Treatment of Cervical Dystonia

Claims

1. A modified botulinum neurotoxin A (BoNT / A) for use in the treatment of cervical dystonia, wherein the modified BoNT / A is administered by intramuscular injection into the affected muscle of the neck of a subject, where the modified BoNT / A is administered as a single dose exceeding 17,000 pg of modified BoNT / A, where at least a single standard dose is injected into the affected neck muscle, where the total dose administered during treatment is up to 400,000 pg of modified BoNT / A, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor-binding domain of BoNT / B (H с domain).

2. A method for treating cervical dystonia, wherein the method comprises administering modified BoNT / A by intramuscular injection into the affected neck muscle of a subject, where the modified BoNT / A is administered as a single dose exceeding 17,000 pg of modified BoNT / A, where at least a single standard dose is injected into the affected neck muscle, where the total dose administered during treatment is up to 400,000 pg of modified BoNT / A, and where the modified BoNT / A includes the light chain and translocation domain of BoNT / A, and the receptor-binding domain of BoNT / B (H С domain).

3. Use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for the treatment of cervical dystonia, wherein the modified BoNT / A is administered by intramuscular injection into the affected muscle of the neck of a subject, where the modified BoNT / A is administered as a single dose exceeding 17,000 pg of modified BoNT / A, where at least a single standard dose is injected into the affected neck muscle, where the total dose administered during treatment is up to 400,000 pg of modified BoNT / A, and where the modified BoNT / A includes the light chain and translocation domain of BoNT / A, and the receptor-binding domain of BoNT / B (H С domain).

4. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the total dose administered is from 170,000 pg to 400,000 pg (e.g. from 170,000 pg to 400,000 pg) of modified BoNT / A.

5. A modified BoNT / A for use, method or use according to any one of claims 1-4, wherein the total dose administered is from 170,000 pg up to 360,000 pg (e.g., more than 170,000 pg up to 360,000 pg) of modified BoNT / A 6. The modified BoNT / A for use, method or use according to any one of claims 1 to 4, wherein the total dose administered is from 250,000 pg to 400,000 pg (e.g. from 250,000 up to 360,000 pg) of the modified BoNT / A.

7. A modified BoNT / A for use, method or use according to any one of claims 1 to 5, wherein the total dose administered is from 200,000 pg to 300,000 pg, such as from 240,000 pg to 260,000 pg (e.g. 250,000 pg) of modified BoNT / A.

8. A modified BoNT / A for use, method or use according to any one of claims 1-4 or 6, wherein the total dose administered is from 300,000 up to 400,000 pg, such as from 350,000 pg to 370,000 pg (e.g. 360,000 pg) of 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 during treatment is up to 250,000 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 during treatment is up to 360,000 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 during treatment is at least 250,000 pg of modified BoNT / A.

12. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the single dose exceeds from 17,000 up to 40,000 pg (e.g. from 17,001 up to 40,000 pg) of the modified BoNT / A.

13. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the single dose exceeds from 17,000 pg up to 36,000 pg (e.g. from 17,001 pg up to 36,000 pg) of the modified BoNT / A.

14. The modified BoNT / A for use, method or use according to any one of claims 1-2, wherein the single dose is from 25,000 to 40,000 pg (e.g. from 25,000 to 36,000 pg) of the modified BoNT / A.

15. A modified BoNT / A for use, method or use according to any one of claims 1-12 or 14, wherein the total dose administered is from 30,000 up to 40,000 pg, such as from 35,000 to 37,000 pg (preferably 36,000 pg) of modified BoNT / A.

16. A modified BoNT / A for use, method or use according to any one of claims 1 to 13, wherein the single dose is from 20,000 to 30,000 pg, such as from 24,000 to 26,000 pg (preferably 25,000 pg) of modified BoNT / A.

17. A modified botulinum neurotoxin A (BoNT / A) for use in the treatment of cervical dystonia, wherein the modified BoNT / A is administered by intramuscular injection into the affected muscle of the neck of a subject, where the modified BoNT / A is administered as a single dose exceeding 707 U of modified BoNT / A, where 1 U is the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) in mice, where at least a single standard dose is injected into the affected neck muscle, where the total dose administered during treatment is up to 16,639 U of modified BoNT / A, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor-binding domain of BoNT / B (H С domain).

18. A method for treating cervical dystonia comprising administering modified BoNT / A by intramuscular injection into the affected neck muscle of a subject, wherein the modified BoNT / A is administered as a single dose exceeding 707 U of modified BoNT / A, wherein 1 U is the amount of modified BoNT / A that corresponds to the calculated median lethal dose (LD 50 ) in mice, where at least a single standard dose is injected into the affected neck muscle, where the total dose administered during treatment is up to 16,639 U of modified BoNT / A, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor-binding domain of BoNT / B (H С domain).

19. Use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for the treatment of cervical dystonia, wherein the modified BoNT / A is administered by intramuscular injection into the affected muscle of the neck of a subject, where the modified BoNT / A is administered as a single dose exceeding 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 ) in mice, where at least a single standard dose is injected into the affected neck muscle, where the total dose administered during treatment is up to 16,639 U of modified BoNT / A, and where the modified BoNT / A contains the light chain and translocation domain of BoNT / A, and the receptor-binding domain of BoNT / B (H сdomain).

20. The modified BoNT / A for use, method or use according to any one of claims 17-19, wherein the total dose administered is from 7072 units up to 16639 units (e.g., more than 7072 units up to 16639 units) of the modified BoNT / A.

21. The modified BoNT / A for use, method or use according to any one of claims 17-20, wherein the total dose administered is from 10,399 units to 16,639 units (e.g. from 10,399 units up to 14,975 units) of the modified BoNT / A.

22. The modified BoNT / A for use, method or use according to any one of claims 17-20, wherein the total dose administered is from 8319 to 12479 units, such as from 9983 to 10815 units (e.g. 10399 units) of modified BoNT / A.

23. The modified BoNT / A for use, method or use according to any one of claims 17-21, wherein the total dose administered is from 12479 to 16639 units, such as from 14559 to 15391 units (such as 14975 units) of modified BoNT / A.

24. The modified BoNT / A for use, method or use according to any one of claims 17-23, wherein the total dose administered during treatment is up to 14975 U of modified BoNT / A.

25. A modified BoNT / A for use, method or use according to any one of claims 17-22, wherein the total dose administered during treatment is up to 10,399 units.

26. A modified BoNT / A for use, method or use according to any one of claims 17-25, wherein the single dose exceeds 707 units up to 1664 units (e.g. from 707, 2 or 708 units up to 1664 units) of modified BoNT / A.

27. A modified BoNT / A for use, method or use according to any one of claims 17-26, wherein the single dose exceeds 707 units up to 1498 units (e.g. from 707, 2 or 708 units up to 1498 units) of modified BoNT / A.

28. The modified BoNT / A for use, method or use according to any one of claims 17-26, wherein the unit dose is from 1040 units up to 1664 units (e.g. from 1040 units to 1498 units) of the modified BoNT / A.

29. A modified BoNT / A for use, method or use according to any one of claims 17-27, wherein the unit dose is from 832 to 1248 units, such as from 998 to 1082 units (preferably 1040 units) of modified BoNT / A.

30. A modified BoNT / A for use, method or use according to any one of claims 17-26 or 28, wherein the unit dose is from 1248 units to 1664 units, such as from 1456 to 1539 units (preferably 1498 units) of modified BoNT / A.

31. 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 with SEQ ID NO: 6, or comprises the polypeptide sequence of SEQ ID NO: 6, or consists of the polypeptide sequence of SEQ ID NO:

6.

32. A modified BoNT / A for use, method or use 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, obtainable by a method comprising contacting a single-chain modified BoNT / A 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.

33. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the original methionine amino acid residue of the polypeptide sequence of the modified BoNT / A is optional.

34. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the original methionine amino acid residue of the polypeptide sequence of the modified BoNT / A is absent.

35. A modified BoNT / A for use, method or use 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.

36. 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 ED 50 =dose required to obtain a DAS score of 2.

37. A modified BoNI / A for use, method or use according to any of the preceding claims, wherein the affected neck muscle is selected from: the sternocleidomastoid muscle, the splenius capitis muscle, the splenius cervicis muscle, the scalene complex (e.g., the anterior scalene and / or the middle scalene), the trapezius muscle (e.g., the upper trapezius), the levator scapulae muscle, the semispinalis capitis muscle, the longissimus capitis muscle (e.g., the longissimus capitis and / or the longissimus colli muscle), the posterior paravertebral muscles and the submental complex (e.g., the digastric muscle, the geniohyoid muscle, the mylohyoid muscle, the mylohyoid boutonniere and / or the stylohyoid muscle), the descending part of the trapezius, the superior nuchal line-clavicle (lateral part), the spinous process C3-Th3-mastoid process, spinous process Th3-Th5-transverse process C1-C2, transverse process C3-Th6, spinous process C3-Th1-superior nuchal line,transverse process of Th1-Th6-spinous process of C2-C7, transverse process of C3-Th3-mastoid process, transverse process of Th1-Th6-transverse process of C2-C6, inferior oblique muscle of the capitis, spinous process of C2-transverse process of C1, suprasternal fossa and clavicle (medial part)-mastoid process and superior nuchal line, transverse process of C1-C4-scapula (superior angle), transverse process of C2-C7-first rib, transverse process of C3-C6-first rib, longissimus colli, transverse process of C3-C6-occipital bone (basilar part), longissimus colli and transverse process of C2-C5-atlas (anterior tubercle)., 38. The modified BoNT / A for use, method or use according to any one of the preceding claims, wherein the affected neck muscle is selected from: the sternocleidomastoid muscle (e.g., the left or right sternocleidomastoid muscle), the splenius capitis muscle (e.g., the left or right splenius capitis muscle), the scalenus anterior muscle, the scalenus middle muscle, the trapezius muscle (e.g., the left or right trapezius muscle, such as the left or right upper trapezius muscle), the levator scapulae muscle (e.g., the left or right levator scapulae muscle), the semispinalis capitis muscle (e.g., the left or right semispinalis capitis muscle), the middle part of the semispinalis capitis muscle, the longissimus muscle (e.g., the left or right longissimus capitis and / or the longissimus colli muscle), the splenius capitis muscle, the scalenus complex (e.g., the anterior scalenus muscle or the middle scalenus muscle), the posterior paravertebral muscles (e.g., the posterior scalene muscle,scalenus medius and / or scalenus anterior, preferably scalenus posterior), submental complex (e.g. digastric, geniohyoid, mylohyoid, mylohyoid boutonniere and / or stylohyoid), descending trapezius, superior nuchal line-clavicle (lateral part), spinous process of C3-Th3-mastoid, spinous process of Th3-Th5-transverse process of C1-C2, transverse process of C3-Th6, spinous process of C3-Th1-superior nuchal line, transverse process of Th1-Th6-spinous process of C2-C7, transverse process of C3-Th3-mastoid, transverse process of Th1-Th6-transverse process of C2-C6, inferior oblique muscle of the head, superior oblique muscle of the head, spinous process of C2-transverse process of C1, suprasternal fossa and clavicle (medial part)-mastoid process and superior nuchal line, transverse process of C1-C4-scapula (upper angle), transverse process of C2-C7-first rib,transverse process of C3-C6 of the first rib, longissimus capitis, superior transverse process of C3-C6 of the occipital bone (basilar part), longissimus capitis, semispinalis capitis, spinalis capitis, rectus capitis posterior major, rectus capitis posterior minor, rectus capitis anterior, multifidus, and transverse process of C2-C5 of the atlas (anterior tubercle)., 39. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the affected muscle(s) of the neck comprises the sternocleidomastoid muscle (e.g., left or right sternocleidomastoid muscle), splenius capitis (e.g., left or right splenius capitis), scalenus anterior, scalenus middle, trapezius (e.g., left or right trapezius, such as left or right upper trapezius), levator scapulae (e.g., left or right levator scapulae), semispinalis capitis (e.g., left or right semispinalis capitis), middle portion of semispinalis capitis, longissimus (e.g., left or right longissimus capitis and / or longissimus colli), scalenus capitis, complex scalene muscles (e.g., anterior scalene or middle scalene), posterior paravertebral muscles (e.g., posterior scalene,scalenus medius and / or scalenus anterior, preferably scalenus posterior), submental complex (e.g. digastric, geniohyoid, mylohyoid, mylohyoid boutonniere and / or stylohyoid), descending trapezius, superior nuchal line-clavicle (lateral part), C3 spinous process-Th3-mastoid process, Th3 spinous process-Th5-C1 transverse process, C3 transverse process-Th6, C3 spinous process-Th1-superior nuchal line, Th1 transverse process-Th6-C2 spinous process, C3 transverse process-Th7, C3 transverse process-Th3-mastoid process, transverse process Th1-Th6-transverse process of C2-C6, inferior oblique muscle of the head, superior oblique muscle of the head, spinous process of C2-transverse process of C1, suprasternal fossa and clavicle- (medial part)-mastoid process and superior nuchal line, transverse process of C1-C4-scapula (upper angle), transverse process of C2-C7-first rib,transverse process of C3-C6-first rib, longissimus capitis, superior transverse process of C3-C6-occipital bone (basilar part), longissimus capitis, semispinalis capitis, spinalis capitis, rectus capitis posterior major, rectus capitis posterior minor, rectus capitis anterior, multifidus or transverse process of C2-C5-atlas (anterior tubercle)., 40. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the modified BoNT / A is administered to one or more affected muscles of the neck selected from: M. semispinalis cervicis, M. levator scapulae, M. splenius cervicis, M. longissimus cervicis, M. trapezius (e.g. M. trapezius pars descendens), M. sternocleidomastoideus, M. semispinalis capitis, M. obliquus capitis inferior, M. longissimus capitis, M. splenius capitis, M. scalenus (e.g. M. scalenus anterior, medius and / or posterior), M. longus colli and / or M. longus capitis.

41. The modified BoNT / A for use, method or use according to any of the preceding claims, wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of the neck of a subject and wherein at least a single unit dose is administered into each affected muscle of the neck, preferably wherein the plurality of affected muscles of the neck are selected from: the sternocleidomastoid muscle, the sternocleidomastoid muscle, the splenius capitis muscle, the splenius cervicis muscle, the scalene complex (e.g., the anterior scalene muscle or the middle scalene muscle), the trapezius muscles (e.g., the upper trapezius muscle), the levator scapulae muscle, the semispinalis capitis muscle, the longissimus capitis muscle (e.g., the longissimus capitis and / or the longissimus colli muscle), the posterior paravertebral muscles and the submental complex (e.g., the digastric muscle, the geniohyoid muscle, the mylohyoid muscle, mylohyoid boutonniere and / or stylohyoid muscle),descending part of trapezius muscle, superior nuchal line-clavicle (lateral part), spinous process of C3-Th3-mastoid process, spinous process of Th3-Th5-transverse process of C1-C2, transverse process of C3-Th6, spinous process of C3-Th1-superior nuchal line, transverse process of Th1-Th6-spinous process of C2-C7, transverse process of C3-Th3-mastoid process, transverse process of Th1-Th6-transverse process of C2-C6, inferior oblique muscle of the capitis, spinous process of C2-transverse process of C1, suprasternal fossa and clavicle (medial part)-mastoid process and superior nuchal line, transverse process of C1-C4-scapula (superior angle), transverse process of C2-C7-first rib, transverse process of C3-C6-first rib, longissimus colli, transverse process of C2-C6-occipital bone (basilar part), longissimus colli and transverse process of C2-C5-atlas (anterior tubercle)., 42. The modified BoNT / A for use, method or use according to any one of the preceding claims, wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected neck muscles of a subject, and wherein at least a single unit dose is administered into each affected neck muscle, wherein the plurality of affected neck muscles are selected from: the sternocleidomastoid muscle (e.g., the left or right sternocleidomastoid muscle), the splenius capitis muscle (e.g., the left or right splenius capitis muscle), the scalenus anterior muscle, the scalenus middle muscle, the trapezius muscle (e.g., the left or right trapezius muscle (e.g., the left or right upper trapezius muscle), the levator scapulae muscle (e.g., the left or right levator scapulae muscle), the semispinalis capitis muscle (e.g., the left or right semispinalis capitis muscle), the middle portion of the semispinalis capitis muscle, the longissimus capitis muscle (e.g., the left or right longissimus capitis and / or the longissimus neck muscles),splenius muscle of the neck, scalene complex (e.g., anterior scalene and / or middle scalene), posterior paravertebral muscles (e.g., posterior scalene, middle scalene and / or anterior scalene, preferably posterior scalene), submental complex (e.g., digastric, geniohyoid, mylohyoid, mylohyoid boutonniere and / or stylohyoid), descending part of trapezius, superior nuchal line-clavicle (lateral part), spinous process of C3-Th3-mastoid process, spinous process of Th3-Th5-transverse process of C1-C2, transverse process of C3-Th6, spinous process of C3-Th1-superior nuchal line, transverse process of Th1-Th6-spinous process of C2-C7, transverse process of C3-Th3-mastoid process, transverse process of Th1-Th6-transverse process of C2-C6, inferior oblique muscle of the head, superior oblique muscle of the head, spinous process of C2-transverse process of