Methods for accelerating bone and cartilage growth and repair
AssigneeUniversity of Southern California
InventorsKathleen E. Rodgers, Gere S. DiZerega
Life of this patent
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Abstract
The present invention provides improved methods, kits, and compositions for enhancing bone, cartilage and cartilage repair, bone and prosthesis implantation, and attachment and fixation of cartilage and cartilage to bone or other tissues, and chondrocyte proliferation comprising the administration of an effective amount of angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (AII), AII analogues, AII fragments or analogues thereof or AII AT2 type 2 receptor agonists.
Claims35
A method for enhancing bone repair in a mammal, comprising the administration of an amount effective for enhancing bone repair in the mammal of at least one active agent comprising a sequence of at least three contiguous amino acids of groups R1-R8 in the sequence of general formula I
- R1-R2-R3-R4-R5-R6-R7-R8
- wherein R1 is selected from H, Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me2Gly, Pro, Bet, Glu(NH2), Gly, Asp(NH2) and Suc,
- R2 is selected from Arg, Lys, Ala, Orn, Citron, Ser(Ac), Sar, D-Arg and D-Lys;
- R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;
- R4 is selected from the group consisting of Tyr, Tyr(PO3)2, Thr, Ala, Ser, homoSer and azaTyr;
- R5 is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;
- R6 is selected from the group consisting of His, Arg or 6-NH2-Phe;
- R7 is selected from the group consisting of Pro or Ala;
- and
- R8 is selected from the group consisting of Phe, Phe(Br), Ile and Tyr;
- excluding sequences including R4 as a terminal Tyr group, or is absent.
An improved method for bone and prosthesis implantation in a mammal, comprising the administration of an amount effective for enhancing bone and prosthesis implantation in the mammal of at least one active agent comprising a sequence of at least three contiguous amino acids of groups R1-R8 in the sequence of general formula I
- R1-R2-R3-R4-R5-R6-R7-R8
- wherein R1 is selected from H, Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me2Gly, Pro, Bet, Glu(NH2), Gly, Asp(NH2, and Suc
- R2 is selected from Arg, Lys, Ala, Orn, Citron, Ser(Ac), Sar, D-Arg and D-Lys;
- R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;
- R4 is selected from the group consisting of Tyr, Tyr(PO3)2, Thr, Ala, Ser;
- homoSer and azaTyr;
- R5 is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;
- R6 is selected from the group consisting of His, Arg or 6-NH2-Phe;
- R7 is selected from the group consisting of Pro or Ala;
- and
- R8 is selected from the group consisting of Phe, Phe(Br), Ile and Tyr;
- excluding sequences including R4 as a terminal Tyr group, or is absent.
A kit for enhancing bone repair in a mammal, comprising:
- (a) administering an amount effective for enhancing bone repair in the mammal of at least one active agent comprising a sequence comprising a sequence of at least three contiguous amino acids of groups R1-R8 in the sequence of general formula I
- R1-R2-R3-R4-R5-R6-R7-R8
- wherein R1 is selected from H, Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me2Gly, Pro, Bet, Glu(NH2), Gly, Asp(NH2) and Suc,
- R1 is selected from Arg, Lys, Ala, Om, Citron, Ser(Ac), Sar, D-Arg and D-Lys;
- R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;
- R4 is selected from the group consisting of Tyr, Tyr(PO3)2, Thr, Ala, Ser, homoSer and azaTyr;
- R5 is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;
- R6 is selected from the group consisting of His, Arg or 6-NH2-Phe;
- R7 is selected from the group consisting of Pro or Ala;
- and
- R8 is selected from the group consisting of Phe, Phe(Br), Ile and Tyr;
- excluding sequences including R4 as a terminal Tyr group, or is absent;
- and
- (b) instructions for using the amount effective of active agent to enhance bone repair in a mammal.
A method for enhancing cartilage repair in a mammal, comprising the administration of an amount effective to enhance cartilage repair to the mammal of at least one active agent comprising a sequence of at least three contiguous amino acids of groups R1-R8 in the sequence of general formula I
- R1-R2-R3-R4-R5-R6-R7-R8
- wherein R1 is selected from H, Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me2Gly, Pro, Bet, Glu(NH2), Gly, Asp(NH2) and Suc,
- R2 is selected from Arg, Lys, Ala, Orn, Citron, Ser(Ac), Sar, D-Arg and D-Lys;
- R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;
- R4 is selected from the group consisting of Tyr, Tyr(PO3)2, Thr, Ala, Ser, homoSer and azaTyr;
- R5 is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;
- R6 is selected from the group consisting of His, Arg or 6-NH2-Phe;
- R7 is selected from the group consisting of Pro or Ala;
- and
- R8 is selected from the group consisting of Phe, Phe(Br), Ile and Tyr;
- excluding sequences including R4 as a terminal Tyr group, or is absent.
An improved method for attachment and fixation of cartilage implants to bone or other tissue in a mammal, comprising the administration of an amount effective for attaching and fixing cartilage implants to bone or other tissue in a mammal of at least one active agent comprising a sequence of at least three contiguous amino acids of groups R1-R8 in the sequence of general formula I
- R1-R2-R3-R4-R5-R6-R7-R8
- wherein R1 is selected from H, Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me2Gly, Pro, Bet, Glu(NH2), Gly, Asp(NH2) and Suc,
- R2 is selected from Arg, Lys, Ala, Om, Citron, Ser(Ac), Sar, D-Arg and D-Lys;
- R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;
- R4 is selected from the group consisting of Tyr, Tyr(PO3)2, Thr, Ala, Ser, homoSer and azaTyr;
- R5 is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;
- R6 is selected from the group consisting of His, Arg or 6-NH2-Phe;
- R7 is selected from the group consisting of Pro or Ala;
- and
- R8 is selected from the group consisting of Phe, Phe(Br), Ile and Tyr;
- excluding sequences including R4 as a terminal Tyr group, or is absent.
