APPLICATION OF IRAK4 MODULATORS FOR GENE THERAPY

Claims

1. A method for delivering a nucleic acid to a cell of an individual in need thereof, the method comprising a) administration of an IRAK modulator to the individual and b) administering the gene therapy agent to the individual.

2. A method for treating an individual in need thereof using a gene therapy agent, the method comprising a) administration of an IRAK modulator to the individual and b) administering the gene therapy agent to the individual.

3. A method for improving gene therapy in an individual, the method comprising a) administration of an IRAK modulator to the individual and b) administering the gene therapy agent to the individual.

4. A method for suppressing an immune response to a gene therapy agent in an individual in need thereof, the method comprising a) administration of an IRAK modulator to the individual and b) administering the gene therapy agent to the individual.

5. The method according to any one of claims 1-4, wherein the IRAK modulator provides modulation of the activity or expression of the IRAK protein kinase.

6. The method according to claim 5, wherein the IRAK protein kinase is IRAK-1 protein kinase, IRAK-2 protein kinase, IRAK-3 protein kinase, or IRAK-4 protein kinase.

7. The method according to any one of claims 1-6, wherein the IRAK modulator provides modulation of the activity or expression of the protein kinase IRAK-4.

8. The method according to any one of claims 1-7, wherein the IRAK modulator is an agent that provides destruction of IRAK, an IRAK inhibitor, or an agent that confers loss of function to IRAK.

9. The method according to any one of claims 1-8, wherein the IRAK modulator is a small molecule.

10. The method according to any one of paragraphs 1-9, wherein the IRAK modulator comprises a compound of formula [I], [I], or its pharmaceutically acceptable salt, where X 1is a divalent moiety selected from the covalent bond, -CH2-, -C(O)-, -C(S)- and R 1a represents hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or an optionally substituted aliphatic C 1-4 group; each R 2a independently represents hydrogen, R 6a , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2or -N(R)S(O)2R; ring A a is a bicyclic or tricyclic ring selected from ring B ais a fused ring selected from a 6-membered aryl containing 0-2 nitrogen atoms, a 5-7-membered partially saturated carbocyclyl, a 5-7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 3a selected from hydrogen, halogen, -OR, -N(R)2, or -SR; each R 4a independently represents hydrogen, R 6a , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, N(R)C(O)R, -N(R)C(O)NR2or -N(R)S(O)2R; R 5a represents hydrogen, aliphatic C 1-4 group or -CN; each R 6a independently represents an optionally substituted group selected from aliphatic C 1-6group, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; ring A is a 4- to 10-membered saturated monocyclic or bicyclic carbocyclic or heterocyclic ring containing 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ring C is phenyl or a 5- to 10-membered monocyclic or bicyclic heteroaryl ring containing 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of L 2 and L 3 independently represents a covalent bond or a divalent straight or branched saturated or unsaturated C 1-3a hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2- or -CR=CR-; each R 1 independently represents hydrogen, R 5 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CFR2, -CF2(R), -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR or -C(O)NR2; each R independently represents hydrogen or an optionally substituted group selected from aliphatic C 1-6 group, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic group containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two R groups on the same atom are optionally taken together with their intervening atom to form an optionally substituted 4-11-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, bridged bicyclic, spirocyclic, 5- or heteroaryl ring containing 0-3 heteroatoms, in addition to the atom to which they are attached, independently selected from nitrogen, oxygen and sulfur; each R 2 independently represents hydrogen, R 5 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CF2(R), -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2 or -N(R)S(O)2R; R 4 selected from hydrogen or an optionally substituted group selected from aliphatic C 1-6groups or a 4-11-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic or heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; ring D is phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5- to 6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R 3 independently represents hydrogen, R 5 , halogen, -CN, -NO2, -OR, -SR, -NR 2 , -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2) 2, -CF2(R), -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2or -N(R)S(O)2R; each R 5 independently represents an optionally substituted group selected from aliphatic C 1-6 group, phenyl, a 3-7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; n is 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4, and p is 0, 1, 2, 3, or 4.

11. The method according to any one of paragraphs 1-9, wherein the IRAK modulator comprises any of the compounds of formulas [II]-[V], (II), [III] or or a pharmaceutically acceptable salt thereof.

