Ala Pro Asn Val Val Val Val Met Val Asp Gly Trp Pro Thr Asp Lys Val Glu Glu Ala Ser Arg Leu Ala Arg Val Ser Gly Ile Asn Ile Phe Phe Ile Thr Ile Glu Gly Ala Ala Glu Asn Glu Lys Gln Tyr Val Val Glu Pro Asn Phe Ala Asn Lys Ala Val 8g (2) INFORMATION FOR SEQ ID N0:4:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 178 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single {D) TOPOLOGY: unknown (ii) MOLECULE TYPE: cDNA to mRNA
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(vi) ORIGINAL SOURCE:
(F) TISSUE TYPE: Sequence encoding vitreous humor (xi)SEQUENCE DESCRIPTION: N0:4:
SEQ
ID
LeuAsn SerAlaAsp IleGlyPhe ValIleAsp GlySerSer SerVal GlyThr GlyAsnPhe ArgThrVal LeuGlnPhe ValThrAsn LeuThr LysGlu PheGluIle SerAspThr AspThrArg IleGlyAla ValGln TyrThr TyrGluGln ArgLeuGlu PheGlyPhe AspLysTyr SerSer LysPro AspIleLeu AsnAlaIle LysArgVal GlyTyrTrp SerGly GlyThr SerThrGly AlaAlaIle AsnPheAla LeuGluGln LeuPhe LysLys SerLysPro AsnLysArg LysLeuMet IleLeuIle ThrAsp GlyArg SerTyrAsp AspValArg IleProAla MetAlaAla HisLeu LysGly ValIleThr TyrAlaIle GlyValAla TrpAlaAla GlnGlu GluLeu GluValIle AlaThrHis ProAlaArg AspHisSer PhePhe ValAsp GluPheAsp AsnLeuHis GlnTyrVal ProArgIle IleGln AsnIle
The patient's serum may be used as a carrier for the polypeptides and proteins, since it would be a compatible carrier for use in the patient. A concentration of about O.OOlo to 5% vitrin is suggested. Whole blood can be drawn from the patient before surgery and the serum collected for use as a carrier for the vitrin. For example, 50 ml of blood is drawn from a patient for purposes of obtaining serum. To the serum obtained from the above sample is added 1 mg of vitrin. The serum containing the vitrin is then applied to a hip prosthesis and the surgical site during surgical implanta-tion.
The partial sequence of the bovine cDNA has been deposit-ed in Genbank and given the number AF063832. The full length human cDNA sequence has been deposited and assigned the number AF 063833.
8a SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) APPLICANT: UAB RESEARCH FOUNDATION
(ii) TITLE OF INVENTION: Human Vitreous and Pharmaceutical Compositions (iii) NUMBER OF SEQUENCES: 4 (iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: Glenna Hendricks (B) STREET: P.O. Box 2509 (C) CITY: Fairfax (D) STATE: VA
(E) COUNTRY: U.S.A.
(F) ZIP: 22031 (v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: PatentIn Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER: 2,255,477 (B) FILING DATE: 11-DEC-1998 (C) CLASSIFICATION:
(viii) ATTORNEY/AGENT INFORMATION:
(A) NAME: COTE, France (B) REGISTRATION NUMBER: 4166 (C) REFERENCE/DOCKET NUMBER: 12452-24 FC/gC
(ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: 514-845-7126 (B) TELEFAX: 514-288-8389 (C) TELEX:
(2) INFORMATION FOR SEQ ID NO:1:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2547 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: cDNA to mRNA
