Compositions and methods for the treatment of disorders related to cdkl5 deficiency

Claims

1. Adeno-associated virus (AAV) particle, characterized in that it comprises: a) an AAV capsid variant comprising an amino acid sequence having the following formula: [N1]-[N2]-[N3], wherein: (i) optionally [N1] comprises X1, X2 and X3, wherein at least one of X1, X2 or X3 is G; (ii) [N2] comprises the SPH amino acid sequence; and (iii) [N3] comprises X4, X5 and X6, wherein at least one of X4, X5 or X6 is a basic amino acid; and b) a viral genome comprising a sequence encoding cyclin-dependent kinase type 5 (CDKL5).

2. AAV particle according to claim 1, characterized in that the amino acid sequence [N1]-[N2]-[N3] is in hypervariable loop IV of the AAV capsid variant.

3. AAV particle according to claim 1 or 2, characterized in that an AAV capsid variant is an AAV9 capsid variant.

4. AAV particle according to any one of claims 1 to 3, characterized in that [N1] comprises X1, X2 and X3, wherein at least one of X1, X2 or X3 is G.

5. AAV particle according to any one of claims 1 to 4, characterized in that [N2]-[N3] comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941).

6. Adeno-associated virus (AAV) particle, characterized in that it comprises a viral genome comprising a sequence encoding cyclin-dependent kinase type 5 (CDKL5) and Petition 870250085885, dated 09 / 23 / 2025, page 723 / 769 2 / 23 a capsid variant of AAV9 comprising the amino acid sequence of SPHSKA (SEQ ID NO: 941).

7. AAV particle according to claim 6, characterized in that the amino acid sequence of SPHSKA (SEQ ID NO: 941) is in hypervariable loop IV of the AAV9 capsid variant.

8. AAV particle according to claim 6 or 7, characterized in that the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present immediately after an amino acid position that corresponds to position 455 of SEQ ID NO: 4 or SEQ ID NO:

36.

9. AAV particle according to any one of claims 6 to 8, characterized in that a capsid variant of AAV9 also comprises one, two or all of: an N at an amino acid position corresponding to position 452, an E at an amino acid position corresponding to position 451 and / or a V at an amino acid position corresponding to position 453 of SEQ ID NO:

4.

10. AAV particle according to any one of claims 6 to 9, characterized in that a capsid variant of AAV9 comprises the amino acid sequence KTENVSGSPHSKAQNQQT (SEQ ID NO: 3272).

11. AAV particle according to any one of claims 6 to 10, characterized in that an AAV9 capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence having at least 90% identity with SEQ ID NO: 4; (ii) a VP2 protein comprising an amino acid sequence having at least 90% identity with positions 138 to 742 of SEQ ID NO: 4; and / or (iii) a VP3 protein comprising an amino acid sequence having at least 90% identity with positions 203 to 742 of SEQ ID NO:

4.

12. AAV particle according to any one of claims 6 to 11, characterized in that an AAV9 capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence having at least 95% identity with SEQ ID NO: 4; (ii) a VP2 protein comprising an amino acid sequence having at least 95% identity with positions 138 to 742 of SEQ ID NO: 4; and / or (iii) a VP3 protein comprising an amino acid sequence having at least 95% identity with positions 203 to 742 of SEQ ID NO:

4.

13. AAV particle according to any one of claims 6 to 12, characterized in that an AAV9 capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence having at least 99% identity with SEQ ID NO: 4; (ii) a VP2 protein comprising an amino acid sequence having at least 99% identity with positions 138 to 742 of SEQ ID NO: 4; and / or (iii) a VP3 protein comprising an amino acid sequence having at least 99% identity with positions 203 to 742 of SEQ ID NO:

4.

14. AAV particle according to any one of claims 6 to 13, characterized in that a variant of Petition 870250085885, dated 09 / 23 / 2025, p. 725 / 769 4 / 23 AAV9 capsid comprises: (i) a VP1 protein comprising the amino acid sequence from SEQ ID NO: 4; (ii) a VP2 protein comprising the amino acid sequence from positions 138 to 742 of SEQ ID NO: 4; and / or (iii) a VP3 protein comprising the amino acid sequence from positions 203 to 742 of SEQ ID NO:

4.

