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Wo2018/191520 (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 2018/191520 Al 18 October 2018 (18.10.2018) W !P O PCT (51) International Patent Classification: Institute, Inc., 415 Main Street, Cambridge, Massachusetts C12N 5/071 (2010.01) 02142 (US). HABER, Adam [US/US]; c/o The Broad In stitute, Inc., 415 Main Street, Cambridge, Massachusetts (21) International Application Number: 02142 (US). MONTORO, Daniel [US/US]; 185 Cam PCT/US2018/027337 bridge Street, Boston, Massachusetts 021 14 (US). (22) International Filing Date: (72) Inventor: ROZENBLATT-ROSEN, Orit; c/o The Broad 12 April 2018 (12.04.2018) Institute, Inc., 415 Main Street, Cambridge, Massachusetts (25) Filing Language: English 02142 (US). (26) Publication Langi English (74) Agent: TALAPATRA, Sunit et al; Foley & Lardner LLP, 3000 K Street, N.W., Suite 600, Washington, District of C o (30) Priority Data: lumbia 20007-5 143 (US). 62/484,782 12 April 2017 (12.04.2017) US (81) Designated States (unless otherwise indicated, for every (71) Applicants: THE BROAD INSTITUTE, INC. [US/US]; kind of national protection available): AE, AG, AL, AM, 415 Main Street, Cambridge, Massachusetts 02142 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (US). THE GENERAL HOSPITAL CORPORATION CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, [US/US]; 55 Fruit Street, Boston, Massachusetts 021 14 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (US). TECH¬ MASSACHUSETTS INSTITUTE OF HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, [US/US]; 77 Massachusetts Avenue, Cam NOLOGY KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, bridge, Massachusetts 02139 (US). MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (72) Inventors; and OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (71) Applicants: RAJAGOPAL, Jayaraj [US/US]; 185 Cam SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, bridge Street, Boston, Massachusetts 021 14 (US). REGEV, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. Aviv [US/US]; 15a Ellsworth Ave, Cambridge, Massachu (84) Designated States (unless otherwise indicated, for every setts 02139 (US). BITON, Moshe [US/US]; c/o The Broad kind of regional protection available): ARIPO (BW, GH, (54) Title: RESPIRATORY AND SWEAT GLAND IONOCYTES (57) Abstract: Provided herein are methods and compositions for identi fying ionocytes from respiratory epithelial cells, and uses of such cells for treatment of inflammatory lung disease. Also provided herein are methods and compositions for modulating respiratory tract epithelial cell prolifera tion, differentiation, maintenance, and/or function. o 00 o [Continued on nextpage] WO 2018/191520 Al llll II II 11III II I I II II II 111II III II I II 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, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) Respiratory and Sweat Gland Ionocytes CONTRIBUTORS Jayaraj Rajagopal, Aviv Regev, Moshe Biton, Adam Haber, Daniel Montoro, Avinash Waghray, Orit Rozenblatt-Rosen [0001] Reference is made to U.S. provisional application serial No. 62/484,782 filed on April 12, 2017. Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention. All applications, and all documents cited herein or during their prosecution ("appln cited documents") and all documents cited or referenced in the appln cited documents, and all documents cited or referenced herein ("herein cited documents"), and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference. FIELD OF THE INVENTION [0002] This invention relates generally to compositions and methods for identifying ionocytes in respiratory epithelial cells and/or sweat gland cells. This invention also relates generally to modulating, controlling or otherwise influencing respiratory epithelial cell and/or sweat gland cell proliferation, differentiation, maintenance and function by using the ionocyte thereof. The invention further relates to methods for for treating inflammatory lung diseases by using pulmonary ionocytes and treating diseases associated with sweat gland disorder by using sweat gland ionocytes. BACKGROUND [0003] Lung diseases, including respiratory diseases, are a major cause of mortality and morbidity worldwide. Inflammatory lung diseases, which affect the respiratory system to varying degrees, have been greatly increasing for several decades, in particular in industrialized countries. The number of worldwide deaths related to these diseases is estimated at more than 3 million per year. [0004] A common symptom of inflammatory lung disease is fluid buid-up in the