Compositions and methods for optimized treatment of Pompe disease

Claims

1. A method of treating Pompe disease in a human patient in need thereof, comprising administering to the patient (i) a therapeutically effective amount of a viral vector containing a transgene encoding acid alpha-glucosidase (GAA), and (ii) a corticosteroid.

2. A method for reducing glycogen accumulation in muscle tissue and / or neuronal tissue in a human patient diagnosed with Pompe disease, comprising administering to the patient (i) a therapeutically effective amount of a viral vector comprising a transgene encoding GAA, and (ii) a corticosteroid.

3. A method for improving lung function in a human patient diagnosed with Pompe disease, comprising administering to the patient (i) a therapeutically effective amount of a viral vector containing a transgene encoding GAA, and (ii) a corticosteroid.

4. A method for increasing the expression of GAA in a human patient diagnosed with Pompe disease, comprising administering to the patient (i) a therapeutically effective amount of a viral vector containing a transgene encoding GAA, and (ii) a corticosteroid.

5. The method according to any one of claims 1-4, characterized in that the corticosteroid is administered to the patient in one or more doses, the administration of which begins within 48 weeks after the administration of the viral vector to the patient, optionally, the corticosteroid is administered to the patient in one or more doses, the administration of which begins within 36 weeks or 24 weeks after the administration of the viral vector to the patient.

6. The method according to any one of claims 1-5, characterized in that the corticosteroid is administered to the patient in one or more doses, the administration of which begins within 12 weeks after the administration of the viral vector to the patient, optionally, the corticosteroid is administered to the patient in one or more doses, the administration of which begins within 10 weeks, 8 weeks, 6 weeks or 4 weeks after the administration of the viral vector to the patient.

7. The method according to claim 6, characterized in that the corticosteroid is administered to the patient in one or more doses, the administration of which begins on the same day when the viral vector is administered to the patient.

8. A method of treating Pompe disease in a human patient in need thereof who has previously been administered a corticosteroid, comprising administering to the patient a therapeutically effective amount of a viral vector containing a transgene encoding GAA.

9. A method for reducing glycogen accumulation in muscle tissue and / or neuronal tissue in a human patient diagnosed with Pompe disease who has previously been administered a corticosteroid, comprising administering to the patient a therapeutically effective amount of a viral vector containing a transgene encoding GAA.

10. A method for improving lung function in a human patient diagnosed with Pompe disease who has previously been administered a corticosteroid, comprising administering to the patient a therapeutically effective amount of a viral vector containing a transgene encoding GAA.

11. A method for increasing the expression of GAA in a human patient diagnosed with Pompe disease who has previously been administered a corticosteroid, comprising administering to the patient a therapeutically effective amount of a viral vector containing a transgene encoding GAA.

12. The method according to any of paragraphs 1-11, characterized in that the viral vector is administered to the patient in an amount of 1×10 13 vg / kg up to 3×10 14vg / kg, it is not necessary to administer the viral vector to the patient in an amount of 1×10 13 vg / kg up to 6×10 13 vg / kg, from 1×10 13 vg / kg up to 5×10 13 vg / kg, from 1×10 13 vg / kg up to 4×10 13 vg / kg, from 1×10 13 vg / kg up to 3×10 13 vg / kg, from 2×10 13 vg / kg up to 6×10 13 vg / kg, from 2×10 13 vg / kg up to 5×10 13 vg / kg or from 2×10 13 vg / kg up to 4×10 13 vg / kg.

13. The method according to any of paragraphs 1-12, characterized in that the viral vector is administered to the patient in an amount of 3×10 13 vg / kg up to 6×10 13 vg / kg.

14. The method according to any one of paragraphs 1-13, characterized in that the age of the patient at the time of administration of the viral vector is one year or more.

15. The method according to paragraph 14, characterized in that the age of the patient at the time of administration of the viral vector is 18 years or older.

16. The method according to any of paragraphs 1-13, characterized in that the age of the patient at the time of administration of the viral vector is from one year to 40 years.

