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1. WO2020223576 - FRATAXIN-SENSITIVE MARKERS FOR DETERMINING EFFECTIVENESS OF FRATAXIN REPLACEMENT THERAPY

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CLAIMS

1. A method for evaluating effectiveness of frataxin (FXN) replacement therapy, the method comprising:

(a) determining an FXN replacement expression profile for one or more FXN-sensitive genomic markers (FSGMs) in a sample from an FXN deficient patient following treatment with FXN replacement therapy;

(b) comparing the patient FXN replacement expression profile with a baseline FXN(-) expression profile; and

(c) using the comparison to determine effectiveness of the FXN replacement therapy;

wherein the one or more FSGMs are any one or more markers defined in Table 2, Table 4 and/or Figure 3.

2. The method according to claim 1, further comprising determining a baseline FXN(-) expression profile for one or more FXN-sensitive genomic markers (FSGMs) in a sample from a patient exhibiting FXN deficiency prior to FXN replacement therapy.

3. The method according to claim 2, wherein the one or more FSGMs comprise at least one or any combination of more than one of a gene encoding a secreted protein, a mitochondrial gene, a EGR-family gene, insulin-like gene, ribosome depletion response gene, mitochondrial energy production gene, proteasome regulation gene, ribosomal function gene, respiratory chain gene, cardiac muscle development gene, macromolecule catabolism gene, a translational initiation gene, mitochondrial components gene, oxidative phosphorylation gene, negative regulation of macromolecule metabolic process gene, or regulation of apoptotic process gene, or a protein encoded by any of these genes.

4. The method of claim 1, wherein the one or more FSGMs comprise a secreted protein.

5. The method of claim 1, wherein the one or more FSGMs comprise one or more of

CYR61, ADAMTS1, ASPN, FAM177A, IGF1, LOX, NRTN, SERPINE1, STC1, and THBS1.

6. The method of claim 1, wherein the one or more FSGMs comprise CYR61.

7. The method according to claim 1, wherein the one or more FSGMs comprise one or more of NR4A1, PTP4A1, ATF3, BTG2, EGR1, EGR2, EGR3, CYR61, and ABCE1.

8. The method according to claim 1, wherein the one or more FSGMs comprise one or more of EGR1, EGR2, EGR3 and IGF1.

9. The method according to claim 1, wherein the one or more FSGMs comprise one or more of MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-C03, MT-ATP6, MT-ATP8, and CYCS.

10. The method according to claim 1, wherein the one or more FSGMs comprise one or more of OPS2, VBP1, PSMA3, SLIRP, CUL2, DCUN1D1, UBE2D3, ZNRF1, RNF2, and LAMP2.

11. The method according to claim 1, wherein the one or more FSGMs comprise one or more of RPS 15A, EIF1AX, RPL24, RPL32, RPL26, RPL10, RPL39, RPL38, RPS27L, and ABCE1.

12. The method according to claim 1, wherein the one or more FSGMs comprise one or more of MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-C03, and CYCS.

13. The method according to claim 1, wherein the one or more FSGMs comprise one or more of NR4A1, EGR1, EGR3, ADAMTS 1, THBS 1, SERPINE1, IGF1, PTGS2, and CYR61.

14. The method according to claim 1, wherein the one or more FSGMs comprise one or more of PSMA3, CUL2, UBE2D3, ZNRF1, RPS15A, RPL24, RPL32, RPL26, RPL10, RPL39, and RPL38.

15. The method according to claim 1, wherein the one or more FSGMs comprise one or more of ABCE1, RPS 15A, EIF1AX, RPL24, RPL32, RPL26, RPL10, RPL39, and RPL38.

16. The method according to claim 1, wherein the one or more FSGMs comprise one or more of MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-C03, MT-ATP6, MT-ATP8, CYCS, TMEM-126 A, MAO A, and ABCE1.

17. The method according to claim 1, wherein the one or more FSGMs comprise one or more of MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-C03, MT-ATP6, and MT-ATP8.

