Methods for Monitoring Responsiveness to Anti-SMAD7 Therapy

Abstract

Methods for monitoring whether a subject will be sensitive or resistant to treatment with an anti-SMAD7 therapy are disclosed. The methods are based on the determining of the amount of CCR9+ FOXP3+ T cells, CCR9+ IFN-gamma+ T cells, CCR9+IL17A+ T cells, FOXP3+ T cells, IFN-gamma+ T cells, and/or IL17A+ T cells in a sample from the subject. Measurement of T cell populations may be determined by flow cytometry, immunohistochemsistry, and/or ELISA.

1 - 20 . (canceled) 
     
     
         21 . A method for determining the responsiveness of a subject having an Inflammatory Bowel Disease (IBD) to treatment with at least one anti-Mothers Against Decapentaplegic Homolog 7 (anti-SMAD7) therapy, the method comprising:
 determining the amount of at least one cell population selected from the group consisting of: Chemokine (C-C) Motif Receptor 9+ (CCR9+) Forkhead Box P3+ (FoxP3+) T cells, CCR9+ Interferon-gamma+ (IFN-gamma+) T cells, CCR9+ Interleukin 17A+ (IL17A+) T cells, FoxP3+ T cells, IFN-gamma+ T cells, and IL17A+ T cells, in at least one sample from the subject,   wherein, modulation in the amount of the at least one cell population in the at least one sample relative to a known control level of the corresponding cell population is predictive of responsiveness of the subject having IBD to the anti-SMAD7 therapy.   
     
     
         22 . The method of  claim 21 , wherein two or more of the following are identified to assist in determining the responsiveness of the subject:
 an increase in the amount of CCR9+ FoxP3+ T cells indicates that the subject is likely to respond, or is responsive, to the anti-SMAD7 therapy;   a decrease in the amount of CCR9+ IFN-gamma+ T cells indicates that the subject is likely to respond, or is responsive, to the anti-SMAD7 therapy;   a decrease in the amount of CCR9+ IL17A+ T cells indicates that the subject is likely to respond, or is responsive, to the anti-SMAD7 therapy;   a decrease in the amount of FoxP3+ T cells indicates that the subject is likely to respond, or is responsive, to the anti-SMAD7 therapy;   a decrease in the amount of IFN-gamma+ T cells indicates that the subject is likely to respond, or is responsive, to the anti-SMAD7 therapy;   a decrease in the amount of IL17A+ T cells indicates that the subject is likely to respond, or is responsive, to the anti-SMAD7 therapy.   
     
     
         23 . The method of  claim 21 , wherein said determining the amount of the at least one cell population is carried out in vitro. 
     
     
         24 . The method of  claim 21 , wherein the sample is from a subject that is receiving the at least one anti-SMAD7 therapy when the at least one sample is obtained. 
     
     
         25 . The method of  claim 21 , wherein the Inflammatory Bowel Disease (IBD) is selected from the group consisting of Crohn's disease (CD) and ulcerative colitis (UC). 
     
     
         26 . The method of  claim 21 , wherein at least one of: an increase in the amount of CCR9+ FoxP3+ T cells, a decrease in the amount of CCR9+ IFN-gamma+ T cells, a decrease in the amount of CCR9+ IL17A+ T cells, a decrease in the amount of FoxP3+ T cells, a decrease in the amount of IFN-γ+ T cells, or a decrease in the amount of IL17A+ T cells indicates that the subject is likely to enter remission. 
     
     
         27 . The method of  claim 21 , wherein the amount of the at least one cell population is determined by flow cytometry, by immunohistochemistry, and/or by RNA/DNA analysis. 
     
     
         28 . The method of  claim 27 , wherein the flow cytometry and/or the immunohistochemistry is performed using an antibody selected from the group consisting of: an anti-CCR9 antibody, an anti-FoxP3 antibody, an anti-IFN-gamma antibody, and an anti-IL17A antibody. 
     
     
         29 . The method of  claim 21 , wherein the control level is a baseline level of at least one cell population obtained from the patient prior to administration of the at least one anti-SMAD7 therapy or obtained immediately after the administration of the at least one anti-SMAD7 therapy. 
     
     
         30 . The method of  claim 21 , wherein the at least one anti-SMAD7 therapy is an anti-SMAD7 antisense therapy. 
     
     
         31 . The method of  claim 30 , wherein the anti-SMAD7 antisense therapy is an anti-SMAD7 antisense oligonucleotide comprising the nucleotide sequence of SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, or SEQ ID NO: 9. 
     
     
         32 . The method of  claim 21 , wherein the at least one sample from the subject is a peripheral blood sample. 
     
     
         33 . A method of treating an Inflammatory Bowel Disease (IBD) in a subject in need thereof, the method comprising administering an anti-SMAD7 therapy to a subject who has been determined to have an increased amount of a cell population of CCR9+ FoxP3+ cells, and/or a decreased amount of at least one cell population selected from the group consisting of CCR9+ IFN-gamma+ T cells, CCR9+ IL17A+ T cells, FoxP3+ T cells, IFN-gamma+ T cells, and IL17A+ T cells, relative to a known control level of the corresponding cell population, in response to administration of the anti-SMAD7 therapy,
 wherein the amount of the cell population is measured in a peripheral blood sample from the subject.   
     
     
         34 . The method of  claim 33 , wherein the subject has been determined to have two or more of the following:
 an increase in the amount of CCR9+ FoxP3+ T cells that indicates that the subject is likely to respond, or is responsive, to the anti-SMAD7 therapy;   a decrease in the amount of CCR9+ IFN-gamma+ T cells that indicates that the subject is likely to respond, or is responsive, to the anti-SMAD7 therapy;   a decrease in the amount of CCR9+ IL17A+ T cells that indicates that the subject is likely to respond, or is responsive, to the anti-SMAD7 therapy;   a decrease in the amount of FoxP3+ T cells that indicates that the subject is likely to respond, or is responsive, to the anti-SMAD7 therapy;   a decrease in the amount of IFN-gamma+ T cells that indicates that the subject is likely to respond, or is responsive, to the anti-SMAD7 therapy;   a decrease in the amount of IL17A+ T cells that indicates that the subject is likely to respond, or is responsive, to the anti-SMAD7 therapy.   
     
     
         35 . The method of  claim 33 , wherein the increase or the decrease in the amount of the cell population is determined by a method carried out in vitro. 
     
     
         36 . The method of  claim 33 , wherein the Inflammatory Bowel Disease (IBD) is Crohn's disease (CD) and/or ulcerative colitis (UC). 
     
     
         37 . The method of  claim 33 , wherein the increase in the amount of CCR9+ FoxP3+ T cells, and/or the decrease in the amount of CCR9+ IFN-gamma+ T cells, the decrease in the amount of CCR9+ IL17A+ T cells, the decrease in the amount of FoxP3+ T cells, the decrease in the amount of IFN-gamma+ T cells, or the decrease in the amount of IL17A+ T cells indicates that the subject is likely to enter remission. 
     
     
         38 . The method of  claim 33 , wherein the increase or the decrease in the amount of the cell population is determined by flow cytometry, by immunohistochemistry, and/or by RNA/DNA analysis. 
     
     
         39 . The method of  claim 38 , wherein the flow cytometry and/or the immunohistochemistry is performed using an antibody selected from the group consisting of: an anti-CCR9 antibody, an anti-FoxP3 antibody, an anti-IFN-gamma antibody, and an anti-IL17A antibody. 
     
     
         40 . The method of  claim 33 , wherein the control level is a baseline level of the corresponding cell population obtained from the subject prior to administration of the anti-SMAD7 therapy, or obtained immediately after the administration of the anti-SMAD7 therapy. 
     
     
         41 . The method of  claim 33 , wherein the anti-SMAD7 therapy is an anti-SMAD7 antisense therapy. 
     
     
         42 . The method of  claim 41 , wherein the anti-SMAD7 antisense therapy is an anti-SMAD7 antisense oligonucleotide comprising the antisense oligonucleotide sequence of SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, or SEQ ID NO: 9. 
     
     
         43 . The method of  claim 33 , wherein the increase or the decrease in the amount of the cell population is determined by a method performed in vitro using at least one antibody against a cell marker of CCR9+ FoxP3+ T cells, CCR9+ IFN-gamma+ T cells, CCR9+ IL17A+ T cells, FoxP3+ T cells, IFN-gamma+ T cells, and/or IL17A+ T cells.