15. AAV particle according to any one of claims 6 to 13, characterized in that a capsid variant of AAV9 comprises: (i) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately after an amino acid position corresponding to position 455 of SEQ ID NO: 4; (ii) an E at an amino acid position corresponding to position 451 and a V at an amino acid position corresponding to position 453 of SEQ ID NO: 4; and (iii) no other modifications relative to wild-type AAV9.

16. AAV particle according to any one of claims 6 to 8, characterized in that a capsid variant of AAV9 also comprises one, two or all of: an E at an amino acid position corresponding to position 451, an R at an amino acid position corresponding to position 452 and / or a V at an amino acid position corresponding to position 453 of SEQ ID NO:

36.

17. AAV particle according to any one of claims 6 to 8 and 16, characterized in that a capsid variant of AAV9 comprises the amino acid sequence KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589). Petition 870250085885, dated 23 / 09 / 2025, p. 726 / 769 5 / 23 18. AAV particle according to any one of claims 6 to 8, 16 and 17, characterized in that an AAV9 capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence having at least 90% identity with SEQ ID NO: 36; (ii) a VP2 protein comprising an amino acid sequence having at least 90% identity with positions 138 to 742 of SEQ ID NO: 36; and / or (iii) a VP3 protein comprising an amino acid sequence having at least 90% identity with positions 203 to 742 of SEQ ID NO:

36.

19. AAV particle according to any one of claims 6 to 8 and 16 to 18, characterized in that an AAV9 capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence having at least 95% identity with SEQ ID NO: 36; (ii) a VP2 protein comprising an amino acid sequence having at least 95% identity with positions 138 to 742 of SEQ ID NO: 36; and / or (iii) a VP3 protein comprising an amino acid sequence having at least 95% identity with positions 203 to 742 of SEQ ID NO:

36.

20. AAV particle according to any one of claims 6 to 8 and 16 to 19, characterized in that an AAV9 capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence having at least 99% identity with SEQ ID NO: 36; Petition 870250085885, dated 23 / 09 / 2025, p. 727 / 769 6 / 23 (ii) a VP2 protein comprising an amino acid sequence having at least 99% identity with positions 138 to 742 of SEQ ID NO: 36; and / or (iii) a VP3 protein comprising an amino acid sequence having at least 99% identity with positions 203 to 742 of SEQ ID NO:

36.

21. AAV particle according to any one of claims 6 to 8 and 16 to 20, characterized in that an AAV9 capsid variant comprises: (i) a VP1 protein comprising the amino acid sequence from SEQ ID NO: 36; (ii) a VP2 protein comprising the amino acid sequence from positions 138 to 742 of SEQ ID NO: 36; and / or (iii) a VP3 protein comprising the amino acid sequence from positions 203 to 742 of SEQ ID NO:

36.

22. AAV particle according to any one of claims 6 to 8 and 16 to 20, characterized in that a capsid variant of AAV9 comprises: (i) the amino acid sequence SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately after an amino acid position corresponding to position 455 of SEQ ID NO: 36; (ii) an E at an amino acid position corresponding to position 451, an R at an amino acid position corresponding to position 452, and a V at an amino acid position corresponding to position 453 of SEQ ID NO: 36; and (iii) none of the other modifications relating to wild-type AAV9.

23. AAV particle according to any one of claims 1 to 4, characterized in that [N1]-[N2]-[N3] is present immediately after a position corresponding to the position of amino acid 452 of SEQ ID NO: 982; and wherein an AAV capsid variant comprises an amino acid sequence that is at least 90% identical, for example, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical, to the amino acid sequence of SEQ ID NO: 982, for example, at positions 203 to 742 of SEQ ID NO:

982.

24. AAV particle according to claim 23, characterized in that [N1] comprises GHD.

25. AAV particle according to claim 23 or 24, characterized in that [N1] comprises amino acid G at a position corresponding to position 453, amino acid H at position 454, and amino acid D at position 455 of SEQ ID NO: 138 or SEQ ID NO:

982.

