Method relating to myostatin pathway inhibition
The present invention provides a method for determining whether a patient will respond to treatment with a myostatin pathway inhibitor, the method comprising: (a) determining a level of myostatin and/or activin type II receptor (ActRII) and/or follistatin in at least one muscle biopsy obtained from a treatment target muscle in a subject having or suspected of having muscle atrophy or a muscle wasting condition; and (b) determining a level of myostatin and/or follistatin in a systemic sample obtained from the patient, wherein if: (i) the level of myostatin in the systemic sample is higher than a threshold and/or if the level of follistatin in the sample is lower than a threshold; and (ii) the level of myostatin and/or ActRII receptor in the at least one biopsy sample is higher than a threshold level and/or if the level of follistatin in the at least one biopsy sample is lower than a threshold level, the patient will respond to treatment.
1. A method for determining whether a subject having or suspected of having a muscle atrophy or a muscle wasting condition will respond to treatment with a myostatin pathway inhibitor, the method comprising:
(a) measuring a level of myostatin in a systemic sample obtained from the subject,
(b) selecting a subject wherein the level of myostatin in the systemic sample is higher than myostatin levels in systemic samples from individuals with significant muscle atrophy and/or severe or advanced muscle wasting conditions, but below myostatin levels in systemic samples from healthy individuals; and (c) administering a myostatin pathway inhibitor to the subject of (b).
2. The method according to claim 1 , wherein the myostatin is measured as protein or mRNA.
3. The method according to claim 1 , wherein the myostatin is measured in a pro-peptide or mature protein form.
4. The method according to claim 1 , wherein the systemic sample is a whole blood sample, a serum sample, a plasma sample or a urine sample.
5. The method according to claim 1 , wherein the muscle atrophy or muscle wasting condition is a muscle dystrophy; a central or spinal muscular atrophy;
a neurogenic muscular atrophy; a congenital myopathy; or an ‘idiopathic’ muscle wasting condition.
6. The method according to claim 1 , wherein the myostatin pathway inhibitor is a myostatin antagonist or an ActRII antagonist.
7. The method according to claim 6 , wherein the myostatin antagonist is an anti-myostatin antibody, a myostatin decoy, a follistatin or a follistatin analogue.
8. The method according to claim 6 , wherein the ActRII antagonist is an anti-ActRII antibody, an ActRII decoy or an inhibitor of effectors downstream of the ActRII.
9. A method for treating muscle atrophy or a muscle wasting condition, the method comprising:
(a) measuring a level of myostatin in a systemic sample obtained from a subject having or suspected of having the muscle atrophy or the muscle wasting condition;
(b) selecting a subject wherein the level of myostatin in the systemic sample is higher than myostatin levels in systemic samples from individuals with significatn muscle atrophy and/or severe or advanced muscle wasting conditions, but below myostation levels in systemic samples from healthy individuals;and
(c) administering a treatment for the muscle atrophy or the muscle wasting condition to the subject of (b).
10. A method for determining inclusion of a subject, having or suspected of having muscle atrophy or a muscle wasting condition into a clinical trial for evaluation of a myostatin pathway inhibitor, the method comprising:
(a) measuring a level of myostatin in a systemic sample obtained from the subject,
(b) selecting a subject wherein the level of myostatin in the systemic sample is higher than myostatin levels in systemic samples from individuals with significant muscle atrophy and/or severe or advanced muscle wasting conditions, but below myostatin levelss in systemic samples from healthy individuals; and
(c) including the subject of (b) in the clinical trial;
(d) commencing the clinical trial; and
(e) administering the myostatin pathway inhibitor to the subject.
11. The method according to claim 9 , wherein the myostatin is measured as protein or mRNA.
12. The method according to claim 9 , wherein the myostatin is measured in a pro-peptide or mature protein form.
13. The method according to claim 9 , wherein the systemic sample is a whole blood sample, a serum sample, a plasma sample or a urine sample.
14. The method according to claim 9 , wherein the muscle atrophy or muscle wasting condition is a muscle dystrophy; a central or spinal muscular atrophy;
a neurogenic muscular atrophy; a congenital myopathy; or an ‘idiopathic’ muscle wasting condition.
15. The method according to claim 9 , wherein the myostatin pathway inhibitor is a myostatin antagonist or an ActRII antagonist.
