Stat6 sirna

Abstract

The disclosure concerns nucleic acid silencing molecule comprising or consisting of a small interfering RNA (siRNA) that reduces the expression of Signal Transducer and Activator of Transcription 6 (STAT6). The disclosure also concerns an in vitro method for reducing expression of STAT6 in a cell. The disclosure further concerns a method of treating a disease in a subject, comprising administering to the subject a composition comprising the nucleic acid silencing molecule comprising or consisting of a siRNA that reduces the expression of STAT6, and a related medical use.

Description

[0001] STAT6 SIRNA

[0002] FIELD OF THE DISCLOSURE

[0003] The disclosure concerns nucleic acid silencing molecule comprising or consisting of a small interfering RNA (siRNA) that reduces the expression of Signal Transducer and Activator of Transcription 6 (STAT6). The disclosure also concerns an in vitro method for reducing expression of STAT6 in a cell. The disclosure further concerns a method of treating a disease in a subject, comprising administering to the subject a composition comprising the nucleic acid silencing molecule comprising or consisting of a siRNA that reduces the expression of STAT6, and a related medical use.

[0004] BACKGROUND

[0005] The Signal Transducers and Activators of Transcription (STATs) are a family of SH2-containing transcription factors. STATs reside in the cytoplasm in an inactive form, until they are activated by phosphorylation by a Janus kinase (JAK). JAKs are associated with the signalling chains of the hematoprotein family of cytokine receptors. When such receptors bind cytokine, they dimerise. This allows the JAKs on the signalling chains to cross-phosphorylate each other, stimulating their kinase activity. They are then able to recruit STATs by phosphorylating a conserved tyrosine residue at the carboxy terminal. This brings about a conformational change in the STAT, which forms a dimer capable of exerting downstream effects. In particular, the phosphorylated STAT dimer enters the nucleus and acts as a transcription factor to initiate the expression of certain genes. The genes regulated by STATs include those which are associated with growth and differentiation of particular subsets of lymphocytes.

[0006] STATs are therefore activated by cytokine, growth factor and hormonal signalling. Seven STATs, exist namely STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6. Typically, a cytokine activates one type of STAT. IL-4 and IL-13, for instance, each activate STAT6. In turn, STAT6 initiates expression of genes required for Th2 cell development.

[0007] Th2 helper cells lend T cell help to a humoral immune response (i.e. antibody- mediated immunity). Their effector cytokines are IL-4, IL-5, IL-9, IL- 10, IL- 13 and IL-25, and their main effector cells are eosinophils, basophils, and mast cells as well as B cells, and IL-4 / IL-5 CD4 T cells. Th2 cells have important roles in immunity against extracellular parasites, bacteria and allergens. However, overactivation of Th2 cells may result in inflammatory and / or allergic diseases, such as allergic rhinitis, atopic dermatitis, and asthma.

[0008] STAT6 is also highly expressed in several types of cancer (including breast, pancreatic, endometrial, intestinal, skin, lung, prostate, thyroid and colorectal cancer), and has key roles in the initiation of tumorigenesis and malignant transformation. In cancer cells, STAT6 regulates the expression of genes involved in immune and inflammatory responses, cell survival, tumour proliferation and metastasis. Cancers expressing STAT6 have been shown to be associated with lower survival rates, increased lymph node metastasis, and detrimental alterations in the inflammatory response.

[0009] Mechanisms for reducing STAT6 expression are therefore desirable for treating a range of diseases.

[0010] SUMMARY OF THE DISCLOSURE

[0011] The inventors have identified a number of novel and advantageous small interfering RNAs (siRNAs) that reduce the expression of STAT6. The newly-identified STAT6 siRNAs may be used to treat diseases in which STAT6 expression causes or contributes to a detrimental clinical effect. The STAT6 siRNAs of the disclosure may, for instance, to treat cancer, or a disorder of the immune system. The STAT6 siRNAs of the disclosure may, for instance, to treat an inflammatory disease.

[0012] Accordingly, the disclosure provides a nucleic acid silencing molecule comprising or consisting of a small interfering siRNA that reduces the expression of STAT6, wherein the wherein the siRNA targets exon 5, 15, 19 or 10 of STAT6.

[0013] The disclosure further provides: an in vitro method for reducing expression of STAT6 in a cell, comprising contacting the cell with the nucleic acid silencing molecule of the disclosure; a method of treating a disease in a subject, comprising administering to the subject a composition comprising the nucleic acid silencing molecule of the disclosure. a composition comprising the nucleic acid silencing molecule of the disclosure, for use in a method of treating disease. DESCRIPTION OF THE FIGURES

[0014] Figure 1: Depiction of A) siRNAl, B) siRNAlw, C) siRNAla, D) siRNAlb, E) siRNAlc and F) siRNAl d.

[0015] Figure 2: Depiction of A) siRNA2, B) siRNA2a, C) siRNA2b, D) siRNA2c and E) siRNA2d.

[0016] Figure 3: Depiction of A) siRNA3, B) siRNA3a, C) siRNA3b, D) siRNA3c and E) siRNA3d.

[0017] Figure 2: Depiction of A) siRNA4, B) siRNA4a, C) siRNA4b, D) siRNA4c and E) siRNA4d.

[0018] DESCRIPTION OF THE SEQUENCE LISTING

[0019] SEQ ID NO: 1 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNAl.

[0020] SEQ ID NO: 2 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNAlw.

[0021] SEQ ID NO: 3 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNAla.

[0022] SEQ ID NO: 4 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNAlb.

[0023] SEQ ID NO: 5 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNAlc.

[0024] SEQ ID NO: 6 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNAl d.

[0025] SEQ ID NO: 7 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNA2.

[0026] SEQ ID NO: 8 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNA2a.

[0027] SEQ ID NO: 9 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNA2b.

[0028] SEQ ID NO: 10 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNA2c. SEQ ID NO: 11 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNA2d.

[0029] SEQ ID NO: 12 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNA3.

[0030] SEQ ID NO: 13 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNA3a.

[0031] SEQ ID NO: 14 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNA3b.

[0032] SEQ ID NO: 15 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNA3c.

[0033] SEQ ID NO: 16 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNA3d.

[0034] SEQ ID NO: 17 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNA4.

[0035] SEQ ID NO: 18 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNA4a.

[0036] SEQ ID NO: 19 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNA4b.

[0037] SEQ ID NO: 20 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNA4c.

[0038] SEQ ID NO: 21 - Base sequence (i.e. unmodified nucleotide sequence) of sense strand of siRNA4d.

[0039] SEQ ID NO: 22 - Preferred modified nucleotide sequence of sense strand of siRNAl.

[0040] SEQ ID NO: 23 - Preferred modified nucleotide sequence of sense strand of siRNA Iw.

[0041] SEQ ID NO: 24 - Preferred modified nucleotide sequence of sense strand of siRNA la.

[0042] SEQ ID NO: 25 - Preferred modified nucleotide sequence of sense strand of siRNAlb.

[0043] SEQ ID NO: 26 - Preferred modified nucleotide sequence of sense strand of siRNAl c. SEQ ID NO: 27 - Preferred modified nucleotide sequence of sense strand of siRNAld.

[0044] SEQ ID NO: 28 - Preferred modified nucleotide sequence of sense strand of siRNA2.

[0045] SEQ ID NO: 29 - Preferred modified nucleotide sequence of sense strand of siRNA2a.

[0046] SEQ ID NO: 30 - Preferred modified nucleotide sequence of sense strand of siRNA2b.

[0047] SEQ ID NO: 31 - Preferred modified nucleotide sequence of sense strand of siRNA2c.

[0048] SEQ ID NO: 32 - Preferred modified nucleotide sequence of sense strand of siRNA2d.

[0049] SEQ ID NO: 33 - Preferred modified nucleotide sequence of sense strand of siRNA3.

[0050] SEQ ID NO: 34 - Preferred modified nucleotide sequence of sense strand of siRNA3a.

[0051] SEQ ID NO: 35 - Preferred modified nucleotide sequence of sense strand of siRNA3b.

[0052] SEQ ID NO: 36 - Preferred modified nucleotide sequence of sense strand of siRNA3c.

[0053] SEQ ID NO: 37 - Preferred modified nucleotide sequence of sense strand of siRNA3d.

[0054] SEQ ID NO: 38 - Preferred modified nucleotide sequence of sense strand of siRNA4.

[0055] SEQ ID NO: 39 - Preferred modified nucleotide sequence of sense strand of siRNA4a.

[0056] SEQ ID NO: 40 - Preferred modified nucleotide sequence of sense strand of siRNA4b.

[0057] SEQ ID NO: 41 - Preferred modified nucleotide sequence of sense strand of siRNA4c.

[0058] SEQ ID NO: 42 - Preferred modified nucleotide sequence of sense strand of siRNA4d. SEQ ID NO: 43 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNAl.

[0059] SEQ ID NO: 44 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNAlw.

[0060] SEQ ID NO: 45 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNAl a.

[0061] SEQ ID NO: 46 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNAlb.

[0062] SEQ ID NO: 47 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNAl c.

[0063] SEQ ID NO: 48 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNAl d.

[0064] SEQ ID NO: 49 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNA2.

[0065] SEQ ID NO: 50 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNA2a.

[0066] SEQ ID NO: 51 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNA2b.

[0067] SEQ ID NO: 52 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNA2c.

[0068] SEQ ID NO: 53 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNA2d.

[0069] SEQ ID NO: 54 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNA3.

[0070] SEQ ID NO: 55 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNA3a.

[0071] SEQ ID NO: 56 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNA3b.

[0072] SEQ ID NO: 57 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNA3c.

[0073] SEQ ID NO: 58 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNA3d. SEQ ID NO: 59 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNA4.

[0074] SEQ ID NO: 60 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNA4a.

[0075] SEQ ID NO: 61 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNA4b.

[0076] SEQ ID NO: 62 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNA4c.

[0077] SEQ ID NO: 63 - Base sequence (i.e. unmodified nucleotide sequence) of antisense strand of siRNA4d.

[0078] SEQ ID NO: 64 - Preferred modified nucleotide sequence of antisense strand of siRNAl.

[0079] SEQ ID NO: 65 - Preferred modified nucleotide sequence of antisense strand of siRNA Iw.

[0080] SEQ ID NO: 66 - Preferred modified nucleotide sequence of antisense strand of siRNA la.

[0081] SEQ ID NO: 67 - Preferred modified nucleotide sequence of antisense strand of siRNAlb.

[0082] SEQ ID NO: 68 - Preferred modified nucleotide sequence of antisense strand of siRNAl c.

