Use of c-type natriuretic peptide variants to treat osteoarthritis
The disclosure relates to the use of variants of C-type natriuretic peptide (CNP) to treat osteoarthritis, to ameliorate one or more symptoms of osteoarthritis, and to treat disorders having an osteoarthritis component.
1. A method of treating osteoarthritis in a subject, comprising intraarticularly administering a composition comprising a C-type natriuretic peptide (CNP) variant to the subject at a dose of from 5 μg/kg to 800 μg/kg of the CNP variant, wherein the CNP variant is selected from the group consisting of:
(SEQ ID NO: 1)
PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
(Pro-Gly-CNP37);
(SEQ ID NO: 2)
GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
(Gly-CNP37);
(SEQ ID NO: 43)
QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC
[CNP-37(M32N)]
(SEQ ID NO: 44)
PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
(Pro-CNP37);
(SEQ ID NO: 45)
MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
(Met-CNP37);
(SEQ ID NO: 46)
GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC
[Gly-CN P-37(M32N)]; and
(SEQ ID NO: 47)
MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
(Met-Gly-CNP37).
2. The method of claim 1 , wherein said method ameliorates a symptom of osteoarthritis in the subject.
3. The method of claim 1 , wherein said method increases motor skills or mobility in the subject.
4. The method of claim 1 , wherein said method inhibits degeneration of mobility in the subject.
5. The method of claim 1 , wherein said method increases range of motion in an affected joint of the subject.
6. The method of claim 5 , wherein the range of motion of an affected joint is determined by measuring hip flexion, hip extension, hip abduction, hip adduction, knee flexion, or knee extension.
7. The method of claim 1 , wherein said method decreases stiffness in an affected joint of the subject.
8. The method of claim 1 , wherein said method decreases synovial inflammation in the subject.
9. A method of increasing cartilage growth or slowing cartilage degeneration in a subject having osteoarthritis, comprising intraarticularly administering a composition comprising a C-type natriuretic peptide (CNP) variant to the subject at a dose of from 5 μg/kg to 800 μg/kg of the CNP variant, wherein the CNP variant is selected from the group consisting of:
(SEQ ID NO: 1)
PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
(Pro-Gly-CNP37);
(SEQ ID NO: 2)
GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
(Gly-CNP37);
(SEQ ID NO: 43)
QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC
[CNP-37(M32N)]
(SEQ ID NO: 44)
PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
(Pro-CNP37);
(SEQ ID NO: 45)
MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
(Met-CNP37);
(SEQ ID NO: 46)
GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC
[Gly-CN P-37(M32N)]; and
(SEQ ID NO: 47)
MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
(Met-Gly-CNP37).
10. The method of claim 9 , wherein the increase in cartilage growth or slowing of cartilage degeneration is observed in a joint of the subject.
11. A method of reducing osteophyte growth in a subject having osteoarthritis or having an injury or trauma in a joint, comprising intraarticularly administering a composition comprising a C-type natriuretic peptide (CNP) variant to the subject at a dose of from 5 g/kg to 800 μg/kg of the CNP variant, wherein the CNP variant is selected from the group consisting of:
(SEQ ID NO: 1)
PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
(Pro-Gly-CNP37);
(SEQ ID NO: 2)
GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
(Gly-CNP37);
(SEQ ID NO: 43)
QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC
[CNP-37(M32N)]
(SEQ ID NO: 44)
PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
(Pro-CNP37);
(SEQ ID NO: 45)
MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
(Met-CNP37);
(SEQ ID NO: 46)
GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC
[Gly-CN P-37(M32N)]; and
(SEQ ID NO: 47)
MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
(Met-Gly-CNP37).
12. The method of claim 11 , wherein the subject has osteoarthritis.
13. The method of claim 12 , wherein the osteoarthritis is primary or secondary osteoarthritis.
14. The method of claim 12 , wherein the CNP variant is administered after cartilage degeneration has occurred.
15. The method of claim 11 , wherein the subject has an injury or trauma in a joint, and wherein the CNP variant is administered within one month of the joint injury or trauma.
16. The method of claim 11 , further comprising administration of a second agent.
17. The method of claim 11 , wherein the subject is identified as having increased levels of at least one cartilage-associated biomarker.
18. The method of claim 17 , wherein the at least one cartilage-associated biomarker is selected from the group consisting of CNP, cyclic guanosine monophosphate (cGMP), propeptides of collagen type II and fragments thereof, collagen type II and fragments thereof, osteocalcin, proliferating cell nuclear antigen (PCNA), propeptides of type I procollagen (PINP) and fragments thereof, collagen type I and fragments thereof, and aggrecan chondroitin sulfate.