Treatment of limb spasticity

Claims

1. A modified botulinum neurotoxin A (BoNT / A) for use in the treatment of limb spasticity, wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a standard dose of over 17,000 pg of modified BoNT / A, into multiple affected muscles, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered into the affected muscle of the first group and / or a plurality of unit doses are administered into the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 600,000 pg, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (the H domain С ).

2. A method of treating limb spasticity comprising administering a modified botulinum neurotoxin A (BoNT / A) by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a standard dose of over 17,000 pg of modified BoNT / A, into multiple affected muscles, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered into the affected muscle of the first group and / or a plurality of unit doses are administered into the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 600,000 pg, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (the H domain С ).

3. Use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for the treatment of limb spasticity, wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a standard dose of over 17,000 pg of modified BoNT / A, into multiple affected muscles, where several affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered into the affected muscle of the first group and / or a plurality of unit doses are administered into the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 600,000 pg, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (the H domain С ).

4. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the standard dose is from more than 17,000 pg to no more than 40,000 pg (e.g. from 17,001 pg to no more than 40,000 pg) of the modified BoNT / A.

5. The modified BoNT / A for use, method or use according to any of the preceding claims, wherein the standard dose is from 20,000 pg to 30,000 pg, preferably from 24,000 pg to 26,000 pg, more preferably 25,000 pg of the modified BoNT / A.

6. Modified BoNT / A for use, method or use according to any one of claims 1 to 4, wherein the standard dose is from 30,000 pg to 40,000 pg, preferably from 35,000 pg to 37,000 pg, more preferably 36,000 pg of modified BoNT / A.

7. A modified BoNT / A for use, method or use according to any one of claims 1 to 4, wherein the standard dose is from more than 23,000 pg to no more than 38,000 pg (e.g. from 23,001 pg to no more than 38,000 pg) of the modified BoNT / A.

8. A modified BoNT / A for use, method or use according to any one of claims 1-4 or 6-7, wherein the standard dose is from more than 34,000 pg to no more than 38,000 pg (e.g. from 34,001 pg to no more than 38,000 pg) of the modified BoNT / A.

9. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the total dose administered is from 250,000 pg to 600,000 pg (e.g. from 255,000 pg to 600,000 pg) of modified BoNT / A.

10. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the total dose administered is from more than 255,000 pg to 600,000 pg of modified BoNT / A.

11. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the total dose administered is from 350,000 to 600,000 pg of modified BoNT / A.

12. The modified BoNT / A for use, method or use according to any one of claims 1 to 10, wherein the total dose administered is from 300,000 pg to 450,000 pg, preferably from 360,000 pg to 390,000 pg, more preferably not more than 375,000 pg of the modified BoNT / A.

13. The modified BoNT / A for use, method or use according to any one of claims 1 to 11, wherein the total dose administered is from 450,000 pg to 600,000 pg, preferably from 525,000 pg to 555,000 pg, more preferably not more than 540,000 pg of the modified BoNT / A.

14. A modified BoNT / A for use, method or use according to any one of claims 1-11 or 13, wherein the total dose administered is from 500,000 to 600,000 pg of modified BoNT / A.

15. A modified botulinum neurotoxin A (BoNT / A) for use in the treatment of limb spasticity, wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, where the modified BoNT / A is administered as a standard dose of more than 707 units of modified BoNT / A into a plurality of affected muscles, and where 1 unit represents the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) for mice, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered into the affected muscle of the first group and / or a plurality of unit doses are administered into the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 24985 units, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (the H domain С ).

16. A method of treating limb spasticity comprising administering a modified botulinum neurotoxin A (BoNT / A) by intramuscular injection into a plurality of affected muscles of a subject, where the modified BoNT / A is administered as a standard dose of more than 707 units of modified BoNT / A into a plurality of affected muscles, and where 1 unit represents the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) for mice, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered into the affected muscle of the first group and / or a plurality of unit doses are administered into the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 24985 units, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (the H domain С ).

17. Use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for the treatment of limb spasticity, wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, where the modified BoNT / A is administered as a standard dose of more than 707 units of modified BoNT / A into a plurality of affected muscles, and where 1 unit represents the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) for mice, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered into the affected muscle of the first group and / or a plurality of unit doses are administered into the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 24985 units, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (the H domain С ).