26. AAV particle according to any one of claims 23 to 25, characterized in that [N3] comprises KSG.

27. AAV particle according to any one of claims 23 to 26, characterized in that an AAV capsid variant comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity with SEQ ID NO: 982; (ii) a VP2 protein comprising the amino acid sequence from positions 138 to 742 of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity with positions 138 to 742 of SEQ ID NO: 982; or (iii) a VP3 protein comprising the sequence of Petition 870250085885, dated 09 / 23 / 2025, p. 729 / 769 8 / 23 amino acid from positions 203 to 742 of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity with positions 203 to 742 of SEQ ID NO:

982.

28. AAV particle according to any one of claims 23 to 27, characterized in that an AAV capsid variant comprises: (i) a VP1 protein comprising the amino acid sequence from SEQ ID NO: 982 or an amino acid sequence having at least 95% identity with SEQ ID NO: 982; (ii) a VP2 protein comprising the amino acid sequence from positions 138 to 742 of SEQ ID NO: 982 or an amino acid sequence having at least 95% identity with positions 138 to 742 of SEQ ID NO: 982; or (iii) a VP3 protein comprising the amino acid sequence from positions 203 to 742 of SEQ ID NO: 982 or an amino acid sequence having at least 95% identity with positions 203 to 742 of SEQ ID NO:

982.

29. AAV particle according to any one of claims 23 to 28, characterized in that an AAV capsid variant comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 99% identity with SEQ ID NO: 982; (ii) a VP2 protein comprising the amino acid sequence of positions 138 to 742 of SEQ ID NO: 982 or an amino acid sequence having at least 99% identity with positions 138 to 742 of SEQ ID NO: 982; or (iii) a VP3 protein comprising the amino acid sequence from positions 203 to 742 of SEQ ID NO: 982 or an amino acid sequence having at least 99% identity with Petition 870250085885, dated 23 / 09 / 2025, p. 730 / 769 9 / 23 positions 203 to 742 of SEQ ID NO:

982.

30. AAV particle according to any one of claims 23 to 29, characterized in that an AAV capsid variant comprises: (i) a VP1 protein comprising the amino acid sequence from SEQ ID NO: 982; (ii) a VP2 protein comprising the amino acid sequence from positions 138 to 742 of SEQ ID NO: 982; or (iii) a VP3 protein comprising the amino acid sequence from positions 203 to 742 of SEQ ID NO:

982.

31. AAV particle according to any one of claims 1 to 30, characterized in that the viral genome encodes a wild-type CDKL5 protein or a fragment thereof.

32. AAV particle according to any one of claims 1 to 31, characterized in that the viral genome encodes a human CDKL5 protein.

33. AAV particle according to claim 31 or 32, characterized in that the CDKL5 protein comprises the amino acid sequence of SEQ ID NO: 6413.

34. AAV particle according to any one of claims 1 to 33, characterized in that the CDKL5 coding sequence comprises a nucleotide sequence that is at least 90% identical (for example, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical) with SEQ ID NO: 6414.

35. AAV particle according to claim 34, characterized in that the CDKL5 coding sequence comprises a nucleotide sequence that is at least 95% identical to SEQ ID NO: 6414.

36. AAV particle according to claim 35, characterized in that the coding sequence of CDKL5 comprises a nucleotide sequence that is at least 99% identical to SEQ ID NO: 6414.

37. AAV particle according to claim 36, characterized in that the coding sequence of CDKL5 comprises the nucleotide sequence of SEQ ID NO: 6414.

38. AAV particle according to claim 37, characterized in that the coding sequence of CDKL5 consists of the nucleotide sequence with SEQ ID NO: 6414.

39. AAV particle according to any one of claims 1 to 38, characterized in that the viral genome comprises a promoter operably linked to the CDKL5 coding sequence.