12. The method according to any one of claims 1-9, wherein the IRAK modulator is a compound of formula [II], an IRAK-4 degrading agent 1 based on PROTAC or PF 06650833.

13. The method according to any one of claims 1-9, wherein the IRAK modulator is CRISPR, siRNA, shRNA, miRNA, RNAi agent, antisense RNA, ribozyme, or DNAzyme.

14. The method according to any one of claims 1-13, wherein the IRAK modulator blocks the function of TLR9.

15. The method according to any one of claims 1-14, wherein the gene therapy agent comprises a viral vector.

16. The method of claim 15, wherein the viral vector is an AAV particle.

17. The method according to claim 16, where the AAV particle contains AAV1 capsid, AAV2 capsid, AAV3 capsid, AAV4 capsid, AAV5 capsid, AAV6 capsid, AAV7 capsid, AAV8 capsid, AAVrh8 capsid, AAV9 capsid, AAV10 capsid, AAVrh10 capsid, AAV11 capsid, AAV12 capsid, capsid AAVrh32.33, AAV-XL32 capsid, AAV-XL32.1 capsid, AAV LK03 capsid, AAV2R471A capsid, AAV2 / 2-7m8 capsid, AAV DJ capsid, AAV DJ8 capsid, AAV2 N587A capsid, AAV2 E548A capsid, AAV2 N708A capsid, AAV capsid V708K, goat AAV capsid, chimeric capsid AAV1 / AAV2, bovine AAV capsid, murine AAV capsid, rAAV2 / HBoV1 (chimeric AAV / human bocavirus 1), AAV2HBKO capsid, AAVPHP.B capsid or AAVPHP.eB capsid, or a functional variant thereof.

18. The method of claim 17, wherein the AAV capsid comprises a tyrosine mutation, a mutation affecting heparin binding, or an HBKO mutation.

19. The method of any one of claims 16-18, wherein the AAV viral particle comprises an AAV genome comprising one or more inverted terminal repeats (ITRs), wherein the one or more ITRs are AAV1 ITR, AAV2 ITR, AAV3 ITR, AAV4 ITR, AAV5 ITR, AAV6 ITR, AAV7 ITR, AAV8 ITR, AAVrh8 ITR, AAV9 ITR, AAV10 ITR, AAVrh10 ITR, AAV11 ITR or AAV12 ITR.

20. The method of claim 19, wherein the one or more ITRs and the capsid of the AAV particle are derived from the same AAV serotype.

21. The method of claim 19, wherein the one or more ITRs and capsid of the AAV particles are obtained from different AAV serotypes.

22. The method according to claim 15, wherein the viral vector is an adenovirus particle.

23. The method according to claim 22, wherein the adenovirus particle comprises a capsid from adenovirus serotype 2, 1, 5, 6, 19, 3, 11, 7, 14, 16, 21, 12, 18, 31, 8, 9, 10, 13, 15, 17, 19, 20, 22, 23, 24-30, 37, 40, 41, AdHu2, AdHu 3, AdHu4, AdHu24, AdHu26, AdHu34, AdHu35, AdHu36, AdHu37, AdHu41, AdHu48, AdHu49, AdHu50, AdC6, AdC7, AdC69, bovine Ad type 3, canine Ad type 2, Ad sheep or Ad pig type 3 or its functional variant.

24. The method according to claim 15, wherein the viral vector is a lentiviral particle.

25. The method according to claim 24, wherein the recombinant lentiviral particle is pseudotyped with vesicular stomatitis virus (VSV), lymphatic choriomeningitis virus (LCMV), Ross River virus (RRV), Ebola virus, Marburg virus, Mokola virus, rabies virus, RD114 or a functional variant thereof.

26. The method of claim 15, wherein the viral vector is a herpes simplex virus (HSV) particle.

27. The method of claim 26, wherein the HSV particle is an HSV-1 particle or an HSV-2 particle or a functional variant thereof.

28. The method according to any one of claims 1-14, wherein the gene therapy agent comprises a lipid nanoparticle.

29. The method according to any one of claims 1-28, wherein the gene therapy agent comprises a nucleic acid encoding a heterologous transgene.