18. A modified BoNT / A for use, method or use according to any one of claims 15-17, wherein the standard dose is from more than 707 units to no more than 1664 units (e.g. from 708 units to no more than 1664 units) of the modified BoNT / A.

19. Modified BoNT / A for use, method or use according to any one of claims 15-18, wherein the standard dose is from 832 units to 1248 units, preferably from 998 units to 1082 units, more preferably 1040 units of modified BoNT / A.

20. Modified BoNT / A for use, method or use according to any one of claims 15-18, wherein the standard dose is from 1248 units to 1664 units, preferably from 1456 units to 1539 units, more preferably 1498 units of modified BoNT / A.

21. A modified BoNT / A for use, method or use according to any one of claims 15-18, wherein the standard dose is from more than 949 units to no more than 1581 units or from more than 957 units to no more than 1581 units (e.g. from 950 units to no more than 1581 units or from 958 units to no more than 1581 units) of the modified BoNT / A.

22. A modified BoNT / A for use, method or use according to any of claims 15-18 or 20-21, wherein the standard dose is from more than 1414 units to no more than 1581 units (e.g. from 1415 units to no more than 1581 units) of the modified BoNT / A.

23. A modified BoNT / A for use, method or use according to any one of claims 15-22, wherein the total dose administered is from 10,399 units to 24,985 units (e.g. from 10,607 units to 24,985 units) of modified BoNT / A.

24. A modified BoNT / A for use, method or use according to any one of claims 15-23, wherein the total dose administered is more than 10,607 units to 24,985 units of modified BoNT / A.

25. Modified BoNT / A for use, method or use according to any one of claims 15-24, wherein the total dose administered is from 12479 units to 18719 units, preferably from 14975 units to 16223 units, more preferably not more than 15599 units of modified BoNT / A.

26. A modified BoNT / A for use, method or use according to any one of claims 12-20, wherein the total dose administered is from 14,559 units to 24,985 units of modified BoNT / A.

27. Modified BoNT / A for use, method or use according to any one of claims 15-24 or 26, wherein the total dose administered is from 18719 units to 24985 units, preferably from 21839 units to 23087 units, more preferably not more than 22463 units of modified BoNT / A.

28. A modified BoNT / A for use, method or use according to any of claims 15-24 or 26-27, wherein the total dose administered is from 20,799 units to 24,985 units of modified BoNT / A.

29. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the spasticity is adult limb spasticity and the subject is an adult subject.

30. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the limb spasticity is upper limb spasticity.

31. A modified botulinum neurotoxin A (BoNT / A) for use in the treatment of limb spasticity in children, wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a standard dose of more than 8500 pg of modified BoNT / A, into multiple affected muscles, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered into the affected muscle of the first group and / or a plurality of unit doses are administered into the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 300,000 pg, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (the H domain С ).

32. A method of treating limb spasticity in children comprising administering a modified botulinum neurotoxin A (BoNT / A) by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a standard dose of more than 8500 pg of modified BoNT / A, into multiple affected muscles, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered into the affected muscle of the first group and / or a plurality of unit doses are administered into the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 300,000 pg, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (the H domain С ).

33. Use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for the treatment of limb spasticity in children, wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a standard dose of more than 8500 pg of modified BoNT / A, into multiple affected muscles, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered into the affected muscle of the first group and / or a plurality of unit doses are administered into the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 300,000 pg, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (the H domain С ).

34. A modified BoNT / A for use, method or use according to any one of claims 31-33, wherein the standard dose is from greater than 8500 pg to no more than 20000 pg (e.g. from 8501 pg to no more than 20000 pg) of the modified BoNT / A, preferably wherein the standard dose is from greater than 8500 pg to no more than 18000 pg.

35. The modified BoNT / A for use, method or use according to any one of claims 31-34, wherein the standard dose is from 10,000 pg to 15,000, preferably from 12,000 pg to 13,000 pg, more preferably 12,500 pg of the modified BoNT / A.

36. Modified BoNT / A for use, method or use according to any one of claims 31-34, wherein the standard dose is from 15,000 pg to 20,000, preferably from 17,500 pg to 18,500 pg, more preferably 18,000 pg of modified BoNT / A.

37. A modified BoNT / A for use, method or use according to any one of claims 31-34, wherein the standard dose is from more than 11,500 pg to no more than 19,000 pg (e.g. from 11,501 pg to no more than 19,000 pg) of the modified BoNT / A.