18. The method according to claim 1, wherein the one or more FSGMs comprise one or more of ABCE1, RPL26, RPL38, RPL10, RPL32, RPS15A, RPL24, RPL39, SLIRP, COPS2, DCUN1D1, RNF2, EGR1, BTG2, ATF3, PTGS2, IGF1, SERPINE1, and THBS1.

19. The method according to claim 1, wherein the one or more FSGMs comprise one or more of RPL26, THBS1, SERPINE1, IGF1, PTGS2, RPL10, RPS27L, CYCS, ATF3, BTG2, EGR1, EGR3, and CYR61.

20. The method according to claim 1, wherein the one or more FSGMs are upregulated following treatment with FXN replacement therapy.

21. The method according to claim 20, wherein the one or more FSGMs that are upregulated following treatment with FXN replacement therapy are mt-RNRl, mt-RNR2, ADNP, AI480526, C230034021RIK, CCDC85B, CCDC85C, CTCFL, NRTN, PDE4A, PHF1, RPL37RT,

SLC26A10, SNORD17, SUV420H2, WNK2, YAM1 or ZNRF1.

22. The method according to claim 1, wherein the one or more FSGMs are downregulated following treatment with FXN replacement therapy.

23. The method according to claim 22, wherein the one or more FSGMs that are

downregulated following treatment with FXN replacement therapy are CYR61, mt-ATP6, mt-ATP8, mt-C02, mt-C03, mt-NDl, mt-ND2, mt-ND3 and mt-ND4, EGR1, EGR2, EGR3, IGF1, LAMP2, or SLIRP.

24. The method according to any of the preceding claims, wherein determining an FXN expression profile for FSGMs comprises determining an FXN feature vector of values indicative of expression of the FSGMs.

25. The method according to claim 24, wherein using the comparison to determine effectiveness of the FXN replacement therapy comprises determining first and second FXN feature vectors for the patient FXN replacement expression profile and the baseline FXN(-) expression profile respectively and determining a distance between the feature vectors.

26. The method according to claim 25, wherein determining the distance between the feature vectors comprises determining a scalar product of the first and second feature vectors.

27. The method according to any one of claims 25 or 26, further comprising determining a third feature vector for a normal FXN expression profile for the FSGMs for a healthy subject.

28. The method according to claim 27, further comprising determining a distance between the second and third feature vectors.

29. The method according to claim 28, further comprising determining a distance between the first and third feature vectors, and normalizing the distance between the first and third feature vectors to the distance between the second and third feature vectors.

30. The method according to claim 29, further comprising using the normalized distance to determine effectiveness of the FXN replacement therapy.

31. The method according to claim 1, wherein the expression profile is determined by any one of sequencing, hybridization or amplification of the sample RNA.

32. The method according to claim 1, wherein the expression profile is determined by HPLC/UV-Vis spectroscopy, enzymatic analysis, mass spectrometry, NMR, immunoassay, ELISA, or any combination thereof.

33. The method according to claim 1, further comprising modifying treatment with the FXN replacement therapy when the FXN replacement therapy is indicated as being ineffective.

34. The method according to claim 1, wherein the patient is suffering from Freidrich’s Ataxia (FRDA).

35. The method according to claim 1, further comprising obtaining a biological sample from a patient exhibiting FXN deficiency.

36. A method for evaluating effectiveness of frataxin (FXN) replacement therapy, the method comprising:

(a) determining an FXN replacement expression profile for one or more FXN-sensitive genomic markers (FSGMs) in a sample from an FXN deficient patient following treatment with FXN replacement therapy, wherein the one or more FSGMs comprise a secreted protein selected from Table 2, Table 4 and/or Figure 3;

(b) comparing the patient FXN replacement expression profile with a baseline FXN(-) expression profile; and

(c) using the comparison to determine effectiveness of the FXN replacement therapy.

37. The method of claim 36, wherein the FXN replacement therapy comprises treatment with an FXN fusion protein.

38. The method of claim 36, wherein the FXN replacement therapy comprises treatment with CTI-1601.

39. The method according to claim 36, wherein the expression profile is determined by any one of sequencing, hybridization or amplification of the sample RNA.

