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1. (WO2019045775) IPSC-DERIVED SECRETOME COMPOSITIONS, AND RELATED SYSTEMS AND METHODS
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What is claimed is:

1. A method of manufacturing an induced pluripotent stem cell (iPSC)-derived secretome composition tailored for treatment of a particular subject or particular group of subjects, said method comprising the steps of:

(a) identifying, as compatible with the particular subject or particular group of subjects, one or more iPSCs and/or one or more iPSC-derived cells;

(b) retrieving compatible cells corresponding to the one or more iPSCs and/or one or more iPSC-derived cells identified as compatible with the particular subject or particular group of subjects; and

(c) producing the iPSC-derived secretome composition using the retrieved compatible cells.

2. The method of claim 1, wherein the one or more iPSCs and/or the one or more iPSC-derived cells are human cells.

3. The method of claim 1 or claim 2, wherein the iPSC-derived secretome composition comprises one or more desired compatible-cell-secreted species.

4. The method of claim 3, wherein the one or more desired compatible-cell-secreted species comprise one or more desired compatible-cell-secreted molecules and/or one or more desired compatible-cell-secreted biological elements.

5. The method of claim 3, wherein the one or more desired compatible-cell-secreted species comprise one or more cytokines.

6. The method of claim 3, wherein the one or more desired compatible-cell-secreted species comprise one or more exosomes and/or one or more microvesicles.

7. The method of any one of the preceding claims, wherein step (c) comprises extracting one or more desired compatible-cell-secreted molecules and/or one or more desired biological elements from the retrieved compatible cells.

8. The method of any one of the preceding claims, wherein step (b) comprises deriving the compatible cells from a biological sample of the particular subject.

9. The method of any one of the preceding claims, wherein step (c) comprises producing a lyophilized iPSC-derived secretome composition.

10. The method of any one of the preceding claims, wherein the retrieved compatible cells comprise one or more members selected from the group consisting of induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), Retinal Pigment Epithelium (RPEs), chondrocytes, hematopoietic stem cells (HSCs), blood progenitor cells, and embryoid bodies.

11. The method of any one of the preceding claims, wherein the particular subject or the particular group of subjects is/are human.

12. The method of any one of the preceding claims, wherein the one or more iPSCs and/or one or more iPSC-derived cells are stored in a physical repository.

13. The method of any one of the preceding claims, wherein step (b) comprises obtaining the compatible cells from a physical repository.

14. The method of any one of the preceding claims, wherein step (b) comprises retrieving, by a processor of a computing device, one or more data entries corresponding to the compatible cells using a processor-based query from a user, wherein the query comprises an identification of a cell type indicative of compatibility with the particular subject or particular group of subjects.

15. The method of claim 14, wherein the identification of cell type indicative of compatibility with the particular subject or particular group of subjects comprises one or more of (i) to (iii): (i) an HLA match, (ii) an ABO blood type match, and (iii) an RHD blood group match.

16. The method of any one of the preceding claims, wherein the iPSC-derived secretome composition comprises the retrieved compatible cells.

17. The method of any one of the preceding claims, wherein step (c) comprises forming the retrieved compatible cells into a macroscopic structure suitable for topical application to the subject.

18. The method of claim 16, wherein the macroscopic structure is a sheet.

19. The method of any one of the preceding claims, wherein producing the iPSC-derived secretome composition in step (c) comprises exposing the compatible cells to culture media.

20. The method of claim 19, wherein the iPSC-derived secretome composition comprises the compatible cells, the culture media, and the one or more desired compatible-cell-secreted species.

21. The method of any one of the preceding claims, wherein step (c) comprises producing blood progenitor cells and/or HSCs and/or MSCs and/or embryoid bodies and/or RPEs and/or chondrocytes from the one or more iPSCs identified as compatible with the particular subject or particular group of subjects.

22. The method of claim 21, comprising producing the iPSC-derived secretome composition from the produced blood progenitor cells, and/or produced HSCs, and/or produced MSCs, and/or produced embryoid bodies, and/or produced RPEs, and/or produced chondrocytes.

23. The method of any one of the preceding claims, wherein the iPSC-derived secretome composition is a treatment spray, or a treatment cream, or a lotion.

24. The method of any one of claims 1 to 22, wherein the iPSC-derived secretome composition is a treatment injection.

25. A method of manufacturing an induced pluripotent stem cell (iPSC)-derived secretome composition tailored for treatment of a particular subject or particular group of subjects, said method comprising the steps of:

(a) storing, by a processor of a computing device, a database comprising a data entry corresponding to each of a plurality of characterized cells in a physical repository, wherein the characterized cells comprise iPSCs and/or iPSC-derived cells;

(b) receiving, by the processor, a query from a user comprising an identification of a cell type of the particular subject or particular group of subjects;

(c) matching, by the processor, the query to one or more data entries of the database, each of the matching data entries corresponding to each of the plurality of characterized cells having a cell type compatible with the particular subject or particular group of subjects, thereby identifying as compatible with the subject the one or more characterized cells;

(d) retrieving, from a physical repository, compatible cells corresponding to the one or more characterized cells identified as compatible with the particular subject or particular group of subjects; and

(e) producing the iPSC-derived secretome composition using the retrieved compatible cells.

26. The method of claim 25, wherein:

the data entry corresponding to each of the plurality of characterized cells comprises a set of characterized HLA loci corresponding to the cell,

the query comprises a set of queried HLA loci for the particular subject or the particular group of subjects, and

the one or more matched data entries of the database are each representative of one or more characterized compatible cells matching the queried HLA loci.

27. The method of claim 26, wherein the plurality of characterized cells in the physical repository are immortalized.

28. The method of claim 26 or claim 27, wherein the set of characterized HLA loci corresponding to each of the plurality of characterized cells comprises a set of at least 3 HLA loci, wherein the at least 3 HLA loci are HLA-A, HLA-B, and HLA-DRB.

29. The method of claim 26 or claim 27, wherein the set of characterized HLA loci corresponding to each of the plurality of characterized cells comprises a set of at least 9 given loci, wherein the at least 9 given loci are HLA-A, HLA-B, HLA-C, HLA-DRB l, HLA-DRB 3, HLA-DRB4, HLA-DRB 5, HLA-DQB1, HLA-DPB 1.

30. The method of claim 28, wherein the set of characterized HLA loci corresponding to each of the plurality of characterized cells comprises at least 3 given loci selected from the group consisting of HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DRB3, HLA-DRB4, HLA-DRB5, HLA-DQB 1 , and HLA-DPB 1.

31. The method of any one of claims 26 to 30, wherein each of the one or more matching data entries of the database exactly match or partially match the set of queried HLA loci for the particular subject or the particular group of subjects.

32. The method of any one of claims 25 to 31, wherein the data entry for each of the plurality of characterized cells further comprises ABO blood type and the query further comprises ABO blood type, and wherein the one or more matching data entries of the database representative of the one or more characterized compatible cells match the queried HLA loci and the queried ABO blood type.

33. The method of any one of claims 25 to 32, wherein the data entry for each of the plurality of characterized cells further comprises RHD blood group and the query further comprises RHD blood group, and wherein the one or more matching data entries of the database representative of the one or more characterized compatible cells match the queried RHD blood group and the queried HLA loci.

34. The method of any one of claims 25 to 33, wherein the queried HLA loci correspond to the particular subject or particular group of subjects in need of an HLA matched iPSC-derived secretome composition.

35. The method of claim 34, wherein the HLA matched iPSC-derived secretome composition is selected from one or more iPSC-derived secretome compositions, each derived from the one or more characterized compatible cells corresponding to each of the one or more data entries of the database that exactly match or partially match the queried HLA loci of the particular subject.

36. The method of any one of claims 25 to 35, wherein one or more of the queried HLA loci is determined by processing and analyzing a biological sample from the particular subject in need of the HLA match.

37. The method of claim 32, wherein the queried ABO blood type, is determined by processing and analyzing a biological sample from the particular subject in need of an ABO match.

38. The method of claim 33, wherein the queried RHD blood group is determined by processing and analyzing a biological sample from the particular subject in need of a RHD blood group match.

39. The method of any one of claims 25 to 38, wherein the physical repository comprises one or more liquid nitrogen storage tanks.

40. The method of any one of claims 25 to 39, comprising producing blood progenitor cells and/or HSCs and/or MSCs and/or RPEs and/or chondrocytes from each of the one or more characterized compatible cells corresponding to the one or more data entries matching the queried HLA loci.

41. The method of any one of claims 25 to 40, further comprising administering the iPSC-derived secretome composition to the particular subject or particular group of subjects.

42. The method of claim 41, wherein the administering step comprises administering the iPSC-derived secretome composition to the particular subject or particular group of subjects for treatment of a known disease, injury, or condition in the particular subject or particular group of subjects, wherein the known disease, injury, or condition is a member selected from the group consisting of lung disease, rheumatic diseases, cardiovascular disease, cancer, arthritis, traumatic brain injury, central nervous system (CNS) injury, and inflammation.

43. The method of any one of claims 25 to 42, wherein the database comprises a data entry corresponding to each of a plurality of iPSC super donor cell lines, wherein the data entry for each super donor cell line comprises a set of characterized HLA loci corresponding to the super donor cell line.

44. The method of claim 43, wherein each of the plurality of iPSC super donor cell lines can be used for treatment of a particular subject or particular group of subjects having matching HLA loci with lower risk of immune rejection by the particular subject or particular group of subjects.

45. The method of claim 43 or claim 44, further comprising determining the_set of characterized HLA loci corresponding to each of the plurality of super donor cell lines by processing and analyzing one or more biological samples collected from each of one or more super donor individuals.

46. The method of claim 45, wherein the step of determining the set of characterized HLA loci corresponding to each of the plurality of super donor cell lines comprises identifying a set of at least 3 HLA loci, wherein the at least 3 HLA loci are HLA-A, HLA-B, and HLA-DRB.

47. The method of claim 45, wherein the step of determining the set of characterized HLA loci corresponding to each of the plurality of the super donor cell lines comprises identifying a set of at least 9 HLA loci, wherein the at least 9 HLA loci are HLA-A, HLA-B, HLA-C, HLA-DRB 1, HLA-DRB 3, HLA-DRB4, HLA-DRB 5, HLA-DQB1, and HLA-DPB 1.

48. The method of claim 47, wherein the set of characterized HLA loci corresponding to each of the plurality of the super donor cell lines comprises at least 3 HLA loci selected from the group consisting of HLA-A, HLA-B, HLA-C, HLA-DRBl, HLA-DRB3, HLA-DRB4, HLA-DRB5, HLA-DQB1, and HLA-DPB1.

49. The method of any one of claims 43 to 48, wherein the set of characterized HLA loci corresponding to each of the plurality of the super donor cell lines are homozygous for HLA-A, HLA-B, and DRB-1.

50. The method of claim 49, wherein the homozygous set of characterized HLA loci belong to a set of most-common HLA loci for a given population that matches a majority of the given population .

51. The method of any one of claims 43 to 50, wherein the homozygous set of characterized HLA loci comprise homozygous HLA loci in at least 3 major sites wherein the major sites are members selected from the group consisting of HLA-A, HLA-B, HLA-C, HLA-DRBl, HLA-DRB3, HLA-DRB4, HLA-DRB5, HLA-DQB1, and HLA-DPB1.

52. The method of any one of claims 43 to 51, wherein the plurality of iPSC super donor cell lines match at least 70% of the population from which the particular subject originates.

53. The method of any one of claims 43 to 52, wherein the iPSC-derived secretome composition is produced using one of the plurality of iPSC super donor cell lines.

54. The method of claim 53, comprising exposing the iPSC super donor cell line used to produce the iPSC-derived secretome composition to culture media.

55. The method of claim 54, wherein the iPSC-derived secretome composition comprises cells from the iPSC super donor cell line, the culture media, and one or more desired compatible-cell-secreted species.

56. The method of claims 55, wherein the one or more desired compatible-cell-secreted species comprise one or more desired compatible-cell-secreted molecules and/or one or more desired compatible-cell-secreted biological elements.

57. The method of claim 55, wherein the one or more desired compatible-cell-secreted species comprise one or more exosomes and/or one or more microvesicles.

58. The method of any one of claims 43 to 57, comprising producing blood progenitor cells and/or HSCs and/or MSCs and/or RPEs and/or chondrocytes from each of one or more iPSC super donor cell lines identified as compatible with the particular subject or particular group of subjects.

59. The method of any one of claims 25 to 58, wherein the iPSC-derived secretome composition is a treatment spray.

60. The method of any one of claims 25 to 58, wherein the iPSC-derived secretome composition is a treatment lotion or a treatment cream.

61. The method of any one of claims 25 to 60, wherein the iPSC-derived secretome composition comprises one or more proteins listed in Table 1, and/or Table 2, and/or Table 3, and/or Table 4.

62. The method of any one of claims 25 to 61, wherein the iPSC-derived secretome composition is for internal use.

63. The method of claim 62, wherein the iPSC-derived secretome composition is an injection.

64. The method of any one of claims 25 to 61, wherein the iPSC-derived secretome composition is lyophilized.

65. The method of any one of claims 25 to 61, comprising engineering the compatible cells to upregulate production of one or more desired proteins in the iPSC-derived secretome

composition.

66. The method of claim 65, wherein the compatible cells are engineered using

CRISPR/Cas9 technology.

67. The method of claim 65 or 66, comprising removing and/or replacing and/or editing one or more genes of the compatible cells so as to increase the likelihood of the upregulation of one or more desired proteins in the iPSC-derived secretome composition.

68. A composition of matter comprising an iPSC-derived secretome composition comprising one or more desired compatible-cell-secreted species, wherein the composition is produced by the method of any one of the preceding claims.

69. The composition of claim 68, wherein the iPSC-derived secretome composition is a member selected from the group consisting of a treatment spray, a treatment cream, a treatment lotion, and a treatment injection.

70. The composition of claim 68 or 69, wherein the iPSC-derived secretome composition comprises compatible cells, conditioned culture media, and one or more of the desired compatible-cell-secreted species.

71. The composition of claim 70, wherein the iPSC-derived secretome composition comprises one or more additives.

72. The composition of claim 71, wherein the one or more additives comprises one or more nutrients and/or one or more supplements.

73. The composition of any one of claims 68 to 72, wherein the iPSC-derived secretome composition comprises iPS cells that are derived from a biological sample of a particular subject.

74. The composition of any one of claims 68 to 73, wherein the iPSC-derived secretome composition comprises compatible cells retrieved from a physical repository, wherein the compatible cells are identified as compatible with the particular subject or a particular group of subjects.

75. The composition of claim 74, wherein the compatible cells are identified as compatible with the particular subject or the particular group of subjects using an identification of cell type indicative of compatibility with the particular subject or particular group of subjects, wherein the identification of cell type indicative of compatibility comprises one or more of (i) to (iii): (i) an HLA match, (ii) an ABO blood type match, and (iii) an RHD blood group match having the same HLA loci, and/or ABO blood type, and/or RHD blood group as the.

76. The composition of any one of claims 68 to 75, wherein the iPSC-derived secretome composition comprises one or more compatible-cell-secreted species.

77. The composition of claim 76, wherein the one or more compatible-cell-secreted species are one or more members selected from the group consisting of cytokines, miRNA, siRNA, proteins, organic molecules, inorganic molecules, and biological elements.

78. The composition of any one of claims 68 to 77, wherein the iPSC-derived secretome composition comprises one or more proteins listed in Table 1, and/or Table 2, and/or Table 3, and/or Table 4.

79. The composition of any one of claims 68 to 78, wherein the iPSC-derived secretome composition is formulated internal use .

80. The composition of any one of claim 79, wherein the iPSC derived secretome composition is formulated for use in an injection.

81. The composition of any one of claims 68 to 78, wherein the iPSC-derived secretome composition is lyophilized.

82. The composition of any one of claims 68 to 81, wherein the iPSC-derived secretome composition comprises engineered compatible cells.

83. The composition of claim 82, wherein the engineered compatible cells are modified to upregulate and/or downregulate production of one or more desired proteins in the iPSC-derived secretome composition.

84. The composition of claim 82 or claim 83, wherein the engineered compatible cells are modified using CRISPR/Cas9 technology.

85. A method of storing an induced pluripotent stem cell (iPSC)-derived secretome composition tailored for treatment of a particular subject or particular group of subjects, said method comprising the steps of:

(a) identifying, by a processor of a computing device, as compatible with the particular subject or particular group of subjects, one or more iPSC-derived secretome compositions derived using compatible cells corresponding to the one or more iPSCs and/or iPSC-derived cells identified as compatible with the particular subject or particular group of subjects;

(b) labelling, by a processor of a computing device, the one or more iPSC-derived secretome compositions with a label, wherein the label comprises information relating to the iPSCs and/or iPSC-derived cells, and a classification of the iPSC and/or IPSC-derived cells the iPSC-derived secretome composition is derived from; and

(c) storing, by a processor of a computing device, a database comprising a data entry corresponding to each label in a physical repository.

86. The method of claim 85, wherein the label is a physical label and/or a digital label.

87. The method of claim 85 or claim 86, wherein the label comprises information relating to one or more of (i) to (iii) as follows:

(i) the iPSCs and/or iPSC-derived cells the iPSC-derived secretome composition is derived from;

(ii) one or more HLA loci, and/or ABO blood type, and/or RHD blood group compatible with the labeled iPSC-derived secretome composition; and

(iii) one or more other iPSC-derived secretome compositions stored in the physical repository that are compatible with the particular subject or particular group of subjects, wherein the HLA loci, and/or ABO blood type, and/or RHD blood group of the one or more other iPSC-derived secretome compositions are identical to or match the HLA loci, and/or ABO blood type, and/or RHD blood group of the iPSCs and/or iPSC-derived cells of (i).

88. A method of retrieving one or more produced, labeled and stored iPSC-derived secretome compositions derived using iPSCs and/or iPSC-derived cells, said method comprising the steps of:

(a) identifying, by a processor of a computing device, as compatible with a particular subject or particular group of subjects, one or more iPSC-derived secretome compositions derived using one or more iPSCs and/or iPSC-derived cells identified as compatible with the particular subject or particular group of subjects;

(b) retrieving from a physical repository the one or more compatible iPSC-derived secretome compositions corresponding to the one or more iPSCs and/or iPSC-derived cells identified as compatible with the particular subject or particular group of subjects; and

(c) updating, by a processor of a computing device, a database comprising data entries corresponding to the particular subject or particular group of subjects.

89. The method of claim 88, wherein the retrieved one or more iPSC-derived secretome compositions is administered as treatment to the subject.

90. The method of claim 89, wherein the treatment is a spray.

91. The method of claim 89, wherein the treatment is a cream and/or lotion.

92. The method of claim 89, wherein the treatment is an injection.

93. A method of administering an iPSC-derived secretome composition tailored for treatment of a particular subject or particular group of subjects, said method comprising the steps of:

(a) identifying the particular subject or particular group of subjects as having a deficiency in one or more substances;

(b) identifying, as compatible with the particular subject or particular group of subjects, one or more iPSCs and/or one or more iPSC-derived cells;

(c) retrieving compatible cells corresponding to the one or more iPSCs and/or one or more iPSC-derived cells identified as compatible with the particular subject or particular group of subjects;

- I l l -

(d) producing the iPSC-derived secretome composition using the retrieved compatible cells, wherein the iPSC-derived secretome composition comprises the one or more substances deficient in the particular subject or the particular group of subjects; and

(e) administering to the particular subject or particular group of subjects the iPSC-derived secretome composition.

94. The method of claim 93, wherein the one or more substances comprise one or more cell-secreted molecules and/or cell-secreted biological elements.

95. The method of claim 93 or claim 94, wherein the iPSC-derived secretome composition comprises the one or more cell-secreted substances identified to be deficient in the particular subject or the particular group of subjects.

96. The method of any one of claims 93 to 95, wherein step (d) comprises extracting the secretomes of the retrieved compatible cells.

97. The method of any one of claims 93 to 96, wherein step (c) comprises obtaining the compatible cells from a physical repository.

98. The method of any one of claims 93 to 97, wherein the compatible cells are one or more members selected from the group consisting of iPSCs, MSCs, RPEs, chondrocytes, embryoid bodies, HSCs, and blood progenitor cells.

99. The method of any one of claims 93 to 98, wherein step (c) comprises retrieving the compatible cells using a processor-based query from a user, wherein the query comprises an identification of a cell type indicative of compatibility with the particular subject or particular group of subjects.

100. The method of claim 99, wherein the identification of cell type indicative of compatibility with the particular subject or particular group of subjects comprises one or more of (i) to (iii): (i) an HLA match, (ii) an ABO blood type match, and (iii) an RHD blood group match.

101. The method of any one of claims 93 to 100, wherein step (b) comprises identifying, one or more stored and labeled iPSC-derived secretome compositions within the physical repository derived using one or more iPSCs and/or one or more iPSC-derived cells identified as compatible with the particular subject or group of subjects.

102. The method of any one of claims 93 to 101, wherein step (c) comprises retrieving, the one or more identified iPSC-derived secretome compositions corresponding to the one or more iPSCs and/or one or more iPSC-derived cells identified as compatible with the particular subject or particular group of subjects.

103. The method of any one of claims 93 to 102, wherein step (d) comprises producing a lyophilized iPSC-derived secretome composition.

104. The method of any one of claims 93 to 103, wherein the iPSC-derived secretome composition is administered as treatment to the particular subject or particular group of subjects.

105. The method of claim 104, wherein the treatment is a spray.

106. The method of claim 104, wherein the treatment is a cream and/or lotion.

107. The method any one of claims 93 to 106, wherein the iPSC-derived secretome composition comprises one or more proteins listed in Table 1, and/or Table 2, and/or Table 3, and/or Table 4.

108. The method any one of claims 93 to 107, wherein the iPSC-derived secretome composition is for internal use.

109. The method of claim 108, wherein the iPSC derived secretome composition is an injection.

110. The method of any one of claims 93 to 109, wherein the iPSC-derived secretome composition is lyophilized.

111. The method of any one of claims 93 to 110, comprising engineering the compatible cells to upregulate and/or downregulate production of one or more desired proteins in the iPSC-derived secretome composition.

112. The method of claim 111, wherein the compatible cells are engineered using

CRISPR/Cas9 technology.

113. The method of claim 111 or claim 112, comprising removing and/or replacing and/or editing one or more genes of the compatible cells so as to increase the likelihood of the upregulation and/or downregulation of one or more desired proteins in the iPSC-derived secretome composition.

114. The method of any one of claims 93 to 113, wherein the iPSC-derived secretome composition comprises exosomes.

115. The method of any one of claims 93 to 114, wherein the iPSC-derived secretome composition comprises microvesicles.

116. The method of claim 114, wherein the exosomes comprise proteins, and/or siRNAs, and/or miRNAs.

117. The method of claim 115, wherein the microvesicles comprise proteins, and/or siRNAs, and/or miRNAs.

118. The method of any one of claims 93 to 117, wherein the iPSC-derived secretome composition comprises one or more compatible cell types.

119. A method of treating a condition in a subject, the method comprising:

identifying, as compatible with the subject, an iPSC-derived secretome composition; and administering the iPSC-derived secretome composition to the subject.

120. The method of claim 119, wherein the iPSC-derived secretome composition comprises one or more proteins listed in Table 1, and/or Table 2, and/or Table 3, and/or Table 4.

121. The method of claim 119 or claim 120, wherein the step of identifying the compatible iPSC-derived secretome composition comprises the steps of:

determining HLA loci, and/or ABO blood type, and/or RHD blood group associated with one or more iPSCs and/or one or more iPSC-derived cells from which the iPSC-derived secretome composition is derived; and

matching, by a processor of a computing device, the determined HLA loci, and/or ABO blood type, and/or RHD blood group of the iPSC-derived secretome composition with the HLA loci, and/or ABO blood type, and/or RHD blood group of the subject, wherein a match is an exact match or a partial match.