Antisense oligomers for the treatment of chronic kidney disease

Abstract

Compounds complementary to the target region within the pre-mRNA of the human uromodulin (UMOD) gene, such as oligomers, peptide-oligomer conjugates, and targeting sequences, as well as pharmaceutical compositions thereof, are provided herein. Methods for treating diseases or disorders associated with abnormal UMOD expression using these compounds and compositions are also provided herein. This disclosure relates to antisense oligomers or pharmaceutically acceptable salts thereof for the treatment of chronic kidney disease (CKD), as well as related compositions and methods.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 462,389, filed on 27 April 2023 under 35 U.S.C. § 119(e), the disclosure of which is incorporated herein by reference in its entirety. Sequence List This application includes a sequence listing submitted electronically in XML format, which is incorporated herein by reference in its entirety. The XML copy, created on 25 April 2024, is named 4140_075PC02_Seqlisting_ST26 and has a size of 944,270 bytes. [Background technology]

[0002] background Antisense technology provides a means for modulating the expression of one or more specific gene products, including alternative splicing products, and is uniquely useful in therapeutic, diagnostic, and research applications. The underlying principle of antisense technology is that an antisense compound (e.g., an oligomer) hybridizes to a target nucleic acid and modulates gene expression activity, such as transcription, splicing, or translation, through one of several antisense mechanisms. Due to the sequence specificity of antisense compounds, they are attractive as tools for target validation and gene functionalization, as well as as therapeutic agents, for selectively modulating the expression of disease-related genes.

[0003] Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare group of genetic disorders characterized by tubular damage and interstitial fibrosis in the absence of glomerular lesions. Affected individuals present with progressive chronic kidney disease (CKD), normal to mild proteinuria, and kidneys of normal size, and often have a positive family history of autosomal dominant inheritance. Progression to end-stage kidney disease (ESKD) is inevitable in ADTKD. Genes that cause different forms of ADTKD include UMOD, MUC1, REN, and HNF1B. Deficiencies in these genes result in uromodulin kidney disease (UKD), mucin-1 kidney disease, familial juvenile hyperuricemia nephropathy type 2 (FJHN2), and early-onset adult-onset diabetes mellitus type 5 (MODY5), respectively. When the cause of ADTKD is unknown or genetic testing has not been performed, it is referred to as ADTKD-NOS.

[0004] Uromodulin-associated autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD) is caused by mutations in the UMOD gene, which encodes the GPI-anchored glycoprotein uromodulin (UMOD) or tam-horsefall protein (THP). Clinical signs of ADTKD-UMOD usually first appear in adolescence, and progression to end-stage renal disease occurs between the ages of 30 and 70.

[0005] Treatment for ADTKD-UMOD includes drug therapy strategies and kidney transplantation. Drug therapy strategies focus on treating symptoms such as gout and hyperuricemia, rather than the underlying disease. For example, many ADTKD-UMOD patients receive lifelong treatment with allopurinol to treat and prevent gout, but there is very little and insufficient evidence that allopurinol slows the progression of the disease. On the other hand, kidney transplantation cures ADTKD-UMOD because the transplanted kidney does not develop the disease. However, patients often have to wait a long time to receive a transplant, and organ transplantation inherently carries risks. Certain treatments for hereditary chronic kidney diseases, including ADTKD-UMOD, through targeted delivery of compounds to diseased cells can avoid the need for invasive treatment modalities such as kidney transplantation, slow or halt the progression of CKD, and eliminate or improve the symptoms of the disease. [Overview of the project] [Means for solving the problem]

[0006] overview This disclosure relates to antisense oligomers or pharmaceutically acceptable salts thereof for the treatment of chronic kidney disease (CKD), as well as related compositions and methods. In certain embodiments, the chronic kidney disease is uromodulin-associated autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD) (also known as uromodulin kidney disease (UKD)).

[0007] Accordingly, the following are provided: an antisense oligomer or a pharmaceutically acceptable salt thereof comprising a non-natural chemical skeleton and a targeting sequence of 13 to 30 bases in length that is complementary to a target region in the pre-mRNA of the human uromodulin (UMOD) gene (SEQ ID NO: 1), wherein the targeting region is an intron / exon junction or an internal exon region of the human UMOD gene pre-mRNA.

[0008] While we do not wish to be constrained by theory, the antisense oligomers or pharmaceutically acceptable salts thereof disclosed herein are useful in a method of inducing exon skipping in human UMOD pre-mRNA to generate immature stop codons, thereby triggering nonsense-mediated disintegration in lesional cells and reducing UMOD aggregation. Accordingly, the antisense oligomers or pharmaceutically acceptable salts thereof provided herein are useful in the treatment of a variety of conditions and symptoms, including but not limited to chronic kidney disease (CKD), in subjects requiring treatment. In a particular embodiment, chronic kidney disease is ADTKD-UMOD.

[0009] In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof is a phosphorodiamidate morpholino oligomer (PMO). In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof further comprises a delivery agent including, but not limited to, a cell-permeable peptide (CPP), an antibody, an antibody fragment, an antigen-binding fragment of an antibody, at least one ligand, or a combination thereof.

[0010] In one embodiment, the antisense oligomer of structural formula (I): [ka] or a pharmaceutically acceptable salt thereof During the ceremony, A' is -OH, [ka] Selected from, R 5 is -C(O)(O-alkyl) x -OH, x is 3 to 10, and each alkyl group is independently C each time it appears. 2~6 - Is it alkyl? or R 5 H, -C(O)C 1~6 -alkyl, trityl, monomethoxytrityl, -(C 1~6-(alkyl)-R 6 、-(C 1~6 -heteroalkyl)-R 6 、-C 6~10 -aryl-R 6 、5- to 10-membered heteroaryl-R 6 、-C(O)O-(C 1~6 -alkyl)-R 6 、-C(O)O-aryl-R 6 、-C(O)O-(5- to 10-membered heteroaryl)-R 6 、and

Chemical Structure

[0011] In another embodiment, the antisense oligomer of structural formula (IA): [ka] or a pharmaceutically acceptable salt thereof During the ceremony, A' is, [ka] The part selected from, Antisense oligomers or pharmaceutically acceptable salts thereof are provided herein. 2 , R 9 , and t are as described for equation (I).

[0012] In another embodiment, the antisense oligomer of structural formula (II): [ka] Or pharmaceutically acceptable salts thereof are provided herein. t, G, and R2 This is as described for equation (I).

[0013] In yet another embodiment, the antisense oligomer of structural formula (III): [ka] Or a pharmaceutically acceptable salt thereof is provided herein. n is 11 to 28, and R 2 This is as described for equation (I).

[0014] In one embodiment, the antisense oligomer of structural formula (IV): [ka] However, this is provided herein. n is as described for formula (III), and R 2 This is as described for equation (I).

[0015] In another embodiment, a pharmaceutical composition comprising an antisense oligomer or a pharmaceutically acceptable salt thereof as described herein and a pharmaceutically acceptable carrier is provided herein.

[0016] In one embodiment, a method for treating a disease is provided herein, comprising administering to a subject a therapeutically effective amount of an antisense oligomer or a pharmaceutically acceptable salt thereof as described herein. In another embodiment, a method for treating a disease is provided herein, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition, wherein the composition comprises an antisense oligomer or a pharmaceutically acceptable salt thereof as described herein.

[0017] In some embodiments, antisense oligomers or pharmaceutically acceptable salts thereof, as described herein, are used to treat chronic kidney disease (CKD), including autosomal dominant tubulointerstitial kidney disease-uromodulin (ADTKD-UMOD). [Brief explanation of the drawing]

[0018] [Figure 1A] Figure 1A shows a bar graph illustrating antisense microwalk data for various target regions within exon 2 of the human UMOD gene pre-mRNA described in Example 2. Each compound was administered at 20 μM. Figure 1B shows a bar graph illustrating antisense microwalk data for various target regions within exon 5 of the human UMOD gene pre-mRNA. Each compound was administered at 20 μM. Figure 1C shows a bar graph illustrating antisense microwalks for various target regions within exon 6 of the human UMOD gene pre-mRNA. Each compound was administered at 20 μM. Figure 1D shows a bar graph illustrating antisense microwalks for various target region data within exon 8 of the human UM UMOD OD gene pre-mRNA. Each compound was administered at 20 μM. Figure 1E is a bar graph illustrating knockdown of UMOD expression in mIMCD-3 cells treated with four different PPMOs at a single dose. Each PPMO compound was administered at 20 μM. [Figure 1B] Same as above. [Figure 1C] Same as above. [Figure 1D] Same as above. [Figure 1E] Same as above.

[0019] [Figure 2A] Figure 2A shows a bar graph of UMOD expression knockdown in mIMCD-3 cells treated with seven different PPMOs at two doses, as described in Example 3. Each PPMO compound was administered at 10 μM and 20 μM. Figure 2B shows a bar graph of UMOD expression knockdown in mIMCD-3 cells treated with three different PPMOs at various doses. Each PPMO compound was administered at 2.5 μM, 5 μM, 10 μM, and 20 μM. [Figure 2B] Same as above.

[0020] [Figure 3A-B] Figure 3A shows a photograph of a histological section of a kidney co-stained with NCC to show distal tubular epithelial cells and with EGFP to show PPMO activity, as described in Example 4. Figure 3B shows a bar graph of PPMO activity in distal tubular epithelial cells. The compound was administered at a low dose of 10 mg / kg and a high dose of 80 mg / kg. Figure 3C shows a photograph of a histological section of a kidney co-stained with NKCC2 to show TAL cells in the loop of Henle and with EGFP to show PPMO activity. Figure 3D shows a bar graph of PPMO activity in TAL cells. The compound was administered at a low dose of 10 mg / kg and a high dose of 80 mg / kg. Figure 3E shows a photograph of a histological section of a kidney co-stained with UMOD and EGFP to show PPMO activity. [Figure 3C-D] Same as above. [Figure 3E] Same as above.

[0021] [Figure 4A] Figure 4A shows a bar graph indicating UMOD mRNA expression 7 days after IV injection of PPMO targeting UMOD. As described in Example 5, the compound was administered at a low dose of 30 mg / kg and a high dose of 100 mg / kg. Figure 4B shows a bar graph indicating UMOD protein levels 7 days after IV injection of PPMO targeting UMOD. The compound was administered at a low dose of 30 mg / kg and a high dose of 100 mg / kg. Figure 4C shows a line graph indicating UMOD mRNA expression at various time points after IV injection of PPMO targeting UMOD. The compound was administered at 30 mg / kg. Figures 4D-4E are graphical representations of UMOD protein levels at various time points after IV injection of PPMO targeting UMOD. The compound was administered at 30 mg / kg. [Figure 4B] Same as above. [Figure 4C] Same as above. [Figure 4D] Same as above. [Figure 4E] Same as above.

[0022] [Figure 5A-B] Figure 5A shows a bar graph showing UMOD protein levels in the kidneys of 12-week-old UMODC39F mice, the data shown were obtained as described in Example 6. Figure 5B shows a bar graph showing UMOD protein levels in the urine of 12-week-old UMODC39F mice. Figure 5C shows a line graph showing urea levels in the serum of 0–12-week-old UMODC39F mice. Figure 5D shows a line graph showing urea levels in the urine of 0–12-week-old UMODC39F mice. Figure 5E shows a bar graph showing UMOD protein levels in the kidneys of UMODC39F mice 7 days after IV injection of PPMO targeting UMOD. The compound was administered at 100 mg / kg. [Figure 5C] Same as above. [Figure 5D] Same as above. [Figure 5E] Same as above.

[0023] [Figure 6] Figure 6 is a photograph showing co-staining of EGFP and UMOD on a kidney histological section to illustrate PPMO activity in cells expressing UMOD. The compound was administered at 80 mg / kg, as described in Example 7.

[0024] [Figure 7] Figure 7 is a photograph showing EGFP co-staining of kidney histological sections to illustrate PPMO activity in kidney cells. The compound was administered at 80 mg / kg, as described in Example 8.

[0025] [Figure 8A-B]Figure 8A is a bar graph showing the percentage change in mRNA expression in C57BL / 6 mice following saline treatment. The compound was administered at 0, 12.5, 25, 50, 100, and 150 mg / kg, as described in Example 9. The compound (Theompound) was administered at 0 (saline), 12.5, 25, 50, 100, and 150 mg / kg. Figure 8B is a bar graph showing UMOD protein levels in C57BL / 6 mice. The compound was administered at 0 (saline), 12.5, 25, 50, 100, and 150 mg / kg. Figure 8C shows PPMO concentrations in the kidney at various PPMO doses. [Figure 8C] Same as above.

[0026] [Figure 9A] Figure 9A is a bar graph showing UMOD protein levels in the kidney. Total UMOD protein in the kidney is shown. Figure 9B is a bar graph showing UMOD protein levels in urine. As described in Example 10, mice were intravenously injected with either 30 mg / kg or 100 mg / kg of PPMO once or twice, with a one-week interval between injections, and the animals were euthanized (were taken down) 7 or 14 days after injection. Total UMOD protein in the kidney is shown in Figures 9A and B. [Figure 9B] Same as above.

[0027] [Figure 10A-B] Figure 10A is a photograph showing a histological section of a kidney from an untreated 8-week-old UMODC93F mouse to demonstrate UMOD expression, as described in Example 6. Figure 10B is a photograph showing a histological section of a kidney from an untreated 1-year-old UMODC93F mouse to demonstrate UMOD expression.

[0028] [Figure 11A]Figure 11A is a bar graph showing the percentage change in mRNA expression in response to saline treatment. Figure 11B is a bar graph showing UMOD protein levels in the kidney in response to saline treatment. Figure 11C is a bar graph showing UMOD protein levels in urine in response to saline treatment. As described in Example 11, mice were intravenously injected with 100 mg / kg of PPMO, and the animals were euthanized 7, 14, 21, 28, or 42 days after injection. [Figure 11B] Same as above. [Figure 11C] Same as above.

[0029] [Figure 12A-B] Figure 12A is a bar graph showing the amount of PPMO in the kidneys of UMODC93F / WT mice after administration of PPMO. Figure 12B is a bar graph showing UMOD mRNA in the kidneys of UMODC93F / WT mice after administration of PPMO. Figures 12C-12F are diagrams of the blood chemistry panel after administration of PPMO to UMODC93F / WT mice. Figure 12C shows the blood urea nitrogen (BUN) level, Figure 12D shows the blood alkaline phosphatase (ALP) level, Figure 12E shows the blood aspartate aminotransferase (AST) level, and Figure 12F shows the blood alanine aminotransferase (ALT) level. As described in Example 12, heterozygous UMODC93F mice were intravenously injected with 30 mg / kg or 100 mg / kg of PPMO once, twice, or four times, and euthanized after 4 weeks. [Figure 12C-D] Same as above. [Figure 12E-F] Same as above.

[0030] [Figure 13]Figure 13 illustrates the sequencing results of RNA from cells or mice treated with exon 5 skipping PPMO to detect exon skipping. Imcd3 cells were treated with PPMO for 3 days as described in Example 13 and compared with untreated cells or mice. As further described in Example 13, WT, heterozygous, or homozygous UMODC93F mice were treated with intravenous injection of 100 mg / kg of PPMO, and kidneys were collected 7 days after injection. Total RNA was extracted from cells or kidney homogenates, and Ex4-6 of UMOD was PCR amplified. The amplicon pool was subjected to amplicon sequencing. Junctions showing more than 5% reads compared to WT exon junctions are observed.

[0031] [Figure 14] Figure 14 is a schematic diagram showing PPMO for exons 2, 5, 6, 8, and 9. The total amount of UMOD is measured by qRT-PCR using a primer set targeting exons 10 and 11. The amount of UMOD mRNA remaining after nonsense-mediated decay induced by exon skipping is measured.

[0032] [Figure 15A-B] Figure 15A is a bar graph showing UMOD protein in TALH cells. TALH cells were cultured in Transwell plates until confluent, as described in Example 14. Figure 15B is a bar graph showing UMOD protein in secretory medium. Figure 15C is a bar graph showing TEER (membrane integrity measurement, which reveals membrane integrity). Primary cells of the thick ascending limb of the loop of Henle (TALH) were isolated and purified from human kidney, as described in Example 14. Samples were treated with 10 μM or 30 μM PPMO 5.20 or PPMO 6.6, and after 48 hours, UMOD protein levels in cells and medium were analyzed to determine TEER. [Figure 15C] Same as above. [Modes for carrying out the invention]

[0033] Detailed explanation Antisense oligomers or pharmaceutically acceptable salts thereof are provided herein, comprising a non-natural chemical skeleton and a targeting sequence of 13 to 30 bases in length that is complementary to a target region in the pre-mRNA of the human UMOD gene (SEQ ID NO: 1). The target region may be an intron / exon junction or an internal exon region of the human UMOD gene pre-mRNA. Such antisense oligomers or pharmaceutically acceptable salts thereof are useful for treating a variety of diseases, including but not limited to chronic kidney disease (CKD) (e.g., uromodulin-associated autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD)).

[0034] Certain embodiments relate to a method for inducing exon skipping in human UMOD pre-mRNA in cells to generate immature stop codons, comprising contacting cells with an antisense oligomer of sufficient length and complementarity to specifically hybridize to a region within the human UMOD gene, such that UMOD expression is reduced. In some embodiments, the cells are those in a subject, and the method involves administering the antisense oligomer or a pharmaceutically acceptable salt to the subject. In certain embodiments, the method involves contacting cells with the antisense oligomer or a pharmaceutically acceptable salt thereof. In some embodiments, the cells, e.g., kidney cells (e.g., distal renal tubular cells) or muscle cells, are diseased cells. In some embodiments, retention of the UMOD protein in the endoplasmic reticulum (ER) is reduced. In some embodiments, the methods provided herein relate to the reduction or mitigation of ER stress, unfold protein response (UPR), mitochondrial dysfunction, protein homeostasis deficiency, autophagy in TAL cells, apoptosis of TAL epithelial cells, inflammatory lesions, fibrosis, tubular atrophy, cystic dilation, and / or progressive loss of renal function. In some embodiments, NKCC2 activity in TAL is restored, resulting in, for example, normal urate excretion.

[0035] In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof further comprises a delivery agent. In certain embodiments, the delivery agent facilitates the delivery of a therapeutic molecular payload (e.g., an antisense oligomer) to a cell. In certain embodiments, the delivery agent increases the uptake of the therapeutic molecular payload in a cell. In some embodiments, the delivery agent is a cell-permeable peptide, an antibody, an antibody fragment, an antigen fragment of an antibody, at least one ligand, a nanocarrier, or a combination thereof. In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof comprises a cell-permeable peptide, where the cell-permeable peptide is any peptide provided herein or known in the art.

[0036] In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof is bound (e.g., covalently) to or associated with a delivery agent, such as a cell-permeable peptide, an antibody, an antibody fragment, an antigenic fragment of an antibody, at least one ligand, a nanocarrier, or a combination thereof, or to a complex thereof.

[0037] Certain embodiments of this disclosure relate to a complex comprising a delivery agent (e.g., a cell-permeable peptide or antibody) bound to or associated with a molecular payload (e.g., an oligomer or a pharmaceutically acceptable salt thereof). In some embodiments, the delivery agent specifically binds to a cell surface receptor that undergoes internal migration on cells, including but not limited to kidney cells and muscle cells. In some embodiments, the molecular payload promotes the expression or activity of a functional UMOD protein. In some embodiments, the molecular payload is an oligomer, e.g., an antisense oligomer, e.g., an oligomer that causes exon skipping in mRNA expressed from a mutant UMOD-ADTKD allele. In some embodiments, the complex provided herein is useful for delivering a molecular payload that increases or restores the expression or activity of a functional UMOD. Accordingly, in some embodiments, the complex provided herein includes a delivery agent that specifically binds to a receptor on the surface of a cell (e.g., a kidney cell) for the purpose of delivering the molecular payload to the cell. In some embodiments, the complex is taken up by the cell by receptor-mediated internal migration, after which the molecular payload is released to perform its function inside the cell. For example, a complex engineered to deliver an oligomer may release the oligomer so that it can promote the expression of a functional UMOD in cells (e.g., kidney cells, muscle cells, etc.) (e.g., through an exon skipping mechanism). In some embodiments, the oligomer is released by cleavage of a covalent linker connecting the oligomer to the complex's delivery agent (e.g., endosomal cleavage).

[0038] Provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antisense oligomer or a pharmaceutically acceptable salt thereof, wherein the antisense oligomer comprises a targeting sequence of 13 to 30 bases in length that is complementary to a non-natural chemical skeleton and a target region in the pre-mRNA of the human UMOD gene (SEQ ID NO: 1). The target region may be an intron / exon junction or an internal exon region of the human UMOD gene pre-mRNA.

[0039] Methods for treating various diseases, including but not limited to chronic kidney disease (CKD) (e.g., uromodulin-associated autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD)), in subjects requiring treatment are also provided herein. I. Definition

[0040] Unless otherwise indicated, the following terms used herein have the following meanings:

[0041] The term "approximately" is understood by those skilled in the art and varies to some extent depending on the context in which it is used. When used herein in reference to measurable values, such as quantities or durations of time, the term "approximately" means to include a variation of ±10%.

[0042] The term "alkyl" in certain embodiments refers to a saturated linear or branched hydrocarbon moiety containing 1 to 6 or 1 to 8 carbon atoms, respectively. 1~6 -Examples of alkyl moieties include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, and n-hexyl moieties. 1~8 -Examples of alkyl moieties include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, and octyl moieties.

[0043] The number of carbon atoms in an alkyl substituent is determined by the prefix "C". x~y " or "C x ~C y This can be shown by , where x is the minimum number of carbon atoms in the substituent and y is the maximum number. Similarly, C x The term "chain" refers to an alkyl chain containing x carbon atoms.

[0044] The term "heteroalkyl," either by itself or in combination with other terms, means a stable linear or branched alkyl group consisting of the indicated number of carbon atoms and up to five heteroatoms selected from O, N, S, and P, unless otherwise specified, where the nitrogen, sulfur, and phosphorus atoms may be oxidized as necessary, and the nitrogen heteroatom may be quaternized as necessary. The heteroatoms may be positioned at any position in the heteroalkyl group, including between the remainder of the heteroalkyl group and the fragment to which it is bonded, and to the most distal carbon atom in the heteroalkyl group. Examples include -O-CH2-CH2-, -O-CH2-CH2-CH3, -CH2-CH2-CH2-OH, -(O-CH2-CH2)3-OH-, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, and -CH2-CH2-S(=O)-CH3. Up to three heteroatoms may be consecutive, for example, -CH2-NH-OCH3 or -CH2-CH2-SS-CH3.

[0045] When used alone or in combination with other terms, the term “aryl” means a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), unless otherwise specified, where such rings may be linked to each other in a pendant-like manner, as in biphenyl, or fused, as in naphthalene. Examples of aryl groups include phenyl, anthrasyl, and naphthyl. In various embodiments, examples of aryl groups include phenyl (i.e., C6-aryl) and biphenyl (i.e., C6-aryl). 12 Examples include -aryl groups. In some embodiments, the aryl group has 6 to 16 carbon atoms (i.e., C 6~16 -aryl). In some embodiments, the aryl group has 6 to 12 carbon atoms (i.e., C 6~12 -aryl). In some embodiments, the aryl group has six carbon atoms (i.e., C6-aryl).

[0046] As used herein, the terms "heteroaryl" or "heteroaromatic" refer to heterocyclic rings having aromatic characteristics. Heteroaryl substituents may be defined by the number of carbon atoms, for example, C 1~9 - Heteroaryl indicates the number of carbon atoms contained in the heteroaryl group, without including the number of heteroatoms. For example, C 1~9 - Heteroaryls contain an additional 1 to 4 heteroatoms. Polycyclic heteroaryls may contain one or more partially saturated rings. Non-limiting examples of heteroaryls include pyridyl, pyrazinyl, pyrimidinyl (e.g., including 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (e.g., including 2-pyrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (e.g., including 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0047] Non-limiting examples of polycyclic heterocyclic and heteroaryl compounds include indolyls (e.g., including 3-, 4-, 5-, 6-, and 7-indolyls), indolinyls, quinolyls, tetrahydroquinolyls, isoquinolyls (e.g., including 1- and 5-isoquinolyls), 1,2,3,4-tetrahydroisoquinolyls, synnolinyls, quinoxalinyls (e.g., including 2- and 5-quinoxalinyls), quinazolinyls, phthalazinyls, 1,8-naphthilidinyls, 1,4-benzodioxanyls, coumarins, dihydrocoumarins, 1,5-naphthilidinyls, benzofuryls (e.g., Examples include 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (e.g., including 3-,4-,5-,6-, and 7-benzofuryl), benzoxazolyl, benzothiazolyl (e.g., including 2-benzothiazolyl and 5-benzothiazolyl), prinyl, benzimidazolyl (e.g., including 2-benzimidazolyl), benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.

[0048] The term “protecting group” or “chemical protecting group” refers to a chemical moiety that blocks some or all of the reactive moieties of a compound, preventing such moieties from participating in chemical reactions until the protecting group is removed, such as those listed and described in TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, 3rd ed. John Wiley & Sons (1999). When different protecting groups are used, it may be beneficial that each (different) protecting group can be removed by different means. Differential removal of such protecting groups is possible by protecting groups that are cleaved under completely different reaction conditions. For example, protecting groups can be removed by acid, base, and hydrolysis. Groups such as trityl, monomethoxytrityl, dimethoxytrityl, acetal, and tert-butyldimethylsilyl can be used to protect carboxy and hydroxy reactive moieties in the presence of an amino group protected by a Cbz group, which is acid-unstable and can be removed by hydrolysis, and an Fmoc group, which is base-unstable. The carboxylic acid moiety can be blocked with a base-unstable group, such as methyl or ethyl, without limitation, and the hydroxy-reactive moiety can be blocked with an acid-unstable group, such as acetyl, or with a carbamate that is stable to both acids and bases but can be removed by hydrolysis, in the presence of an amine blocked with a tert-butylcarbamate.

[0049] The carboxylic acid and hydroxyl-reactive moieties can also be blocked with hydrolytically removable protecting groups, such as the benzyl group, while the amine group can be blocked with a base-unstable group, such as Fmoc. A particularly useful amine protecting group for the synthesis of compounds of formula (I) is trifluoroacetamide. The carboxylic acid-reactive moiety can be blocked with oxidatively removable protecting groups, such as 2,4-dimethoxybenzyl, while the coexisting amino group can be blocked with a fluoride-unstable silylcarbamate.

[0050] Allyl blocking groups are useful in the presence of acid and base protecting groups because the former are stable and can later be removed by a metal or pi-acid catalyst. For example, allyl-blocked carboxylic acids can be deprotected in a palladium(O)-catalyzed reaction in the presence of an acid-unstable t-butylcarbamate or a base-unstable acetate amine protecting group. Yet another form of protecting group is a resin to which a compound or intermediate can be bound. As long as the residue is bound to the resin, its functional group is blocked and cannot react. Once released from the resin, the functional group becomes available for reaction.

[0051] The terms “nucleic acid base,” “base pairing moiety,” “nucleic acid base pairing moiety,” or “base” refer to the heterocyclic ring portion of nucleosides, nucleotides, and / or morpholino subunits. Nucleic acid bases may be naturally occurring (e.g., uracil, thymine, adenine, cytosine, and guanine), or modified or analogous versions of these naturally occurring nucleic acid bases, for example, one or more nitrogen atoms of a nucleic acid base may be independently replaced by carbon in each instance. Exemplary analogs include hypoxanthine (the base component of the nucleoside inosine), 2,6-diaminopurine, 5-methylcytosine, C5-propynyl modified pyrimidine, and 10-(9-(aminoethoxy)phenoxadinyl) (G-clamp).

[0052] Further examples of base-pairing moieties include, but are not limited to, uracil, thymine, adenine, cytosine, guanine, and hypoxanthine (each with its amino group protected by an acyl protecting group), 2-fluorouracil, 2-fluorocytosine, 5-bromouracil, 5-iodouracil, 2,6-diaminopurine, azacytosine, pyrimidine analogs such as pseudoisocytosine and pseudouracil, and other modified nucleic acid bases such as 8-substituted purines, xanthines, or hypoxanthines (the latter two being natural degradation products). Modified nucleic acid bases disclosed in Chiu and Rana (2003) RNA 9:1034-1048, Limbach et al. (1994) Nucleic Acids Res. 22:2183-2196, and Revankar and Rao, Comprehensive Natural Products Chemistry, vol. 7, 313 are also intended, and their contents are incorporated herein by reference.

[0053] Further examples of base-pairing moieties include, but are not limited to, extended-size nucleic acid bases to which one or more benzene rings are attached. Nucleic acid base substitutions described in the Glen Research catalog (www.glenresearch.com), Krueger AT et al. (2007) Acc. Chem. Res. 40:141-150, Kool ET (2002) Acc. Chem. Res. 35:936-943, Benner SA et al. (2005) Nat. Rev. Genet. 6:553-543, Romesberg FE et al. (2003) Curr. Opin. Chem. Biol. 7:723-733, and Hirao, I (2006) Curr. Opin. Chem. Biol. 10:622-627 are intended to be useful in the synthesis of the oligomers described herein, and these contents are incorporated herein by reference. Examples of extended-size nucleic acid bases are shown below. [ka]

[0054] As used herein, the terms "-G-R6", "-G-R6-Ac", and "R6G" are interchangeable and refer to the peptide moiety conjugated to the antisense oligomer or its pharmaceutically acceptable salt. In various embodiments, "G" represents a glycine residue conjugated to "R6" by an amide bond, and each "R" represents an arginine residue conjugated to one another by an amide bond, so that "R6" means six arginine residues conjugated to one another by an amide bond. The arginine residues may have any configuration; for example, an arginine residue may be an L-arginine residue, a D-arginine residue, or a mixture of D- and L-arginine residues. "Ac" represents an acetyl group conjugated to the C-terminal R residue. In certain embodiments, "-G-R6" or "-G-R6-Ac" is conjugated to the morpholine ring nitrogen of the most 3' morpholino subunit of the PMO antisense oligomer or a pharmaceutically acceptable salt of the present disclosure. In some embodiments, "-G-R6" or "-G-R6-Ac" is conjugated to the 3' end of the antisense oligomer or a pharmaceutically acceptable salt of the present disclosure, and is given the following formula: [ka] It belongs to them.

[0055] The term “oligonucleotide” or “oligomer” refers to a compound comprising multiple linked nucleosides, nucleotides, or combinations of both nucleosides and nucleotides. In certain embodiments provided herein, the oligomer is a morpholino-oligomer. It should be understood that the term “oligonucleotide” or “oligomer” includes its pharmaceutically acceptable salts (e.g., acid addition salts, e.g., HCl salts).

[0056] As used herein, the terms “antisense oligomer” or “antisense compound” are interchangeable and refer to a sequence of subunits having bases supported on a skeletal subunit, each composed of a ribose or other pentose sugar or morpholino group, where the skeletal groups are linked by inter-subunit ligations that allow the bases in the compound to hybridize to a target sequence in a nucleic acid (typically RNA) by Watson-Crick base pairing, forming a nucleic acid:oligomer heteroduplex within the target sequence. The oligomer may have full or near-full sequence complementarity to the target sequence. Such an antisense oligomer or a pharmaceutically acceptable salt thereof may be designed to block or inhibit the translation of mRNA containing the target sequence and may be referred to as “directed” to the sequence into which it hybridizes.

[0057] Phosphothioate-modified oligomers, peptide nucleic acids (PNAs), locked nucleic acids (LNAs), 2'-fluoro-modified oligomers, 2'-O,4'-C-ethylene-bridged nucleic acids (ENAs), tricyclo-DNA, tricyclo(tricylo)-DNA phosphorothioate-modified oligomers, 2'-O-[2-(N-methylcarbamoyl)ethyl]-modified oligomers, 2'-O-methylphosphorothioate-modified oligomers, 2'-O-methoxyethyl (2'-O-MOE)-modified oligomers, and 2'-O-methyl oligomers, or combinations thereof, as well as other antisense agents known in the art, are also construed herein as types of “antisense oligomers” or “antisense compounds” (including pharmaceutically acceptable salts thereof).

[0058] Antisense oligomers or their pharmaceutically acceptable salts "specifically" hybridize to the target polynucleotide when the oligomer hybridizes to the target under physiological conditions, and the Tm is above 37°C, above 45°C, at least 50°C, typically 60°C–80°C, or higher. The "Tm" of the oligomer is the temperature at which 50% hybridizes to the complementary polynucleotide. Tm is determined under standard conditions in physiological saline, for example, as described in Miyada et al. (1987) Methods Enzymol. 154:94–107. Such hybridization may result from "near" or "substantial" complementarity, as well as complete complementarity, of the antisense oligomer or its pharmaceutically acceptable salt to the target sequence.

[0059] The terms “complementary” and “complementarity” refer to oligomers (i.e., sequences of nucleotides) that are related by base pairing rules. For example, the sequence “TGA(5'-3')” is complementary to the sequence “TCA(5'-3')”. Complementarity may be “partial” where only some of the bases of the nucleic acid match according to base pairing rules, or there may be “complete,” “total,” or “perfect” (100%) complementarity between nucleic acids. The degree of complementarity between nucleic acid strands has a significant effect on the efficiency and strength of hybridization between nucleic acid strands. In some embodiments, the oligomer may contain one or more mismatches with respect to the target RNA (e.g., six, five, four, three, two, or one mismatch). Such hybridization may occur with “near” or “substantial” complementarity of the antisense oligomer to the target sequence, as well as with complete complementarity. In some embodiments, the oligomer may hybridize to the target sequence with approximately 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% complementarity. Variations at any position within the oligomer are included. In certain embodiments, variations in the sequence near the ends of the oligomer, if present, are typically within approximately 6, 5, 4, 3, 2, or 1 nucleotide from the 5' end, 3' end, or both ends.

[0060] The terms "TEG," "EG3," or "triethylene glycol tail" refer to a triethylene glycol moiety conjugated to an oligomer, for example, at its 3' or 5' end. For example, in some embodiments, "TEG" refers to a conjugate of formula (I) where A' is, for example, formula (I): [ka] This includes things that belong to [the group / category].

[0061] Naturally occurring nucleotide bases include adenine, guanine, cytosine, thymine, and uracil, which have the signs A, G, C, T, and U, respectively. Nucleotide bases can also encompass analogues of naturally occurring nucleotide bases. Base pairing typically occurs between purine A and pyrimidine T or U, and between purine G and pyrimidine C.

[0062] Oligomers may also include nucleic acid base modifications or substitutions. Oligomers containing unnatural or substituted bases include oligomers in which one or more of the most commonly found purine or pyrimidine bases in nucleic acids are replaced with less common or unnatural bases. In some embodiments, the nucleic acid bases are covalently linked to the morpholine ring of a nucleotide or nucleoside at the N9 atom of the purine base or at the N1 atom of the pyrimidine base.

[0063] Purine bases have the general formula: [ka] As described, it contains a pyrimidine ring fused to an imidazole ring.

[0064] Adenine and guanine are the two most commonly found purine nucleic acid bases. They can be replaced with other naturally occurring purines, including but not limited to N6-methyladenine, N2-methylguanine, hypoxanthine, and 7-methylguanine.

[0065] Pyrimidine bases have the general formula: [ka] As described, it contains a 6-membered pyrimidine ring.

[0066] Cytosine, uracil, and thymine are the most commonly found pyrimidine bases in nucleic acids. These can be substituted with other naturally occurring pyrimidines, including but not limited to 5-methylcytosine, 5-hydroxymethylcytosine, pseudouracil, and 4-thiouracil. In one embodiment, the oligomers described herein contain a thymine base instead of uracil.

[0067] Other modified or substituted bases include 2,6-diaminopurine, orotic acid, agmatidine, lysidine, 2-thiopyrimidine (e.g., 2-thiouracil, 2-thiothymine), G-clamp and its derivatives, 5-substituted pyrimidine (e.g., 5-halouracil, 5-propynyluracil, 5-propynylcytosine, 5-aminomethyluracil, 5-hydroxymethyluracil, 5-aminomethylcytosine, 5-hydroxymethylcytosine, Super T), 7-deazaguanine, 7-deazaadenine, 7-aza-2,6-diaminopurine, 8-aza-7-deazaguanine, 8-aza-7-deazaadenine, 8-aza-7-deaza-2,6-diaminopurine, Super G, Super Examples include, but are not limited to, A, and N4-ethylcytosine or its derivatives, N2-cyclopentylguanine (cPent-G), N2-cyclopentyl-2-aminopurine (cPent-AP), and N2-propyl-2-aminopurine (Pr-AP), pseudouracil or its derivatives, as well as degenerate or universal bases, such as 2,6-difluorotoluene, or absent bases, such as debase sites (e.g., 1-deoxyribose, 1,2-dideoxyribose, 1-deoxy-2-O-methylribose, or pyrrolidine derivatives in which the ring oxygen is replaced by nitrogen (aza-ribose)). Pseudouracil is a naturally occurring isomerized version of uracil that has a C-glycoside instead of the usual N-glycoside, as in uridine.

[0068] In some embodiments, modified or substituted nucleic acid bases are useful in facilitating the purification of antisense oligomers. For example, in certain embodiments, an antisense oligomer may contain three or more (e.g., three, four, five, six, or more) consecutive guanine bases. In certain antisense oligomers, a sequence of three or more consecutive guanine bases can lead to oligomer aggregation, complicating purification. In such antisense oligomers, one or more of the consecutive guanine bases may be substituted with hypoxanthine. Substitution of one or more guanine residues in a sequence of three or more consecutive guanine residues with hypoxanthine can reduce antisense oligomer aggregation, thereby facilitating purification.

[0069] The oligomers provided herein are synthetic and do not contain antisense compositions of biological origin. The molecules of this disclosure may also be mixed with, encapsulated with, conjugated with, or otherwise associated with other molecules, molecular structures, or mixtures of compounds, such as liposomes, receptor targeting molecules, oral, rectal, topical, or other formulations, to aid in uptake, distribution, or absorption, or a combination thereof.

[0070] As used herein, “nucleic acid analog” refers to nucleic acid molecules that do not exist in nature. Nucleic acids are polymers of nucleotide subunits linked together in a linear structure. Each nucleotide consists of a nitrogen-containing aromatic base bonded to a pentose sugar, which is then bonded to a phosphate group. The consecutive phosphate groups are linked to each other through phosphodiester bonds, forming a polymer. Two common forms of naturally occurring nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). One end of the chain holds a free phosphate group bonded to the 5'-carbon atom of the sugar moiety and is referred to as the 5' end of the molecule. The other end has a free hydroxyl (-OH) group at the 3'-carbon atom of the sugar moiety and is referred to as the 3' end of the molecule. Nucleic acid analogs may include one or more naturally occurring nucleic acid bases, sugars, and / or internucleotide links, such as phosphorodiamidate morpholino oligomers (PMOs). As disclosed herein, in certain embodiments, the “nucleic acid analog” is a PMO, and in certain embodiments, the “nucleic acid analog” is a positively charged cationic PMO.

[0071] A “morpholino oligomer” refers to a polymer molecule having a base-supporting backbone that can hydrogen-bond to a typical polynucleotide, where the polymer lacks a pentose sugar backbone moiety, more specifically a ribose backbone linked by phosphodiester bonds typical of nucleotides and nucleosides, but instead contains a ring nitrogen through which coupling occurs. An exemplary “morpholino” oligomer contains a morpholino subunit structure linked to one another by phosphoramide or phosphorodiaamide linkages, where the morpholino nitrogen of one subunit is bonded to the 5' outer carbon of an adjacent subunit, and each subunit contains a purine or pyrimidine base-pairing moiety that is effective for binding to a base in the polynucleotide by base-specific hydrogen bonding. Morpholino oligomers (including antisense oligomers) are described in detail, for example, U.S. Patents 5,034,506, 5,142,047, 5,166,315, 5,185,444, 5,217,866, 5,506,337, 5,521,063, 5,698,685, 8,076,476, and 8,299,206, as well as PCT Publication WO2009 / 064471, each of which is incorporated herein by reference in its entirety.

[0072] Preferred morpholino oligomers are phosphorodiamidate-linked morpholino oligomers, referred to herein as PMOs. Such oligomers consist of morpholino subunit structures such as those shown below: [ka] In the formula, X is NH2, NHR, or NR2 (R is a lower alkyl (e.g., methyl, ethyl, propyl, etc.)), Y1 is O, Z is O, and Pi and Pj are purine or pyrimidine base-pairing moieties effective for binding to bases in the polynucleotide by base-specific hydrogen bonding. Structures having alternative phosphorodiamidate linkages are also contemplated herein, in the formula, X is a lower alkoxy, e.g., methoxy or ethoxy, Y1 is NH or NR, R is a lower alkyl, and Z is O.

[0073] A typical PMO is one in which the inter-subunit connections are as shown in Table 1 (A1). [Table 1-1] [Table 1-2]

[0074] A "phosphoramide" group contains phosphorus with three oxygen atoms bonded to it and one nitrogen atom bonded to it, while a "phosphodiamidate" group contains phosphorus with two oxygen atoms bonded to it and two nitrogen atoms bonded to it. Representative examples of phosphorodiamidates are shown below: [ka] In the formula, each P in is independently selected from H, a nucleic acid base, and a nucleic acid base functionalized with a chemical protecting group, where the nucleic acid base, independently for each occurrence, includes pyridine, pyrimidine, triazinane, purine, or deaza-purine, and n is an integer from 6 to 38 (i.e., n is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, or 38). In certain embodiments, n is an integer from 11 to 28. The ring nitrogen of the subunit at the 3' end of the PMO may be capped with a capping group, e.g., acetyl, or uncapped with free hydrogen.

[0075] In the uncharged or modified inter-subunit linkages of the antisense oligomers described herein, one nitrogen is always pendanted to the skeletal chain. The second nitrogen in the phosphorodiamidate linkage is typically the ring nitrogen in the morpholino ring structure.

[0076] PMOs are water-soluble, uncharged, or substantially uncharged antisense molecules that inhibit gene expression by preventing the binding or progression of components in splicing or translation mechanisms. PMOs have also been shown to inhibit or block viral replication (Stein, Skilling et al. 2001; McCaffrey, Meuse et al. 2003) and are highly resistant to enzymatic digestion (Hudziak, Barofsky et al. 1996). PMO has demonstrated high antisense specificity and efficacy in vitro in cell-free and cell culture models (Stein, Foster et al. 1997, Summerton and Weller 1997), in vivo in zebrafish, frog, and sea urchin embryos (Heasman, Kofron et al. 2000, Naseviius and Ekker 2000), and in adult animal models, such as rats, mice, rabbits, dogs, and pigs (see, for example, Arora and Iversen 2000, Qin, Taylor et al. 2000, Iversen 2001, Kipshidze, Keane et al. 2001, Dev 2002, Dev, Oldenkamp et al. 2002, Kipshidze, Kim et al. 2002, and Ricker, Mata et al. 2002).

[0077] Antisense PMO oligomers are taken up by cells and have been shown to be consistently effective in vivo with fewer nonspecific effects than other widely used antisense oligomers (see, e.g., P. Iversen, "Phosphoramidite Morpholino Oligomers," in Antisense Drug Technology, ST Crooke, ed., Marcel Dekker, Inc., New York, 2001). Conjugation of PMOs to arginine-rich peptides has been shown to increase their intracellular uptake (see, e.g., U.S. Patent No. 7,468,418, which is incorporated herein by reference in its entirety).

[0078] As used herein, “charged,” “uncharged,” “cationic,” and “anionic” refer to the dominant state of a chemical moiety at a nearly neutral pH, for example, around 6–8. For example, the term may refer to the dominant state of a chemical moiety at a physiological pH, i.e., around 7.4.

[0079] "Cationic PMO" or "PMO+" refers to a phosphorodiamidate morpholino oligomer containing any number of (1-piperazino)phosphinylideneoxy, (1-(4-(ω-guanidino-alkanoyl))-piperazino)phosphinylideneoxy linkages (A2 and A3, see Table 1) as previously described (see, for example, PCT Publication WO2008 / 036127, which is incorporated herein by reference in its entirety).

[0080] The “backbone” of an antisense oligomer (e.g., an uncharged oligomer analog) refers to the structure supporting the base pairing moiety. For example, for a morpholino oligomer, as described herein, the “backbone” includes a morpholino ring structure connected by intersubunit linkages (e.g., phosphorus-containing linkages). A “substantially uncharged backbone” refers to the backbone of an oligomer analog in which less than 50% of the intersubunit linkages are charged at near-neutral pH. For example, a substantially uncharged backbone may include intersubunit linkages that are charged at near-neutral pH, such as less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or even 0%. In some embodiments, a substantially uncharged skeleton includes at most one charged (at physiological pH) subunit linkage for every four uncharged (at physiological pH) linkages, at most one charged (at physiological pH) subunit linkage for every eight uncharged linkages, or at most one charged (at physiological pH) subunit linkage for every sixteen uncharged linkages. In some embodiments, the nucleic acid analogs described herein are entirely uncharged. In certain embodiments, the antisense oligomers disclosed herein or their pharmaceutically acceptable salts include phosphorothioate linkages, phosphodiester linkages, N-(1,3-dimethylimidazolidined-2-yridenyl)phosphoamide linkages (n001), and internucleotide linkages (i.e., skeletons) selected from combinations thereof. In certain embodiments of the oligomers disclosed herein, the linking phosphorus of each phosphorothioate linkage is Sp, and the linking phosphorus of each n001 linkage is Rp. In some embodiments, the oligomers disclosed herein further comprise certain chemical moieties, such as 2'-F, 2'-OMe, and the like.

[0081] In certain embodiments, the compounds described herein comprise or consist of an oligomer or a pharmaceutically acceptable salt thereof containing a targeting (base) sequence complementary to the target nucleic acid. In certain embodiments, the target nucleic acid is an endogenous RNA molecule. In certain embodiments, the target nucleic acid codes for a protein. In certain embodiments, the target nucleic acid is non-coding. In certain such embodiments, the target nucleic acid is selected from mRNA and pre-mRNA, which include introns, exons, intron / exon junctions, and untranslated regions. In certain embodiments, the target RNA is mRNA. In certain embodiments, the target nucleic acid is pre-mRNA. In certain embodiments, the target region is entirely within an exon. In certain embodiments, the target region is entirely within an intron. In certain embodiments, the target region spans an intron / exon junction. In certain embodiments, at least 50% of the target region is within an intron.

[0082] The term "targeted base sequence" or "targeted sequence" refers to a (nucleic acid base) sequence in an antisense oligomer that is complementary or substantially complementary to a target nucleic acid. The entire sequence of the oligomer compound, or only a portion thereof, may be complementary to the target sequence.

[0083] The “target region” refers to a sequence in a nucleic acid that is targeted by the targeting sequence of an antisense oligomer and is therefore complementary, substantially complementary, or partially complementary to it. The entire target region sequence, or only a portion thereof, may be complementary to the targeting sequence of the oligomeric compound described herein. In certain embodiments, multiple antisense compounds are directed to a single target region. In certain embodiments, a naming system based on gene, species, exon number, and annealing coordinates is used herein to identify or indicate the target region or annealing coordinate of the targeted nucleic acid (e.g., a nucleic acid transcript), as follows: G SpZA / D (±X±Y) Here, G is the gene name, Sp stands for species (for example, "H" for humans, "M" for mice), Z is the exon number, A / D is selected from acceptor (A) and donor (D). The "-" symbol indicates the position of an intron. The sign "+" indicates the position of the exon. X is the first 5' base position relative to site A or D. Y is the position of the first 3' base relative to the A or D site.

[0084] The nomenclature begins with the name of the transcript (e.g., uromodulin, UMOD), followed by the species of the target mRNA (e.g., H: human or M: mouse), the target exon number of the specified transcript, and the designation of the acceptor (A) or donor (D) site. Annealing coordinates are indicated by brackets within the pre-mRNA transcript. Intron bases are designated with a negative prefix (-), and exon positions are designated with a positive sign (+). Annealing coordinates are the positions of bases compared to the bases relative to the acceptor or donor site of a reference transcript as shown by the National Center for Biotechnology Information and the Ensembl genome browser 96. See, for example, international application WO2006 / 000057, Aung-Htut, et al. (2019) Int. J. Mol. Sci. 20:5030, and Mann, et al. (2002) J Gene Med. 4:644.

[0085] For example, the fully exon annealing coordinate represented by UMOD H2A(+108+127) indicates a region within the range of nucleotides 108-127, measured from the 5' end of exon 2 (e.g., exon 2 of the human UMOD gene pre-mRNA) (i.e., the region within the range of nucleotides 108-127, measured from the start of exon 2 at the 5' end). The nearest splice site is the acceptor, and therefore these coordinates are preceded by "A".

[0086] As another example, UMOD H5D(+18-2) represents the target exon donor splice site, specifically the last 18 bases of the exon and the first two bases of the intron (i.e., the target region ranging from the 18th nucleotide of exon 5, measured from the 3' end of exon 5 (e.g., human exon 5 of human UMOD gene pre-mRNA), to the 2nd nucleotide of intron 5, measured from the 3' end of exon 5). The nearest splice site is the donor, and therefore these coordinates are preceded by a "D".

[0087] As another example, UMOD H5A(-11+9) represents the last 11 bases of the intron preceding the target exon 5 and the first 9 bases of the target exon 5 (i.e., the target region ranging from the 11th nucleotide of intron 4, measured from the 5' end of exon 5 (e.g., human exon 5 of the human UMOD gene pre-mRNA), to the 9th nucleotide of exon 5, measured from the 5' end of exon 5). The nearest splice site is the acceptor, and therefore these coordinates are preceded by "A".

[0088] The terms "peptide" and "polypeptide" refer to compounds containing multiple linked amino acids. In certain embodiments, the peptides provided herein are cell-permeable peptides (CPPs). In certain embodiments, the polypeptides provided herein are antibodies or fragments thereof.

[0089] As used herein, “cell-permeable peptide” (CPP) or “carrier peptide” is a relatively short peptide that facilitates the uptake of PMO by cells, thereby enabling the delivery of PMO into the cell interior (cytoplasm). In some embodiments, the CPP or carrier peptide is about 4 to about 40 amino acids long. The length of the carrier peptide is not particularly limited and varies in different embodiments. In some embodiments, the carrier peptide contains about 4 to about 35 amino acid subunits. In other embodiments, the carrier peptide contains about 4 to about 30, about 4 to about 25, about 4 to about 20, about 4 to about 15, about 4 to about 10, or about 4 to about 8 amino acid subunits. In various embodiments, the CPP disclosed herein contains an arginine-rich peptide, as further described below. In some embodiments, the CPP or carrier peptide is at least about 4 amino acids long. In some embodiments, the CPP or carrier peptide is up to about 40 amino acids long. In some embodiments, the carrier peptide contains 4 amino acids. In some embodiments, the carrier peptide contains 5 amino acids. In some embodiments, the carrier peptide contains 6 amino acids. In some embodiments, the carrier peptide contains 7 amino acids. In some embodiments, the carrier peptide contains 8 amino acids. In some embodiments, the carrier peptide contains 9 amino acids. In some embodiments, the carrier peptide contains 10 amino acids. In some embodiments, the carrier peptide contains 11 amino acids. In some embodiments, the carrier peptide contains 12 amino acids. In some embodiments, the carrier peptide contains 13 amino acids. In some embodiments, the carrier peptide contains 14 amino acids. In some embodiments, the carrier peptide contains 15 amino acids. In some embodiments, the carrier peptide contains 16 amino acids. In some embodiments, the carrier peptide contains 17 amino acids. In some embodiments, the carrier peptide contains 18 amino acids. In some embodiments, the carrier peptide contains 19 amino acids. In some embodiments, the carrier peptide contains 20 amino acids. In some embodiments, the carrier peptide contains 21 amino acids.In some embodiments, the carrier peptide contains 22 amino acids. In some embodiments, the carrier peptide contains 23 amino acids. In some embodiments, the carrier peptide contains 24 amino acids. In some embodiments, the carrier peptide contains 25 amino acids. In some embodiments, the carrier peptide contains 26 amino acids. In some embodiments, the carrier peptide contains 27 amino acids. In some embodiments, the carrier peptide contains 28 amino acids. In some embodiments, the carrier peptide contains 29 amino acids. In some embodiments, the carrier peptide contains 30 amino acids. In some embodiments, the carrier peptide contains 31 amino acids. In some embodiments, the carrier peptide contains 32 amino acids. In some embodiments, the carrier peptide contains 33 amino acids. In some embodiments, the carrier peptide contains 34 amino acids. In some embodiments, the carrier peptide contains 35 amino acids. In some embodiments, the carrier peptide contains 36 amino acids. In some embodiments, the carrier peptide contains 37 amino acids. In some embodiments, the carrier peptide contains 38 amino acids. In some embodiments, the carrier peptide contains 39 amino acids. In some embodiments, the carrier peptide contains 40 amino acids.

[0090] As used herein, “peptide conjugate phosphorodiamidate-linked morpholino oligomer” or “PPMO” refers to a PMO covalently linked to a peptide, such as a cell-permeable peptide (CPP) or a carrier peptide. The cell-permeable peptide facilitates the uptake of PMO by cells, thereby delivering PMO into the cell interior (cytoplasm). Depending on its amino acid sequence, the CPP may be effective as a whole, or it may be specifically or selectively effective for PMO delivery to a particular type of cell(s). PMO and CPP are typically linked at their ends, for example, the C-terminal end of the CPP may be linked to the 5' end of the PMO, or the 3' end of the PMO may be linked to the N-terminal end of the CPP. PPMO may include uncharged PMO, charged (e.g., cationic) PMO, and mixtures thereof. In some embodiments, the linking portion of the conjugate described herein may be cleaved to release PPMO.

[0091] The carrier peptide can be linked to the nucleic acid analog either directly or via a linker as needed, for example, one or more additional naturally occurring amino acids, such as cysteine ​​(C), glycine (G), or proline (P), or additional amino acid analogs, such as 6-aminohexanoic acid (X) (also represented as Ahx or α) and beta-alanine (B) (also represented as β-Ala or β). Other linking moieties known in the art may also be used.

[0092] An "amino acid subunit" is generally an α-amino acid residue (-CO-CHR-NH-), but may also be a β- or other amino acid residue (e.g., -CO-CH2CHR-NH-), where R is the amino acid side chain.

[0093] The term "naturally occurring amino acids" refers to amino acids found in nature that are present in proteins, such as alanine (A), cysteine ​​(C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), serine (S), threonine (T), valine (V), tryptophan (W), and tyrosine (Y). The term "unnatural amino acids" refers to amino acids that are not found in nature that are not present in proteins, such as beta-alanine (β-Ala, B, or β) and 6-aminohexanoic acid (X, Ahx, or α).

[0094] If a drug can enter a cell by a mechanism other than passive diffusion across the cell membrane, the drug is "actively taken up by mammalian cells." Drugs can be transported by "active transport," which refers to the transport of drugs across mammalian cell membranes, for example, by ATP-dependent transport mechanisms, or by "facilitated transport," which refers to the transport of antisense drugs across the cell membrane by transport mechanisms that require the drug to bind to a transport protein, thereby facilitating the transmembrane passage of the bound drug.

[0095] As used herein, “effective dose” means any amount of a substance that is sufficient to achieve the desired biological outcome. “Therapeutic effective dose” means any amount of a substance that is sufficient to achieve the desired therapeutic outcome.

[0096] As used herein, “Subject” refers to a mammal, which may include mice, rats, hamsters, guinea pigs, rabbits, goats, sheep, cats, dogs, pigs, cattle, horses, non-human primates, such as monkeys, or humans. In certain embodiments, the subject is a human.

[0097] A “treatment” of an individual (e.g., a mammal, e.g., a human) or cell is any type of intervention used to alter the natural course of the individual or cell. Treatment includes, but is not limited to, the administration of a pharmaceutical composition, and treatment may be performed prophylactically or after the onset of a pathological event or contact with a virulence factor. II. Peptide-Oligomers

[0098] Antisense oligomers or pharmaceutically acceptable salts thereof comprising a non-natural chemical skeleton and a targeting sequence of 13 to 30 bases in length complementary to a target region in the pre-mRNA of the human uromodulin (UMOD) gene (SEQ ID NO: 1) are provided herein. In some embodiments, the target region is an intron / exon junction or an exon region of the human UMOD gene pre-mRNA. In other embodiments, the target region is an exon region of the human UMOD gene pre-mRNA.

[0099] In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 30 bases (subunits). In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of at least 13 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of up to 30 bases.

[0100] In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 29 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 28 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 27 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 26 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 25 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 24 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 23 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 22 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 21 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 20 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 19 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 18 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 17 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 16 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 15 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 to 14 bases.

[0101] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 29 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 28 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 27 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 26 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 25 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 24 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 23 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 22 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 21 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 20 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 19 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 18 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 17 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 16 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 to 15 bases.

[0102] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 to 29 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 to 28 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 to 27 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 to 26 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 to 25 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 to 24 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 to 23 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 to 22 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 to 21 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 to 20 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 to 19 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 to 18 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 to 17 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 to 16 bases.

[0103] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 16 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 16 to 29 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 16 to 28 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 16 to 27 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 16 to 26 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 16 to 25 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 16 to 24 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 16 to 23 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 16 to 22 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 16 to 21 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 16 to 20 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 16 to 19 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 16 to 18 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 16 to 17 bases.

[0104] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 17 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 17 to 29 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 17 to 28 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 17 to 27 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 17 to 26 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 17 to 25 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 17 to 24 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 17 to 23 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 17 to 22 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 17 to 21 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 17 to 20 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 17 to 19 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 17 to 18 bases.

[0105] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 18 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 18 to 29 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 18 to 28 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 18 to 27 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 18 to 26 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 18 to 25 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 18 to 24 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 18 to 23 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 18 to 22 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 18 to 21 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 18 to 20 bases. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 18 to 19 bases.

[0106] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 19 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 19 to 29 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 19 to 28 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 19 to 27 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 19 to 26 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 19 to 25 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 19 to 24 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 19 to 23 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 19 to 22 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 19 to 21 bases. In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 19 to 20 bases.

[0107] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 20 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 20 to 29 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 20 to 28 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 20 to 27 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 20 to 26 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 20 to 25 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 20 to 24 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 20 to 23 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 20 to 22 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 20 to 21 bases.

[0108] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 21 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 21 to 29 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 21 to 28 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 21 to 27 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 21 to 26 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 21 to 25 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 21 to 24 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 21 to 23 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 21 to 22 bases.

[0109] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 22 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 22 to 29 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 22 to 28 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 22 to 27 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 22 to 26 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 22 to 25 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 22 to 24 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 22 to 23 bases.

[0110] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 23 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 23 to 29 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 23 to 28 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 23 to 27 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 23 to 26 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 23 to 25 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 23 to 24 bases.

[0111] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 24 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 24 to 29 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 24 to 28 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 24 to 27 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 24 to 26 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 24 to 25 bases.

[0112] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 25 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 25 to 29 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 25 to 28 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 25 to 27 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 25 to 26 bases.

[0113] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 26 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 26 to 29 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 26 to 28 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 26 to 27 bases.

[0114] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 27 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 27 to 29 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 27 to 28 bases.

[0115] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 28 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 28 to 29 bases. In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 28 to 30 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 29 to 30 bases.

[0116] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 13 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 14 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 15 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 16 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 17 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 18 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 19 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 20 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 21 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a length of 22 bases. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a base length of 23. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a base length of 24. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a base length of 25. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a base length of 26. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a base length of 27. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a base length of 28. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a base length of 29. In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a base length of 30.

[0117] In one embodiment, the antisense oligomer contains a targeting sequence complementary to a target region within the pre-mRNA of the human UMOD gene. In one particular embodiment, the target region is an intron / exon junction or an internal exon region of exon 2 (SEQ ID NO: 2), exon 5 (SEQ ID NO: 3), exon 6 (SEQ ID NO: 4), exon 8 (SEQ ID NO: 5), or exon 9 (SEQ ID NO: 6).

[0118] In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof is UMOD H2A(-25-1), UMOD H2A(-18+2), UMOD H2A(-17+3), UMOD H2A(-16+4), UMOD H2A(-15+10), UMOD H2A(+1+25), UMOD H2A(+26+50), UMOD H2A(+51+75), UMOD H2A(+85+104), UMOD H2A(+86+105), UMOD H2A(+95+119), UMOD H2A(+96+115), UMOD H2A(+98+117), UMOD H2A(+101+125), UMOD H2A(+108+127), UMOD H2A(+109+128), UMOD H2A(+110+129), UMOD H2A(+113+132), UMOD H2A(+114+133), UMOD H2A(+118+137), UMOD H2A(+126+150), UMOD H2A(+151+175), UMOD H2D(+15-10), UMOD H5A(-15+5), UMOD H5A(-14+6), UMOD H5A(-11+9), UMOD H5A(-10+10), UMOD H5A(-9+11), UMOD H5A(+50+67), UMOD H5A(+51+75), UMOD H5A(+52+69), UMOD H5A(+76+100), UMOD H5A(+78+95), UMOD H5A(+80+97), UMOD H5A(+82+99), UMOD H5A(+85+102), UMOD H5A(+86+103), UMOD H5A(+91+108), UMOD H5A(+126+150), UMOD H5A(+152+171), UMOD H5A(+153+172), UMOD H5A(+154+173), UMOD H5D(+18-2), UMOD H5D(+17-3), UMOD H5D(+16-4), UMOD H5D(+14-6), UMOD H5D(+13-7), UMOD H5D(+12-8), UMOD H5D(+11-9), UMOD H5D(+10-10), UMOD H6A(+1+25), UMOD H6A(+26+50), UMOD H6A(+48+67), UMOD H6A(+49+68), UMOD H6A(+50+69), UMODH6A(+58+77)、UMOD H6A(+59+78)、UMOD H6A(+60+79)、UMOD H6A(+76+100)、UMOD H6A(+79+98)、UMOD H6A(+101+125)、UMOD H6A(+101+120)、UMOD H6A(+110+129)、UMOD H6A(+111+130)、UMOD H6A(+112+131)、UMOD H6A(+113+132)、UMOD H6A(+119+138)、UMOD H6A(+120+139)、UMOD H6A(+121+140)、UMOD H6A(+122+141)、UMOD H6A(+123+142)、UMOD H6A(+124+143)、UMOD H6A(+130+149)、UMOD H6D(+24-1)、UMOD H6D(+15-5)、UMOD H6D(+14-6)、UMOD H8A(-2+23)、UMOD H8A(+26+50)、UMOD H8A(+51+75)、UMOD H8A(+60+79)、UMOD H8A(+61+80)、UMOD H8A(+62+81)、UMOD H8A(+63+82)、UMOD H8A(+68+87)、UMOD H8A(+69+88)、UMOD H8A(+70+89)、UMOD H8A(+76+95)、UMOD H8A(+76+100)、UMOD H8A(+77+96)、UMOD H8A(+78+97)、UMOD H8A(+79+98)、UMOD H8A(+80+99)、UMOD H8A(+81+100)、UMOD H8A(+82+101)、UMOD H8A(+83+102)、UMOD H8A(+86+105)、UMOD H8A(+94+113)、UMOD H8A(+95+114)、UMOD H8A(+96+115)、UMOD H8A(+101+125)、UMOD H8A(+102+121)、UMOD H8A(+103+122)、UMOD H8A(+104+123)、UMOD H8A(+105+124)、UMOD H8A(+120+139)、UMOD H8A(+121+140)、UMOD H8A(+122+141)、UMOD H8A(+126+150)、UMOD H8A(+128+147)、UMOD H8A(+129+148)、UMODIt has a target region selected from H8A (+133+152), UMOD H8A (+134+153), UMOD H8A (+139+158), UMOD H8D (+19-1), UMOD H8D (+12-13), UMOD H9A (-5+20), UMOD H9A (+1+25), UMOD H9A (+51+75), and UMOD H9D (+7-18).

[0119] In some embodiments, the target region is UMOD H2A(-25-1). In some embodiments, the target region is UMOD H2A(-18+2). In some embodiments, the target region is UMOD H2A(-17+3). In some embodiments, the target region is UMOD H2A(-16+4). In some embodiments, the target region is UMOD H2A(-15+10). In some embodiments, the target region is UMOD H2A(+1+25). In some embodiments, the target region is UMOD H2A(+26+50). In some embodiments, the target region is UMOD H2A(+51+75). In some embodiments, the target region is UMOD H2A(+85+104). In some embodiments, the target region is UMOD H2A(+86+105). In some embodiments, the target region is UMOD H2A(+95+119). UMOD H2A(+96+115). In some embodiments, the target region is UMOD H2A(+98+117). In some embodiments, the target region is UMOD H2A(+101+125). In some embodiments, the target region is UMOD H2A(+108+127). In some embodiments, the target region is UMOD H2A(+109+128). In some embodiments, the target region is UMOD H2A(+110+129). In some embodiments, the target region is UMOD H2A(+113+132). In some embodiments, the target region is UMOD H2A(+114+133). In some embodiments, the target region is UMOD H2A(+118+137). In some embodiments, the target region is UMOD H2A(+126+150). In some embodiments, the target region is UMOD H2A(+151+175). In some embodiments, the target region is UMOD H2D(+15-10). In some embodiments, the target region is UMOD H5A(-15+5). In some embodiments, the target region is UMOD H5A(-14+6). In some embodiments, the target region is UMOD H5A(-11+9). In some embodiments, the target region is UMOD H5A(-10+10).In some embodiments, the target region is UMOD H5A(-9+11). In some embodiments, the target region is UMOD H5A(+50+67). In some embodiments, the target region is UMOD H5A(+51+75). In some embodiments, the target region is UMOD H5A(+52+69). In some embodiments, the target region is UMOD H5A(+76+100). In some embodiments, the target region is UMOD H5A(+78+95). In some embodiments, the target region is UMOD H5A(+80+97). In some embodiments, the target region is UMOD H5A(+82+99). In some embodiments, the target region is UMOD H5A(+85+102). In some embodiments, the target region is UMOD H5A(+86+103). In some embodiments, the target region is UMOD H5A(+91+108). In some embodiments, the target region is UMOD H5A(+126+150). In some embodiments, the target region is UMOD H5A(+152+171). In some embodiments, the target region is UMOD H5A(+153+172). In some embodiments, the target region is UMOD H5A(+154+173). In some embodiments, the target region is UMOD H5D(+18-2). In some embodiments, the target region is UMOD H5D(+17-3). In some embodiments, the target region is UMOD H5D(+16-4). In some embodiments, the target region is UMOD H5D(+14-6). In some embodiments, the target region is UMOD H5D(+13-7). In some embodiments, the target region is UMOD H5D(+12-8). UMOD H5D(+11-9). In some embodiments, the target region is UMOD H5D (+10-10). In some embodiments, the target region is UMOD H6A (+1+25). In some embodiments, the target region is UMOD H6A (+26+50). In some embodiments, the target region is UMOD H6A (+48+67). In some embodiments, the target region is UMOD H6A (+49+68). In some embodiments, the target region is UMOD H6A (+50+69).In some embodiments, the target region is UMOD H6A(+58+77). In some embodiments, the target region is UMOD H6A(+59+78). In some embodiments, the target region is UMOD H6A(+60+79). In some embodiments, the target region is UMOD H6A(+76+100). In some embodiments, the target region is UMOD H6A(+79+98). In some embodiments, the target region is UMOD H6A(+101+125). In some embodiments, the target region is UMOD H6A(+101+120). In some embodiments, the target region is UMOD H6A(+110+129). In some embodiments, the target region is UMOD H6A(+111+130). In some embodiments, the target region is UMOD H6A(+112+131). In some embodiments, the target region is UMOD H6A(+113+132). In some embodiments, the target region is UMOD H6A(+119+138). In some embodiments, the target region is UMOD H6A(+120+139). In some embodiments, the target region is UMOD H6A(+121+140). In some embodiments, the target region is UMOD H6A(+122+141). In some embodiments, the target region is UMOD H6A(+123+142). In some embodiments, the target region is UMOD H6A(+124+143). In some embodiments, the target region is UMOD H6A(+130+149). In some embodiments, the target region is UMOD H6D(+24-1). In some embodiments, the target region is UMOD H6D(+15-5). In some embodiments, the target region is UMOD H6D(+14-6). In some embodiments, the target region is UMOD H8A(-2+23). In some embodiments, the target region is UMOD H8A(+26+50). In some embodiments, the target region is UMOD H8A(+51+75). In some embodiments, the target region is UMOD H8A(+60+79). In some embodiments, the target region is UMOD H8A(+61+80). In some embodiments, the target region is UMOD H8A(+62+81).In some embodiments, the target region is UMOD H8A(+63+82). In some embodiments, the target region is UMOD H8A(+68+87). In some embodiments, the target region is UMOD H8A(+69+88). In some embodiments, the target region is UMOD H8A(+70+89). In some embodiments, the target region is UMOD H8A(+76+95). In some embodiments, the target region is UMOD H8A(+76+100). In some embodiments, the target region is UMOD H8A(+77+96). In some embodiments, the target region is UMOD H8A(+78+97). In some embodiments, the target region is UMOD H8A(+79+98). In some embodiments, the target region is UMOD H8A(+80+99). In some embodiments, the target region is UMOD H8A(+81+100). In some embodiments, the target region is UMOD H8A(+82+101). In some embodiments, the target region is UMOD H8A(+83+102). In some embodiments, the target region is UMOD H8A(+86+105). In some embodiments, the target region is UMOD H8A(+94+113). In some embodiments, the target region is UMOD H8A(+95+114). In some embodiments, the target region is UMOD H8A(+96+115). In some embodiments, the target region is UMOD H8A(+101+125). In some embodiments, the target region is UMOD H8A(+102+121). In some embodiments, the target region is UMOD H8A(+103+122). In some embodiments, the target region is UMOD H8A(+104+123). In some embodiments, the target region is UMOD H8A(+105+124). In some embodiments, the target region is UMOD H8A(+120+139). In some embodiments, the target region is UMOD H8A(+121+140). In some embodiments, the target region is UMOD H8A(+122+141). In some embodiments, the target region is UMOD H8A(+126+150). In some embodiments, the target region is UMOD H8A(+128+147).In some embodiments, the target region is UMOD H8A(+129+148). In some embodiments, the target region is UMOD H8A(+133+152). In some embodiments, the target region is UMOD H8A(+134+153). In some embodiments, the target region is UMOD H8A(+139+158). In some embodiments, the target region is UMOD H8D(+19-1). In some embodiments, the target region is UMOD H8D(+12-13). In some embodiments, the target region is UMOD H9A(-5+20). In some embodiments, the target region is UMOD H9A(+1+25). In some embodiments, the target region is UMOD H9A(+51+75). In some embodiments, the target region is UMOD H9D(+7-18).

[0120] In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof is [ka] [ka] [ka] [ka] It has a targeting sequence that includes a sequence selected from the following.

[0121] In some embodiments, the targeting sequence is sequence number 7. In some embodiments, the targeting sequence is sequence number 8. In some embodiments, the targeting sequence is sequence number 9. In some embodiments, the targeting sequence is sequence number 10. In some embodiments, the targeting sequence is sequence number 11. In some embodiments, the targeting sequence is sequence number 12. In some embodiments, the targeting sequence is sequence number 13. In some embodiments, the targeting sequence is sequence number 14. In some embodiments, the targeting sequence is sequence number 15. In some embodiments, the targeting sequence is sequence number 16. In some embodiments, the targeting sequence is sequence number 17. In some embodiments, the targeting sequence is sequence number 18. In some embodiments, the targeting sequence is sequence number 19. In some embodiments, the targeting sequence is sequence number 20. In some embodiments, the targeting sequence is sequence number 21. In some embodiments, the targeting sequence is sequence number 22. In some embodiments, the targeting sequence is sequence number 23. In some embodiments, the targeting sequence is sequence number 24. In some embodiments, the targeting sequence is sequence number 25. In some embodiments, the targeting sequence is sequence number 26. In some embodiments, the targeting sequence is sequence number 27. In some embodiments, the targeting sequence is sequence number 28. In some embodiments, the targeting sequence is sequence number 29. In some embodiments, the targeting sequence is sequence number 30. In some embodiments, the targeting sequence is sequence number 31. In some embodiments, the targeting sequence is sequence number 32. In some embodiments, the targeting sequence is sequence number 33. In some embodiments, the targeting sequence is sequence number 34. In some embodiments, the targeting sequence is sequence number 35. In some embodiments, the targeting sequence is sequence number 36. In some embodiments, the targeting sequence is sequence number 37. In some embodiments, the targeting sequence is sequence number 38. In some embodiments, the targeting sequence is sequence number 39. In some embodiments, the targeting sequence is sequence number 40. In some embodiments, the targeting sequence is sequence number 41. In some embodiments, the targeting sequence is sequence number 42. In some embodiments, the targeting sequence is sequence number 43.In some embodiments, the targeting sequence is sequence number 44. In some embodiments, the targeting sequence is sequence number 45. In some embodiments, the targeting sequence is sequence number 46. In some embodiments, the targeting sequence is sequence number 47. In some embodiments, the targeting sequence is sequence number 48. In some embodiments, the targeting sequence is sequence number 49. In some embodiments, the targeting sequence is sequence number 50. In some embodiments, the targeting sequence is sequence number 51. In some embodiments, the targeting sequence is sequence number 52. In some embodiments, the targeting sequence is sequence number 53. In some embodiments, the targeting sequence is sequence number 54. In some embodiments, the targeting sequence is sequence number 55. In some embodiments, the targeting sequence is sequence number 56. In some embodiments, the targeting sequence is sequence number 57. In some embodiments, the targeting sequence is sequence number 58. In some embodiments, the targeting sequence is sequence number 59. In some embodiments, the targeting sequence is sequence number 60. In some embodiments, the targeting sequence is sequence number 61. In some embodiments, the targeting sequence is sequence number 62. In some embodiments, the targeting sequence is sequence number 63. In some embodiments, the targeting sequence is sequence number 64. In some embodiments, the targeting sequence is sequence number 65. In some embodiments, the targeting sequence is sequence number 66. In some embodiments, the targeting sequence is sequence number 67. In some embodiments, the targeting sequence is sequence number 68. In some embodiments, the targeting sequence is sequence number 69. In some embodiments, the targeting sequence is sequence number 70. In some embodiments, the targeting sequence is sequence number 71. In some embodiments, the targeting sequence is sequence number 72. In some embodiments, the targeting sequence is sequence number 73. In some embodiments, the targeting sequence is sequence number 74. In some embodiments, the targeting sequence is sequence number 75. In some embodiments, the targeting sequence is sequence number 76. In some embodiments, the targeting sequence is sequence number 77. In some embodiments, the targeting sequence is sequence number 78. In some embodiments, the targeting sequence is sequence number 79. In some embodiments, the targeting sequence is sequence number 80.In some embodiments, the targeting sequence is sequence number 81. In some embodiments, the targeting sequence is sequence number 82. In some embodiments, the targeting sequence is sequence number 83. In some embodiments, the targeting sequence is sequence number 84. In some embodiments, the targeting sequence is sequence number 85. In some embodiments, the targeting sequence is sequence number 86. In some embodiments, the targeting sequence is sequence number 87. In some embodiments, the targeting sequence is sequence number 88. In some embodiments, the targeting sequence is sequence number 89. In some embodiments, the targeting sequence is sequence number 90. In some embodiments, the targeting sequence is sequence number 91. In some embodiments, the targeting sequence is sequence number 92. In some embodiments, the targeting sequence is sequence number 93. In some embodiments, the targeting sequence is sequence number 94. In some embodiments, the targeting sequence is sequence number 95. In some embodiments, the targeting sequence is sequence number 96. In some embodiments, the targeting sequence is sequence number 97. In some embodiments, the targeting sequence is sequence number 98. In some embodiments, the targeting sequence is sequence number 99. In some embodiments, the targeting sequence is sequence number 100. In some embodiments, the targeting sequence is sequence number 101. In some embodiments, the targeting sequence is sequence number 102. In some embodiments, the targeting sequence is sequence number 103. In some embodiments, the targeting sequence is sequence number 104. In some embodiments, the targeting sequence is sequence number 105. In some embodiments, the targeting sequence is sequence number 106. In some embodiments, the targeting sequence is sequence number 107. In some embodiments, the targeting sequence is sequence number 108. In some embodiments, the targeting sequence is sequence number 109. In some embodiments, the targeting sequence is sequence number 110. In some embodiments, the targeting sequence is sequence number 111. In some embodiments, the targeting sequence is sequence number 112. In some embodiments, the targeting sequence is sequence number 113. In some embodiments, the targeting sequence is sequence number 114. In some embodiments, the targeting sequence is sequence number 115. In some embodiments, the targeting sequence is sequence number 116.In some embodiments, the targeting sequence is sequence number 117. In some embodiments, the targeting sequence is sequence number 118. In some embodiments, the targeting sequence is sequence number 119. In some embodiments, the targeting sequence is sequence number 120. In some embodiments, the targeting sequence is sequence number 121. In some embodiments, the targeting sequence is sequence number 122. In some embodiments, the targeting sequence is sequence number 123. In some embodiments, the targeting sequence is sequence number 124. In some embodiments, the targeting sequence is sequence number 125.