30. The method of claim 29, wherein the heterologous transgene is operably linked to a promoter.

31. The method of claim 30, wherein the promoter is a constitutive promoter, a tissue-specific promoter, or an inducible promoter.

32. The method according to any one of claims 1-31, wherein the IRAK modulator is administered before, at the same time as, or after the administration of the gene therapy agent.

33. The method according to any one of claims 1-32, wherein the individual has a disease or disorder suitable for treatment with gene therapy.

34. The method of claim 33, wherein the disease or disorder is a monogenic disease or disorder.

35. The method according to any one of claims 1-34, wherein the gene therapy agent is administered intravenously, intraperitoneally, intraarterially, intramuscularly, subcutaneously, or intrahepatically.

36. The method according to any one of claims 1-35, wherein the IRAK modulator is administered orally, intravenously, intraperitoneally, intraarterially, intramuscularly, subcutaneously, or intrahepatically.

37. A method for delivering a gene therapy agent to a cell of an individual in need thereof, the method comprising a) incubating innate immune system cells from an individual with a gene therapy agent, b) analyzing cells of the innate immune system for the expression of one or more cytokines, wherein the expression of a cytokine signature following incubation with the gene therapy agent enables identification of an individual with innate immunity to the gene therapy agent, c) administering an IRAK modulator to the individual identified in step b), and d) administering the gene therapy agent to the individual identified in step b).

38. A method of treating an individual in need thereof using a gene therapy agent, the method comprising a) incubating innate immune system cells from an individual with a gene therapy agent, b) analyzing cells of the innate immune system for the expression of one or more cytokines, wherein the expression of a cytokine signature following incubation with the gene therapy agent enables identification of an individual with innate immunity to the gene therapy agent, c) administering an IRAK modulator to the individual identified in step b), and d) administering the gene therapy agent to the individual identified in step b).

39. A method for selecting an individual for treatment with a gene therapy agent and an IRAK modulator, the method comprising a) incubating innate immune system cells from an individual with a gene therapy agent, b) analyzing cells of the innate immune system for the expression of one or more cytokines, wherein the expression of the cytokine signature after incubation with the gene therapy agent enables identification of an individual for treatment with the gene therapy agent and the IRAK modulator, c) selecting the individual identified in step b) for treatment with the gene therapy agent and the IRAK modulator.

40. The method according to claim 39, further comprising the steps d) administering an IRAK modulator to the individual identified in step b), and e) administering the gene therapy agent to the individual identified in step b).

41. The method according to any one of claims 37-40, wherein the innate immune system cell is a dendritic cell, a monocyte, a macrophage, or a natural killer (NK) cell.

42. The method according to any one of claims 37-41, wherein the innate immune system cells are isolated from peripheral blood mononuclear cells obtained from an individual.

43. The method according to any one of claims 38-42, wherein the cell of the innate immune system is a dendritic cell.

44. The method of claim 43, wherein the dendritic cell is obtained from a monocyte of an individual.

45. The method according to claim 44, further comprising isolation of monocytes from an individual and incubating monocytes in a dendritic cell culture medium to obtain dendritic cells from monocytes prior to incubating the dendritic cells with the gene therapy agent.

46. ​​The method according to claim 44 or 45, wherein the monocytes are CD14+ monocytes.

47. The method of any one of claims 44-46, wherein the monocytes are incubated with a dendritic cell culture medium for about 5 to about 10 days or about 7 to about 8 days to obtain dendritic cells from the monocytes.

48. The method according to any one of claims 37-47, wherein the innate immune system cells are passaged prior to incubation with the gene therapy agent of step c).

49. The method according to claim 48, wherein the cells of the innate immune system are reseeded into microwell plates.

50. The method according to any one of claims 37-49, wherein the gene therapy agent is a viral vector, and wherein the innate immune system cells are incubated with the viral vector at an MOI of about 1×10 3 up to approximately 1×10 5 or approximately 1×10 4 .

51. The method of any one of claims 37-49, wherein the gene therapy agent is a non-viral vector, and wherein the innate immune system cells are incubated with the non-viral vector at a concentration of from about 1 ng / ml to about 1 mg / ml.

52. The method according to any one of claims 37-51, wherein the innate immune system cells are incubated with the gene therapy agent for from about 12 hours to about 36 hours or about 24 hours.