An improved medium for the culture of chondrocytes wherein the improvement comprises contacting the cells with an amount effective to accelerate proliferation of chondrocytes of at least one active agent comprising a sequence of at least three contiguous amino acids of groups R1-R8 in the sequence of general formula I
- R1-R2-R3-R4-R5-R6-R7-R8
- wherein R1 is selected from H, Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me2Gly, Pro, Bet, Glu(NH2), Gly, Asp(NH2) and Suc,
- R2 is selected from Arg, Lys, Ala, Orn, Citron, Ser(Ac), Sar, D-Arg and D-Lys;
- R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr,
- R4 is selected from the group consisting of Tyr, Tyr(PO3)2, Thr, Ala, Ser, homoSer and azaTyr;
- R5 is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;
- R6 is selected from the group consisting of His, Arg or 6-NH2-Phe;
- R7 is selected from the group consisting of Pro or Ala;
- and
- R8 is selected from the group consisting of Phe, Phe(Br), Ile and Tyr;
- excluding sequences including R4 as a terminal Tyr group, or is absent.
A method for enhancing bone repair in a mammal, comprising the administration of an amount effective for enhancing bone repair in the mammal of at least one active agent of the formula
- Asp-Arg-R1-R2-Ile-His-Pro-R2, wherein
- R1 is selected from the group consisting of Ile, Pro, Ala, Val, Leu, and norLeu;
- R2 is selected from Tyr and Tyr(PO3)2;
- and
- R3 is Phe, or is absent.
An improved method for bone and prosthesis implantation in a mammal, comprising the administration of an amount effective for enhancing bone and prosthesis implantation to the mammal of at least one active agent of the formula
- Asp-Arg-R1I-2-Ile-His-Pro-R2, wherein
- R1 is selected from the group consisting of Ile, Pro, Ala, Val, Leu, and norLeu;
- R2 is selected from Tyr and Tyr(PO3)2;
- and
- R3 is Phe, or is absent.
A method for enhancing cartilage repair in a mammal, comprising the administration of an amount effective to enhance cartilage repair to the mammal of at least one active agent of the formula
- R1-R2-R3-R4-R5-His-Pro-R6, wherein
- R1 is selected from the group consisting of Hydrogen, Gly, and Asp;
- R2 is selected from the group consisting of Arg, Citron, or Ornithine;
- R3 is selected from the group consisting of Val, Ile, Ala, Leu, and norLeu, or Pro;
- R4 is selected from Tyr, Tyr(PO3)2, and Ala;
- R5 is selected from the group consisting of Ile, Ala, Val, Leu, and norLeu;
- and
- R6 is Phe, Ile, or is absent.
An improved method for attachment and fixation of cartilage implants to bone or other tissue in a mammal, comprising the administration of an amount effective for attaching and fixing cartilage implants to bone or other tissue in a mammal of at least one active agent of the formula
- R1-R2-R3-R4-R5-His-Pro-R6, wherein
- R1 is selected from the group consisting of Hydrogen, Gly, and Asp;
- R2 is selected from the group consisting of Arg, Citron, or Ornithine;
- R3 is selected from the group consisting of Val, Ile, Ala, Leu, and norLeu, or Pro;
- R4 is selected from Tyr, Tyr(PO3)2, and Ala;
- R5 is selected from the group consisting of Ile, Ala, Val, Leu, and norLeu;
- and
- R6 is Phe, Ile, or is absent.
A pharmaceutical composition comprising
- (a) an amount effective to enhance bone repair or bone and prosthesis implantation in a mammal of at least one active agent comprising a sequence of the formula
- Asp-Arg-R1-R2-Ile-His-Pro-R2, wherein
- R1 is selected from the group consisting of Ile, Pro, Ala, Val, Leu, and norLeu;
- R2 is selected from Tyr and Tyr(PO3)2;
- and
- R3 is Phe, or is absent;
- and
- (b) an amount effective to enhance bone repair or bone and prosthesis implantation in a mammal of at least one compound selected from bone morphogenic protein-2, bone morphogenic protein-4, bone morphogenic protein-6, bone morphogenic protein-7, transforming growth factor-beta, insulin-like growth factor, and parathyroid hormone;
- and
- (c) a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising
- (a) an amount effective to enhance bone repair or bone and prosthesis implantation in a mammal of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R1-R8 in the sequence of general formula I
- R1-R2-R3-R4-R5-R6-R7-R8
- in which R1 and R2 together form a group of formula
- X—RA—RB—,
- wherein X is H or a one to three peptide group, or is absent,
- RA is suitably selected from H, Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me2Gly, Pro, Bet, Glu(NH2), Gly, Asp(NH2) and Suc,
- RB is suitably selected from Arg, Lys, Ala, Om, Citron, Ser(Ac), Sar, D-Arg and D-Lys;
- R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;
- R4 is selected from the group consisting of Tyr, Tyr(PO3)2, Thr, Ala, Ser, homoSer and azaTyr;
- R5 is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;
- R6 is His, Arg or 6-NH2-Phe;
- R7 is Pro or Ala;
- and
- R8 is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R4 as a terminal Tyr group, or is absent;
- (b) an amount effective to enhance bone repair or bone and prosthesis implantation in a mammal of at least one compound selected from bone morphogenic protein-2, bone morphogenic protein-4, bone morphogenic protein-6, bone morphogenic protein-7, transforming growth factor-beta, insulin-like growth factor, and parathyroid hormone;
- and
- (c) a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.