16. The method according to claim 15 , wherein the myostatin antagonist is an anti-myostatin antibody, a myostatin decoy, a follistatin or a follistatin analogue.
17. The method according to claim 15 , wherein the ActRII antagonist is an anti-ActRII antibody, an ActRII decoy or an inhibitor of effectors downstream of the ActRII.
18. The method according to claim 10 , wherein the myostatin is measured as protein or mRNA.
19. The method according to claim 10 , wherein the myostatin is measured in a pro-peptide or mature protein form.
20. The method according to claim 10 , wherein the systemic sample is a whole blood sample, a serum sample, a plasma sample or a urine sample.
21. The method according to claim 10 , wherein the muscle atrophy or muscle wasting condition is a muscle dystrophy; a central or spinal muscular atrophy;
a neurogenic muscular atrophy; a congenital myopathy; or an ‘idiopathic’ muscle wasting condition.
22. The method according to claim 10 , wherein the myostatin pathway inhibitor is a myostatin antagonist or an ActRII antagonist.
23. The method according to claim 22 , wherein the myostatin antagonist is an anti-myostatin antibody, a myostatin decoy, a follistatin or a follistatin analogue.
24. The method according to claim 22 , wherein the ActRII antagonist is an anti-ActRII antibody, an ActRII decoy or an inhibitor of effectors downstream of the ActRII.
25. A method for determining whether a subject having or suspected of having a muscle atrophy or a muscle wasting condition will respond to treatment with a myostatin pathway inhibitor, the method comprising:
(a) measuring a level of myostatin in at least one muscle biopsy sample obtained from a treatment target muscle in the subject; and
(b) selecting a subject wherein the level of myostatin in the at least one muscle biopsy sample is higher than myostatin levels in muscle biopsy samples from individuals with significant muscle atrophy and/or severe or advanced muscle wasting conditions, but below myostatin levels in muscle biopsy samples from healthy individuals; and
(c) administering a myostatin pathway inhibitor to the subject of (b).
26. The method according to claim 25 , wherein the myostatin is measured as protein or mRNA.
27. The method according to claim 25 , wherein the myostatin is measured in a pro-peptide or mature protein form.
28. The method according to claim 25 , wherein the at least one muscle biopsy sample has been obtained from a skeletal muscle.
29. The method according to claim 25 , wherein the muscle atrophy or muscle wasting condition is a muscle dystrophy; a central or spinal muscular atrophy;
a neurogenic muscular atrophy; a congenital myopathy; or an ‘idiopathic’ muscle wasting condition.
30. The method according to claim 25 , wherein the myostatin pathway inhibitor is a myostatin antagonist or an ActRII antagonist.
31. The method according to claim 30 , wherein the myostatin antagonist is an anti-myostatin antibody, a myostatin decoy, a follistatin or a follistatin analogue.
32. The method according to claim 30 , wherein the ActRII antagonist is an anti-ActRII antibody, an ActRII decoy or an inhibitor of effectors downstream of the ActRII.
33. A method for determining whether a subject having or suspected of having a muscle atrophy or a muscle wasting condition will respond to treatment with a myostatin pathway inhibitor, the method comprising:
(a) measuring a level of myostatin in at least one muscle biopsy obtained from a treatment target muscle in the subject; and
(b) measuring a level of myostatin in a systemic sample obtained from the subject,
(c) selecting a subject wherein:
(i) the level of myostatin in the systemic sample is higher than myostatin levels in systemic samples from individuals with significant muscle atrophy and/or severe or advanced muscle wasting conditions, but below myostatin levels in systemic samples from healthy individuals; and
(ii) the level of myostatin in the at least one muscle biopsy sample is higher than myostatin levels in muscle biopsy samples from individuals with significant muscle atrophy and/or severe or advanced muscle wasting conditions, but below myostatin levels in muscle biopsy samples from heathy individuals; and
(d) administering a myostatin pathway inhibitor to the subject of (c).
34. The method according to claim 33 , wherein the myostatin is measured as protein or mRNA.
35. The method according to claim 33 , wherein the myostatin is measured in a pro-peptide or mature protein form.
36. The method according to claim 33 , wherein the at least one muscle biopsy sample has been obtained from a skeletal muscle.