38. A modified BoNT / A for use, method or use according to any of claims 31-34 or 36-37, wherein the standard dose is from more than 17,000 pg to no more than 19,000 pg (e.g. from 17,001 pg to 19,000 pg) of the modified BoNT / A.

39. A modified BoNT / A for use, method or use according to any one of claims 31-38, wherein the total dose administered is from 125,000 pg to 300,000 pg (e.g. from 127,500 pg to 300,000 pg) of modified BoNT / A.

40. A modified BoNT / A for use, method or use according to any one of claims 31-39, wherein the total dose administered is from more than 127,500 pg to 300,000 pg of modified BoNT / A.

41. A modified BoNT / A for use, method or use according to any one of claims 31-40, wherein the total dose administered is from 175,000 to 300,000 pg of modified BoNT / A.

42. The modified BoNT / A for use, method or use according to any one of claims 31-40, wherein the total dose administered is from 150,000 pg to 225,000 pg, preferably from 180,000 pg to 195,000 pg, more preferably not more than 187,500 pg of the modified BoNT / A.

43. The modified BoNT / A for use, method or use according to any one of claims 31-41, wherein the total dose administered is from 225,000 pg to 300,000 pg, preferably from 262,500 pg to 277,500 pg, more preferably not more than 270,000 pg of the modified BoNT / A.

44. A modified BoNT / A for use, method or use according to any one of claims 31-41 or 43, wherein the total dose administered is from 250,000 to 300,000 pg of modified BoNT / A.

45. A modified BoNT / A for use in the treatment of limb spasticity in children, wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, where the modified BoNT / A is administered as a standard dose of more than 353.5 units of modified BoNT / A into a plurality of affected muscles, and where 1 unit represents the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) for mice, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered into the affected muscle of the first group and / or a plurality of unit doses are administered into the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 12479 units, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (the H domain С ).

46. A method of treating limb spasticity in children comprising administering a modified botulinum neurotoxin A (BoNT / A) by intramuscular injection into a plurality of affected muscles of a subject, where the modified BoNT / A is administered as a standard dose of more than 353.5 units of modified BoNT / A into a plurality of affected muscles, and where 1 unit represents the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) for mice, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered into the affected muscle of the first group and / or a plurality of unit doses are administered into the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 12479 units, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (the H domain С ).

47. Use of modified BoNT / A in the manufacture of a medicament for the treatment of limb spasticity in children, wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, where the modified BoNT / A is administered as a standard dose of more than 353.5 units of modified BoNT / A, into a plurality of affected muscles, and where 1 unit represents the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) for mice, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered into the affected muscle of the first group and / or a plurality of unit doses are administered into the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 1247 9 units, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (the H domain С ).

48. A modified BoNT / A for use, method or use according to any one of claims 45-47, wherein the standard dose is from greater than 353.5 to no more than 832 units (e.g. from 354 to no more than 832 units) of modified BoNT / A, preferably wherein the standard dose is from greater than 353.5 to no more than 749 units (e.g. from 354 to no more than 749 units).

49. Modified BoNT / A for use, method or use according to any one of claims 45-48, wherein the standard dose is from 416 units to 624 units, preferably from 499 units to 541 units, more preferably 520 units of modified BoNT / A.

50. Modified BoNT / A for use, method or use according to any one of claims 45-48, wherein the standard dose is from 624 units to 832 units, preferably from 728 units to 770 units, more preferably 749 units of modified BoNT / A.

51. A modified BoNT / A for use, method or use according to any one of claims 45-48, wherein the standard dose is from more than 478 units to no more than 790 units (e.g. from 479 units to no more than 790 units) of the modified BoNT / A.

52. A modified BoNT / A for use, method or use according to any one of claims 45-48, wherein the standard dose is from more than 707 units to no more than 790 units (e.g. from 708 units to no more than 790 units) of the modified BoNT / A.

53. A modified BoNT / A for use, method or use according to any one of claims 45-52, wherein the total dose administered is from 5200 units to 12479 units (e.g. from 5304 units to 12479 units) of modified BoNT / A.

54. A modified BoNT / A for use, method or use according to any one of claims 45-53, wherein the total dose administered is from more than 5304 units to 12479 units of modified BoNT / A.

55. The modified BoNT / A for use, method or use according to any one of claims 45-54, wherein the total dose administered is from 6240 units to 9360 units, preferably from 7488 units to 8112 units, more preferably not more than 7800 units of modified BoNT / A.

