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WO 2019/018441 Al 24 January 2019 (24.01.2019) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2019/018441 Al 24 January 2019 (24.01.2019) W !P O PCT (51) International Patent Classification: TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, C12Q 1/68 (2018.01) G06F 19/00 (2018.01) KM, ML, MR, NE, SN, TD, TG). G01N 33/574 (2006.01) Published: (21) International Application Number: — with international search report (Art. 21(3)) PCT/US2018/042557 — before the expiration of the time limit for amending the (22) International Filing Date: claims and to be republished in the event of receipt of 17 July 2018 (17.07.2018) amendments (Rule 48.2(h)) — with sequence listing part of description (Rule 5.2(a)) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/533,639 17 July 2017 (17.07.2017) US 62/585,534 13 November 2017 (13. 11.2017) US 62/690,304 26 June 2018 (26.06.2018) US (71) Applicant: MASSACHUSETTS INSTITUTE OF TECHNOLOGY [US/US]; 77 Massachusetts Avenue, Cambridge, Massachusetts 02139 (US). (72) Inventors: SHALEK, Alexander K.; c/o 77 Massachu setts Avenue, Cambridge, Massachusetts 02139 (US). OR- DOVAS-MONTANES, Jose; c/o 77 Massachusetts Av enue, Cambridge, Massachusetts 02139 (US). (74) Agent: SCHER, Michael B. et al; Johnson, Marcou & Isaacs, LLC, P.O. Box 691, Hoschton, Georgia 30548 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW,KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (54) Title: CELL ATLAS OF HEALTHY AND DISEASED BARRIER TISSUES 00 (57) Abstract: Embodiments disclosed herein provide a cell atlas of barrier tissues from healthy and diseased subject. The atlas was © obtained by single cell sequencing of approximately 18,036 cells in a surgical data set and 18,704 cells from scrapings. The present invention discloses novel markers for cell types. Moreover, genes associated with disease, including type 2 inflammation are identified. The invention provides for diagnostic assays based on gene markers and cell composition, as well as therapeutic targets for controlling o differentiation, proliferation, maintenance and/or function of the cell types disclosed herein. In addition, novel cell types and methods of quantitating, detecting and isolating the cell types are disclosed. CELL ATLAS OF HEALTHY AND DISEASED BARRIER TISSUES CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application Nos. 62/533,639, filed July 17, 2017, 62/585,534, filed November 13, 2017 and 62/690,304, filed June 26, 2018. The entire contents of the above-identified applications are hereby fully incorporated herein by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH [0002] This invention was made with government support under Grant Nos. OD020839, AI089992, CA217377, AI039671, AI118672, HG006193 and CA202820 awarded by the National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD [0003] The subject matter disclosed herein is generally directed to a cell atlas of barrier tissue cell types in healthy and disease states. The subject matter further relates to novel cell specific and disease specific markers and therapeutic targets. BACKGROUND [0004] Upper respiratory inflammation can afflict individuals on both acute and chronic timescales. Chronic inflammation of the upper airway sinuses is clinically referred to as chronic rhinosinusitis (CRS). The main pathophysiological division within CRS is between individuals who develop an inflamed mucosa (CRSsNP), and those who develop structures known as nasal polyps (CRSwNP), which are outgrowths of cells from the normal mucosa and can completely obstruct nasal passages. Both types of CRS exhibit an inflammatory pattern that is consistent with exuberant Type 2 immunity (T2I). However, our understanding of the drivers of phenotypic divergence and polyp formation remain unclear. SUMMARY OF THE INVENTION [0005] Applicants report the first single-cell transcriptomes for human respiratory epithelial cell subsets, immune cells, and parenchymal cells (18,036 total cells) from an allergic inflammatory disease and map key T2I mediators. [0006] In certain embodiments, the cell type may be detected by measuring one or more markers for each cell type selected from Table 1-15. [0007] In another aspect, the present invention comprises a method for detecting type 2 inflammation, including chronic type 2, inflammation in a barrier tissue, comprising detecting loss of cell type diversity, including increase basal cell composition, by detecting one or more markers from Table 1-15. [0008] In certain embodiments, the cell type as defined by expression of the markers described herein may be obtained by sorting cells based on expression of one or more markers for each cell type according to Table 1-15. In certain example embodiments, the quantity of cells may be determined by cell specific markers and gene expression assigned to each cell. In another aspect, the present invention comprises an isolated barrier cell characterized by expression of one or more markers from Table 1-15. [0009] In another aspect, the present invention provides methods for detecting or quantifying barrier cells in a biological sample of a subject, the method comprising detecting or quantifying in the biological sample barrier cells as defined in any embodiment herein. The barrier cells may be detected or quantified using one or more cell surface markers for a cell type selected from Table 1-15. [0010] In another aspect, the present invention provides for a method of isolating a barrier cell from a biological sample of a subject, the method comprising isolating from the biological sample barrier cells as defined as defined in any embodiment herein. The barrier cell may be isolated using one or more surface markers for a cell type selected from Table 1-15. [0011] In certain embodiments, the barrier may be isolated, detected or quantified using a technique selected from the group consisting of RT-PCR, RNA-seq, single cell RNA-seq, western blot, ELISA, flow cytometry, mass cytometry, fluorescence activated cell sorting, fluorescence microscopy, affinity separation, magnetic cell separation, microfluidic separation, and combinations thereof. [0012] In another aspect, the present invention provides for a method of modulating the barrier cell composition comprising treating a subject with an agent capable of targeting a barrier cell and inducing it to differentiate. [0013] In another aspect, the present invention provides for a method of modulating barrier cell proliferation, differentiation, maintenance and/or function, comprising: contacting a barrier cell or population of barrier cells with a barrier cell modulating agent in an amount sufficient to modify differentiation, maintenance, and/or function of the barrier cell or population of barrier cells as compared to differentiation, maintenance, and/or function of the barrier cell population or population of barrier cells in the absence of the barrier cell modulating agent. [0014] In another aspect, the present invention provides for a method for modulating cellular interactions within cellular ensembles, comprising administering to a cellular ensemble a modulating agent in an amount sufficient to change or modify extracellular signaling from a first cell type such that a change in one or more cell states is induced in a second cell type. In certain embodiments, the cellular ensemble is a two dimensional (2D) or three dimensional (3D) in vitro or ex vivo culture, a tissue on a chip, an organoid, or in vivo cells within a defined tissue, tissue compartment, or signaling microenvironment. [0015] In certain embodiments, the first cell type comprises one or more pathogenic cells and the second cell type comprises on or more host cell types. In certain embodiments, the first cell type comprises one or more diseased cell types and the second cell type comprises one or more healthy cell types. The one or more diseased cell types may be cancer cells. The first cell type may comprise one or more stem cell types and the second cell type comprises one or more immune cell types. [0016] In certain embodiments, extracellular signaling is receptor-ligand mediated, cytokine/chemokine mediated, or metabolically mediated. In certain embodiments, the cellular ensemble comprises epithelial tissues. The first cell type may be an immune cell and the second cell type may be an epithelial stem cell. The epithelial stem cell may be a basal cell. [0017] In certain embodiments, the modulating agent antagonizes IL-4/13 signaling in the immune cells such that the differentiation of basal cells is induced. [0018] In another aspect, the present invention provides for a method of treating inflammatory disease in barrier tissues comprising administering to a subject in need thereof, an IL-4 and/or IL- 13 modulating agent in an amount sufficient to induce basal cell differentiation.
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