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(vi) ORIGINAL SOURCE:
(F) TISSUE TYPE: Sequence encoding vitreous humor (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:
8b CTGTGTGGTGAAAATTTTTTGP~1~A TTGCCTTCTTCAAACAAGGGTGTCATTCTG 120 8c TGACAAAAAAP,~~AAAAAAAAAAAAAAA 2547 (2) INFORMATION FOR SEQ ID N0:2:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 656 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(v) FRAGMENT TYPE: N-terminal (vi) ORIGINAL SOURCE:
(F) TISSUE TYPE: amino acid sequence of human vitreous humor (xi) SEQUENCE DESCRIPTION:'SEQ ID N0:2:
Met Arg Thr Val Val Leu Thr Met Lys Ala Ser Val Ile Glu Met Phe 8d Leu Val Leu Leu Val Thr Gly Val His Ser Asn Lys Glu Thr Ala Lys Lys Ile Lys Arg Pro Lys Phe Thr Val Pro Gln Ile Asn Cys Asp Val Lys Ala Gly Lys Ile Ile Asp Pro Glu Phe Ile Val Lys Cys Pro Ala Gly Cys Gln Asp Pro Lys Tyr His Val Tyr Gly Thr Asp Val Tyr Thr Ser Tyr Ser Ser Val Cys Gly Ala Ala Val His Ser Ser Val Leu Asp Asp Ser Gly Gly Lys Ile Leu Val Arg Lys Val Ala Gly Gln Ser Gly Tyr Lys Gly Ser Tyr Ser Asn Gly Val Gln Ser Leu Ser Leu Pro Arg Trp Arg Glu Ser Phe Ile Val Leu Glu Ser Lys Pro Lys Lys Gly Val Thr Tyr Pro Ser Ala Leu Thr Tyr Ser Ser Ser Lys Ser Pro Ala Ala Gln Ala Gly Glu Thr Thr Lys Ala Tyr Gln Arg Pro Pro Ile Pro Gly Thr Thr Ala Gln Pro Val Thr Leu Met Gln Leu Leu Ala Val Thr Val Ala Val Ala Thr Pro Thr Thr Leu Pro Arg Pro Ser Pro Ser Ala Ala Ser Thr Thr Ser Ile Pro Arg Pro Gln Ser Val Gly His Arg Ser Gln Glu Met Asp Leu Trp Ser Thr Ala Thr Tyr Thr Ser Ser Gln Asn Arg Pro Arg Ala Asp Pro Gly Leu Val Pro Lys Glu Glu Leu Ser Thr Gln Ser Leu Glu Pro Val Ser Leu Gly Asp Pro Asn Cys Lys Ile Asp Leu Ser Phe Leu Ile Asp Gly Ser Thr Ser Ile Gly Lys Arg Arg Phe Arg Ile Gln Lys Gln Leu Leu Ala Asp Val Ala Gln Ala Leu Asp Ile Gly Pro Ala Gly Pro Leu Met Gly Val Val Gln Tyr Gly Asp Asn Pro Ala 8e Thr His Phe Asn Leu Lys Thr His Thr Asn Ser Arg Asp Leu Lys Thr Ala Ile Glu Lys Ile Thr Gln Arg Gly Gly Leu Ser Asn Val Gly Arg Thr Ile Ser Phe Val Thr Lys Asn Phe Phe Ser Lys Ala Asn Gly Asn Arg Ser Gly Ala Pro Asn Val Val Val Val Met Val Asp Gly Trp Pro Thr Asp Lys Val Glu Glu Ala Ser Arg Leu Ala Arg Val Ser Gly Ile Asn Ile Phe Phe Ile Thr Ile Glu Gly Ala Ala Glu Asn Glu Lys Gln Tyr Val Val Glu Pro Asn Phe Ala Asn Lys Ala Val Cys Arg Thr Asn Gly Phe Tyr Ser Leu His Val Gln Ser Trp Phe Gly Leu His Lys Thr Leu Gln Pro Leu Val Lys Arg Val Cys Asp Thr Asp Arg Leu Ala Cys Ser Lys Thr Cys Leu Asn Ser Ala Asp Ile Gly Phe Val Ile Asp Gly Ser Ser Ser Val Gly Thr Gly Asn Phe Arg Thr Val Leu Gln Phe Val Thr Asn Leu Thr Lys Glu Phe Glu Ile Ser Asp Thr Asp Thr Arg Ile Gly Ala Val Gln Tyr Thr Tyr Glu Gln Arg Leu Glu Phe Gly Phe Asp Lys Tyr Ser Ser Lys Pro Asp Ile Leu Asn Ala Ile Lys Arg Val Gly Tyr Trp Ser Gly Gly Thr Ser Thr Gly Ala Ala Ile Asn Phe Ala Leu Glu Gln Leu Phe Lys Lys Ser Lys Pro Asn Lys Arg Lys Leu Met Ile Leu Ile Thr Asp Gly Arg Ser Tyr Asp Asp Val Arg Ile Pro Ala Met Ala Ala His Leu Lys Gly Val Ile Thr Tyr Ala Ile Gly Val Ala Trp Ala Ala Gln Glu Glu Leu Glu Val Ile Ala Thr His Pro Ala Arg Asp 8f His Ser Phe Phe Val Asp Glu Phe Asp Asn Leu His Gln Tyr Val Pro Arg Ile Ile Gln Asn Ile Cys Thr Glu Phe Asn Ser Gln Pro Arg Asn (2) INFORMATION FOR SEQ ID N0:3:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 160 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: cDNA to mRNA