56. A modified BoNT / A for use, method or use according to any one of claims 45-54, wherein the total dose administered is from 7280 units to 12479 units of modified BoNT / A.

57. Modified BoNT / A for use, method or use according to any one of claims 45-54 or 56, wherein the total dose administered is from 9360 units to 12479 units, preferably from 10920 units to 11544 units, more preferably not more than 11232 units of modified BoNT / A.

58. A modified BoNT / A for use, method or use according to any one of claims 45-54 or 56-57, wherein the total dose administered is from 10,399 units to 12,479 units of modified BoNT / A.

59. A modified BoNT / A for the use, method or use according to any one of claims 31-58, wherein the limb spasticity in children is upper limb spasticity in children.

60. A modified BoNT / A for the use, method or use of any of the preceding claims, wherein: The first group of affected muscles includes: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of gastrocnemius, lateral head of gastrocnemius, flexor digitorum longus, flexor pollicis longus, gastrocnemius, deltoid, levator scapulae, pronator quadratus, flexor pollicis longus, adductor pollicis brevis, palmaris longus, lumbricales, opposing pollicis, adductor magnus, adductor longus, adductor brevis, gracilis, medial hamstrings, lateral hamstrings, tensor fasciae latae, rectus femoris, vastus lateralis, vastus medialis, vastus intermedius,gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, The second group of muscles affected includes: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, and gastrocnemius.

61. A modified botulinum neurotoxin A (BoNT / A) for use in the treatment of limb spasticity (preferably adult limb spasticity), wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a unit dose of 10,000 pg to 20,000 pg (e.g. 14,000 pg to 16,000 pg, preferably 15,000 pg) of the modified BoNT / A to a plurality of affected muscles, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered to the affected muscle of the first group and / or a plurality of unit doses are administered to the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 300,000 pg (e.g. no more than 240,000 pg, preferably no more than 225,000 pg), and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor-binding domain of BoNT / B (domain H C ).

62. A method for treating limb spasticity (preferably limb spasticity in adults) comprising administering a modified botulinum neurotoxin A (BoNT / A) by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a unit dose of 10,000 pg to 20,000 pg (e.g. 14,000 pg to 16,000 pg, preferably 15,000 pg) of the modified BoNT / A to a plurality of affected muscles, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered to the affected muscle of the first group and / or a plurality of unit doses are administered to the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 300,000 pg (e.g. no more than 240,000 pg, preferably no more than 225,000 pg), and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor-binding domain of BoNT / B (domain H C ).

63. Use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for the treatment of limb spasticity (preferably limb spasticity in adults), wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a unit dose of 10,000 pg to 20,000 pg (e.g. 14,000 pg to 16,000 pg, preferably 15,000 pg) of the modified BoNT / A to a plurality of affected muscles, where several affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered to the affected muscle of the first group and / or a plurality of unit doses are administered to the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 300,000 pg (e.g. no more than 240,000 pg, preferably no more than 225,000 pg), and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor-binding domain of BoNT / B (domain H C ).

64. A modified botulinum neurotoxin A (BoNT / A) for use in the treatment of limb spasticity (preferably adult limb spasticity), wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a unit dose of 416 units to 832 units (e.g. 582 units to 666 units, preferably 624 units) of modified BoNT / A to a plurality of affected muscles, and wherein 1 unit is the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) for mice, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered to the affected muscle of the first group and / or a plurality of unit doses are administered to the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 12480 units (e.g. no more than 9990 units, preferably no more than 9360 units), and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (domain H C ).

65. A method for treating limb spasticity (preferably adult limb spasticity) comprising administering a modified botulinum neurotoxin A (BoNT / A) by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a unit dose of 416 units to 832 units (e.g. 582 units to 666 units, preferably 624 units) of modified BoNT / A to a plurality of affected muscles, and wherein 1 unit is the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) for mice, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered to the affected muscle of the first group and / or a plurality of unit doses are administered to the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 12480 units (e.g. no more than 9990 units, preferably no more than 9360 units), and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (domain H C ).

66. Use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for the treatment of limb spasticity (preferably limb spasticity in adults), wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a unit dose of 416 units to 832 units (e.g. 582 units to 666 units, preferably 624 units) of modified BoNT / A to a plurality of affected muscles, and wherein 1 unit is the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) for mice, where several affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered to the affected muscle of the first group and / or a plurality of unit doses are administered to the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 12480 units (e.g. no more than 9990 units, preferably no more than 9360 units), and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (domain H C ).