17. The method of any one of claims 1-16, further comprising monitoring the patient for the development of transaminasemia, hyperbilirubinemia, or one or more symptoms thereof.

18. The method of claim 17, wherein the patient is monitored for the development of transaminasemia, hyperbilirubinemia, or one or more symptoms thereof by assessing a parameter in a blood sample obtained from the patient, wherein a detection that the parameter exceeds a reference level identifies the patient as having transaminasemia, hyperbilirubinemia, or one or more symptoms thereof.

19. The method according to claim 18, characterized in that the parameter includes the level of aspartate aminotransferase, alanine aminotransferase and / or bilirubin in the blood sample.

20. A method for treating Pompe disease in a human patient in need thereof, comprising (a) administration to the patient of a viral vector containing a transgene encoding GAA in an amount of 1×10 13 vg / kg up to 3×10 14 vg / kg, (b) monitor the patient for the development of transaminasemia, hyperbilirubinemia, or one or more of their symptoms, and if the patient develops transaminasemia, hyperbilirubinemia, or one or more of their symptoms, (c) (i) administering a corticosteroid to a patient, (ii) re-administering a corticosteroid to a patient where the patient has previously received corticosteroid treatment following administration of the viral vector, or (iii) increasing the dose and / or frequency of the corticosteroid administered to the patient.

21. A method for reducing the accumulation of glycogen in muscle tissue and / or in nervous tissue in a human patient diagnosed with Pompe disease, comprising: (a) administration to the patient of a viral vector containing a transgene encoding GAA in an amount of 1×10 13 vg / kg up to 3×10 14 vg / kg, (b) monitor the patient for the development of transaminasemia, hyperbilirubinemia, or one or more of their symptoms, and if the patient develops transaminasemia, hyperbilirubinemia, or one or more of their symptoms, (c) (i) administering a corticosteroid to a patient, (ii) re-administering a corticosteroid to a patient where the patient has previously received corticosteroid treatment following administration of the viral vector, or (iii) increasing the dose and / or frequency of the corticosteroid administered to the patient.

22. A method for improving lung function in a patient diagnosed with Pompe disease, comprising: (a) administration to the patient of a viral vector containing a transgene encoding GAA in an amount of 1×10 13 vg / kg up to 3×10 14 vg / kg, (b) monitor the patient for the development of transaminasemia, hyperbilirubinemia, or one or more of their symptoms, and if the patient develops transaminasemia, hyperbilirubinemia, or one or more of their symptoms, (c) (i) administering a corticosteroid to a patient, (ii) re-administering a corticosteroid to a patient where the patient has previously received corticosteroid treatment following administration of the viral vector, or (iii) increasing the dose and / or frequency of the corticosteroid administered to the patient.

23. A method for increasing the expression of GAA in a human patient diagnosed with Pompe disease, comprising: (a) administration to the patient of a viral vector containing a transgene encoding GAA in an amount of 1×10 13 vg / kg up to 3×10 14 vg / kg, (b) monitor the patient for the development of transaminasemia, hyperbilirubinemia, or one or more of their symptoms, and if the patient develops transaminasemia, hyperbilirubinemia, or one or more of their symptoms, (c) (i) administering a corticosteroid to a patient, (ii) re-administering a corticosteroid to a patient where the patient has previously received corticosteroid treatment following administration of the viral vector, or (iii) increasing the dose and / or frequency of the corticosteroid administered to the patient.

24. A method for treating Pompe disease in a human patient in need thereof, comprising (a) administration to the patient of a viral vector containing a transgene encoding GAA in an amount of 1×10 13 vg / kg up to 3×10 14 vg / kg, (b) a determination that the patient has transaminasemia, hyperbilirubinemia, or one or more of their symptoms, and (c) (i) administering a corticosteroid to a patient, (ii) re-administering a corticosteroid to a patient where the patient has previously received corticosteroid treatment following administration of the viral vector, or (iii) increasing the dose and / or frequency of the corticosteroid administered to the patient.