40. AAV particle according to claim 39, characterized in that the promoter is human elongation factor 1 (EF^) α subunit, cytomegalovirus (CMV) immediate early promoter and / or enhancer, chicken β-actin (CBA) promoter, CAG promoter, CAG-derived promoter, β-glucuronidase (GUSB) promoter, ubiquitin C (UBC) promoter, neuron-specific enolase (NSE) promoter, platelet-derived growth factor (PDGF) promoter, platelet-derived growth factor B chain (PDGF-β) promoter, intercellular adhesion molecule 2 (ICAM-2) promoter, synapsin (Syn) promoter, synapsin 1 (Syn1) promoter, methyl-CpG-binding protein 2 (MeCP2) promoter, Ca2+ / calmodulin-dependent protein kinase II (CaMKII) promoter, receptor 2 promoter Metabotropic glutamate (mGluR2), promoter of light (NFL) or heavy (NFH) neurofilament, promoter of nβ2 β-globin minigene, promoter of Petition 870250085885,From 23 / 09 / 2025, page 732 / 769 11 / 23 proenkephalin (PPE), promoter of enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), promoter of glial fibrillary acidic protein (GFAP), promoter of myelin basic protein (MBP), a cardiovascular promoter (e.g., αMHC, cTnT, and CMV-MLC2k), a liver promoter (e.g., hAAT, TBG), a skeletal muscle promoter (e.g., desmin, MCK, C512) or a fragment, e.g., a truncation, or a functional variant thereof.

41. AAV particle according to any one of claims 1 to 40, characterized in that the viral genome also comprises an inverted terminal repeat (ITR) sequence.

42. AAV particle according to claim 41, characterized in that the viral genome comprises an ITR sequence positioned 5' relative to the CDKL5 coding sequence.

43. AAV particle according to claim 41 or 42, characterized in that the viral genome comprises an ITR sequence positioned 3' relative to the CDKL5 coding sequence.

44. AAV particle according to any one of claims 41 to 43, characterized in that the viral genome comprises an ITR sequence positioned 5' relative to the CDKL5 coding sequence, and an ITR sequence positioned 3' relative to the CDKL5 coding sequence.

45. Adeno-associated virus (AAV) particle, characterized in that it comprises a viral genome comprising a sequence encoding cyclin-dependent kinase type 5 (CDKL5) and an AAV capsid variant comprising: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 4; (ii) a VP2 protein comprising the amino acid sequence from positions 138 to 742 of SEQ ID NO: 4; and / or (iii) a VP3 protein comprising the amino acid sequence from positions 203 to 742 of SEQ ID NO:

4.

46. ​​Adeno-associated virus (AAV) particle, characterized in that it comprises a viral genome comprising a sequence encoding cyclin-dependent kinase type 5 (CDKL5) and an AAV capsid variant comprising: (i) a VP1 protein comprising the amino acid sequence from SEQ ID NO: 36; (ii) a VP2 protein comprising the amino acid sequence from positions 138 to 742 of SEQ ID NO: 36; and / or (iii) a VP3 protein comprising the amino acid sequence from positions 203 to 742 of SEQ ID NO:

36.

47. Cell, characterized in that it comprises the AAV particle, as defined in any one of claims 1 to 46, optionally wherein the cell is a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell) or a bacterial cell.

48. A method for preparing the AAV particle, as defined in any one of claims 1 to 46, characterized in that it comprises: (i) providing a cell comprising a viral genome comprising a sequence encoding CDKL5 and a nucleic acid encoding an AAV capsid variant; and (ii) incubating the cell under suitable conditions to encapsulate the viral genome in an AAV capsid variant; thereby preparing the AAV particle.

49. Method according to claim 48, characterized by the fact that: (a) the viral genome comprises a nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence that is at least 90% identical (for example, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical) to the same; and (b) an AAV capsid variant comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having at least 90% identity (for example, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity) with SEQ ID NO: 4;(ii) a VP2 protein comprising the amino acid sequence from positions 138 to 742 of SEQ ID NO: 4 or an amino acid sequence having at least 90% identity (for example, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity) with positions 138 to 742 of SEQ ID NO: 4; or (iii) a VP3 protein comprising the amino acid sequence from positions 203 to 742 of SEQ ID NO: 4 or an amino acid sequence having at least 90% identity (for example, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity) with positions 203 to 742 of SEQ ID NO: 4.; 50. Method according to claim 49, characterized in that an AAV capsid variant comprises the amino acid sequence from SEQ ID NO: 4, the amino acid sequence from positions 138 to 742 of SEQ ID NO: 4 and / or the amino acid sequence from positions 203 to 742 of SEQ ID NO:

4.