67. A modified botulinum neurotoxin A (BoNT / A) for use in the treatment of limb spasticity in children, wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a unit dose of 5000 pg to 10000 pg (e.g. 7000 pg to 8000 pg, preferably 7500 pg) of the modified BoNT / A to a plurality of affected muscles, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered to the affected muscle of the first group and / or a plurality of unit doses are administered to the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 150,000 pg (e.g. no more than 120,000 pg, preferably no more than 112,500 pg), and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor-binding domain of BoNT / B (domain H C ).

68. A method of treating limb spasticity in children comprising administering a modified botulinum neurotoxin A (BoNT / A) by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a unit dose of 5000 pg to 10000 pg (e.g. 7000 pg to 8000 pg, preferably 7500 pg) of the modified BoNT / A to a plurality of affected muscles, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered to the affected muscle of the first group and / or a plurality of unit doses are administered to the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 150,000 pg (e.g. no more than 120,000 pg, preferably no more than 112,500 pg), and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor-binding domain of BoNT / B (domain H C ).

69. Use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for the treatment of limb spasticity in children, wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a unit dose of 5000 pg to 10000 pg (e.g. 7000 pg to 8000 pg, preferably 7500 pg) of the modified BoNT / A to a plurality of affected muscles, where several affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered to the affected muscle of the first group and / or a plurality of unit doses are administered to the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 150,000 pg (e.g. no more than 120,000 pg, preferably no more than 112,500 pg), and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor-binding domain of BoNT / B (domain H C ).

70. A modified botulinum neurotoxin A (BoNT / A) for use in the treatment of limb spasticity in children, wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a unit dose of 208 units to 416 units (e.g. 291 units to 333 units, preferably 312 units) of modified BoNT / A to a plurality of affected muscles, and wherein 1 unit is the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) for mice, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered to the affected muscle of the first group and / or a plurality of unit doses are administered to the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 6240 units (e.g. no more than 4995 units, preferably no more than 4680 units), and where the modified BoNT / A contains the BoNT / A light chain and translocation domain, and the receptor binding domain of BoNT / B (the H domain С ).

71. A method for treating limb spasticity in children comprising administering a modified botulinum neurotoxin A (BoNT / A) by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a unit dose of 208 units to 416 units (e.g. 291 units to 333 units, preferably 312 units) of modified BoNT / A to a plurality of affected muscles, and wherein 1 unit is the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) for mice, where the set of affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered to the affected muscle of the first group and / or a plurality of unit doses are administered to the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 6240 units (e.g. no more than 4995 units, preferably no more than 4680 units), and where the modified BoNT / A contains the BoNT / A light chain and translocation domain, and the receptor binding domain of BoNT / B (the H domain С ).

72. Use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for the treatment of limb spasticity in children, wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of a subject, wherein the modified BoNT / A is administered as a unit dose of 208 units to 416 units (e.g. 291 units to 333 units, preferably 312 units) of modified BoNT / A to a plurality of affected muscles, and wherein 1 unit is the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) for mice, where several affected muscles are selected from: the first group, including: flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, flexor carpi ulnaris, brachioradialis, pronator teres, biceps brachii, medial head of the gastrocnemius muscle (medial gastrocnemius muscle), lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), flexor digitorum longus, flexor pollicis longus, gastrocnemius muscle, deltoid muscle, levator scapulae muscle, pronator quadratus, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, palmaris longus, lumbrical muscles, opposing pollicis muscle, adductor magnus, adductor longus, adductor brevis, gracilis muscle, medial muscles of the posterior surface thighs, lateral muscles of the back of the thigh, tensor fasciae lata, rectus femoris, vastus lateralis,vastus medialis, vastus intermedius, gluteus maximus, tibialis anterior, flexor digitorum brevis, extensor hallucis longus, and flexor hallucis brevis; and, the second group, including: the triceps brachii (long head), subscapularis, pectoralis major (e.g. pectoralis major), latissimus dorsi, biceps brachii, brachialis, soleus, tibialis posterior, brachioradialis, teres major, iliopsoas, adductor magnus, hamstrings (e.g. biceps femoris, semimembranosus, and / or semitendinosus), rectus femoris, and gastrocnemius; and wherein a single unit dose is administered to the affected muscle of the first group and / or a plurality of unit doses are administered to the affected muscle of the second group, and wherein the total dose administered during treatment is no more than 6240 units (e.g. no more than 4995 units, preferably no more than 4680 units), and where the modified BoNT / A contains the BoNT / A light chain and translocation domain, and the receptor binding domain of BoNT / B (the H domain С ).