40. The method according to claim 36, wherein the expression profile is determined by HPLC/UV-Vis spectroscopy, enzymatic analysis, mass spectrometry, NMR, immunoassay, ELISA, or any combination thereof.

41. The method according to claim 36, further comprising modifying treatment with the FXN replacement therapy when the FXN replacement therapy is indicated as being ineffective.

42. The method according to claim 36, wherein the patient is suffering from Freidrich’s Ataxia (FRDA).

43. The method according to claim 36, further comprising obtaining a biological sample from a patient exhibiting FXN deficiency.

44. A method of detecting one or more frataxin- sensitive genomic markers (FSGMs) in a biological sample from a patient suffering from a frataxin (FXN) deficiency by contacting the biological sample, or a portion thereof, with one or more detection reagents specific for detection of one or more FSGMs, wherein the one or more FSGM comprises one or more FSGMs selected from Table 2, Table 4 and/or Figure 3.

45. The method of claim 44, wherein the patient is being treated with a FXN replacement therapy.

46. The method of claim 44, wherein the FXN replacement therapy comprises treatment with an FXN fusion protein.

47. The method of claim 44, wherein the FXN replacement therapy comprises treatment with CTI-1601.

48. The method of claim 44, wherein the one or more FSGMs comprise a secreted protein.

49. The method of claim 44, wherein the one or more FSGMs comprise one or more of CYR61, ADAMTS1, ASPN, FAM177A, IGF1, LOX, NRTN, SERPINE1, STC1, and THBS1.

50. The method of claim 44, wherein the one or more FSGMs comprise CYR61.

51. A method of treatment of a mitochondrial disease, the method comprising:

providing a sample from a subject suffering from FXN deficiency,

determining an FXN expression profile in the sample for one or more FXN-sensitive genomic markers (FSGMs),

comparing the FXN expression profile of the sample with at least one other expression profile selected from the group consisting of normal FXN expression profile for one or more FSGMs, baseline FXN(-) expression profile for one or more FSGMs, and an FXN replacement expression profile for one or more FSGMs,

classifying the sample FXN expression profile as corresponding to a normal FXN expression profile, baseline FXN(-) expression profile or an FXN replacement expression profile,

initiating, increasing or decreasing the dosage of FXN replacement therapy to be administered to the subject based on the classification of the sample FXN expression profile.

52. The method of claim 51, wherein the mitochondrial disease is Friedrich’s Ataxis

(FRDA).

53. The method of claim 51, wherein the one or more FSGMs comprise a secreted protein.

54. The method of claim 51, wherein the one or more FSGMs comprise one or more of

CYR61, ADAMTS 1, ASPN, FAM177A, IGF1, LOX, NRTN, SERPINE1, STC1, and THBS 1.

55. The method of claim 51, wherein the one or more FSGMs comprise CYR61.

56. The method according to claim 51, wherein the one or more FSGMs comprise one or more of NR4A1, PTP4A1, ATF3, BTG2, EGR1, EGR2, EGR3, CYR61, and ABCE1.

57. The method according to claim 51, wherein the one or more FSGMs comprise one or more of EGR1, EGR2, EGR3 and IGF1.

58. The method according to claim 51, wherein the one or more FSGMs comprise one or more of MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-C03, MT-ATP6, MT-ATP8, and CYCS.

59. The method according to claim 51, wherein the one or more FSGMs comprise one or more of OPS2, VBP1, PSMA3, SLIRP, CUL2, DCUN1D1, UBE2D3, ZNRF1, RNF2, and LAMP2.

60. The method according to claim 51, wherein the one or more FSGMs comprise one or more of RPS 15A, EIF1AX, RPL24, RPL32, RPL26, RPL10, RPL39, RPL38, RPS27L, and ABCE1.

61. The method according to claim 51, wherein the one or more FSGMs comprise one or more of MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-C03, and CYCS.

62. The method according to claim 51, wherein the one or more FSGMs comprise one or more of NR4A1, EGR1, EGR3, ADAMTS1, THBS 1, SERPINE1, IGF1, PTGS2, and CYR61.