25. A method for reducing the accumulation of glycogen in muscle tissue and / or in nervous tissue in a human patient diagnosed with Pompe disease, comprising: (a) administration to the patient of a viral vector containing a transgene encoding GAA in an amount of 1×10 13 vg / kg up to 3×10 14 vg / kg, (b) a determination that the patient has transaminasemia, hyperbilirubinemia, or one or more of their symptoms, and (c) (i) administering a corticosteroid to a patient, (ii) re-administering a corticosteroid to a patient where the patient has previously received corticosteroid treatment following administration of the viral vector, or (iii) increasing the dose and / or frequency of the corticosteroid administered to the patient.

26. A method for improving lung function in a patient diagnosed with Pompe disease, comprising: (a) administration to the patient of a viral vector containing a transgene encoding GAA in an amount of 1×10 13 vg / kg up to 3×10 14 vg / kg, (b) a determination that the patient has transaminasemia, hyperbilirubinemia, or one or more of their symptoms, and (c) (i) administering a corticosteroid to a patient, (ii) re-administering a corticosteroid to a patient where the patient has previously received corticosteroid treatment following administration of the viral vector, or (iii) increasing the dose and / or frequency of the corticosteroid administered to the patient.

27. A method for increasing the expression of GAA in a human patient diagnosed with Pompe disease, comprising: (a) administration to the patient of a viral vector containing a transgene encoding GAA in an amount of 1×10 13 vg / kg up to 3×10 14 vg / kg, (b) a determination that the patient has transaminasemia, hyperbilirubinemia, or one or more of their symptoms, and (c) (i) administering a corticosteroid to a patient, (ii) re-administering a corticosteroid to a patient where the patient has previously received corticosteroid treatment following administration of the viral vector, or (iii) increasing the dose and / or frequency of the corticosteroid administered to the patient.

28. The method according to any of paragraphs 19-26, characterized in that the viral vector is administered to the patient in an amount of 1×10 13 vg / kg up to 6×10 13 vg / kg, from 1×10 13 vg / kg up to 5×10 13 vg / kg, from 1×10 13 vg / kg up to 4×10 13 vg / kg, from 1×10 13 vg / kg up to 3×10 13vg / kg, from 2×10 13 vg / kg up to 6×10 13 vg / kg, from 2×10 13 vg / kg up to 5×10 13 vg / kg or from 2×10 13 vg / kg up to 4×10 13 vg / kg.

29. The method according to any of paragraphs 20-28, characterized in that the viral vector is administered to the patient in an amount of 3×10 13 vg / kg up to 6×10 13 vg / kg.

30. The method according to any of paragraphs 20-29, characterized in that the age of the patient at the time of administration of the viral vector is one year or more.

31. The method according to item 30, characterized in that the age of the patient at the time of administration of the viral vector is 18 years or older.

32. The method according to any of paragraphs 20-31, characterized in that the age of the patient at the time of administration of the viral vector is from one year to 40 years.

33. A method for treating or preventing transaminasemia or hyperbilirubinemia in a human patient with Pompe disease who has previously been administered a viral vector containing a transgene encoding GAA in an amount of 1×10 13 vg / kg up to 3×10 14 vg / kg, wherein the method includes administering a corticosteroid to the patient.

34. The method according to item 33, characterized in that the viral vector is administered to the patient in an amount of 1×10 13 vg / kg up to 3×10 14 vg / kg, it is not necessary to administer the viral vector to the patient in an amount of 2×10 13 vg / kg up to 7×10 13 vg / kg, from 2×10 13 vg / kg up to 4×10 13 vg / kg or from 5×10 13 vg / kg up to 7×10 13 vg / kg.

35. The method according to item 33 or 34, characterized in that the viral vector is administered to the patient in an amount of 3×10 13 vg / kg up to 6×10 13 vg / kg.

36. The method according to any of paragraphs 33-35, characterized in that the age of the patient at the time of administration of the viral vector is one year or more.

37. The method according to paragraph 36, characterized in that the age of the patient at the time of administration of the viral vector is 18 years or older.