[0083] SEQ ID NO: 69 - Preferred modified nucleotide sequence of antisense strand of siRNAl d.

[0084] SEQ ID NO: 70 - Preferred modified nucleotide sequence of antisense strand of siRNA2.

[0085] SEQ ID NO: 71 - Preferred modified nucleotide sequence of antisense strand of siRNA2a.

[0086] SEQ ID NO: 72 - Preferred modified nucleotide sequence of antisense strand of siRNA2b.

[0087] SEQ ID NO: 73 - Preferred modified nucleotide sequence of antisense strand of siRNA2c.

[0088] SEQ ID NO: 74 - Preferred modified nucleotide sequence of antisense strand of siRNA2d. SEQ ID NO: 75 - Preferred modified nucleotide sequence of antisense strand of siRNA3.

[0089] SEQ ID NO: 76 - Preferred modified nucleotide sequence of antisense strand of siRNA3a.

[0090] SEQ ID NO: 77 - Preferred modified nucleotide sequence of antisense strand of siRNA3b.

[0091] SEQ ID NO: 78 - Preferred modified nucleotide sequence of antisense strand of siRNA3c.

[0092] SEQ ID NO: 79 - Preferred modified nucleotide sequence of antisense strand of siRNA3d.

[0093] SEQ ID NO: 80 - Preferred modified nucleotide sequence of antisense strand of siRNA4.

[0094] SEQ ID NO: 81 - Preferred modified nucleotide sequence of antisense strand of siRNA4a.

[0095] SEQ ID NO: 82 - Preferred modified nucleotide sequence of antisense strand of siRNA4b.

[0096] SEQ ID NO: 83 - Preferred modified nucleotide sequence of antisense strand of siRNA4c.

[0097] SEQ ID NO: 84 - Preferred modified nucleotide sequence of antisense strand of siRNA4d.

[0098] DETAILED DESCRIPTION

[0099] It is to be understood that different applications of the disclosed methods and products may be tailored to the specific needs in the art. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the disclosure only, and is not intended to be limiting.

[0100] All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

[0101] General definitions Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which this disclosure belongs.

[0102] As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a siRNA” includes “siRNAs”, reference to “antigen” includes two or more such antigens, and the like.

[0103] In general, the term “comprising” is intended to mean including but not limited to. For example, the phrase “a nucleic acid silencing molecule comprising a siRNA” should be interpreted to mean that the nucleic acid silencing molecule contains the siRNA, but that the nucleic acid silencing molecule may contain additional nucleotides or sequences.

[0104] In some aspects of the disclosure, the word “comprising” is replaced with the phrase “consisting of’. The term “consisting of’ is intended to be limiting. For example, the phrase “a nucleic acid silencing molecule consisting of an siRNA” should be understood to mean that the nucleic acid silencing molecule contains the siRNA and no additional nucleotides or sequences.

[0105] The terms “protein” and “polypeptide” are used interchangeably herein, and are intended to refer to a polymeric chain of amino acids of any length.

[0106] For the purpose of this disclosure, in order to determine the percent identity of two sequences (such as two polynucleotide or two polypeptide sequences), the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in a first sequence for optimal alignment with a second sequence). The nucleotide residues at nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide residue as the corresponding position in the second sequence, then the nucleotides are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions / total number of positions in the reference sequence x 100).

[0107] Typically the sequence comparison is carried out over the length of the reference sequence. For example, if the user wished to determine whether a given (“test”) sequence has a certain percentage identity to SEQ ID NO: X, SEQ ID NO: X would be the reference sequence. For example, to assess whether a sequence is at least 80% identical to SEQ ID NO: X (an example of a reference sequence), the skilled person would carry out an alignment over the length of SEQ ID NO: X, and identify how many positions in the test sequence were identical to those of SEQ ID NO: X. If at least 80% of the positions are identical, the test sequence is at least 80% identical to SEQ ID NO: X. If the sequence is shorter than SEQ ID NO: X, the gaps or missing positions should be considered to be nonidentical positions.

[0108] The skilled person is aware of different computer programs that are available to determine the homology or identity between two sequences. For instance, a comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.

[0109] Nucleic acid silencing molecule

[0110] Disclosed herein is a nucleic acid silencing molecule that reduces the expression of STAT6.

[0111] Such a silencing molecule may be used therapeutically to reduce the expression of STAT6. As set out above, STAT6 is highly expressed in numerous cancers, where it regulates the expression of genes involved in the immune response, cell survival, tumour proliferation and metastasis. Therefore, reducing the expression of STAT6 in cancer cells may kill cancer cells, reduce or prevent tumour growth, and reduce or prevent metastasis. Furthermore, expression of STAT6 by immune cells in the tumour microenvironment has been demonstrated to contribute to an immunosuppressive microenvironment that is conducive to tumour maintenance and growth. Reducing expression of STAT6 in the microenvironment may promote the formation of a pro-inflammatory microenvironment that is conducive to the killing of tumour cells.

[0112] It may also be advantageous to reduce the expression of STAT6, for example, in diseases caused by or associated with an overactive Th2 response. Th2 responses have been implicated in inflammatory disease, allergic diseases, graft versus host disease (GVHD) and autoimmune diseases, for example. As STAT6 is a key signalling molecule for the induction and maintenance of Th2 responses, reducing STAT6 expression in a subject may reduce the number and / or activity of Th2 responses in the subject. Clinical signs or symptoms of an overactive Th2 response may therefore be reduced or abolished. Clinical signs or symptoms may be stopped from progressing. Other uses of the nucleic acid silencing molecule disclosed herein may also be envisaged. For example, the nucleic acid silencing molecule may be used to experimentally reduce the expression of STAT6 in vivo or in vitro. In other words, the nucleic acid silencing molecule may be used as a research tool, for instance to investigate cancer, inflammatory disease, allergic diseases or autoimmune diseases.

[0113] Reducing the expression of STAT 6

[0114] The nucleic acid silencing molecule disclosed herein reduces the expression of STAT6. The nucleic acid silencing molecule may, for example, reduce the expression of STAT6 mRNA. The nucleic acid silencing molecule may, for example, reduce the expression of STAT6 protein. The nucleic acid silencing molecule may, for example, reduce the expression of STAT6 mRNA and STAT6 protein. Expression of STAT6 protein may, for example, be reduced as a result of reducing expression of STAT6 mRNA.

[0115] The nucleic acid silencing molecule may, for example, reduce the expression of STAT6 in a cell. The cell may, for example, be human or from a human cell line. The cell may, for example, be in vivo, ex vivo or in vitro. The cell may be a cell contacted with the nucleic acid silencing molecule. Reduced expression of STAT6 in a cell may, for example, refer to a reduction in the amount of STAT6 mRNA and / or STAT6 protein comprised in the cell. Accordingly, a cell that has reduced expression of STAT6 may, for example, comprise a reduced amount of STAT6 mRNA. A cell that has reduced expression of STAT6 may, for example, comprise a reduced amount of STAT6 protein. A cell that has reduced expression of STAT6 may, for example, comprise a reduced amount of STAT6 mRNA and a reduced amount of STAT6 protein.

[0116] The nucleic acid silencing molecule may, for example, reduce the expression of STAT6 in a cell contacted with the nucleic acid silencing molecule relative to a cell not contacted with the nucleic acid silencing molecule. The cell contacted with the nucleic acid silencing molecule may, for example, be human or from a human cell line. The cell contacted with the nucleic acid silencing molecule may, for example, be in vivo, ex vivo or in vitro. The cell not contacted with the nucleic acid silencing molecule may, for example, be human or from a human cell line. The cell not contacted with the nucleic acid silencing molecule may, for example, be in vivo, ex vivo or in vitro. Preferably, the cell contacted with the nucleic acid silencing molecule and the cell not contacted with the nucleic acid silencing molecule are the same type of cell (e.g. a human cell or a cell from a human cell line). Preferably, the cell contacted with the nucleic acid silencing molecule and the cell not contacted with the nucleic acid silencing molecule are under the same conditions (e.g. in vivo, ex vivo or in vitro). The cell not contacted with the nucleic acid silencing molecule may instead be contacted with a control molecule, such as a mock nucleic acid silencing molecule. Mock nucleic acid silencing molecules (such as mock siRNAs) and methods for their design and production are well-known in the art. Reduced expression of STAT6 in a cell contacted with the nucleic acid silencing molecule may, for example, refer to a reduction in the amount of STAT6 mRNA and / or STAT6 protein comprised in the cell relative to a cell not contacted with the nucleic acid silencing molecule. Accordingly, a cell that is contacted with the nucleic acid silencing molecule and that has reduced expression of STAT6 may comprise a reduced amount of STAT6 mRNA relative to a cell not contacted with the nucleic acid silencing molecule. A cell that is contacted with the nucleic acid silencing molecule and that has reduced expression of STAT6 may comprise a reduced amount of STAT6 protein relative to a cell not contacted with the nucleic acid silencing molecule. A cell that is contacted with the nucleic acid silencing molecule and that has reduced expression of STAT6 may comprise a reduced amount of STAT6 mRNA and a reduced amount of STAT6 protein relative to a cell not contacted with the nucleic acid silencing molecule.

[0117] In any of the aspects described above, the nucleic acid silencing molecule may, for example, reduce the expression of STAT6 by at least 30%. In other words, the nucleic acid silencing molecule may reduce the amount of STAT6 mRNA and / or the amount of STAT6 protein by at least 30%. The nucleic acid silencing molecule may, for example, reduce the expression of STAT6 by at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%. In other words, the nucleic acid silencing molecule may, for example, reduce the amount of STAT6 mRNA and / or the amount of STAT6 protein by at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%. The nucleic acid silencing molecule may, for example, reduce the expression of STAT6 by 30% to 99%, such as 35% to 95%, 40% to 90%, 45% to 85%, 50% to 80%, 55% to 75%, or 60% to 70%. That is, the nucleic acid silencing molecule may, for example, reduce amount of STAT6 mRNA and / or the amount of STAT6 protein by 30% to 99%, such as 35% to 95%, 40% to 90%, 45% to 85%, 50% to 80%, 55% to 75%, or 60% to 70%.