73. A modified BoNT / A for the use, method or use of any of the preceding claims, wherein the spasticity is upper limb spasticity and wherein the plurality of affected muscles are selected from: the first group, comprising (preferably consisting of): the flexor digitorum carpi superficialis, the flexor digitorum profundus, the flexor carpi radialis, the flexor carpi ulnaris and the brachioradialis; and the second group, including (preferably consisting of): the brachialis muscle, the biceps brachii, the triceps brachii (long head), the subscapularis muscle, the pectoral muscle (e.g. the pectoralis major) and the latissimus dorsi muscle.

74. A modified BoNT / A for use, method or use according to claim 73, wherein two standard doses are administered to the affected second muscle group.

75. A modified BoNT / A for use, method or use according to any one of claims 1-29, 31-58 or 60-72, wherein at least one of the plurality of affected muscles is selected from: the adductor magnus, the hamstring (e.g. the biceps femoris, semimembranosus and / or semitendinosus) and the rectus femoris.

76. A modified BoNT / A for use, method or use according to any one of claims 1-29, 31-58, 60-72 or 75, wherein the spasticity is lower limb spasticity and wherein the plurality of affected muscles are selected from: a first group comprising (preferably consisting of): the medial head of the gastrocnemius muscle (medial gastrocnemius muscle), the lateral head of the gastrocnemius muscle (lateral gastrocnemius muscle), the tibialis anterior muscle, the flexor digitorum longus, the flexor digitorum brevis, the flexor hallucis longus, the flexor hallucis brevis, the gracilis muscle, and the gluteus maximus muscle; and the second group, including (preferably consisting of): the soleus muscle, the posterior tibialis muscle, the rectus femoris muscle, the posterior thigh muscle (e.g., the biceps femoris muscle, the semimembranosus muscle and / or the semitendinosus muscle) and the adductor magnus muscle.

77. Modified BoNT / A for use, method or use according to claim 76, wherein if the muscle of the second group is: (a) the soleus muscle, into which three standard doses are injected; or (b) the tibialis posterior, rectus femoris, hamstrings (e.g. biceps femoris, semimembranosus and / or semitendinosus) or adductor magnus, into which two standard doses are administered.

78. A modified BoNT / A for use, method or administration according to any of the preceding claims, wherein the total number of unit doses administered during treatment is no more than 15 unit doses.

79. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the modified BoNT / A comprises a polypeptide sequence having at least 70% sequence identity to SEQ ID NO:

6.

80. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the modified BoNT / A comprises the polypeptide sequence of SEQ ID NO:

6.

81. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the modified BoNT / A consists of the polypeptide sequence of SEQ ID NO:

6.

82. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the modified BoNT / A has a safety factor greater than 7, wherein the safety factor is calculated as: the dose of toxin required to produce a -10% change in body weight, measured in pg / mouse, divided by the DAS ED 50 , measured in pg / mouse, where E0 50 = dose required to obtain a DAS score of 2.

83. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the spasticity of the limb is treated for a longer period than with treatment with unmodified BoNT / A (e.g. SEQ ID NO: 2 [such as the two-chain form of SEQ ID NO: 2]).

84. A standard dosage form of modified botulinum neurotoxin A (BoNT / A) (e.g. for the treatment of limb spasticity in adults), wherein the standard dosage form comprises: (a) more than 17,000 pg modified BoNT / A; or (b) more than 707 units of modified BoNT / A, where 1 unit represents the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) for mice; and (c) optionally a pharmaceutically acceptable carrier, excipient, adjuvant and / or salt, where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (the H domain С ).

85. The unit dosage form of claim 84, wherein the unit dosage form comprises from 20,000 pg to 30,000 pg, preferably from 24,000 pg to 26,000 pg, more preferably 25,000 pg of modified BoNT / A.

86. The unit dosage form of claim 84, wherein the unit dosage form comprises from 832 units to 1248 units, preferably from 998 units to 1082 units, more preferably 1040 units of modified BoNT / A.