63. The method according to claim 51, wherein the one or more FSGMs comprise one or more of PSMA3, CUL2, UBE2D3, ZNRF1, RPS15A, RPL24, RPL32, RPL26, RPL10, RPL39, and RPL38.

64. The method according to claim 51, wherein the one or more FSGMs comprise one or more of ABCE1, RPS15A, EIF1AX, RPL24, RPL32, RPL26, RPL10, RPL39, and RPL38.

65. The method according to claim 51, wherein the one or more FSGMs comprise one or more of MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-C03, MT-ATP6, MT-ATP8, CYCS, TMEM-126A, MAO A, and ABCE1.

66. The method according to claim 51, wherein the one or more FSGMs comprise one or more of MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-C03, MT-ATP6, and MT-ATP8.

67. The method according to claim 51, wherein the one or more FSGMs comprise one or more of ABCE1, RPL26, RPL38, RPL10, RPL32, RPS15A, RPL24, RPL39, SLIRP, COPS2, DCUN1D1, RNF2, EGR1, BTG2, ATF3, PTGS2, IGF1, SERPINE1, and THBS1.

68. The method according to claim 51, wherein the one or more FSGMs comprise one or more of RPL26, THBS1, SERPINE1, IGF1, PTGS2, RPL10, RPS27L, CYCS, ATF3, BTG2, EGR1, EGR3, and CYR61.

69. A composition for determining the expression profile of FSGMs, the composition comprising reagents for the detection of at least one or more FSGMs described in Table 2, Table 4 and/or Figure 3.

70. The composition of claim 69, wherein the one or more FSGMs comprise a secreted protein.

71. The composition of claim 69, wherein the one or more FSGMs comprise one or more of CYR61, ADAMTS1, ASPN, FAM177A, IGF1, LOX, NRTN, SERPINE1, STC1, and THBS1.

72. The composition of claim 69, wherein the one or more FSGMs comprise CYR61.

73. A kit for detecting one or more frataxin- sensitive genomic marker (FSGM) in a biological sample from a subject exhibiting frataxin (FXN) deficiency or being treated for FXN deficiency, comprising one or more reagents for measuring the level of the one or more FSGM in the biological sample from the subject, wherein the one or more FSGM comprises one or more FSGMs selected from Table 2, Table 4 and/or Figure 3, and a set of instructions for measuring the level of the FSGM.

74. The kit of claim 73, wherein the reagent is an antibody that binds to the one or more frataxin- sensitive genomic marker (FSGM) or an oligonucleotide that is complementary to the corresponding mRNA of the one or more FSGM.

75. The kit of claim 73, wherein the one or more FSGMs comprise a secreted protein.

76. The kit of claim 73, wherein the one or more FSGMs comprise one or more of CYR61, ADAMTS 1, ASPN, FAM177A, IGF1, LOX, NRTN, SERPINE1, STC1, and THBS 1.

77. The kit of claim 73, wherein the one or more FSGMs comprise CYR61.

78. A panel for use in a method of monitoring or evaluating the efficacy of frataxin (FXN) replacement therapy, the panel comprising one or more detection reagents, wherein each detection reagent is specific for the detection of one or more frataxin- sensitive genomic marker (FSGM), wherein the one or more FSGM comprises one or more markers selected from Table 2, Table 4 and/or Figure 3.

79. The panel of claim 78, wherein the frataxin- sensitive genomic marker (FSGM) comprises at least two or more FSGMs.

80. The panel of claim 78, wherein the one or more FSGMs comprise a secreted protein.

81. The panel of claim 78, wherein the one or more FSGMs comprise one or more of CYR61, ADAMTS 1, ASPN, FAM177A, IGF1, LOX, NRTN, SERPINE1, STC1, and THBS 1.

82. The panel of claim 78, wherein the one or more FSGMs comprise CYR61.

83. A kit comprising the panel of claim 78 and a set of instructions for obtaining information relating to frataxin (FXN) replacement therapy based on a level of the one or more frataxin-sensitive genomic markers (FSGMs).