[0118] Preferably, the nucleic acid silencing molecule reduces the expression of STAT6 in a cell by at least 30%. In other words, the nucleic acid silencing molecule may reduce the amount of STAT6 mRNA and / or the amount of STAT6 protein in a cell by at least 30%. Cell types and conditions for assessment of STAT6 expression are described above. The nucleic acid silencing molecule may, for example, reduce the expression of STAT6 in a cell by at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%. In other words, the nucleic acid silencing molecule may, for example, reduce the amount of STAT6 mRNA and / or the amount of STAT6 protein in a cell by at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%. The nucleic acid silencing molecule may, for example, reduce the expression of STAT6 in a cell by 30% to 99%, such as 35% to 95%, 40% to 90%, 45% to 85%, 50% to 80%, 55% to 75%, or 60% to 70%. That is, the nucleic acid silencing molecule may, for example, reduce amount of STAT6 mRNA and / or the amount of STAT6 protein in a cell by 30% to 99%, such as 35% to 95%, 40% to 90%, 45% to 85%, 50% to 80%, 55% to 75%, or 60% to 70%.

[0119] More preferably, the nucleic acid silencing molecule reduces the expression of STAT6 in a cell contacted with the nucleic acid silencing molecule by at least 30% relative to a cell not contacted with the nucleic acid silencing molecule. In other words, the nucleic acid silencing molecule may reduce the amount of STAT6 mRNA and / or the amount of STAT6 protein in a cell contacted with the nucleic acid silencing molecule by at least 30% relative to a cell not contacted with the nucleic acid silencing molecule. Cell types and conditions for assessment of STAT6 expression are described above. The nucleic acid silencing molecule may, for example, reduce the expression of STAT6 in a cell contacted with the nucleic acid silencing molecule by at least at least 30%, at least 35%, at least 40%, 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% relative to a cell not contacted with the nucleic acid silencing molecule. In other words, the nucleic acid silencing molecule may, for example, reduce the amount of STAT6 mRNA and / or the amount of STAT6 protein in a cell contacted with the nucleic acid silencing molecule by at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% relative to a cell not contacted with the nucleic acid silencing molecule. The nucleic acid silencing molecule may, for example, reduce the expression of STAT6 in a cell contacted with the nucleic acid silencing molecule by 30% to 99%, such as 35% to 95%, 40% to 90%, 45% to 85%, 50% to 80%, 55% to 75%, or 60% to 70% relative to a cell not contacted with the nucleic acid silencing molecule. That is, the nucleic acid silencing molecule may, for example, reduce amount of STAT6 mRNA and / or the amount of STAT6 protein in a cell contacted with the nucleic acid silencing molecule by 30% to 99%, such as 35% to 95%, 40% to 90%, 45% to 85%, 50% to 80%, 55% to 75%, or 60% to 70% relative to a cell not contacted with the nucleic acid silencing molecule.

[0120] In any of the aspects described above, the nucleic acid silencing molecule may reduce the expression of STAT6 by 100%. In other words, the nucleic acid silencing molecule may completely eliminate the expression of STAT6. The nucleic acid silencing molecule may, for example, completely eliminate the expression of STAT6 mRNA (i.e. reduce the expression of STAT6 mRNA by 100%). The nucleic acid silencing molecule may, for example, completely eliminate the expression of STAT6 protein (i.e. reduce the expression of STAT6 protein by 100%). The nucleic acid silencing molecule may, for example, completely eliminate the expression of STAT6 mRNA and STAT6 protein (i.e. reduce the expression of STAT6 mRNA and STAT6 protein by 100%).

[0121] The nucleic acid silencing molecule may, for example, completely eliminate the expression of STAT6 in a cell. Accordingly, the cell may not express STAT6 mRNA and / or STAT6 protein. The cell may, for example, be human or from a human cell line. The cell may, for example, be in vivo, ex vivo or in vitro. The cell may be a cell contacted with the nucleic acid silencing molecule.

[0122] The nucleic acid silencing molecule may, for example, reduce the expression of STAT6 in a cell contacted with the nucleic acid silencing molecule by 100% relative to a cell not contacted with the nucleic acid silencing molecule. The cell contacted with the nucleic acid silencing molecule may, for example, be human or from a human cell line. The cell contacted with the nucleic acid silencing molecule may, for example, be in vivo, ex vivo or in vitro. The cell not contacted with the nucleic acid silencing molecule may, for example, be human or from a human cell line. The cell not contacted with the nucleic acid silencing molecule may, for example, be in vivo, ex vivo or in vitro. Preferably, the cell contacted with the nucleic acid silencing molecule and the cell not contacted with the nucleic acid silencing molecule are the same type of cell (e.g. a human cell or a cell from a human cell line). Preferably, the cell contacted with the nucleic acid silencing molecule and the cell not contacted with the nucleic acid silencing molecule are under the same conditions (e.g. in vivo, ex vivo or in vitro). The cell not contacted with the nucleic acid silencing molecule may instead be contacted with a control molecule, such as a mock nucleic acid silencing molecule. As set out above, mock nucleic acid silencing molecules (such as mock siRNAs and methods for their design and production are well-known in the art.

[0123] Where, as described above, the nucleic acid silencing molecule may, for example, reduce the expression of STAT6 in a cell contacted with the nucleic acid silencing molecule relative to a cell not contacted with the nucleic acid silencing molecule, the expression of IL-4 in the cell may also be reduced by a corresponding percentage relative to a cell not contacted with the nucleic acid silencing molecule.

[0124] Nucleic acid silencing molecule

[0125] In the context of the disclosure, a silencing molecule may be defined as a molecule that reduces or eliminates (i.e. knocks down) expression of a target gene. A silencing molecule may, for example, reduce the amount of the mRNA product of target gene. A silencing molecule may, for example, eliminate the mRNA product of target gene. A silencing molecule may, for example, reduce the amount of the protein product of target gene. A silencing molecule may, for example, eliminate the protein product of target gene. In the present disclosure, the target gene is STAT6.

[0126] In the context of the disclosure, a nucleic acid silencing molecule may be defined as a silencing molecule that comprises or consists of one or more nucleic acids. The nucleic acid silencing molecule of the disclosure may comprise RNA. The nucleic acid silencing molecule of the disclosure may comprise DNA. The nucleic acid silencing molecule of the disclosure may comprise DNA and RNA. The nucleic acid silencing molecule of the disclosure may consist of RNA. The nucleic acid silencing molecule of the disclosure may consist of DNA and RNA.

[0127] The nucleic acid silencing molecule may reduce or eliminate (i.e. knock down) expression of STAT6 by any mechanism known in the art. As the nucleic acid silencing molecule comprises an siRNA, the nucleic acid silencing molecule may reduce or eliminate expression of STAT6 by a known mechanism of siRNA. For instance, the nucleic acid silencing molecule may bind to a mRNA molecule encoded by the STAT6 gene to induce degradation (such as enzymatic degradation) of the mRNA.

[0128] The nucleic acid silencing molecule may be about 10 to about 100 nucleotides in length, such as about 15 to about 95, about 20 to about 90, about 25 to about 85, about 30 to about 80, about 40 to about 75, about 45 to about 70, about 50 to about 65 or about 55 to about 60 nucleotides in length. Preferably, the nucleic acid silencing molecule is less than 50 (such as less than 45, less than 40, less than 35 or less than 30) nucleotides in length. The nucleic acid silencing molecule may, for example be about 15 to about 30 nucleotides in length. For example, the nucleic acid silencing molecule may be about 16 to about 29, about 17 to about 28, about 18 to about 27, about 19 to about 26, or about 20 to about 25 nucleotides in length. Preferably, the nucleic acid molecule is about 20 to about 25 nucleotides in length. The nucleic acid molecule may, for example, be about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29 or about 30 nucleotides in length. The nucleic acid molecule may preferably be about 25 nucleic acids in length. Typical lengths of small interfering RNAs (siRNAs) are well-known in the art.

[0129] The nucleic acid silencing molecule may, for example, comprise one or more 2’-O- methyl (2-’0Me) modified nucleotides or consist of 2’-O-methyl (2-’0Me) modified nucleotides. The nucleic acid silencing molecule may, for example, comprise one or more 2’-fluoro (2’-F) modified nucleotides or consist of 2’-fluoro (2’-F) modified nucleotides. The nucleic acid silencing molecule may, for example, comprise one or more nucleotide phosphorothioates or consist of nucleotide phosphorothioates. 2-’0Me modified nucleotides, 2’-F modified nucleotides and nucleotide phosphorothioates are described in the art.

[0130] The siRNA targets STAT6. Therefore, the nucleic acid silencing molecule may be capable of binding to the RNA encoded by the STAT6 gene. The nucleic acid silencing molecule may be capable of binding to part of the RNA encoded by the STAT6 gene. Binding may, for example, be effected by hybridisation.

[0131] The nucleic acid silencing molecule may be directed to RNA encoded by the STAT6 gene. For example, the nucleic acid silencing molecule may be directed to mRNA encoded by the STAT6 gene. A nucleic acid silencing molecule that is “directed to” a particular nucleic acid sequence is capable of binding to (e.g. hybridising to) that nucleic acid sequence.

[0132] In particular, the siRNA targets exon 5, 15, 19 or 10 of STAT6. Accordingly, the siRNA may bind to a sequence comprised in exon 5, 15, 19 or 10 of mRNA transcribed from STAT6. The siRNA may hybridise to a sequence comprised in exon 5, 15, 19 or 10 of mRNA transcribed from STAT6, for instance by Watson-Crick base pairing. A strand of the siRNA may bind to a sequence comprised in exon 5, 15, 19 or 10 of mRNA transcribed from STAT6. A strand of the siRNA may hybridise to a sequence comprised in exon 5, 15, 19 or 10 of mRNA transcribed from STAT6, for instance by Watson-Crick base pairing.

[0133] In the Examples, siRNAs 1, Iw, la, lb, 1c and Id target exon 5 of STAT6; siRNAs 2, 2a, 2b, 2c and 2d target exon 15 of STAT6; siRNAs 3, 3a, 3b, 3c and 3d target exon 19 of STAT6; and siRNAs 4, 4a, 4b, 4c and 4d target exon 10 of STAT6. Accordingly, an siRNA comprising one of SEQ ID NOs: 1 to 6 or 43 to 48 targets exon 5 of STAT6. An siRNA comprising one of SEQ ID NOs: 7 to 11 or 49 to 53 targets exon 15 of STAT6. An siRNA comprising one of SEQ ID NOs: 12 to 16 or 54 to 58 targets exon 19 of STAT6. An siRNA comprising one of SEQ ID NOs: 17 to 21 or 59 to 63 targets exon 10 of STAT6.

[0134] The nucleic acid silencing molecule may, for example, comprise or consist of comprising or consisting of siRNA that reduces the expression STAT6, wherein the sense strand of the siRNA comprises any one of SEQ ID NOs: 1 to 21 or a nucleotide sequence having at least 75% sequence identity thereto.

[0135] A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs: 1 to 21 may, for example, comprise at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to one of SEQ ID NOs: 1 to 21 respectively. Thus, the sense strand of the siRNA may comprise a nucleotide sequence having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% to one of SEQ ID NOs: 1 to 21.

[0136] A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs: 1 to 21 may comprise one or more (such as two or more, three or more, four or more, or five or more) nucleotide substitutions (such as two or more, three or more, four or more, or five or more) with respect to one of SEQ ID NOs: 1 to 21 respectively. A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs: 1 to 21 may comprise one or more (such as two or more, three or more, four or more, or five or more) nucleotide deletions with respect to one of SEQ ID NOs: 1 to 21 respectively. A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs: 1 to 21 may comprise one or more (such as two or more, three or more, four or more, or five or more) nucleotide insertions with respect to one of SEQ ID NO: 1 to 21 respectively.

[0137] Typically, the siRNA comprised in the nucleic acid silencing molecule further comprises an antisense strand. The antisense strand is capable of hybridising to the sense strand, by Watson-Crick base pairing.

[0138] The nucleic acid molecule may, for example comprise a siRNA in which:

[0139] (1) the sense strand of the siRNA comprises SEQ ID NO: 3 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 45 or a nucleotide sequence having at least 75% sequence identity thereto;

[0140] (2) the sense strand of the siRNA comprises SEQ ID NO: 4 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 46 or a nucleotide sequence having at least 75% sequence identity thereto;

[0141] (3) the sense strand of the siRNA comprises SEQ ID NO: 5 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 47 or a nucleotide sequence having at least 75% sequence identity thereto;

[0142] (4) the sense strand of the siRNA comprises SEQ ID NO: 6 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 48 or a nucleotide sequence having at least 75% sequence identity thereto; (5) the sense strand of the siRNA comprises SEQ ID NO: 1 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 43 or a nucleotide sequence having at least 75% sequence identity thereto;

[0143] (6) the sense strand of the siRNA comprises SEQ ID NO: 2 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 44 or a nucleotide sequence having at least 75% sequence identity thereto;

[0144] (7) the sense strand of the siRNA comprises SEQ ID NO: 7 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 49 or a nucleotide sequence having at least 75% sequence identity thereto;

[0145] (8) the sense strand of the siRNA comprises SEQ ID NO: 8 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 50 or a nucleotide sequence having at least 75% sequence identity thereto;

[0146] (9) the sense strand of the siRNA comprises SEQ ID NO: 9 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 51 or a nucleotide sequence having at least 75% sequence identity thereto;

[0147] (10) the sense strand of the siRNA comprises SEQ ID NO: 10 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 52 or a nucleotide sequence having at least 75% sequence identity thereto;

[0148] (11) the sense strand of the siRNA comprises SEQ ID NO: 11 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 53 or a nucleotide sequence having at least 75% sequence identity thereto;

[0149] (12) the sense strand of the siRNA comprises SEQ ID NO: 12 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 54 or a nucleotide sequence having at least 75% sequence identity thereto;

[0150] (13) the sense strand of the siRNA comprises SEQ ID NO: 13 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 55 or a nucleotide sequence having at least 75% sequence identity thereto;

[0151] (14) the sense strand of the siRNA comprises SEQ ID NO: 14 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 56 or a nucleotide sequence having at least 75% sequence identity thereto;

[0152] (15) the sense strand of the siRNA comprises SEQ ID NO: 15 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 57 or a nucleotide sequence having at least 75% sequence identity thereto;

[0153] (16) the sense strand of the siRNA comprises SEQ ID NO: 16 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 58 or a nucleotide sequence having at least 75% sequence identity thereto;

[0154] (17) the sense strand of the siRNA comprises SEQ ID NO: 17 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 59 or a nucleotide sequence having at least 75% sequence identity thereto;

[0155] (18) the sense strand of the siRNA comprises SEQ ID NO: 18 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 60 or a nucleotide sequence having at least 75% sequence identity thereto;

[0156] (19) the sense strand of the siRNA comprises SEQ ID NO: 19 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 61 or a nucleotide sequence having at least 75% sequence identity thereto;

[0157] (20) the sense strand of the siRNA comprises SEQ ID NO: 20 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 62 or a nucleotide sequence having at least 75% sequence identity thereto; or

[0158] (21) the sense strand of the siRNA comprises SEQ ID NO: 21 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 63 or a nucleotide sequence having at least 75% sequence identity thereto.

[0159] A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs: 43 to 63 may, for example, comprise at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to one of SEQ ID NOs: 1 to 21 respectively. Thus, the antisense strand of the siRNA may comprise a nucleotide sequence having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% to one of SEQ ID NOs: 43 to 63.

[0160] A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs: 43 to 63 may comprise one or more (such as two or more, three or more, four or more, or five or more) nucleotide substitutions (such as two or more, three or more, four or more, or five or more) with respect to one of SEQ ID NOs: 43 to 63 respectively. A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs: 43 to 63 may comprise one or more (such as two or more, three or more, four or more, or five or more) nucleotide deletions with respect to one of SEQ ID NOs: 43 to 63 respectively. A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs: 43 to 63 may comprise one or more (such as two or more, three or more, four or more, or five or more) nucleotide insertions with respect to one of SEQ ID NO: 43 to 63 respectively.

[0161] Any of SEQ ID NOs: 1 to 21 and 43 to 64 may comprise one or more (such as two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, or 19 or more) 2’-O-methyl (2-’OMe) modified nucleotides or consist of 2’-O-methyl (2-’OMe) modified nucleotides. The 2’-O-methyl (2-’OMe) modified nucleotides may be present at any position(s) within SEQ ID NOs: 1 to 21 and 43 to 63.

[0162] Any of SEQ ID NOs: 1 to 21 and 43 to 64 may comprise one or more (such as two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, or 19 or more) 2’-fluoro (2’-F) modified nucleotides or consist of 2’-fluoro (2’-F) modified nucleotides. The 2’-F modified nucleotides may be present at any position(s) within SEQ ID NOs: 1 to 21 and 43 to 63.

[0163] Any of SEQ ID NOs: 1 to 21 and 43 to 63 may comprise one or more (such as two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, or 19 or more) nucleotide phosphorothioates or consist of nucleotide phosphorothioates. The nucleotide phosphorothioate(s) may be present at any position(s) within SEQ ID NOsl to 21 and 43 to 63.

[0164] Any of SEQ ID NOs: 11 to 21 and 43 to 63 may comprise any combination of (i) one or more 2-’OMe modified nucleotides, (ii) one or more 2’-F modified nucleotides, and (iii) one or more nucleotide phosphorothioates. For example, any of SEQ ID NOs: 1 to 21 and 43 to 63 may comprise (i); (ii); (iii); (i) and (ii); (i) and (iii); (ii) and (iii); or (i), (ii) and (iii).

[0165] For illustrative purposes, exemplary modification of SEQ ID NOs: 1 to 21 and 43 to 63 is shown in Figure 1 to 4. Exemplary modifications include 2-’0Me, 2’-F and phosphorothioate modification. The exemplified modifications are not limiting. Any type of chemical modification (for example, 2-’0Me modification, 2’-F modification, nucleotide phosphorothioate modification) may be made at any or all of the exemplified positions. Chemical modifications (for example, 2-’0Me modification, 2’-F modification, modification, nucleotide phosphorothioate modification) may also be made at nonexemplified positions.

[0166] By way of example, the sense strand of the siRNA may comprise any one of SEQ ID NOs: 22 to 42 or a nucleotide sequence having at least 75% sequence identity thereto. A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs: 22 to 42 may, for example, comprise at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to one of SEQ ID NOs: 1 to 21 respectively. Thus, the sense strand of the siRNA may comprise a nucleotide sequence having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% to one of SEQ ID NOs: 22 to 42. A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs: 22 to 42 may comprise one or more (such as two or more, three or more, four or more, or five or more) nucleotide substitutions (such as two or more, three or more, four or more, or five or more) with respect to one of SEQ ID NOs: 22 to 42 respectively. A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs: 22 to 42 may comprise one or more (such as two or more, three or more, four or more, or five or more) nucleotide deletions with respect to one of SEQ ID NOs: 22 to 42 respectively. A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs: 22 to 42 may comprise one or more (such as two or more, three or more, four or more, or five or more) nucleotide insertions with respect to one of SEQ ID NO: 22 to 42 respectively.

[0167] For instance, the nucleic acid molecule may comprise a siRNA in which:

[0168] (1) the sense strand of the siRNA comprises SEQ ID NO: 24 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 66 or a nucleotide sequence having at least 75% sequence identity thereto;

[0169] (2) the sense strand of the siRNA comprises SEQ ID NO: 25 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 67 or a nucleotide sequence having at least 75% sequence identity thereto;

[0170] (3) the sense strand of the siRNA comprises SEQ ID NO: 26 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 68 or a nucleotide sequence having at least 75% sequence identity thereto;

[0171] (4) the sense strand of the siRNA comprises SEQ ID NO: 27 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 69 or a nucleotide sequence having at least 75% sequence identity thereto;

[0172] (5) the sense strand of the siRNA comprises SEQ ID NO: 22 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 64 or a nucleotide sequence having at least 75% sequence identity thereto;

[0173] (6) the sense strand of the siRNA comprises SEQ ID NO: 23 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 65 or a nucleotide sequence having at least 75% sequence identity thereto;

[0174] (7) the sense strand of the siRNA comprises SEQ ID NO: 28 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 70 or a nucleotide sequence having at least 75% sequence identity thereto;

[0175] (8) the sense strand of the siRNA comprises SEQ ID NO: 29 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 71 or a nucleotide sequence having at least 75% sequence identity thereto;

[0176] (9) the sense strand of the siRNA comprises SEQ ID NO: 30 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 72 or a nucleotide sequence having at least 75% sequence identity thereto;

[0177] (10) the sense strand of the siRNA comprises SEQ ID NO: 31 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 73 or a nucleotide sequence having at least 75% sequence identity thereto;

[0178] (11) the sense strand of the siRNA comprises SEQ ID NO: 32 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 74 or a nucleotide sequence having at least 75% sequence identity thereto;

[0179] (12) the sense strand of the siRNA comprises SEQ ID NO: 33 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 75 or a nucleotide sequence having at least 75% sequence identity thereto;

[0180] (13) the sense strand of the siRNA comprises SEQ ID NO: 34 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 76 or a nucleotide sequence having at least 75% sequence identity thereto;

[0181] (14) the sense strand of the siRNA comprises SEQ ID NO: 35 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 77 or a nucleotide sequence having at least 75% sequence identity thereto;

[0182] (15) the sense strand of the siRNA comprises SEQ ID NO: 36 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 78 or a nucleotide sequence having at least 75% sequence identity thereto;

[0183] (16) the sense strand of the siRNA comprises SEQ ID NO: 37 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 79 or a nucleotide sequence having at least 75% sequence identity thereto;

[0184] (17) the sense strand of the siRNA comprises SEQ ID NO: 38 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 80 or a nucleotide sequence having at least 75% sequence identity thereto;

[0185] (18) the sense strand of the siRNA comprises SEQ ID NO: 39 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 81 or a nucleotide sequence having at least 75% sequence identity thereto;

[0186] (19) the sense strand of the siRNA comprises SEQ ID NO: 40 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 82 or a nucleotide sequence having at least 75% sequence identity thereto;

[0187] (20) the sense strand of the siRNA comprises SEQ ID NO: 41 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 83 or a nucleotide sequence having at least 75% sequence identity thereto; or

[0188] (21) the sense strand of the siRNA comprises SEQ ID NO: 42 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 84 or a nucleotide sequence having at least 75% sequence identity thereto.

[0189] A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID

[0190] NOs: 64 to 84 may, for example, comprise at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to one of SEQ ID NOs: 1 to 21 respectively. Thus, the antisense strand of the siRNA may comprise a nucleotide sequence having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% to one of SEQ ID NOs: 64 to 84.

[0191] A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs: 64 to 84 may comprise one or more (such as two or more, three or more, four or more, or five or more) nucleotide substitutions (such as two or more, three or more, four or more, or five or more) with respect to one of SEQ ID NOs: 64 to 84 respectively. A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs: 64 to 84 may comprise one or more (such as two or more, three or more, four or more, or five or more) nucleotide deletions with respect to one of SEQ ID NOs: 64 to 84 respectively. A nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs: 64 to 84 may comprise one or more (such as two or more, three or more, four or more, or five or more) nucleotide insertions with respect to one of SEQ ID NO: 64 to 84 respectively.

[0192] The nucleic acid molecule may, for example comprise a siRNA comprising:

[0193] (1) a sense strand as shown in Figure 1C or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 1C or a nucleotide sequence having at least 75% sequence identity thereto;

[0194] (2) a sense strand as shown in Figure ID or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure ID or a nucleotide sequence having at least 75% sequence identity thereto;

[0195] (3) a sense strand as shown in Figure IE or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure IE or a nucleotide sequence having at least 75% sequence identity thereto;

[0196] (4) a sense strand as shown in Figure IF or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure IF or a nucleotide sequence having at least 75% sequence identity thereto;

[0197] (5) a sense strand as shown in Figure 1 A or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 1 A or a nucleotide sequence having at least 75% sequence identity thereto; (6) a sense strand as shown in Figure IB or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure IB or a nucleotide sequence having at least 75% sequence identity thereto;

[0198] (7) a sense strand as shown in Figure 2A or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 2A or a nucleotide sequence having at least 75% sequence identity thereto;

[0199] (8) a sense strand as shown in Figure 2B or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 2B or a nucleotide sequence having at least 75% sequence identity thereto;

[0200] (9) a sense strand as shown in Figure 2C or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 2C or a nucleotide sequence having at least 75% sequence identity thereto;

[0201] (10) a sense strand as shown in Figure 2D or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 2D or a nucleotide sequence having at least 75% sequence identity thereto;

[0202] (11) a sense strand as shown in Figure 2E or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 2E or a nucleotide sequence having at least 75% sequence identity thereto;

[0203] (12) a sense strand as shown in Figure 3A or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 3A or a nucleotide sequence having at least 75% sequence identity thereto;

[0204] (13) a sense strand as shown in Figure 3B or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 3B or a nucleotide sequence having at least 75% sequence identity thereto;

[0205] (14) a sense strand as shown in Figure 3C or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 3C or a nucleotide sequence having at least 75% sequence identity thereto;

[0206] (15) a sense strand as shown in Figure 3D or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 3D or a nucleotide sequence having at least 75% sequence identity thereto; (16) a sense strand as shown in Figure 3E or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 3E or a nucleotide sequence having at least 75% sequence identity thereto;

[0207] (17) a sense strand as shown in Figure 4 A or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 4A or a nucleotide sequence having at least 75% sequence identity thereto;

[0208] (18) a sense strand as shown in Figure 4B or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 4B or a nucleotide sequence having at least 75% sequence identity thereto;

[0209] (19) a sense strand as shown in Figure 4C or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 4C or a nucleotide sequence having at least 75% sequence identity thereto;

[0210] (20) a sense strand as shown in Figure 4D or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 4D or a nucleotide sequence having at least 75% sequence identity thereto; or

[0211] (21) a sense strand as shown in Figure 4E or a nucleotide sequence having at least 75% sequence identity thereto, and an antisense strand as shown in Figure 4E or a nucleotide sequence having at least 75% sequence identity thereto.

[0212] A nucleotide sequence having at least 75% sequence identity to any sequence shown in Figures 1 to 4, for example, comprise at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to that sequence. Thus, the sense and / or antisense strand of the siRNA may comprise a nucleotide sequence having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% a sequence shown in Figures 1 to 4.

[0213] A nucleotide sequence having at least 75% sequence identity a sequence shown in Figures 1 to 4 may comprise one or more (such as two or more, three or more, four or more, or five or more) nucleotide substitutions (such as two or more, three or more, four or more, or five or more) with respect to that sequence. A nucleotide sequence having at least 75% sequence identity to a sequence shown in Figures 1 to 4 may comprise one or more (such as two or more, three or more, four or more, or five or more) nucleotide deletions with respect to that sequence. A nucleotide sequence having at least 75% sequence identity to a sequence shown in Figures 1 to 4 may comprise one or more (such as two or more, three or more, four or more, or five or more) nucleotide insertions with respect to that sequence.

[0214] Generally speaking, when an siRNA enters a cell, it forms a complex known as RNA-Induced Silencing Complex (RISC). RISC is a multiprotein complex that incorporates one strand of a siRNA. RISC uses the siRNA as a template for recognizing complementary mRNA. When it finds a complementary strand, it activates RNase and cleaves the mRNA. siRNAs often comprise an overhang at their 3’ and / or 5’ end, and it is thought that such overhangs may assist interaction with the RISC, and help to maintain siRNAs and their function in vivo. Accordingly, the nucleic acid silencing molecule of the invention, and / or the siRNA it comprises, may comprise an overhang at their 3’ and / or 5’ end.

[0215] The 3’ end of the sense strand of the siRNA may, for example, overhang the 5’ end of the antisense strand of the siRNA by one or more (such as two or more, three or more, four or more, or five or more) nucleotides. For instance, the 3’ end of the sense strand of the siRNA may overhang the 5’ end of the antisense strand of the siRNA by two nucleotides.

[0216] The 3’ end of the antisense strand of the siRNA may, for example, overhang the 5’ end of the sense strand of the siRNA by one or more (such as two or more, three or more, four or more, or five or more) nucleotides. For instance, the 3’ end of the antisense strand of the siRNA may overhang the 5’ end of the sense strand of the siRNA by two nucleotides.

[0217] The 3’ end of the sense strand of the siRNA may, for example, overhang the 5’ end of the antisense strand of the siRNA by one or more (such as two or more, three or more, four or more, or five or more) nucleotides, and the 3’ end of the antisense strand of the siRNA may, for example, overhang the 5’ end of the sense strand of the siRNA by one or more (such as two or more, three or more, four or more, or five or more) nucleotides. For instance, the 3’ end of the sense strand of the siRNA may overhang the 5’ end of the antisense strand of the siRNA by two nucleotides, and the 3’ end of the antisense strand of the siRNA may overhang the 5’ end of the sense strand of the siRNA by two nucleotides.

[0218] In certain circumstances, though, siRNAs lacking an overhang at the 3’ end of the sense strand are beneficial. Therefore, in some preferred aspects of the disclosure, the 3’ end of the sense strand of the siRNA does not overhang the 5’ end of the antisense strand of the siRNA.

[0219] Exemplary overhangs are shown in Figures 1 to 4.

[0220] Conjugation

[0221] The nucleic acid silencing molecule may be conjugated to one or more non-nucleic acid moieties. For example, the nucleic acid silencing molecule may be conjugated to two or more, three or more, four or more, or five or more non-nucleic-acid moieties.

[0222] Preferably, the non-nucleic acid moiety is a delivery moiety. A delivery moiety is a molecule that assists in the in vivo delivery of a nucleic acid silencing molecule. For example, the delivery moiety may facilitate delivery of a nucleic acid silencing molecule to a target organ, tissue, or cell type. Any of the non-nucleic acid moieties mentioned below may function as a delivery moiety.

[0223] The non-nucleic acid moiety may, for example, be hydrophobic. The non-nucleic acid moiety may, for example, comprise a lipid. For example, the non-nucleic acid moiety may comprise cholesterol, a fatty acid, a triglyceride or a phospholipid. The fatty acid may, be saturated or unsaturated. The unsaturated fatty acid may be polyunsaturated. Preferably, the non-nucleic acid moiety comprises cholesterol or a polyunsaturated fatty acid.

[0224] The non-nucleic acid moiety may, for example, comprise a peptide, a polypeptide, or a protein. For example, the non-nucleic acid moiety may comprise a peptide ligand. The peptide or peptide ligand, may, for example, be a cognate ligand for a receptor present on the surface of a target cell, or a cell comprised in a target tissue or target organ. The non-nucleic acid moiety may, for example, comprise an antibody or antibody fragment. The antibody or antibody fragment, may, for example, be capable of binding to an antigen present on the surface of a target cell, or a cell comprised in a target tissue or organ. The antibody fragment may, for example, comprise or consist of a scFv, a Fab, a modified Fab, a Fab’, a modified Fab’, a F(ab’)2, or a scFv2.

[0225] The non-nucleic acid moiety may, for example, comprise a saccharide, disaccharide or polysaccharide. The non-nucleic acid moiety may, for example, comprise an amino sugar. Preferably, the non-nucleic acid moiety comprises N-Acetylgalactosamine (GalNAc). GalNAc is capable of binding to the asialoglycoprotein receptor (ASGPR), which is expressed on the surface of liver hepatocytes. Thus, by conjugating the nucleic acid silencing molecule to GalNAc, it is possible to deliver the nucleic acid silencing molecule specifically to liver hepatocytes. GalNAc is highly potent and has been demonstrated to dramatically increase the uptake of nucleic acid silencing molecules by hepatocytes, and to prolong its duration. Studies in mice have also suggested some biodistribution of GalN Ac-conjugated oligonucleotides in the kidney.

[0226] The non-nucleic acid moiety may, for example, comprise a nanoparticle. Suitable nanoparticles are known in the art. Methods for the production of such nanoparticles are also known. The nanoparticle may, for example, be a lipid nanoparticle, a liposome, polymeric nanoparticle, an inorganic nanoparticle, a virus-like particle (VLP), a selfassembling protein, a calcium phosphate nanoparticle, a silicon nanoparticle or a gold nanoparticle. Preferably, the nanoparticle is a lipid nanoparticle. Conjugation of a nucleic acid silencing molecule to a lipid nanoparticle may enhance the biodistribution and uptake of the nucleic acid silencing molecule in the liver and the kidney.

[0227] Method of treatment and medical use

[0228] Disclosed herein is a method of treating a disease in a subject, comprising administering to the subject a composition comprising the nucleic acid silencing molecule of the disclosure.

[0229] Also disclosed herein is a composition for use in a method of treating a disease in a subject, wherein the composition comprises the nucleic acid silencing molecule of the disclosure and the method comprises administering the nucleic acid silencing molecule to the subject.

[0230] Nucleic acid silencing molecule

[0231] The method of treatment and medical use described herein comprise administering to the subject a composition comprising a nucleic acid silencing molecule that reduces the expression of STAT6. Such nucleic acid silencing molecules are described in detail above. Any of the aspects described above in connection with the nucleic acid silencing molecule of the disclosure may equally apply to the method of treatment of the disclosure or to the medical use of the disclosure. The composition may comprise one or more nucleic acid silencing molecules that reduce the expression of STAT6. For example, the composition may comprise two or more, five or more, ten or more, 20 or more, 50 or more, 100 or more, 200 or more, 500 or more, 1000 or more, 2000 or more, 5000 or more, 10000 or more, 20000 or more, 50000 or more, 100000 or more, 200000 or more, 500000 or more, 1000000 or more, 2000000 or more, 5000000 or more, 1 x 107or more, 2 x 107or more, 5 x 107or more, 1 x 108or more, 2 x 108or more, 5 x 108or more, 1 x 109or more, 2 x 109or more, or 5 x 109or more nucleic acid silencing molecules that reduce the expression of STAT6 per dose. Preferably, all of the more nucleic acid silencing molecules comprised in one dose of the composition comprise the same nucleotide sequence.

[0232] In one aspect, the nucleic acid silencing molecule may comprise one or more nucleotide phosphorothioates, or consist of nucleotide phosphorothioates. When the composition comprises two or more such nucleic acid silencing molecules, each of the two or more nucleic acid silencing molecules may be of one stereoisomer. Preferably, the composition comprises no further nucleic acid silencing molecules. This ensures the stereopurity of the composition. Stereopurity of nucleic acid silencing molecules is described in the art, for example in Iwamoto et al. (2017), Nature Biotechnology, 35:9, 845-851.

[0233] Reducing the expression of STAT 6

[0234] The nucleic acid silencing molecule comprised in the composition reduces the expression of STAT6. Reduced expression of STAT6 is described in detail above in connection with the nucleic acid silencing molecule of the disclosure. Any of the aspects described in connection with the nucleic acid silencing molecule of the disclosure may equally apply to the method of treatment of the disclosure or to the medical use of the disclosure.

[0235] Disease

[0236] Numerous conditions may be treated by reducing the expression of STAT6. For instance, as set out above, STAT6 is highly expressed in many cancers, where it regulates the expression of genes involved in the immune response, cell survival, tumour proliferation and metastasis. Therefore, reducing the expression of STAT6 in cancer cells may kill cancer cells, reduce or prevent tumour growth, and reduce or prevent metastasis. Furthermore, expression of STAT6 by immune cells in the tumour microenvironment has been demonstrated to contribute to an immunosuppressive microenvironment that is conducive to tumour maintenance and growth. Reducing expression of STAT6 in the microenvironment may promote the formation of a pro-inflammatory microenvironment that is conducive to the killing of tumour cells.

[0237] Reduction of STAT6 expression may also be beneficial in diseases caused by or associated with an overactive Th2 response. Th2 responses have been implicated in inflammatory disease, allergic diseases, autoimmune diseases and graft versus host disease (GVHD), for example. As STAT6 is a key signalling molecule for the induction and maintenance of Th2 responses, reducing STAT6 expression in a subject may reduce the number and / or activity of Th2 responses in the subject. Clinical signs or symptoms of an overactive Th2 response may therefore be reduced or abolished. Clinical signs or symptoms may be stopped from progressing.

[0238] Accordingly, the disease to be treated may be cancer. The cancer may, for example, be a cancer in which cells express, or overexpress, STAT6. The cancer may, for example, a solid tumour. For instance, the cancer may be anal cancer, bile duct cancer (cholangiocarcinoma), bladder cancer, blood cancer, bone cancer, bowel cancer, brain tumours, breast cancer, colorectal cancer, cervical cancer, endocrine tumours, eye cancer (such as ocular melanoma), fallopian tube cancer, gall bladder cancer, head and / or neck cancer, Kaposi's sarcoma, kidney cancer, larynx cancer, liver cancer, lung cancer, lymph node cancer, melanoma, mesothelioma, myeloma, neuroendocrine tumours, ovarian cancer, oesophageal cancer, pancreatic cancer, penis cancer, primary peritoneal cancer, prostate cancer, Pseudomyxoma peritonei, skin cancer, small bowel cancer, soft tissue sarcoma, spinal cord tumours, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, trachea cancer, unknown primary cancer, vagina cancer, vulva cancer or endometrial cancer. The cancer may, for example, be a leukemia, a myeloma or a lymphoma. The cancer may be primary cancer or secondary cancer.

[0239] Alternatively, the disease may be a disease in which the subject may benefit from a reduction or relative reduction in antigen-specific Th2 responses. Relative reduction of antigen-specific Th2 responses may, for example, refer to shifting the balance of an antigen-specific T-cell response response away from Th2. For instance, the balance may be shifted towards one or more other T helper subsets, such as Thl, Thl7, Treg and Tfh.

[0240] The disease may, for instance, be an inflammatory disease. A major example of inflammatory disease is asthma. The disease may therefore be asthma. Other inflammatory diseases include ankylosing spondylitis, antiphospholipid antibody syndrome, chronic recurrent multifocal osteomyelitis, gout, Henoch-Schonlein purpura, dermatomyositis, idiopathic arthritis, scleroderma, Kawasaki disease, mixed connective tissue disease, myositis, post-streptococcal inflammatory syndromes, psoriatic arthritis, reactive arthritis, scleroderma, spondyloarthritis, systemic juvenile idiopathic arthritis, undifferentiated connective tissue disease, uveitis and vasculitis.

[0241] The disease may, for instance, be an allergic disease, such as atopic dermatitis, allergic airway inflammation or allergic rhinitis.

[0242] The disease may, for instance, be an autoimmune condition, such as alopecia areata, autoimmune encephalomyelitis, autoimmune hemolytic anemia, autoimmune hepatitis, dermatomyositis, diabetes (type 1), autoimmune juvenile idiopathic arthritis, glomerulonephritis, Graves’ disease, Guillain-Barre syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, autoimmune myocarditis, multiple sclerosis, pemphigus / pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma / systemic sclerosis, Sjogren’s syndrome, systemic lupus erythematosus, autoimmune thyroiditis, uveitis or vitiligo.

[0243] The disease may, for instance, be GVHD.

[0244] Subject

[0245] The subject may, for example, be a mammal. The mammal may, for example, be a human or a non-human mammal such as a dog, cat, horse or farm animal. Preferably, the subject is a human.

[0246] The subject may, for example, be an adult. The subject may, for example, be a juvenile.

[0247] Administration and formulation

[0248] The composition may be administered by any route. Suitable routes include, but are not limited to, the intravenous, intratracheal, intranasal, intrathecal, intracerebral ventricular, intramuscular, intraperitoneal, subcutaneous, intradermal, transdermal and oral / buccal routes.

[0249] The composition may comprise a delivery vehicle that optimises delivery of the nucleic acid silencing molecule in vivo. Suitable delivery vehicles are known in the art and include, for example, cell-targeting moi eties, cell-penetrating moieties, lipids, lipoproteins, liposomes, lipoplexes, peptides, GalNAc, antibodies, aptamers, nanoparticles, exosomes, spherical nucleic acids, and DNA cages.

[0250] The compositions may be prepared together with a physiologically acceptable carrier or diluent. Typically, such compositions are prepared as liquid suspensions of nucleic acid silencing molecules and / or delivery vehicle-linked nucleic acid silencing molecules. The nucleic acid silencing molecules and / or delivery vehicle-linked nucleic acid silencing molecules may be mixed with an excipient which is pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, of the like and combinations thereof. In addition, if desired, the pharmaceutical compositions may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, and / or pH buffering agents.

[0251] The nucleic acid silencing molecules and / or delivery vehicle-linked nucleic acid silencing molecules are administered in a manner compatible with the dosage formulation and in such amount will be therapeutically effective. The quantity to be administered depends on the subject to be treated, the disease to be treated, and the capacity of the subject’s immune system. Precise amounts of nucleic acid silencing molecules and / or delivery vehicle-linked nucleic acid silencing molecules required to be administered may depend on the judgement of the practitioner and may be peculiar to each subject.

[0252] Combination therapy

[0253] The composition may be administered as part of a combination therapy. That is, the method of treatment or medical use may comprise administering to the subject a further therapeutic composition or a therapeutic regimen. Administration of a further composition or a therapeutic regimen may, for example, be desirable when the nucleic acid silencing molecule reduces rather than eliminates STAT6 expression. In some cases, though, reduction (rather than elimination) of STAT6 expression may be sufficient to effect treatment of the disease. The composition may be administered as part of a combination therapy in conjunction with any available therapeutic composition or therapeutic regimen for a particular disease.

[0254] For instance, when the disease is cancer, the composition may be used in combination with (i) surgical resection, (ii) radiation therapy, and / or (iii) systemic therapy. For example, the composition may be used in combination with: (i); (ii); (iii); (i) and (ii); (i) and (iii); (ii) and (iii); or (i), (ii) and (iii).

[0255] The systemic therapy may comprise or consist of (a) a chemotherapy. The systemic therapy may comprise or consist of (b) an immunotherapy. The systemic therapy may comprise or consist of (c) a targeted therapy. For example, the systemic therapy may comprise or consist of (a); (b); (c); (a) and (b); (a) and (c); (b) and (c); or (a), (b) and (c).

[0256] Chemotherapies are well-known in the art. Such chemotherapies may, for example, comprise a platinum-based anti -neoplastic drug, such as cisplatin or carboplatin. Such chemotherapies may, for example, comprise an anti-metabolite, such as fluorouracil (5- FU), gemcitabine or methotrexate. Such chemotherapies may, for example, comprise a taxane drug, such as docetaxel or paclitaxel. Such chemotherapies may, for example, comprise an anthracycline, such as doxorubicin. Such chemotherapies may, for example, comprise a vinca alkaloid, such as vinblastine. Such chemotherapies may, for example, comprise an anti-tumour antibiotic, such as mitomycin. Such chemotherapies may, for example, comprise an alkylating agent, such as ifosfamide.

[0257] Immunotherapies are well-known in the art. Such immunotherapies may, for example, include therapeutic immune cells, immunomodulators, checkpoint inhibitors, and vaccines. Therapeutic immune cells may include T cells, for instance engineered T cells such as CAR T cells or T cells expressing an engineered TCR. Immunomodulators may include, for example, interleukins, cytokines, chemokines, and immunomodulatory imide drugs. Immunomodulators may, for example, include Multikine (Leukocyte Interleukin, Injection). Immunomodulators, may, for example, include monalizumab, a humanized anti-NKG2A blocking antibody that prevents the inhibition of CD8+ T cells and NK cell by tumour cells expressing HLA-E. Checkpoint inhibitors may, for instance, include CTLA-4 inhibitors or PD-1 axis binding antagonists. PD-1 axis binding antagonists may, for instance, include pembrolizumab, nivolumab, avelumab and atezolizumab. Checkpoint inhibitors and PD-1 axis binding antagonists are described in detail below. Vaccines may include, for example, vidutolimod (CMP-001) which is a toll-like receptor 9 (TLR9) agonist cancer vaccine.

[0258] Targeted therapies well-known in the art. The term targeted therapy is a term of art that refers to treatments that target specific genes and proteins that help cancer cells survive and grow. Targeted therapies may, for example, include an inhibitor of fibroblast growth factor receptor (such as erdafitinib), an antibody-drug conjugate (such as enfortumab vedotin-ejfv or sacituzumab govitecan). Enfortumab vedotin-ejfv is a conjugate of a nectin-4-directed antibody and a microtubule inhibitor. Sacituzumab govitecan is a conjugate of a Trop-2-directed antibody and a topoisomerase inhibitor.

[0259] When the disease is a disease in which the subject may benefit from a reduction or relative reduction in antigen-specific Th2 responses, the composition may be used in combination with an immunosuppressive drug, for example. Other drugs of potential use in combination treatment may depend on the disease to be treated. Treatments for inflammatory diseases, allergic diseases, autoimmune diseases and GVHD are well-known in the art, and may be used in combination with the nucleic acid silencing molecule of the disclosure.

[0260] In combination therapy, the composition that comprises a nucleic acid silencing molecule that reduces the expression of STAT6 is administered in such an amount that will be therapeutically effective in combination with administration of the further therapeutic composition or therapeutic regimen. The further therapeutic composition is administered, in such an amount that will be therapeutically effective in combination with the composition that comprises a nucleic acid silencing molecule that reduces the expression of STAT6. The composition that comprises a nucleic acid silencing molecule that reduces the expression of STAT6 and the further therapeutic composition may be administered together, for instance at the same time. The composition that comprises a nucleic acid silencing molecule that reduces the expression of STAT6 and the further therapeutic composition may be administered separately, for instance at a different time. For example, the composition that comprises a nucleic acid silencing molecule that reduces the expression of STAT6 may be administered before the further therapeutic composition. The composition that comprises a nucleic acid silencing molecule that reduces the expression of STAT6 may be administered after the further therapeutic composition. Administration of the composition that comprises a nucleic acid silencing molecule that reduces the expression of STAT6 may be alternated with administration of the further therapeutic composition.

[0261] In another aspect of combination therapy, the composition that comprises a nucleic acid silencing molecule that reduces the expression of STAT6 is administered in such an amount that it will be therapeutically effective in combination with the additional therapeutic regimen. The therapeutic regimen is implemented to the extent that it will be therapeutically effective in combination with administration of the composition that comprises a nucleic acid silencing molecule that reduces the expression of STAT6. The composition that comprises a nucleic acid silencing molecule that reduces the expression of STAT6 may be administered before, during or after implementation of the therapeutic regimen. Preferably, the composition that comprises a nucleic acid silencing molecule that reduces the expression of STAT6 is administered during implementation of the therapeutic regimen.

[0262] In vitro method

[0263] As set out above, the nucleic acid silencing molecule disclosed herein may be used to reduce the expression of STAT6 in vitro. For example, the nucleic acid silencing molecule may be used as a research tool, for instance to investigate cancer, inflammatory disease, allergic diseases or autoimmune diseases. Accordingly, the present disclosure provides an in vitro method for reducing expression of STAT6 in a cell, comprising contacting the cell with the nucleic acid silencing molecule of the disclosure.

[0264] The cell may be any type of cell. For example, the cell may be from any tissue. The cell may be from any species. Preferably, the cell is human. The cell may be a healthy cell, or a diseased cell. The diseased cell may, for example, be a cancer cell. The cell may be a naturally occurring cell. The cell may be from a cell line.

[0265] Mechanisms for contacting a cell with a nucleic acid silencing molecule are well known in the art. Contacting may, for example, take place in a well of a microwell plate, or in another type of vessel such as a cell culture flask or a test tube. The contacting step may be performed prior to, or concurrently with, culture of the cell. The conditions required for the culture of various cell types are well known in the art.

[0266] The cell may be contacted with one or more molecules additional to the nucleic acid silencing molecule. The additional molecule may be another nucleic acid silencing molecule that targets STAT6. The additional molecule may be a nucleic acid silencing molecule that targets a gene other than STAT6, such as a different gene involved in Th2 induction and maintenance or another gene that is overexpressed in cancer cells. Preferably, the additional molecule may facilitate reduction or elimination of STAT6 expression by the nucleic acid silencing molecule.

[0267] EXAMPLES

[0268] The following Examples illustrate the disclosure.

[0269] Example 1

[0270] To address the need for therapies that effectively reduce expression of STAT6, siRNAs targeting STAT6 were generated. The siRNAs are shown in Figures 1 to 4. The sequences of the sense strand of each siRNA are also shown in Table 1. The sequences of the antisense strand of each siRNA are shown in Table 2. In each case, the “base sequence” refers to the unmodified nucleotide sequence of the strand. The “modified sequence” shows the particular combinations and positions of modified (2-’0Me, 2’-F, phosphorothioated) nucleotides used for optimal inhibition of STAT6 expression.

[0271] Table 1: sense strands of siRNAs of the disclosure

[0272] dT = T DNA

[0273] N*N = phosphorothioatemC,mA,mG,mU = 2’-0Me modified nucleotidefA,fC,fG,fU = 2’-F modified nucleotide

[0274] Table 2: antisense strands of siRNAs of the disclosure dT = T DNA

[0275] N*N = phosphorothioatemC,mA,mG,mU = 2’-0Me modified nucleotidefA,fC,fG,fU = 2’-F modified nucleotide At least the siRNAs in family 1 (i.e. siRNAs 1, Iw, la, lb, 1c and Id) have advantageous properties. In particular, siRNAs in family 1 have been shown to slow tumour growth. They may therefore be used to treat cancer, such as STAT6-expressing cancer.

[0276] In addition, siRNAs in family 1 target both human and murine STAT6. They can therefore be used in xenograft tumour models to block STAT6 regardless of whether it is produced by human cancer cells or mouse stromal cells within the tumour microenvironment. They can also be used in syngraft tumour models in which all STAT6 is exclusively murine; or in mouse or rat models of inflammation that will only involve rodent STAT6.

[0277] Example 2

[0278] The potency of siRNAs designed in Example 1 is tested in vitro to assess their ability to reduce expression of STAT6. Potency is investigated, for example, by measuring levels of STAT6 mRNA expression by RT-qPCR, within a biologically-relevant time period after transfection of cultured cells. Potency is further investigated by, for example, measuring levels of STAT6 protein expression by transfected cells using Western blot analysis, within a biologically-relevant time period after transfection.

[0279] In more detail, potency of siRNAs 1, Iw, la, lb, 1c, Id, 2, 2a, 2b, 2c, 2d, 3, 3a, 3b, 3c, 3d, 4, 4a, 4b, 4c and 4d (in base sequence form and modified form) is assessed in A549 lung adenocarcinoma cells, THP-1 cells, and peripheral blood mononuclear cells (PBMCs). A549 cells are lung alveolar epithelial cells that respond to IL4 and IL13 to activate STAT6. They model lung inflammatory responses in asthma. They also model cancer. THP-1 is a monocyte cell line, which may model inflammatory diseases.

[0280] Each cell type is (a) transfected with one of the siRNAs in the absence lipofectamine and, in a separate reaction, (b) transfected with one of the siRNAs in the presence lipofectamine. Transfections are set up in at least triplicate.

[0281] Over a time course, cells are stimulated with IL-4 and / or IL-13, in various concentrations. In particular, cells are stimulated with IL-4. STAT6 expression is then measured at an endpoint. In particular, STAT6 expression is measured at message level, by quantifying STAT-6 mRNA by RT-PCR. Total STAT6 expression is also measured at the protein level by Western blot analysis. Activated STAT6 is measured by Western analysis with using phospho-STAT6 Tyr641 antibody to detect phosphorylated STAT6 protein. STAT6 activity is measured indirectly, by assessing expression of the cell surface protein CD23 (e.g. by flow cytometry or immunofluorescent imaging), or secretion of CCL17 by immunoassay.

[0282] Functional assays of stimulated cells are also performed, to quantify cell proliferation and / or apoptosis.

[0283] Tested siRNAs, especially those comprising 2’0Me and / or 2’F modifications effectively decrease the level of STAT6 expression. Proliferation is reduced, and / or apoptosis is increased, by transfection, especially with siRNAs comprising 2’0Me and / or 2’F modifications. Thus, tested siRNAs show surprisingly better efficacy than known and / or unmodified siRNA sequences, in particular decreasing the level of STAT6 expression, reducing proliferation, and / or increasing apoptosis.

[0284] Example 3 siRNAs 1, Iw, la, lb, 1c, Id, 2, 2a, 2b, 2c, 2d, 3, 3a, 3b, 3c, 3d, 4, 4a, 4b, 4c and 4d are further tested (in base sequence form and modified form) in HT-29 cells. HT-29 is a human colorectal adenocarcinoma cell line with epithelial morphology. STAT6 is strongly expressed in various tumours and is most highly expressed in malignant lymphomas and pancreatic, colorectal, prostate and breast cancers. STAT6 expression in colorectal cancer is associated with an increased malignancy, poor prognosis and reduced survival rates.