53. The method according to any one of claims 37-52, wherein the cytokine signature comprises increased expression of one or more of IL6, TNFα, IL-1β, MCP1 and MIP-1α.

54. The method according to any one of claims 37-53, wherein the cytokine signature comprises increased expression of IL6, TNFα, IL-1β, MCP1 and MIP-1α.

55. The method according to any one of claims 37-53, wherein the cytokine signature comprises increased expression of IL6, TNFα and IL-1β.

56. The method according to any one of claims 37-55, wherein the expression of cytokines in the cytokine signature is increased compared to a suitable control.

57. The method of claim 56, wherein the suitable control is the expression of cytokines in the cytokine signature from innate immune system cells that have not been incubated with the gene therapy agent, or wherein the suitable control is the expression of cytokines in the cytokine signature from innate immune system cells prior to incubation with the gene therapy agent.

58. The method according to any one of claims 37-57, wherein the IRAK modulator provides modulation of the activity of the IRAK protein kinase.

59. The method according to claim 58, wherein the IRAK protein kinase is IRAK-1 protein kinase, IRAK-2 protein kinase, IRAK-3 protein kinase, or IRAK-4 protein kinase.

60. The method according to any one of claims 37-59, wherein the IRAK modulator provides modulation of the activity of the protein kinase IRAK-4.

61. The method according to any one of claims 37-60, wherein the IRAK modulator is an agent that provides destruction of IRAK, an IRAK inhibitor, or an agent that confers loss of function to IRAK.

62. The method according to any one of claims 37-61, wherein the IRAK modulator is a small molecule.

63. The method according to any one of paragraphs 37-62, wherein the IRAK modulator comprises a compound of formula [I], [I], or its pharmaceutically acceptable salt, where X 1 is a divalent moiety selected from the covalent bond, -CH2-, -C(O)-, -C(S)- and R 1a represents hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or an optionally substituted aliphatic C 1-4 group; each R 2a independently represents hydrogen, R 6a, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2or -N(R)S(O)2R; ring A a is a bicyclic or tricyclic ring selected from ring B a is a fused ring selected from a 6-membered aryl containing 0-2 nitrogen atoms, a 5-7-membered partially saturated carbocyclyl, a 5-7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 3a selected from hydrogen, halogen, -OR, -N(R)2, or -SR; each R 4a independently represents hydrogen, R6a , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, N(R)C(O)R, -N(R)C(O)NR2or -N(R)S(O)2R; R 5a represents hydrogen, aliphatic C 1-4 group or -CN; each R 6a independently represents an optionally substituted group selected from aliphatic C 1-6 group, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; ring A is a 4- to 10-membered saturated monocyclic or bicyclic carbocyclic or heterocyclic ring containing 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ring C is phenyl or a 5- to 10-membered monocyclic or bicyclic heteroaryl ring containing 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of L 2 and L 3 independently represents a covalent bond or a divalent straight or branched saturated or unsaturated C 1-3 a hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2- or -CR=CR-; each R 1 independently represents hydrogen, R 5 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CFR2, -CF2(R), -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR or -C(O)NR2; each R independently represents hydrogen or an optionally substituted group selected from aliphatic C 1-6group, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic group containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two R groups on the same atom are optionally taken together with their intervening atom to form an optionally substituted 4-11-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, bridged bicyclic, spirocyclic, 5- or heteroaryl ring containing 0-3 heteroatoms, in addition to the atom to which they are attached, independently selected from nitrogen, oxygen and sulfur; each R 2 independently represents hydrogen, R 5, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2)2, -CF2(R), -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2 or -N(R)S(O)2R; R 4 selected from hydrogen or an optionally substituted group selected from aliphatic C 1-6 groups or a 4-11-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic or heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; ring D is phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5- to 6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R 3 independently represents hydrogen, R 5 , halogen, -CN, -NO2, -OR, -SR, -NR 2 , -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)(NR)R, -P(O)(OR)2, -P(O)(NR2) 2 , -CF2(R), -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2or -N(R)S(O)2R; each R 5 independently represents an optionally substituted group selected from aliphatic C 1-6group, phenyl, a 3-7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; n is 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4, and p is 0, 1, 2, 3, or 4.