37. The method according to claim 33 , wherein the systemic sample is a whole blood sample, a serum sample, a plasma sample or a urine sample.
38. The method according to claim 33 , wherein the muscle atrophy or muscle wasting condition is a muscle dystrophy; a central or spinal muscular atrophy;
a neurogenic muscular atrophy; a congenital myopathy; or an ‘idiopathic’ muscle wasting condition.
39. The method according to claim 33 , wherein the myostatin pathway inhibitor is a myostatin antagonist or an ActRII antagonist.
40. The method according to claim 39 , wherein the myostatin antagonist is an anti-myostatin antibody, a myostatin decoy, a follistatin or a follistatin analogue.
41. The method according to claim 39 , wherein the ActRII antagonist is an anti-ActRII antibody, an ActRII decoy or an inhibitor of effectors downstream of the ActRII.
42. A method for treating muscle atrophy or a muscle wasting condition, the method comprising:
(a) measuring a level of myostatin in at least one muscle biopsy obtained from a treatment target muscle in a subject having or suspected of having the muscle atrophy or the muscle wasting condition; and
(b) selecting a subject wherein the level of myostatin in the at least one muscle biopsy sample is higher than myostatin levels in muscle biopsy samples from individuals with significant muscle atrophy and/or severe or advanced muscle wasting conditions, but below myostatin levels in muscle biopsy samples from healthy individuals; and (c) administering a treatment for the muscle atrophy or the muscle wasting condition to the subject of (b).
43. The method according to claim 42 , wherein the myostatin is measured as protein or mRNA.
44. The method according to claim 42 , wherein the myostatin is measured in a pro-peptide or mature protein form.
45. The method according to claim 42 , wherein the at least one muscle biopsy sample has been obtained from a skeletal muscle.
46. The method according to claim 42 , wherein the systemic sample is a whole blood sample, a serum sample, a plasma sample or a urine sample.
47. The method according to claim 42 , wherein the muscle atrophy or muscle wasting condition is a muscle dystrophy; a central or spinal muscular atrophy;
a neurogenic muscular atrophy; a congenital myopathy; or an ‘idiopathic’ muscle wasting condition.
48. The method according to claim 42 , wherein the myostatin pathway inhibitor is a myostatin antagonist or an ActRII antagonist.
49. The method according to claim 48 , wherein the myostatin antagonist is an anti-myostatin antibody, a myostatin decoy, a follistatin or a follistatin analogue.
50. The method according to claim 48 , wherein the ActRII antagonist is an anti-ActRII antibody, an ActRII decoy or an inhibitor of effectors downstream of the ActRII.
51. A method for treating muscle atrophy or a muscle wasting condition, the method comprising:
(a) measuring a level of myostatin in at least one muscle biopsy sample obtained from a treatment target muscle in a subject having or suspected of having the muscle atrophy or the muscle wasting condition; and
(b) measuring a level of myostatin in a systemic sample obtained from the subject;
(c) selecting a subject wherein:
(i) the level of myostatin in the systemic sample is higher than myostatin levels in systemic samples from individuals with significant muscle atrophy and/or severe or advanced muscle wasting conditions, but below myostatin levels in systemic samples from healthy individuals; and
(ii) the level of myostatin in the at least one muscle biopsy sample is higher than myostatin levels in muscle biopsy samples from individuals with significant muscle atrophy and/or severe or advanced muscle wasting conditions, but below myostatin levels in muscle biopsy samples from healthy individuals; and (d) administering a treatment for the muscle atrophy or the muscle wasting condition to the subject of (c).
52. The method according to claim 51 , wherein the myostatin is measured as protein or mRNA.
53. The method according to claim 51 , wherein the myostatin is measured in a pro-peptide or mature protein form.
54. The method according to claim 51 , wherein the at least one muscle biopsy sample has been obtained from a skeletal muscle.
55. The method according to claim 51 , wherein the systemic sample is a whole blood sample, a serum sample, a plasma sample or a urine sample.
56. The method according to claim 51 , wherein the muscle atrophy or muscle wasting condition is a muscle dystrophy; a central or spinal muscular atrophy;
a neurogenic muscular atrophy; a congenital myopathy; or an ‘idiopathic’ muscle wasting condition.
57. The method according to claim 51 , wherein the myostatin pathway inhibitor is a myostatin antagonist or an ActRII antagonist.