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(vi) ORIGINAL SOURCE:
(F) TISSUE TYPE: Sequence encoding vitreous humor (xi) SEQUENCE DESCRIPTION: SEQ ID N0:3:
Lys Ile Asp Leu Ser Phe Leu Ile Asp Gly Ser Thr Ser Ile Gly Lys Arg Arg Phe Arg Ile Gln Lys Gln Leu Leu Ala Asp Val Ala Gln Ala Leu Asp Ile Gly Pro Ala Gly Pro Leu Met Gly Val Val Gln Tyr Gly Asp Asn Pro Ala Thr His Phe Asn Leu Lys Thr His Thr Asn Ser Arg Asp Leu Lys Thr Ala Ile Glu Lys Ile Thr Gln Arg Gly Gly Leu Ser Asn Val Gly Arg Thr Ile Ser Phe Val Thr Lys Asn Phe Phe Ser Lys Ala Asn Gly Asn Arg Ser Gly Ala Pro Asn Val Val Val Val Met Val Asp Gly Trp Pro Thr Asp Lys Val Glu Glu Ala Ser Arg Leu Ala Arg Val Ser Gly Ile Asn Ile Phe Phe Ile Thr Ile Glu Gly Ala Ala Glu Asn Glu Lys Gln Tyr Val Val Glu Pro Asn Phe Ala Asn Lys Ala Val 8g (2) INFORMATION FOR SEQ ID N0:4:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 178 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single {D) TOPOLOGY: unknown (ii) MOLECULE TYPE: cDNA to mRNA
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(vi) ORIGINAL SOURCE:
(F) TISSUE TYPE: Sequence encoding vitreous humor (xi)SEQUENCE DESCRIPTION: N0:4:
SEQ
ID
LeuAsn SerAlaAsp IleGlyPhe ValIleAsp GlySerSer SerVal GlyThr GlyAsnPhe ArgThrVal LeuGlnPhe ValThrAsn LeuThr LysGlu PheGluIle SerAspThr AspThrArg IleGlyAla ValGln TyrThr TyrGluGln ArgLeuGlu PheGlyPhe AspLysTyr SerSer LysPro AspIleLeu AsnAlaIle LysArgVal GlyTyrTrp SerGly GlyThr SerThrGly AlaAlaIle AsnPheAla LeuGluGln LeuPhe LysLys SerLysPro AsnLysArg LysLeuMet IleLeuIle ThrAsp GlyArg SerTyrAsp AspValArg IleProAla MetAlaAla HisLeu LysGly ValIleThr TyrAlaIle GlyValAla TrpAlaAla GlnGlu GluLeu GluValIle AlaThrHis ProAlaArg AspHisSer PhePhe ValAsp GluPheAsp AsnLeuHis GlnTyrVal ProArgIle IleGln AsnIle
Claims (7)
1. A polypeptide or protein containing at least one von Willebrand sequence of human vitreous.
2. A polypeptide of claim 1 which contains the sequence K I D L S F L I D G S T S I G K R R F R I
Q K Q L L A D V A Q A L D I G P A G P L M
G V V Q Y G D N P A T H F N L K T H T N S
R D L K T A I E K I T Q R G G L S N V G R
T I S F V T K N F F S K A N G N R S G A P
N V V V V M V D G W P T D K V E E A S R L
A R V S G I N I F F I T I E G A A E N E K
Q Y V V E P N F A N K A V (SEQ ID NO:9).
Q K Q L L A D V A Q A L D I G P A G P L M
G V V Q Y G D N P A T H F N L K T H T N S
R D L K T A I E K I T Q R G G L S N V G R
T I S F V T K N F F S K A N G N R S G A P
N V V V V M V D G W P T D K V E E A S R L
A R V S G I N I F F I T I E G A A E N E K
Q Y V V E P N F A N K A V (SEQ ID NO:9).