[0285] HT-29 cells are (a) transfected with one of the siRNAs in the absence of lipofectamine and, in a separate transfection, (b) with one of the siRNAs in the presence lipofectamine. Transfections are set up in at least triplicate.

[0286] After a biologically relevant period of time, STAT6 expression is measured. In particular, STAT6 expression is measured at message level, by quantifying STAT-6 mRNA by RT-PCR. STAT6 expression is also measured at the protein level, by Western blotting. Western blotting may measure total STAT6, or phosphorylated STAT6 using phospo-STAT6 Tyr641 antibody as the detection antibody.

[0287] Functional assays of transfected cells are also performed, with proliferation and / or apoptosis measured at various time points. Tested siRNAs, especially those comprising 2’0Me and / or 2’F modifications effectively decrease the level of STAT6 expression. Proliferation is reduced, and / or apoptosis is increased, by transfection, especially with siRNAs comprising 2’0Me and / or 2’F modifications. Thus, tested siRNAs show surprisingly better efficacy than known and / or unmodified siRNA sequences, in particular decreasing the level of STAT6 expression, reducing proliferation, and / or increasing apoptosis.

Claims

CLAIMS1. A nucleic acid silencing molecule comprising or consisting of a small interfering RNA (siRNA) that reduces the expression of Signal Transducer and Activator of Transcription 6 (STAT6), wherein the siRNA targets exon 5, 15, 19 or 10 of STAT6.

2. The nucleic acid silencing molecule of claim 1, wherein the sense strand of the siRNA comprises any one of SEQ ID NOs: 5, 3, 4, 6, 8 to 11, 13 to 16 and 18 to 21 or a nucleotide sequence having at least 75% sequence identity thereto, optionally wherein the sense strand of the siRNA comprises a nucleotide sequence having at least 80%, at least 90% or at least 95% sequence identity to any one of SEQ ID NOs: 5, 3, 4, 6, 8 to 11, 13 to 16 and 18 to 21.

3. The nucleic acid silencing molecule of claim 1 or 2, wherein:(a) the sense strand of the siRNA comprises SEQ ID NO: 5 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 47 or a nucleotide sequence having at least 75% sequence identity thereto;(b) the sense strand of the siRNA comprises SEQ ID NO: 3 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 45 or a nucleotide sequence having at least 75% sequence identity thereto;(c) the sense strand of the siRNA comprises SEQ ID NO: 4 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 46 or a nucleotide sequence having at least 75% sequence identity thereto;(d) the sense strand of the siRNA comprises SEQ ID NO: 6 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 48 or a nucleotide sequence having at least 75% sequence identity thereto;(e) the sense strand of the siRNA comprises SEQ ID NO: 8 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 50 or a nucleotide sequence having at least 75% sequence identity thereto;(f) the sense strand of the siRNA comprises SEQ ID NO: 9 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 51 or a nucleotide sequence having at least 75% sequence identity thereto;(g) the sense strand of the siRNA comprises SEQ ID NO: 10 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 52 or a nucleotide sequence having at least 75% sequence identity thereto;(h) the sense strand of the siRNA comprises SEQ ID NO: 11 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 53 or a nucleotide sequence having at least 75% sequence identity thereto;(i) the sense strand of the siRNA comprises SEQ ID NO: 13 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 55 or a nucleotide sequence having at least 75% sequence identity thereto;(j) the sense strand of the siRNA comprises SEQ ID NO: 14 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNAcomprises SEQ ID NO: 56 or a nucleotide sequence having at least 75% sequence identity thereto;(k) the sense strand of the siRNA comprises SEQ ID NO: 15 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 57 or a nucleotide sequence having at least 75% sequence identity thereto;(l) the sense strand of the siRNA comprises SEQ ID NO: 16 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 58 or a nucleotide sequence having at least 75% sequence identity thereto;(m) the sense strand of the siRNA comprises SEQ ID NO: 18 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 60 or a nucleotide sequence having at least 75% sequence identity thereto;(n) the sense strand of the siRNA comprises SEQ ID NO: 19 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 61 or a nucleotide sequence having at least 75% sequence identity thereto;(o) the sense strand of the siRNA comprises SEQ ID NO: 20 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 62 or a nucleotide sequence having at least 75% sequence identity thereto; or(p) the sense strand of the siRNA comprises SEQ ID NO: 21 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 63 or a nucleotide sequence having at least 75% sequence identity thereto.

4. The nucleic acid silencing molecule of claim 3, wherein the antisense strand of the siRNA comprises a nucleotide sequence having at least 80%, at least 90% or at least 95% sequence identity to the respective one of SEQ ID NOs:45 to 48, 50 to 53, 55 to 58 and 60 to 63.

5. The nucleic acid silencing molecule of any one of the preceding claims, wherein the nucleic acid silencing molecule comprises one or more 2’-O-methyl (2-’0Me) modified nucleotides or consists of 2’-O-methyl (2’-0Me) modified nucleotides.

6. The nucleic acid silencing molecule of any one of the preceding claims, wherein the nucleic acid silencing molecule comprises one or more 2’ -fluoro (2’-F) modified nucleotides or consists of 2’-fluoro (2’-F) modified nucleotides.

7. The nucleic acid silencing molecule of any one of the preceding claims, wherein the nucleic acid silencing molecule comprises one or more nucleoside phosphorothioates or consists of nucleoside phosphorothioates.

8. The nucleic acid silencing molecule of any one of the preceding claims, wherein the nucleotide sequence comprised in the nucleic acid silencing molecule is about 15 to about 30 nucleotides in length, optionally about 20 to about 25 nucleotides in length.

9. The nucleic acid silencing molecule of any one of the preceding claims, wherein the sense strand of the siRNA comprises any one of SEQ ID NOs: 24 to 27, 29 to 32, 34 to 37 and 39 to 42, or a nucleotide sequence having at least 75% sequence identity thereto.

10. The nucleic acid silencing molecule of any one of the preceding claims, wherein the sense strand of the siRNA comprises a nucleotide sequence having at least 80%, at least 90% or at least 95% sequence identity to any one of SEQ ID NOs: 24 to 27, 29 to 32, 34 to 37 and 39 to 42.

11. The nucleic acid silencing molecule of any one of the preceding claims, wherein:(a) the sense strand of the siRNA comprises SEQ ID NO: 26 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 68 or a nucleotide sequence having at least 75% sequence identity thereto;(b) the sense strand of the siRNA comprises SEQ ID NO: 24 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 66 or a nucleotide sequence having at least 75% sequence identity thereto;(c) the sense strand of the siRNA comprises SEQ ID NO: 25 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 67 or a nucleotide sequence having at least 75% sequence identity thereto;(d) the sense strand of the siRNA comprises SEQ ID NO: 27 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 69 or a nucleotide sequence having at least 75% sequence identity thereto;(e) the sense strand of the siRNA comprises SEQ ID NO: 29 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 71 or a nucleotide sequence having at least 75% sequence identity thereto;(f) the sense strand of the siRNA comprises SEQ ID NO: 30 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 72 or a nucleotide sequence having at least 75% sequence identity thereto;(g) the sense strand of the siRNA comprises SEQ ID NO: 31 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 73 or a nucleotide sequence having at least 75% sequence identity thereto;(h) the sense strand of the siRNA comprises SEQ ID NO: 32 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 74 or a nucleotide sequence having at least 75% sequence identity thereto;(i) the sense strand of the siRNA comprises SEQ ID NO: 34 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 76 or a nucleotide sequence having at least 75% sequence identity thereto;(j) the sense strand of the siRNA comprises SEQ ID NO: 35 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 77 or a nucleotide sequence having at least 75% sequence identity thereto;(k) the sense strand of the siRNA comprises SEQ ID NO: 36 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 78 or a nucleotide sequence having at least 75% sequence identity thereto;(l) the sense strand of the siRNA comprises SEQ ID NO: 37 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 79 or a nucleotide sequence having at least 75% sequence identity thereto;(m) the sense strand of the siRNA comprises SEQ ID NO: 39 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 81 or a nucleotide sequence having at least 75% sequence identity thereto;(n) the sense strand of the siRNA comprises SEQ ID NO: 40 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 82 or a nucleotide sequence having at least 75% sequence identity thereto;(o) the sense strand of the siRNA comprises SEQ ID NO: 41 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 83 or a nucleotide sequence having at least 75% sequence identity thereto; or(p) the sense strand of the siRNA comprises SEQ ID NO: 42 or a nucleotide sequence having at least 75% sequence identity thereto, and the antisense strand of the siRNA comprises SEQ ID NO: 84 or a nucleotide sequence having at least 75% sequence identity thereto.

12. The nucleic acid silencing molecule of claim 11, wherein the antisense strand of the siRNA comprises a nucleotide sequence having at least 80%, at least 90% or at least 95% sequence identity to the respective one of SEQ ID NOs:66 to 69, 71 to 74, 76 to 79 and 81 to 84.

13. The nucleic acid silencing molecule of any one of the preceding claims, wherein the nucleic acid silencing molecule is conjugated to one or more non-nucleic acid moieties.

14. The nucleic acid silencing molecule of any one of claims 3(c), 3(a), 3(d), 3(f), 3(g), 3(h), 3(j), 3(k), 3(1), 3(n), 3(o), 3(p), 11(c), 11(a), 11(d), 11(f), 11(g), 11(h), 1 l(j), 1 l(k),11(1), 1 l(n), 1 l(o) and 11 (p) wherein the 3’ end of the sense strand of the siRNA does not overhang the 5’ end of the antisense strand of the siRNA.

15. An in vitro method for reducing expression of STAT6 in a cell, comprising contacting the cell with the nucleic acid silencing molecule of any one of the preceding claims.

16. A method of treating a disease in a subject, comprising administering to the subject a composition comprising the nucleic acid silencing molecule of any one of claims 1 to 14.

17. The method of claim 16, wherein the disease is cancer.

18. The method of claim 16, wherein the disease is a disease in which the subject may benefit from a reduction or relative reduction in antigen-specific Th2 responses.

19. The method of claim 16 or 18, wherein the disease is an inflammatory disease.

20. The method of claim 16 or 18, wherein the disease is an allergic disease.

21. The method of claim 16 or 18, wherein the disease is an autoimmune disease.

22. The method of claim 16 or 18, wherein the disease is graft versus host disease(GVHD).

23. A composition comprising the nucleic acid silencing molecule of any one of claims 1 to 14, for use in a method of any one of claims 16 to 22.

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