38. The method according to any of paragraphs 33-36, characterized in that the age of the patient at the time of administration of the viral vector is from one year to 40 years.

39. The method according to any one of paragraphs 1-38, characterized in that the viral vector is administered to the patient in a single dose containing the specified amount.

40. The method according to any one of paragraphs 1-38, characterized in that the viral vector is administered to the patient in two or more doses, which together constitute the specified amount.

41. The method according to any one of paragraphs 1-38, characterized in that the viral vector is administered to the patient in two or more doses, each of which individually contains the specified amount.

42. The method according to claim 40 or 41, characterized in that two or more doses are administered with an interval between administrations of one year or more.

43. The method according to item 40 or 41, characterized in that two or more doses are administered to the patient with an interval between administrations of 12 months.

44. The method according to any one of claims 1-43, characterized in that the viral vector is selected from the group consisting of adeno-associated virus (AAV), adenovirus, lentivirus, retrovirus, poxvirus, baculovirus, herpes simplex virus, vaccinia virus and a synthetic virus.

45. The method according to claim 44, characterized in that the viral vector is AAV.

46. The method according to claim 45, characterized in that the AAV is a serotype of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh10 or AAVrh74.

47. The method according to claim 46, characterized in that the viral vector is a pseudotyped AAV.

48. The method according to claim 47, characterized in that the pseudotyped AAV is AAV2 / 8.

49. The method according to claim 48, characterized in that the pseudotyped AAV is AAV2 / 9.

50. The method according to any one of claims 1-49, characterized in that the transgene encoding GAA is operably linked to a promoter that induces expression of the transgene in a muscle and / or neuronal cell.

51. The method according to claim 50, wherein the promoter is a muscle MSC promoter, an MSC promoter, a chicken beta-actin promoter, a CMV promoter, a myosin light chain-2 promoter, an alpha-actin promoter, a troponin 1 promoter, a Na exchanger promoter + / Ca 2+ , dystrophin promoter, alpha7 integrin promoter, brain natriuretic peptide promoter, alpha-B-crystallin / small heat shock protein promoter, alpha-myosin heavy chain promoter, or atrial natriuretic factor promoter.

52. The method according to any one of claims 1-51, characterized in that the GAA is functionally linked to an enhancer that induces expression of the transgene in a muscle and / or neuronal cell.

53. The method according to claim 52, characterized in that the enhancer is a CMV enhancer, a MEF2 enhancer, or a MyoD enhancer.

54. The method according to any one of paragraphs 1-53, characterized in that the viral vector is administered to the patient by intravenous, intrathecal, intracisternal, intracerebroventricular or intramuscular administration.

55. The method according to any one of paragraphs 1-54, characterized in that the corticosteroid is prednisolone.

56. The method according to item 55, characterized in that the corticosteroid is administered to the patient in a single dose.

57. The method according to claim 55 or 56, characterized in that the corticosteroid is administered to the patient in multiple doses.

58. The method according to item 56 or 57, characterized in that the corticosteroid is administered to the patient in an amount from 0.1 mg / kg / dose to 2 mg / kg / dose.

59. The method according to claim 58, characterized in that the corticosteroid is administered to the patient in an amount of 0.5 mg / kg / dose, while the corticosteroid is optionally administered to the patient in an amount of 1 mg / kg / dose or 2 mg / kg / dose.

60. The method according to paragraph 56 or 57, characterized in that the corticosteroid is administered to the patient in an amount from 1 mg to 120 mg.

61. The method according to claim 60, characterized in that the corticosteroid is administered to the patient in an amount of 30 mg.

62. The method according to claim 60, characterized in that the corticosteroid is administered to the patient in an amount of 60 mg.

63. The method according to claim 60, characterized in that the corticosteroid is administered to the patient in an amount of 120 mg.

64. The method according to any one of paragraphs 59-63, characterized in that the corticosteroid is administered to the patient in one or more doses per day, week or month.