51. Method according to claim 48, characterized in that: (a) the viral genome comprises a nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence that is at least 90% identical (for example, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical) to the same; and (b) an AAV capsid variant comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence having at least 90% identity (for example, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity) with SEQ ID NO: 36;(ii) a VP2 protein comprising the amino acid sequence from positions 138 to 742 of SEQ ID NO: 36 or an amino acid sequence having at least 90% identity (for example, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity) with positions 138 to 742 of SEQ ID NO: 36; or (iii) a VP3 protein comprising the amino acid sequence from positions 203 to 742 of SEQ ID NO: 36 or an amino acid sequence having at least 90% identity (for example, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity) with positions 203 to 742 of SEQ ID NO: 36.; 52. Method according to claim 51, characterized in that an AAV capsid variant comprises the amino acid sequence from SEQ ID NO: 36, the amino acid sequence from positions 138 to 742 of SEQ ID NO: 36 and / or the amino acid sequence from positions 203 to 742 of SEQ ID NO:

36.

53. Method according to claim 48, characterized in that: (a) the viral genome comprises a nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence that is at least 90% identical (for example, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical) to the same; and (b) an AAV capsid variant comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity (for example, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity) with SEQ ID NO: 982;(ii) a VP2 protein comprising the amino acid sequence from positions 138 to 742 of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity (for example, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity) with positions 138 to 742 of SEQ ID NO: 982; or (iii) a VP3 protein comprising the sequence of Petition 870250085885, dated 23 / 09 / 2025, p. 737 / 769 16 / 23 amino acid from positions 203 to 742 of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity (for example, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity) with positions 203 to 742 of SEQ ID NO: 982.; 54. Method according to claim 53, characterized in that an AAV capsid variant comprises the amino acid sequence from SEQ ID NO: 982, the amino acid sequence from positions 138 to 742 of SEQ ID NO: 982 and / or the amino acid sequence from positions 203 to 742 of SEQ ID NO:

982.

55. Method according to any one of claims 48 to 54, characterized in that it also comprises, prior to step (i), the introduction of a first nucleic acid molecule comprising the viral genome into the cell.

56. Method according to any one of claims 48 to 55, characterized in that the cell comprises a second nucleic acid molecule encoding an AAV capsid variant, optionally wherein the method also comprises, prior to step (i), introducing the second nucleic acid molecule into the cell.

57. A method according to any one of claims 48 to 56, characterized in that the cell comprises a mammalian cell (for example, an HEK293 cell), an insect cell (for example, an Sf9 cell), or a bacterial cell.

58. Pharmaceutical composition, characterized in that it comprises the AAV particle, as defined in any one of claims 1 to 46, and a pharmaceutically acceptable excipient.

59. Pharmaceutical composition, characterized by the fact that Petition 870250085885, dated 09 / 23 / 2025, pp. 738 / 769 17 / 23 comprising the AAV particle according to any of claims 5 to 22, and a pharmaceutically acceptable excipient.

60. Pharmaceutical composition, characterized in that it comprises the AAV particle, as defined in any one of claims 9 to 15 and 45, and a pharmaceutically acceptable excipient.

61. Pharmaceutical composition, characterized in that it comprises the AAV particle as defined in any one of claims 16 to 22 and 46, and a pharmaceutically acceptable excipient.

62. A method for delivering an AAV particle encoding a CDKL5 protein to an individual, characterized in that it comprises administering to the individual an effective amount of the pharmaceutical composition as defined in any one of claims 58 to 61 or the AAV particle as defined in any one of claims 1 to 46.

63. Method according to claim 62, characterized in that the individual has, has been diagnosed with, or is at risk of having a CDKL5-related disorder, optionally wherein the CDKL5-related disorder is a CDKL5-related neurodegenerative or neuromuscular disorder.

64. Method according to claim 62 or 63, characterized in that the individual has, has been diagnosed with, or is at risk of having CDD, developmental and epileptic encephalopathy, or atypical Rett syndrome.