lung, which is caused by an imbalance between fluid extravasation and fluid resorption. Oftentimes, the permeability of the lung tissue is damaged in patients with inflammatory lung disease, causing an increased fluid supply in tissues or organs (e.g., in the lungs). As a result, of the increased fluid accumulation, gas exchange in the tissue or organ is impeded or restricted, thus preventing or inhibiting oxygen from reaching the organism's blood. [0005] Current treatments are directed to reducing symptoms of lung disease and offer little to no prospect of cure or complete disease reversal. There is a need for a therapy that prevents, delays or reverses the progression of inflammatory lung diseases, for example by reversing the fluid build-up in the lung. SUMMARY [0006] The inventors have identified novel ionocytes from respiratory epithelial cells, and novel markers and networks driving the regulation and differentiation of lung stem cells and respiratory epithelial cells, have identified markers capable of identifying new subpopulations of cells, and identified the crucial role of ionocytes in controlling respiratory epithelial cell function. [0007] In some embodiments, the invention provides a method for modulating respiratory epithelial cell proliferation, differentiation, maintenance, and/or function, the method comprising contacting a respiratory epithelial ionocyte cell or a population of respiratory epithelial ionocyte cells with an ionocyte modulating agent in an amount sufficient to modify proliferation, differentiation, maintenance, and/or function of the respiratory epithelial ionocyte cell or population of respiratory epithelial ionocyte cells. [0008] In some embodiments, the respiratory epithelial cell is a laryngeal epithelial cell, a tracheal epithelial cell, a bronchial epithelial cell, or a submucosal gland cell. [0009] In some embodiments, the invention provides a method for modulating sweat gland cell proliferation, differentiation, maintenance, and/or function, the method comprising contacting a sweat gland ionocyte cell or a population of sweat gland ionocyte cells with an ionocyte modulating agent in an amount sufficient to modify proliferation, differentiation, maintenance, and/or function of the respiratory epithelial ionocyte cell or population of respiratory epithelial ionocyte cells. [0010] In some embodiments, such modulation of the respiratory epithelial cell proliferation, differentiation, maintenance, and/or function modulates inflammation of the respiratory system. [0011] In some embodiments, the modulating agent modulates expression and/or activity of one or more of FOXI1, FOXI2, ASCL3, V-Type Proton ATPase, CFTR, PPARG, Cochlin, STAP1, P2RY14, MOXD1, GM933, ATP6V1C2, ATP6V0D2, ASGR1, and ASGR2. In some embodiments, the expression and/or activity of FOXI2 is modulated. In some embodiments, the expression and/or activity of one or more of FOXI1, FOXI2, ASCL3, V-Type Proton ATPases, CFTR, PPARG, Cochlin, STAP1, P2RY14, MOXD1, GM933, ATP6V1C2, ATP6V0D2, ASGR1, and ASGR2 is upregulated. In some embodiments, the expression and/or activity of FOXI2 is upregulated. In other embodiments, the expression and/or activity of one or more of FOXI1, FOXI2, ASCL3, V- Type Proton ATPases, CFTR, PPARG, Cochlin, STAPl, P2RY14, MOXD1, GM933, ATP6V1C2, ATP6V0D2, ASGR1, and ASGR2 is downregulated. In some embodiments, the expression and/or activity of FOXI2 is downregulated. [0012] In some embodiments, the upregulation or downregulation of one or more of these genes alters Notch signaling pathway function in the cell. In some embodiments, the upregulation or downregulation of one or more of these changes induces a change in one or more genes or proteins, which are the effectors of ionocyte specification. In some embodiments, the effectors are one or more gene and/or protein in the Notch signaling pathway. In some embodiments, the effector is one or more of Notchl, Notch2, Jag2, Dill, D112, and Jag2. [0013] In a specific embodiment, the modulating agent is a small molecule, a protein, a polypeptide, an antibody or an antigen binding fragment thereof, or a nucleic acid. In some embodiment, the modulating agent is an agonist of one or more of FOXI1, FOXI2, ASCL3, V-Type Proton ATPases, CFTR, PPARG, Cochlin, STAPl, P2RY14, MOXD1, GM933, ATP6V1C2, ATP6V0D2, ASGR1, and ASGR2. Preferably said agonist increases expression of one or more of FOXI1, FOXI2, ASCL3, V-Type Proton ATPase, CFTR, PPARG, Cochlin, STAPl, P2RY14, MOXD1, GM933, ATP6V1C2, ATP6V0D2, ASGR1, and ASGR2.
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