65. The method according to claim 64, characterized in that the corticosteroid is administered to the patient in one or more doses per day, optionally, the corticosteroid is administered to the patient in one dose per day, two doses per day, three doses per day, four doses per day, or five doses per day.

66. The method according to item 65, characterized in that the corticosteroid is administered to the patient in one dose per day.

67. The method according to any one of paragraphs 55-66, characterized in that the corticosteroid is administered to the patient in an amount from 1 mg / day to 120 mg / day.

68. The method according to any one of paragraphs 55-67, characterized in that the corticosteroid is administered to the patient in an amount of 30 mg / day.

69. The method according to any one of paragraphs 55-67, characterized in that the corticosteroid is administered to the patient in an amount of 60 mg / day.

70. The method according to any one of paragraphs 55-67, characterized in that the corticosteroid is administered to the patient in an amount of 120 mg / day.

71. The method according to any one of paragraphs 55-70, characterized in that the corticosteroid is administered to the patient in the form of a standard dosage form containing 5 mg of the corticosteroid.

72. The method according to any one of paragraphs 55-70, characterized in that the corticosteroid is administered to the patient in the form of a standard dosage form containing 10 mg of the corticosteroid.

73. The method according to any one of paragraphs 55-70, characterized in that the corticosteroid is administered to the patient in the form of a standard dosage form containing 15 mg of the corticosteroid.

74. The method according to any one of paragraphs 55-70, characterized in that the corticosteroid is administered to the patient in the form of a standard dosage form containing 30 mg of the corticosteroid.

75. The method according to any one of paragraphs 55-74, characterized in that the corticosteroid is administered to the patient orally.

76. The method according to any one of paragraphs 1-75, characterized in that the patient has no history of transaminasemia or hyperbilirubinemia.

77. The method according to item 76, characterized in that the patient does not have a history of any underlying liver disease.

78. The method according to any one of paragraphs 1-77, characterized in that the age of the patient at the time of administration of the viral vector is from one year to 40 years.

79. The method according to any one of claims 1-78, characterized in that the patient exhibits symptoms selected from feeding difficulties, growth retardation, hypotension, progressive weakness, respiratory failure, severe enlargement of the tongue, and thickening of the heart muscle.

80. The method according to any one of paragraphs 1-79, characterized in that the patient receives replacement therapy with the GAA enzyme.

81. The method according to any one of claims 1-80, characterized in that after the introduction of the viral vector, the patient's endogenous GAA activity is from 50% to 200% of the endogenous GAA activity of a person of the same sex and similar body mass index who does not suffer from Pompe disease.

82. The method according to any one of embodiments 1-81, characterized in that after administration of the viral vector, the patient experiences a decrease in the level of glycogen in skeletal muscle, cardiac muscle and / or neuronal tissue.

83. The method according to any one of claims 17-82, characterized in that the patient is determined to have transaminasemia or one or more symptoms thereof based on the detection that the patient has a liver function test level of one or more transaminases that is elevated or decreased relative to a reference level.

84. The method according to claim 83, characterized in that the level of one or more transaminases includes the level of aspartate aminotransferase and / or alanine aminotransferase.

85. The method according to any one of claims 17-84, characterized in that the patient is determined to have transaminasemia or one or more symptoms thereof based on the detection that the patient has an alanine aminotransferase level in a liver function test that exceeds 50 U / L.

86. The method according to any one of claims 17-85, characterized in that the patient is determined to have transaminasemia or one or more symptoms thereof based on the detection that the patient has an aspartate aminotransferase level in a liver function test that exceeds 50 U / L.

87. A kit containing a viral vector including a transgene encoding GAA and instructions for use, wherein the instructions for use contain instructions for the user of the kit regarding the administration of the viral vector to a patient with Pompe disease in accordance with the method of any one of claims 1-86.

88. A kit containing a corticosteroid and instructions for use, wherein the instructions for use contain directions for the user of the kit regarding the administration of the corticosteroid to a patient for the treatment or prevention of transaminasemia or hyperbilirubinemia in accordance with the method of any one of claims 1-86.