87. The unit dosage form of claim 84, wherein the unit dosage form comprises from 30,000 pg to 40,000 pg, preferably from 35,000 pg to 37,000 pg, more preferably 36,000 pg of modified BoNT / A.

88. The unit dosage form of claim 84, wherein the unit dosage form comprises from 1248 units to 1664 units, preferably from 1456 units to 1539 units, more preferably 1498 units of modified BoNT / A.

89. A standard dosage form of modified botulinum neurotoxin A (BoNT / A) for the treatment of children (e.g. for the treatment of limb spasticity in children), wherein the standard dosage form comprises: (a) more than 8500 pg modified BoNT / A; or (b) more than 353.5 units of modified BoNT / A, where 1 unit is the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) for mice; and optionally a pharmaceutically acceptable carrier, excipient, adjuvant and / or salt, where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor binding domain of BoNT / B (the H domain С ).

90. The unit dosage form of claim 89, wherein the unit dosage form comprises from 10,000 pg to 15,000 pg, preferably from 12,000 pg to 13,000 pg, more preferably 12,500 pg of modified BoNT / A.

91. The unit dosage form of claim 89, wherein the unit dosage form contains from 416 units to 624 units, preferably from 499 units to 541 units, more preferably 520 units of modified BoNT / A.

92. The unit dosage form of claim 89, wherein the unit dosage form contains from 15,000 pg to 20,000 pg, preferably from 17,500 pg to 18,500 pg, more preferably 18,000 pg of modified BoNT / A.

93. The unit dosage form of claim 89, wherein the unit dosage form comprises from 624 units to 832 units, preferably from 728 units to 770 units, more preferably 749 units of modified BoNT / A.

94. A modified BoNT / A for use, method, use or unit dosage form according to any of the preceding claims, wherein the modified BoNT / A is a double-chain modified BoNT / A, wherein the L-chain is linked to the H-chain via a disulfide bond, obtained by a method comprising contacting a single-chain modified BoNT / A comprising (or consisting of) SEQ ID NO: 6 with a protease that hydrolyzes the peptide bond in its activation loop, thereby converting the single-chain modified BoNT / A into the corresponding double-chain modified BoNT / A.

95. A modified BoNT / A for use, method, use or unit dosage form according to any of the preceding claims, wherein the initial amino acid methionine residue of the polypeptide sequence of the modified BoNT / A is optional.

96. A modified BoNT / A for use, method, use or unit dosage form according to any of the preceding claims, wherein the initial amino acid methionine residue of the polypeptide sequence of the modified BoNT / A is absent.

97. A modified BoNT / A for use, method, use or unit dosage form according to any of the preceding claims, wherein the H domain с BoNT / B comprises one or more substitution mutations selected from the group consisting of: E1191M; S1199Y; V1118M; Y1183M; E1191I; E1191Q; E1191T; S1199F; S1199L; S1201V; and combinations thereof, preferably wherein the H domain С BoNT / B contains mutations such as the substitutions E1191M and S1199Y.

98. A modified BoNT / A for use, method, use or unit dosage form according to any of the preceding claims, wherein the modified BoNT / A is a double-chain modified BoNT / A comprising (or consisting of) a light chain comprising SEQ ID NO: 11 or 12 (preferably SEQ ID NO: 11) and a heavy chain comprising SEQ ID NO: 13, wherein the light chain and the heavy chain are linked together by a disulfide bond.

99. A set containing: (a) a unit dosage form according to any one of paragraphs 84 to 98; and (b) instructions for its use in the treatment of limb spasticity; and (c) optionally, a diluent.

100. A standard dosage form according to any one of paragraphs 84-88 or 94-98 for use in the treatment of limb spasticity in adults.

101. A method for treating limb spasticity in adults, comprising administering to a subject a dosage form according to any one of paragraphs 84-88 or 94-98.

102. Use of a standard dosage form according to any of paragraphs 84-88 or 94-98 in the manufacture of a medicinal product for the treatment of limb spasticity in adults.

103. A standard dosage form according to any of paragraphs 89-98 for use in the treatment of limb spasticity in children.

104. A method for treating limb spasticity in children, comprising administering to the subject a dosage form according to any one of paragraphs 89-98.

105. Use of a standard dosage form according to any of paragraphs 89-98 in the manufacture of a medicinal product for the treatment of limb spasticity in children.