64. The method according to any one of paragraphs 37-62, wherein the IRAK modulator comprises any of the compounds of formulas [II]-[V], (II), [III] or or a pharmaceutically acceptable salt thereof.

65. The method according to any one of claims 37-62, wherein the IRAK modulator is a compound of formula [II], an IRAK-4 degrading agent 1 based on PROTAC or PF 06650833.

66. The method according to any one of claims 37-61, wherein the IRAK modulator is CRISPR, siRNA, shRNA, miRNA, RNAi agent, antisense RNA, ribozyme, or DNAzyme.

67. The method according to any one of claims 37-66, wherein the IRAK modulator blocks the function of TLR9.

68. The method according to any one of claims 37-67, wherein the gene therapy agent is a viral vector.

69. The method of claim 68, wherein the viral vector is an AAV particle.

70. The method according to claim 69, where the AAV particle contains AAV1 capsid, AAV2 capsid, AAV3 capsid, AAV4 capsid, AAV5 capsid, AAV6 capsid, AAV7 capsid, AAV8 capsid, AAVrh8 capsid, AAV9 capsid, AAV10 capsid, AAVrh10 capsid, AAV11 capsid, AAV12 capsid, capsid AAVrh32.33, AAV-XL32 capsid, AAV-XL32.1 capsid, AAV LK03 capsid, AAV2R471A capsid, AAV2 / 2-7m8 capsid, AAV DJ capsid, AAV DJ8 capsid, AAV2 N587A capsid, AAV2 E548A capsid, AAV2 N708A capsid, AAV capsid V708K, goat AAV capsid, chimeric capsid AAV1 / AAV2, bovine AAV capsid, murine AAV capsid, rAAV2 / HBoV1 (chimeric AAV / human bocavirus 1), AAV2HBKO capsid, AAVPHP.B capsid or AAVPHP.eB capsid, or a functional variant thereof.

71. The method of claim 70, wherein the AAV capsid comprises a tyrosine mutation, a mutation affecting heparin binding, or an HBKO mutation.

72. The method of any one of claims 69-71, wherein the AAV viral particle comprises an AAV genome comprising one or more inverted terminal repeats (ITRs), wherein the one or more ITRs are AAV1 ITR, AAV2 ITR, AAV3 ITR, AAV4 ITR, AAV5 ITR, AAV6 ITR, AAV7 ITR, AAV8 ITR, AAVrh8 ITR, AAV9 ITR, AAV10 ITR, AAVrh10 ITR, AAV11 ITR, or AAV12 ITR.

73. The method of claim 72, wherein the one or more ITRs and the capsid of the AAV particle are derived from the same AAV serotype.

74. The method of claim 72, wherein the one or more ITRs and capsid of the AAV particles are obtained from different AAV serotypes.

75. The method according to claim 68, wherein the viral vector is an adenovirus particle.

76. The method according to claim 75, wherein the adenovirus particle comprises a capsid from adenovirus serotype 2, 1, 5, 6, 19, 3, 11, 7, 14, 16, 21, 12, 18, 31, 8, 9, 10, 13, 15, 17, 19, 20, 22, 23, 24-30, 37, 40, 41, AdHu2, AdHu 3, AdHu4, AdHu24, AdHu26, AdHu34, AdHu35, AdHu36, AdHu37, AdHu41, AdHu48, AdHu49, AdHu50, AdC6, AdC7, AdC69, bovine Ad type 3, canine Ad type 2, Ad sheep or Ad pig type 3 or its functional variant.

77. The method according to claim 68, wherein the viral vector is a lentiviral particle.

78. The method according to claim 77, wherein the recombinant lentiviral particle is pseudotyped with vesicular stomatitis virus (VSV), lymphatic choriomeningitis virus (LCMV), Ross River virus (RRV), Ebola virus, Marburg virus, Mokola virus, rabies virus, RD114 or a functional variant thereof.

79. The method according to claim 68, wherein the viral vector is a particle of the herpes simplex virus (HSV).

80. The method of claim 79, wherein the HSV particle is an HSV-1 particle or an HSV-2 particle or a functional variant thereof.

81. The method according to any one of claims 37-80, wherein the gene therapy agent is a lipid nanoparticle.

82. The method according to any one of claims 37-81, wherein the gene therapy agent comprises a nucleic acid encoding a heterologous transgene.