65. A method of treating an individual having or being diagnosed with a CDKL5-related disorder, characterized in that it comprises administering to the individual an effective amount of the pharmaceutical composition as defined in any one of claims 58 to 61 or the AAV particle as defined in Petition 870250085885, dated 09 / 23 / 2025, pp. 739 / 769 18 / 23 any one of claims 1 to 46.

66. A method for treating an individual having or being diagnosed with a CDKL5-related disorder, characterized in that it comprises administering to the individual an effective amount of the pharmaceutical composition as defined in claim 60 or the AAV particle as defined in any of claims 9 to 15 and 45.

67. A method for treating an individual having or being diagnosed with a CDKL5-related disorder, characterized in that it comprises administering to the individual an effective amount of the pharmaceutical composition according to claim 61, or the AAV particle as defined in any one of claims 16 to 22 and 46.

68. A method for treating an individual having or being diagnosed with a CDKL5-related disorder, characterized in that it comprises administering to the individual an effective amount of the pharmaceutical composition as defined in claim 59 or the AAV particle, as defined in any one of claims 5 to 22.

69. Method according to claim 35, characterized in that the CDKL5-related disorder is a neurodegenerative or neuromuscular disorder related to CDKL5.

70. Method according to claim 69, characterized in that the neurodegenerative or neuromuscular disorder related to CDKL5 is CDD, developmental encephalopathy 2, and epileptic or atypical Rett syndrome.

71. A method for treating an individual having CDKL5 deficiency disorder (CDD) or diagnosed with CDD, characterized in that it comprises administering to the individual an effective amount of the pharmaceutical composition as defined in any one of claims 58 to 61 or the AAV particle as defined in any of claims 1 to 46.

72. A method for treating an individual having CDKL5 deficiency disorder (CDD) or diagnosed with CDKL5 deficiency disorder (CDD), characterized in that it comprises administering to the individual an effective amount of the pharmaceutical composition as defined in claim 60 or the AAV particle as defined in any of claims 9 to 15 and 45.

73. A method for treating an individual having CDKL5 deficiency disorder (CDD) or diagnosed with CDKL5 deficiency disorder (CDD), characterized in that it comprises administering to the individual an effective amount of the pharmaceutical composition as defined in claim 61 or the AAV particle as defined in any of claims 16 to 22 and 46.

74. A method for treating an individual having CDKL5 deficiency disorder (CDD) or diagnosed with CDKL5 deficiency disorder (CDD), characterized in that it comprises administering to the individual an effective amount of a pharmaceutical composition as defined in claim 59 or the AAV particle as defined in any of claims 5 to 22.

75. A method according to any one of claims 32 to 38, characterized in that the individual has one or more mutations in the CDKL5 gene.

76. A method according to any one of claims 62 to 75, characterized in that the individual has a reduced level of CDKL5 activity when compared to a reference level in an individual who does not have a CDKL5-related disorder.

77. Method according to any of claims 65 to 76, characterized in that the administration results in Petition 870250085885, dated 09 / 23 / 2025, pp. 741 / 769 20 / 23 in preventing progression of the disorder in the individual.

78. A method according to any one of claims 65 to 77, characterized in that administration results in the improvement of at least one symptom of the disorder and / or an alteration in one or more biomarkers of the disorder.

79. Method according to claim 78, characterized in that one or more biomarkers comprise a neurofilament light chain or a marker of CDKL5 activity, for example, as measured by phosphorylation levels of substrate proteins, for example, MECP2, or as measured by mass spectrometry.

80. A method according to any one of claims 65 to 77, characterized in that the treatment results in the improvement of at least one symptom, optionally wherein at least one symptom comprises epilepsy (e.g., early-onset epilepsy), autism, cognitive deficits, limited motor skills, sleep difficulties, visual impairment, low muscle tone, gastrointestinal reflux, behavioral symptoms (including episodes of laughter or crying that occur without apparent reason, hypersensitivity to touch, and interrupted sleep), alterations in facial appearance (including microcephaly, high and wide forehead, large and deep-set eyes, smaller than normal space between the nose and upper lip, upturned nose, full lips, and widely spaced teeth), difficulties standing and walking, small and cold feet, lack of or poor eye contact, frequent sideways glances, cortical visual impairment or cortical blindness, bruxism, limited or absent speech,Eating difficulties, stereotypies, limited ability to perform small, focused hand movements, gastroesophageal reflux, constipation, or a combination thereof.