3. A polypeptide of claim 1 which contains the sequence L N S A D I G F V I D G S S S V G T G N F
R T V L Q F V T N L T K E F E I S D T D T
R I G A V Q Y T Y E Q R L E F G F D K Y S
S K P D I L N A I K R V G Y W S G G T S T
G A A I N F A L E Q L F K K S K P N K R K
L M I L I T D G R S Y D D V R I P A M A A
H L K G V I T Y A I G V A W A A Q E E L E
V I A T H P A R D H S F F V D E F D N L H
Q Y V P R I I Q N I (SEQ ID NO:10)
R T V L Q F V T N L T K E F E I S D T D T
R I G A V Q Y T Y E Q R L E F G F D K Y S
S K P D I L N A I K R V G Y W S G G T S T
G A A I N F A L E Q L F K K S K P N K R K
L M I L I T D G R S Y D D V R I P A M A A
H L K G V I T Y A I G V A W A A Q E E L E
V I A T H P A R D H S F F V D E F D N L H
Q Y V P R I I Q N I (SEQ ID NO:10)
4. A composition of matter comprising a polypeptide or protein of claim 1 in a pharmaceutically acceptable carrier.
5. A composition of claim 4 wherein the polypeptide contains the sequence K I D L S F L I D G S T S I G K R R F R I
Q K Q L L A D V A Q A L D I G P A G P L M
G V V Q Y G D N P A T H F N L K T H T N S
R D L K T A I E K I T Q R G G L S N V G R
T I S F V T K N F F S K A N G N R S G A P
N V V V V M V D G W P T D K V E E A S R L
A R V S G I N I F F I T I E G A A E N E K
Q Y V V E P N F A N K A V (SEQ ID NO. 9).
Q K Q L L A D V A Q A L D I G P A G P L M
G V V Q Y G D N P A T H F N L K T H T N S
R D L K T A I E K I T Q R G G L S N V G R
T I S F V T K N F F S K A N G N R S G A P
N V V V V M V D G W P T D K V E E A S R L
A R V S G I N I F F I T I E G A A E N E K
Q Y V V E P N F A N K A V (SEQ ID NO. 9).
6. A composition of claim 4 containing a polypeptide which contains the sequence L N S A D I G F V I D G S S S V G T G N F
R T V L Q F V T N L T K E F E I S D T D T
R I G A V Q Y T Y E Q R L E F G F D K Y S
S K P D I L N A I K R V G Y W S G G T S T
G A A I N F A L E Q L F K K S K P N K R K
L M I L I T D G R S Y D D V R I P A M A A
H L K G V I T Y A I G V A W A A Q E E L E
V I A T H P A R D H S F F V D E F D N L H
Q Y V P R I I Q N I (SEQ ID NO. 10).
R T V L Q F V T N L T K E F E I S D T D T
R I G A V Q Y T Y E Q R L E F G F D K Y S
S K P D I L N A I K R V G Y W S G G T S T
G A A I N F A L E Q L F K K S K P N K R K
L M I L I T D G R S Y D D V R I P A M A A
H L K G V I T Y A I G V A W A A Q E E L E
V I A T H P A R D H S F F V D E F D N L H
Q Y V P R I I Q N I (SEQ ID NO. 10).
7. A composition of claim 4 wherein the carrier is patient serum.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2255477 CA2255477A1 (en) | 1998-12-11 | 1998-12-11 | Human vitreous and pharmaceutical compositions |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2255477 CA2255477A1 (en) | 1998-12-11 | 1998-12-11 | Human vitreous and pharmaceutical compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2255477A1 true CA2255477A1 (en) | 2000-06-11 |
Family
ID=29425789
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2255477 Abandoned CA2255477A1 (en) | 1998-12-11 | 1998-12-11 | Human vitreous and pharmaceutical compositions |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2255477A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001042466A2 (en) * | 1999-12-09 | 2001-06-14 | Zymogenetics, Inc. | Zvwf1: a member of the von willebrand factor type a domain superfamily |
-
1998
- 1998-12-11 CA CA 2255477 patent/CA2255477A1/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001042466A2 (en) * | 1999-12-09 | 2001-06-14 | Zymogenetics, Inc. | Zvwf1: a member of the von willebrand factor type a domain superfamily |
| WO2001042466A3 (en) * | 1999-12-09 | 2002-01-10 | Zymogenetics Inc | Zvwf1: a member of the von willebrand factor type a domain superfamily |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |