PLACENTA-DERVIED NK CELLS AS A SENOL YTIC FOR THERAPEUTIC AND OTHER USES
Provided herein are methods of killing senescent cells, e.g., killing senescent cells in a human subject. Also provided herein are methods of treating a disease or disorder associated with cellular senescence in a subject in need thereof comprising administering to the subject an effective amount of placenta-derived NK cells to the subject. The present invention also provides compositions comprising NK, e.g., CYNK cells, for killing senescent cells and for the treatment of a disease or disorder associated with cellular senescence.
1 . A method of killing senescent cells comprising contacting the senescent cells with placenta-derived natural killer (NK) cells.
2 . A method of treating a disease or disorder associated with cellular senescence in a subject in need thereof comprising administering to the subject an effective amount of placenta-derived NK cells to the subject so as thereby to provide an effective treatment of the disease or disorder in the subject.
3 . The method of claim 1 or claim 2 , wherein the placenta-derived NK cells comprise at least 20% CD56+CD3− natural killer cells.
4 . The method of claim 1 or claim 2 , wherein the placenta-derived NK cells comprise at least 40% CD56+CD3− natural killer cells.
5 . The method of claim 1 or claim 2 , wherein the placenta-derived NK cells comprise at least 60% CD56+CD3− natural killer cells.
6 . The method of claim 1 or claim 2 , wherein the placenta-derived NK cells comprise at least 80% CD56+CD3− natural killer cells.
7 . The method of any of claims 1-6 , wherein said placenta derived natural killer cells are human placenta derived natural killer cells.
8 . The method of any of claims 1-6 , wherein said placenta derived natural killer cells are hematopoietic stem cell-derived natural killer cells.
9 . The method of any of claims 1-6 , wherein said placenta derived natural killer cells are CD34+ hematopoietic stem cell-derived natural killer cells.
10 . The method of any of claims 1-6 , wherein said placenta derived natural killer cells are CYNK cells.
11 . The method of any one of claims 1-10 , wherein the NK cells are characterized by expression of one or more markers selected from the group consisting of FGFBP2, GZMH, CCL3L3, GZMM, CXCR4, ZEB2, KLF2, LITAF, RORA, LYAR, CNOT1, IFNG, DUSP2, ATG2A, CD7, PMAIP1, PPP2R5C, NR4A2, ZFP36L2, PIK3R1, KLRF1, SNHG9, MT2A, RGS2, CHD1, DUSP1, EML4, ZFP36, ZC3H12A, DNAJB6, SBDS, IRF1, TSC22D3, TSPYL2, PNRC1, ISCA1, JUNB, WHAMM, RICTOR, TNFAIP3, EPC1, MVD, CLK1, ARL4C, REL, KMT2E, YPEL5, AMD1, BTG2, and IDS which is lower than expression of said markers in peripheral blood natural killer cells and/or expression of one or more markers selected from the group consisting of NDFIP2, LINC00996, MAL, CCL1, MB, SPINK2, C15orf48, CAMK1, KLRC1, TNFSF10, TNFRSF18, IL32, CAPG, AC092580.4, S100A11, TNFRSF4, ENO1, FCER1G, CCND2, KRT81, MRPS6, ANXA2, PTGER2, GLO1, HAVCR2, PYCARD, LAT2, SLC16A3, COTL1, PKM, TALDO1, CD96, NCR3, KRT86, STMN1, LTB, ARPC1B, ARPC5, FKBP1A, TIMP1, GZMK, CD59, PGK1, RGS10, EVL, RAC2, LGALS1, ITGB7, TUBB, PGAM1, PRF1, GZMB, IL2RB, KLRC2, and KLRB1 which is higher than expression of said markers in peripheral blood natural killer cells.
12 . The method of any one of claims 1-11 , wherein the NK cells are characterized by expression of one or more markers selected from the group consisting of FGFBP2, GZMH, CCL3L3, GZMM, CXCR4, ZEB2, KLF2, LITAF, RORA, LYAR, CNOT1, IFNG, DUSP2, ATG2A, CD7, PMAIP1, PPP2R5C, NR4A2, ZFP36L2, PIK3R1, KLRF1, SNHG9, MT2A, RGS2, CHD1, DUSP1, EML4, ZFP36, ZC3H12A, DNAJB6, SBDS, IRF1, TSC22D3, TSPYL2, PNRC1, ISCA1, JUNB, WHAMM, RICTOR, TNFAIP3, EPC1, MVD, CLK1, ARL4C, REL, KMT2E, YPEL5, AMD1, BTG2, and IDS which is lower than expression of said markers in peripheral blood natural killer cells.
13 . The method of claim 12 , wherein expression of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more markers selected from the group consisting of FGFBP2, GZMH, CCL3L3, GZMM, CXCR4, ZEB2, KLF2, LITAF, RORA, LYAR, CNOT1, IFNG, DUSP2, ATG2A, CD7, PMAIP1, PPP2R5C, NR4A2, ZFP36L2, PIK3R1, KLRF1, SNHG9, MT2A, RGS2, CHD1, DUSP1, EML4, ZFP36, ZC3H12A, DNAJB6, SBDS, IRF1, TSC22D3, TSPYL2, PNRC1, ISCA1, JUNB, WHAMM, RICTOR, TNFAIP3, EPC1, MVD, CLK1, ARL4C, REL, KMT2E, YPEL5, AMD1, BTG2, and IDS is lower than expression of said markers in peripheral blood natural killer cells.
14 . The method of any one of claims 1-13 , wherein the NK cells are characterized by expression of one or more markers selected from the group consisting of NDFIP2, LINC00996, MAL, CCL1, MB, SPINK2, C15orf48, CAMK1, KLRC1, TNFSF10, TNFRSF18, IL32, CAPG, AC092580.4, S100A11, TNFRSF4, ENO1, FCER1G, CCND2, KRT81, MRPS6, ANXA2, PTGER2, GLO1, HAVCR2, PYCARD, LAT2, SLC16A3, COTL1, PKM, TALDO1, CD96, NCR3, KRT86, STMN1, LTB, ARPC1B, ARPC5, FKBP1A, TIMP1, GZMK, CD59, PGK1, RGS10, EVL, RAC2, LGALS1, ITGB7, TUBB, PGAM1, PRF1, GZMB, IL2RB, KLRC2, and KLRB1 which is higher than expression of said markers in peripheral blood natural killer cells.
15 . The method of claim 14 , wherein expression of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more markers selected from the group consisting of NDFIP2, LINC00996, MAL, CCL1, MB, SPINK2, C15orf48, CAMK1, KLRC1, TNFSF10, TNFRSF18, IL32, CAPG, AC092580.4, S100A11, TNFRSF4, ENO1, FCER1G, CCND2, KRT81, MRPS6, ANXA2, PTGER2, GLO1, HAVCR2, PYCARD, LAT2, SLC16A3, COTL1, PKM, TALDO1, CD96, NCR3, KRT86, STMN1, LTB, ARPC1B, ARPC5, FKBP1A, TIMP1, GZMK, CD59, PGK1, RGS10, EVL, RAC2, LGALS1, ITGB7, TUBB, PGAM1, PRF1, GZMB, IL2RB, KLRC2, and KLRB1 is higher than expression of said markers in peripheral blood natural killer cells.
16 . The method of any one of claims 1-15 , wherein the NK cells are prepared by the methods presented herein.
17 . The method of any one of claims 2-16 , wherein the disease or disorder is a fibrotic disease or disorder.
18 . The method of any one of claims 2-16 , wherein the disease or disorder is a inflamatory disease or disorder.
19 . The method of any one of claims 2-16 , wherein the disease or disorder is a metabolic disease or disorder.
20 . The method of any one of claims 2-19 , wherein the disease or disorder is a liver disease or disorder.
21 . The method of any one of claims 2-19 , wherein the disease or disorder is a kidney disease or disorder.
22 . The method of any one of claims 2-19 , wherein the disease or disorder is a lung disease or disorder.
23 . The method of any one of claims 2-19 , wherein the disease or disorder is a eye disease or disorder.
24 . The method of any one of claims 2-19 , wherein the disease or disorder is a skeletal disease or disorder.
25 . The method of any one of claims 2-19 , wherein the disease or disorder is a skin disease or disorder.
26 . The method of any one of claims 2-19 , wherein the disease or disorder is a gastrointestinal disease or disorder.
27 . The method of any one of claims 2-19 , wherein the disease or disorder is a bone marrow disease or disorder.
28 . The method of any one of claims 2-19 , wherein the disease or disorder is a cardiovascular disease or disorder.
29 . The method of any one of claims 2-19 , wherein the disease or disorder is a circulatory disease or disorder.
30 . The method of any one of claims 2-19 , wherein the disease or disorder is a neuronal disease or disorder.
31 . The method of any one of claims 2-19 , wherein the disease or disorder is an age-related disease or disorder.
32 . The method of any one of claims 2-19 , wherein the disease or disorder is osteoarthritis.
33 . The method of any one of claims 2-19 , wherein the disease or disorder is intervertebral disc degeneration.
34 . The method of any one of claims 2-19 , wherein the disease or disorder is atherosclerosis.
35 . The method of any one of claims 2-19 , wherein the disease or disorder is hardening of the arteries.
36 . The method of any one of claims 2-19 , wherein the disease or disorder is heart disease.
37 . The method of any one of claims 2-19 , wherein the disease or disorder is neurodegeneration.
38 . The method of any one of claims 2-19 , wherein the disease or disorder is neuroinflammation.
39 . The method of any one of claims 2-19 , wherein the disease or disorder is Alzheimer's disease.
40 . The method of any one of claims 2-19 , wherein the disease or disorder is myeloproliferative neoplasm (MPN).
41 . The method of any one of claims 2-19 , wherein the disease or disorder is myelodysplastic syndrome (MDS).
42 . The method of any one of claims 2-19 , wherein the disease or disorder is osteoporosis.
43 . The method of any one of claims 2-19 , wherein the disease or disorder is age-induced frailty.
44 . The method of any one of claims 2-43 , wherein the effective treatment comprises a reduction in fibrosis.
45 . The method of any one of claims 2-43 , wherein the effective treatment comprises a reduction in inflammation.
46 . The method of any one of claims 2-43 , wherein the effective treatment comprises a reduction in senescent cell numbers.
47 . The method of any one of claims 2-43 , wherein the effective treatment comprises a reduction in relative senescent cell numbers.
48 . The method of any one of claims 2-43 , wherein the effective treatment comprises an increase in organ or tissue function.
49 . The method of claim 1 , wherein the senescent cell is selected from the group consisting of a senescent fibroblast, a senescent pre-adipocyte, a senescent epithelial cell, a senescent chondrocyte, a senescent intervertebral disc cell, a senescent satellite cell, a senescent muscle cell, a senescent liver cell, a senescent kidney cell, a senescent liver cell, a senescent kidney cell, a senescent bone marrow cell, a senescent vascular cell, a senescent immune cell, a senescent heart cell, a senescent arterial cell, a senescent veinous cell, a senescent gastrointestinal cell, a senescent neuron, and a senescent endothelial cell.
50 . A composition comprising placenta-derived NK cells for use in killing senescent cells in a subject.
51 . Use of composition comprising placenta-derived NK cells for the manufacture of a medicament for killing senescent cells in a subject.
52 . A composition comprising placenta-derived NK cells for use treating a disease or disorder associated with cellular senescence in a subject.
Use of a composition comprising placenta-derived NK cells for use treating a disease or disorder associated with cellular senescence in a subject.