81. Method according to any of the claims Petition 870250085885, dated 09 / 23 / 2025, pp. 742 / 769 21 / 23 tions 62 to 80, characterized by the fact that the individual is a human.

82. A method according to any one of claims 62 to 81, characterized in that the AAV particle is released to a cell, tissue or region of the CNS, for example, a region of the brain or spinal cord, for example, the parenchyma, the cortex, the substantia nigra, the cerebellum, the caudate nucleus, the striatum, the corpus callosum, the cerebellum, the caudate-putamen brainstem, thalamus, superior colliculus, spinal cord or a combination thereof and / or neurons, or a combination thereof.

83. A method according to any one of claims 62 to 82, characterized in that it also comprises evaluating, for example, measuring, the expression level of CDKL5, for example, CDKL5 gene expression, CDKL5 mRNA expression and / or CDKL5 protein expression, in the individual, for example, in a cell, tissue or fluid of the individual.

84. Method according to claim 83, characterized in that the expression level of the CDKL5 protein is measured by an ELISA, a Western blot, or an immunohistochemistry assay.

85. Method according to claim 83 or 84, characterized in that the assessment of the CDKL5 expression level is performed before and after administration of the AAV particle, optionally wherein the CDKL5 expression level before administration is compared to the CDKL5 expression level after administration.

86. Method according to any one of claims 83 to 85, characterized in that it comprises evaluating the expression level of CDKL5 in a cell or tissue of the central nervous system (e.g., parenchyma).

87. Method according to any one of claims 83 to 86, characterized in that the individual's level of CDKL5 protein expression after administration is increased relative to the individual's level of CDKL5 protein expression before administration.

88. Method according to any one of claims 62 to 87, characterized in that it also comprises evaluating, for example, measuring, the level of CDKL5 activity in the individual, for example, in a cell or tissue of the individual.

89. Method according to any one of claims 65 to 88, characterized in that administration results in an increase in: (i) CDKL5 activity in a cell, tissue (e.g., a CNS cell or tissue, e.g., the cortex, striatum, thalamus, cerebellum and / or brainstem) and / or fluid (e.g., CSF and / or serum) of the individual, relative to the CDKL5 activity in the individual before administration; (ii) viral genomes (VG) per cell level in a CNS tissue (e.g., the cortex, striatum, thalamus, cerebellum, brainstem and / or spinal cord) of the individual, relative to the individual's VG per cell level in a peripheral tissue; and / or (iii) CDKL5 mRNA expression in a cell or tissue (e.g., a CNS cell or tissue, e.g., the cortex, thalamus, and / or brainstem) of the individual, as compared to CDKL5 mRNA expression in the individual prior to administration.

90. Method according to any one of claims 65 to 89, characterized in that it also comprises administering to the individual an additional agent suitable for the treatment or prevention of a CDKL5-related disorder; optionally wherein the additional agent comprises one or more antiepileptic drugs (for example, valproate, levetiracetam, clobazam, lamotrigine, ganaxolone, topiramate or a combination thereof).

91. A method according to any one of claims 65 to 90, characterized in that it also comprises administering an immunosuppressant to the individual.

92. Method according to claim 91, characterized in that the immunosuppressant comprises a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone and / or dexamethasone), rapamycin, mycophenolate mofetil, tacrolimus, rituximab and / or eculizumab hydroxychloroquine.

93. Pharmaceutical composition according to any one of claims 58 to 61 or AAV particle according to any one of claims 1 to 46, characterized in that it is for use in the treatment of a CDKL5-related disorder; wherein, optionally, the CDKL5-related disorder is CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy or atypical Rett syndrome.

94. Use of the pharmaceutical composition as defined in any one of claims 58 to 61 or of the AAV particle as defined in any one of claims 1 to 46, characterized in that it is in the manufacture of a medicament for the treatment of a CDKL5-related disorder; wherein, optionally, the CDKL5-related disorder is CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy or atypical Rett syndrome.

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