C1,suprasternal fossa and clavicle (medial part) - mastoid process and superior nuchal line, transverse process of C1-C4-scapula (superior angle), transverse process of C2-C7-first rib, transverse process of C3-C6-first rib, longissimus capitis, superior transverse process of C3-C6-occipital bone (basilar part), longissimus capitis, semispinalis capitis, spinalis capitis, posterior rectus capitis major, posterior rectus capitis minor, anterior rectus capitis, multifidus muscle and transverse process of C2-C5-atlas (anterior tubercle)., 43. The modified BoNT / A for use, method or use according to any of the preceding claims, wherein the modified BoNT / A is administered by intramuscular injection into a plurality of affected muscles of the neck of a subject, and wherein at least a single unit dose is administered into each affected muscle of the neck, wherein the plurality of affected muscles of the neck comprise: the sternocleidomastoid muscle (e.g., the left or right sternocleidomastoid muscle), the splenius capitis muscle (e.g., the left or right splenius capitis muscle), the scalenus anterior muscle, the scalenus middle muscle, the trapezius muscle (e.g., the left or right trapezius muscle (e.g., the left or right upper trapezius muscle), the levator scapulae muscle (e.g., the left or right levator scapulae muscle), the semispinalis capitis muscle (e.g., the left or right semispinalis capitis muscle), the middle part of the semispinalis muscle head, longissimus muscle (e.g. left or right longissimus capitis and / or longissimus colli),splenius muscle of the neck, scalene complex (e.g., anterior scalene and / or middle scalene), posterior paravertebral muscles (e.g., posterior scalene, middle scalene and / or anterior scalene, preferably posterior scalene), submental complex (e.g., digastric, geniohyoid, mylohyoid, mylohyoid boutonniere and / or stylohyoid), descending trapezius, superior nuchal line-clavicle (lateral part), spinous process of C3-Th3-mastoid process, spinous process of Th3-Th5-transverse process of C1-C2, transverse process of C3-Th6, spinous process C3-Th1-superior nuchal line, transverse process of Th1-Tp6-spinous process of C2-C7, transverse process of C3-Th3-mastoid process, transverse process of Th1-Th6-transverse process of C2-C6, inferior oblique muscle of the head, superior oblique muscle of the head, spinous process of C2-transverse process of C1,suprasternal fossa and clavicle (medial part)-mastoid process and superior nuchal line, transverse process of C1-C4-scapula (superior angle), transverse process of C2-C7-first rib, transverse process of C3-C6-first rib, longissimus capitis, superior transverse process of C3-C6-occipital bone (basilar part), longissimus capitis, semispinalis capitis, spinalis capitis, rectus capitis posterior major, rectus capitis posterior minor, rectus capitis anterior, multifidus and / or transverse process of C2-C5-atlas (anterior tubercle)., 44. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein a single unit dose of the modified BoNT / A is administered to one or more affected muscles of the neck selected from the first group consisting of: M. splenius cervicis, M. obliquus capitis inferior, M. semispinalis cervicis, M. scalenus (e.g. M. scalenus anterior, medius and / or posterior), M. longissimus capitis, M. longus colli and / or M. longus capitis; and / or a single or multiple single dose of modified BoNT / A is administered into one or more affected neck muscles selected from the second group consisting of: M. splenius capitis, M. longissimus cervicis, M. trapezius (e.g. M. trapezius pars descendens), M. sternocleidomastoideus, M. semispinalis capitis and / or M. levator scapulae.

45. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein a single unit dose of the modified BoNT / A is administered to one or more affected muscles of the neck selected from the first group consisting of: M. splenius cervicis, M. obliquus capitis inferior, M. semispinalis cervicis, M. scalenus (e.g. M. scalenus anterior, medius and / or posterior), M. longissimus capitis, M. longus colli and / or M. longus capitis; and / or multiple single doses (preferably two single doses) of modified BoNT / A are administered into one or more affected neck muscles selected from the second group consisting of: M. splenius capitis, M. longissimus cervicis, M. trapezius (e.g. M. trapezius pars descendens), M. sternocleidomastoideus, M. semispinalis capitis and / or M. levator scapulae.

46. ​​A modified BoNT / A for use, method or administration according to claim 44 or 45, wherein the unit dose is: (a) from 20,000 pg to 30,000 pg, such as from 24,000 pg to 26,000 pg (preferably 25,000 pg) of modified BoNT / A; or (b) from 30,000 to 40,000 pg, such as from 35,000 pg to 37,000 pg (preferably 36,000 pg) of modified BoNT / A.

47. A modified BoNT / A for use, method or use according to any one of claims 44-46, wherein the total number of unit doses administered during treatment is up to 10 unit doses or up to 7 unit doses.

48. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the modified BoNT / A is administered as a single dose per injection site into the affected neck muscle, or wherein the modified BoNT / A is administered in a dose less than a single dose per injection site.

49. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein a single unit dose is administered to multiple injection sites in the affected neck muscle and / or two or more unit doses are administered to multiple injection sites in the affected neck muscle.

50. A modified BoNT / A for use, method or administration according to any of the preceding claims, wherein a single unit dose is administered into the affected neck muscle (e.g. a single unit dose is administered into each affected neck muscle).

51. A modified BoNT / A for use, method or use according to any of the preceding claims, wherein the cervical dystonia is treated for a longer period of time than with treatment with unmodified BoNT / A (e.g. SEQ ID NO:2 [e.g. the double chain form of SEQ ID NO:2]).

52. A unit dosage form of modified BoNT / A (e.g. for the treatment of cervical dystonia), wherein the unit dosage form comprises: (a) 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 ) in mice; or (b) more than 17,000 pg modified BoNT / A; (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 (H С domain).

53. A set containing: (a) a unit dosage form according to paragraph 52; (b) instructions for its use in the treatment of cervical dystonia; (c) optionally, a diluent.