58. The method according to claim 57 , wherein the myostatin antagonist is an anti-myostatin antibody, a myostatin decoy, a follistatin or a follistatin analogue.
59. The method according to claim 57 , wherein the ActRII antagonist is an anti-ActRII antibody, an ActRII decoy or an inhibitor of effectors downstream of the ActRII.
60. A method for determining inclusion of a subject, having or suspected of having muscle atrophy or a muscle wasting condition into a clinical trial for evaluation of a myostatin pathway inhibitor, the method comprising:
(a) measuring a level of myostatin in at least one muscle biopsy obtained from a treatment target muscle in the subject; and
(b) selecting a subject wherein the level of myostatin in the at least one muscle biopsy sample is higher than myostatin levels in muscle biopsy samples from individuals with significant muscle atrophy and/or severe or advanced muscle wasting conditions, but below myostatin levels in muscle biopsy samples from healthy individuals;and
(c) including the subject of (b) in the clinical trial;
(d) commencing the clinical trial; and
(e) administering the myostatin pathway inhibitor to the subject.
61. The method according to claim 60 , wherein the myostatin is measured as protein or mRNA.
62. The method according to claim 60 , wherein the myostatin is measured in a pro-peptide or mature protein form.
63. The method according to claim 60 , wherein the at least one muscle biopsy sample has been obtained from a skeletal muscle.
64. The method according to claim 60 , wherein the muscle atrophy or muscle wasting condition is a muscle dystrophy; a central or spinal muscular atrophy;
a neurogenic muscular atrophy; a congenital myopathy; or an ‘idiopathic’ muscle wasting condition.
65. The method according to claim 60 , wherein the myostatin pathway inhibitor is a myostatin antagonist or an ActRII antagonist.
66. The method according to claim 65 , wherein the myostatin antagonist is an anti-myostatin antibody, a myostatin decoy, a follistatin or a follistatin analogue.
67. The method according to claim 65 , wherein the ActRII antagonist is an anti-ActRII antibody, an ActRII decoy or an inhibitor of effectors downstream of the ActRII.
68. A method for determining inclusion of a subject, having or suspected of having muscle atrophy or a muscle wasting condition into a clinical trial for evaluation of a myostatin pathway inhibitor, the method comprising:
(a) measuring a level of myostatin in at least one muscle biopsy obtained from a treatment target muscle in the subject; and
(b) measuring a level of myostatin in a systemic sample obtained from the subject;
(c) selecting a subject wherein:
(i) the level of myostatin in the systemic sample is higher than myostatin levels in systemic samples from individuals with significant muscle atrophy and/or severe or advanced muscle wasting conditions, but below myostatin levels in systemic samples from healthy individuals; and
(ii) the level of myostatin in the at least one muscle biopsy sample is higher than myostatin levels in muscle biopsy samples from individuals with significant muscle atrophy and/or severe or advanced muscle wasting conditions, but below myostatin levels in muscle biopshy samples from healthy individuals;
(d) including the subject of (c) in the clinical trial;
(e) commencing the clinical trial; and
(f) administering the myostatin pathway inhibitor to the subject.
69. The method according to claim 68 , wherein the myostatin is measured as protein or mRNA.
70. The method according to claim 68 , wherein the myostatin is measured in a pro-peptide or mature protein form.
71. The method according to claim 68 , wherein the at least one muscle biopsy sample has been obtained from a skeletal muscle.
72. The method according to claim 68 , wherein the systemic sample is a whole blood sample, a serum sample, a plasma sample or a urine sample.
73. The method according to claim 68 , wherein the muscle atrophy or muscle wasting condition is a muscle dystrophy; a central or spinal muscular atrophy;
a neurogenic muscular atrophy; a congenital myopathy; or an ‘idiopathic’ muscle wasting condition.
74. The method according to claim 68 , wherein the myostatin pathway inhibitor is a myostatin antagonist or an ActRII antagonist.
75. The method according to claim 74 , wherein the myostatin antagonist is an anti-myostatin antibody, a myostatin decoy, a follistatin or a follistatin analogue.
76. The method according to claim 74 , wherein the ActRII antagonist is an anti-ActRII antibody, an ActRII decoy or an inhibitor of effectors downstream of the ActRII.