83. The method of claim 82, wherein the heterologous transgene is operably linked to a promoter.

84. The method of claim 83, wherein the promoter is a constitutive promoter, a tissue-specific promoter, or an inducible promoter.

85. The method according to any one of claims 37-84, wherein the IRAK modulator is administered before, at the same time as, or after the administration of the gene therapy agent.

86. The method according to any one of claims 37-85, wherein the individual has a disease or disorder suitable for treatment with gene therapy.

87. The method of claim 86, wherein the disease or disorder is a monogenic disease or disorder.

88. The method according to any one of paragraphs 37-87, wherein the gene therapy agent is administered intravenously, intraperitoneally, intraarterially, intramuscularly, subcutaneously, or intrahepatically.

89. The method according to any one of claims 37-88, wherein the IRAK modulator is administered orally, intravenously, intraperitoneally, intraarterially, intramuscularly, subcutaneously, or intrahepatically.

90. The method according to any one of claims 1-89, wherein the IRAK modulator provides for a reduction in the number of activated T cells.

91. Use of a composition in the manufacture of a medicinal product for delivering a nucleic acid to a cell of an individual in need thereof, wherein the composition comprises a gene therapy agent, and wherein the composition is formulated for use in combination with an IRAK modulator.

92. Use of a composition in the manufacture of a medicinal product for delivering a nucleic acid to a cell of an individual in need thereof, wherein the composition comprises an IRAK modulator, and wherein the composition is formulated for use in combination with a gene therapy agent.

93. Use of a composition in the manufacture of a medicinal product for the treatment of an individual in need of gene therapy, wherein the composition comprises a gene therapy agent, and wherein the composition is formulated for use in combination with an IRAK modulator.

94. Use of a composition in the manufacture of a medicinal product for the treatment of an individual in need of gene therapy, wherein the composition comprises an IRAK modulator, and wherein the composition is formulated for use in combination with a gene therapy agent.

95. Use of a composition in the manufacture of a medicinal product for modulating an immune response to a gene therapy agent in an individual in need of gene therapy, wherein the composition comprises the gene therapy agent, and wherein the composition is formulated for use in combination with an IRAK modulator.

96. Use of a composition in the manufacture of a medicinal product for modulating an immune response to a gene therapy agent in an individual, wherein the composition comprises an IRAK modulator, and wherein the composition is formulated for use in combination with the gene therapy agent.

97. The use according to any one of claims 91-96, wherein the gene therapy agent is an AAV particle, an adenovirus particle, a lentivirus particle, an HSV particle, or a lipid nanoparticle.

98. The use according to any one of paragraphs 91-97, wherein the IRAK modulator is an agent that ensures the destruction of IRAK-4.

99. A composition comprising a gene therapy agent for use in delivering a nucleic acid to a cell of an individual in need thereof, wherein the gene therapy agent is used in combination with an IRAK modulator.

100. A composition comprising an IRAK modulator for use in delivering a nucleic acid to a cell of an individual in need thereof, wherein the IRAK modulator is used in combination with a gene therapy agent.

101. A composition comprising a gene therapy agent for use in the treatment of an individual in need of gene therapy, wherein the gene therapy agent is used in combination with an IRAK modulator.

102. A composition comprising an IRAK modulator for use in treating an individual in need of gene therapy, wherein the IRAK modulator is used in combination with a gene therapy agent.

103. A composition comprising an IRAK modulator for modulating an immune response to a gene therapy agent in an individual in need of gene therapy, wherein the IRAK modulator is used in combination with the gene therapy agent.

104. A composition comprising an IRAK modulator for suppressing an immune response to a gene therapy agent in an individual in need of gene therapy, wherein the IRAK modulator is used in combination with the gene therapy agent.

105. The composition of any one of claims 99-104, wherein the gene therapy agent is an AAV particle, an adenovirus particle, a lentivirus particle, an HSV particle, or a lipid nanoparticle.

106. The composition of any one of claims 99-105, wherein the IRAK modulator is an agent that provides destruction of IRAK-4.

107. A kit for use according to the method according to any of paragraphs 1-90.

108. A set for use according to any of paragraphs 91-98.

109. A kit containing a composition according to any one of paragraphs 99-106.