[0122] In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof is [ka] It has a targeting sequence that includes a sequence selected from the following.

[0123] In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof is [ka] It has a targeting sequence that includes a sequence selected from the following.

[0124] In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof is [ka] [ka] It has a targeting sequence that includes a sequence selected from the following.

[0125] In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof is [ka] [ka] It has a targeting sequence that includes a sequence selected from the following.

[0126] In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof is [ka] It has a targeting sequence that includes a sequence selected from the following.

[0127] In one embodiment, the target region is the intron / exon junction or exon interior region of exon 2 (sequence number 2). In a particular embodiment, the target region of exon 2 is H2A(-25-1), H2A(-18+2), H2A(-17+3), H2A(-16+4), H2A(-15+10), H2A(+1+25), H2A(+26+50), H2A(+51+75), H2A(+85+104), H2A(+86+105), H2A(+95+119), H2A(+96+11 5) Selected from H2A(+98+117), H2A(+101+125), H2A(+108+127), H2A(+109+128), H2A(+110+129), H2A(+113+132), H2A(+114+133), H2A(+118+137), H2A(+126+150), H2A(+151+175), and H2D(+15-10).

[0128] In some embodiments, the targeting sequence includes a sequence selected from sequence numbers 7 to 29.

[0129] The target region of exon 2 is selected from H2A(-15+10), H2A(+1+25), H2A(+26+50), H2A(+51+75), H2A(+85+104), H2A(+86+105), H2A(+95+119), H2A(+101+125), H2A(+110+129), H2A(+118+137), H2A(+126+150), and H2A(+151+175).

[0130] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region of exon 2 (SEQ ID NO: 2), where the targeting sequence is [ka] Includes an array selected from.

[0131] In some embodiments, the targeting sequence is sequence number 11. In some embodiments, the targeting sequence is sequence number 12. In some embodiments, the targeting sequence is sequence number 13. In some embodiments, the targeting sequence is sequence number 14. In some embodiments, the targeting sequence is sequence number 15. In some embodiments, the targeting sequence is sequence number 16. In some embodiments, the targeting sequence is sequence number 17. In some embodiments, the targeting sequence is sequence number 20. In some embodiments, the targeting sequence is sequence number 23. In some embodiments, the targeting sequence is sequence number 26. In some embodiments, the targeting sequence is sequence number 27. In some embodiments, the targeting sequence is sequence number 28.

[0132] In some embodiments, the target region is H2A(-15+10). In some embodiments, the target region is H2A(+1+25). In some embodiments, the target region is H2A(+26+50). In some embodiments, the target region is H2A(+51+75). In some embodiments, the target region is H2A(+85+104). In some embodiments, the target region is H2A(+86+105). In some embodiments, the target region is H2A(+95+119). In some embodiments, the target region is H2A(+101+125). In some embodiments, the target region is H2A(+110+129). In some embodiments, the target region is H2A(+118+137). In some embodiments, the target region is H2A(+126+150). In some embodiments, the target region is H2A(+151+175).

[0133] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 51 to 119, measured from the 5' end of exon 2 of human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 154. In a further embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 51 to 105, measured from the 5' end of exon 2 of human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 155. In yet another embodiment, the target region is H2A(+51+75). In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing SEQ ID NO: 14.

[0134] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 85 to 119, measured from the 5' end of exon 2 of human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 156. In a further embodiment, the target region is selected from H2A(+85+104), H2A(+86+105), and H2A(+95+119). In yet another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 15-17.

[0135] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region within the range of nucleotide 15 of intron 1 measured from the 5' end of exon 2 to nucleotide 25 of exon 2 measured from the 5' end of exon 2 of human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 157. In a further embodiment, the target region is selected from H2A(-15+10) and H2A(+1+25). In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing SEQ ID NO: 11 or 12.

[0136] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region within the range of nucleotides 118 to 150 of exon 2, measured from the 5' end of exon 2 of the human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 158. In a further embodiment, the target region is selected from H2A(+118+137) and H2A(+126+150). In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing SEQ ID NO: 26 or 27.

[0137] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region of exon 2 selected from H2A(+101+125), H2A(+110+129), and H2A(+151+175). In a further embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence selected from SEQ ID NOs. 20, 21, and 28.

[0138] In another embodiment, the target region is the intron / exon junction or exon interior region of exon 5 (sequence number 3). In a particular embodiment, the target region of exon 5 is H5A(-15+5), H5A(-14+6), H5A(-11+9), H5A(-10+10), H5A(-9+11), H5A(+50+67), H5A(+51+75), H5A(+52+69), H5A(+76+100), H5A(+78+95), H5A(+80+97), H5A(+82+99), H5A(+85+102), H The sequences are selected from 5A(+86+103), H5A(+91+108), H5A(+126+150), H5A(+152+171), H5A(+153+172), H5A(+154+173), H5D(+18-2), H5D(+17-3), H5D(+16-4), H5D(+14-6), H5D(+13-7), H5D(+12-8), H5D(+11-9), and H5D(+10-10). In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region of exon 5, and the targeting sequence includes a sequence selected from SEQ ID NOs. 30-55. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region of exon 5, the targeting sequence includes sequences selected from SEQ ID NOs: 30-33, 35, 37-40, 44, 46-48, and 50-53.

[0139] In a particular embodiment, the target region of exon 5 is selected from H5A(-15+5), H5A(-14+6), H5A(-11+9), H5A(-10+10), H5A(+51+75), H5A(+76+100), H5A(+78+95), H5A(+80+97), H5A(+82+99), H5A(+126+150), H5A(+153+172), H5A(+154+173), H5D(+18-2), H5D(+16-4), H5D(+14-6), H5D(+13-7), and H5D(+12-8). In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region of exon 5, and the targeting sequence is [ka] [ka] Includes an array selected from.

[0140] In some embodiments, the targeting sequence is sequence number 30. In some embodiments, the targeting sequence is sequence number 31. In some embodiments, the targeting sequence is sequence number 32. In some embodiments, the targeting sequence is sequence number 33. In some embodiments, the targeting sequence is sequence number 35. In some embodiments, the targeting sequence is sequence number 37. In some embodiments, the targeting sequence is sequence number 38. In some embodiments, the targeting sequence is sequence number 39. In some embodiments, the targeting sequence is sequence number 40. In some embodiments, the targeting sequence is sequence number 44. In some embodiments, the targeting sequence is sequence number 46. In some embodiments, the targeting sequence is sequence number 47. In some embodiments, the targeting sequence is sequence number 48. In some embodiments, the targeting sequence is sequence number 50. In some embodiments, the targeting sequence is sequence number 51. In some embodiments, the targeting sequence is sequence number 52. In some embodiments, the targeting sequence is sequence number 53.

[0141] In some embodiments, the target region is H5A(-15+5). In some embodiments, the target region is H5A(-14+6). In some embodiments, the target region is H5A(-11+9). In some embodiments, the target region is H5A(-10+10). In some embodiments, the target region is H5A(+51+75). In some embodiments, the target region is H5A(+76+100). In some embodiments, the target region is H5A(+78+95). In some embodiments, the target region is H5A(+80+97). In some embodiments, the target region is H5A(+82+99). In some embodiments, the target region is H5A(+126+150). In some embodiments, the target region is H5A(+153+172). In some embodiments, the target region is H5A(+154+173). In some embodiments, the target region is H5D(+18-2). In some embodiments, the target region is H5D(+16-4). In some embodiments, the target region is H5D(+14-6). In some embodiments, the target region is H5D(+13-7). In some embodiments, the target region is H5D(+12-8).

[0142] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region within the range of the 15th nucleotide of intron 4 measured from the 5' end of exon 5 to the 10th nucleotide of exon 5 measured from the 5' end of exon 5 of human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 159. In a further embodiment, the target region is selected from H5A(-15+5), H5A(-14+6), H5A(-11+9), and H5A(-10+10). In yet another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 30-33.

[0143] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region H5A(+51+75). In a further embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NO: 35.

[0144] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 76 to 100, measured from the 5' end of exon 5 of human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 37. In a further embodiment, the target region is selected from H5A(+76+100), H5A(+78+95), H5A(+80+97), and H5A(+82+99). In one embodiment, the target region is H5A(+76+100). In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing SEQ ID NO: 37.

[0145] In one embodiment, the target region is H5A(+78+95). In another embodiment, the target region is H5A(+78+95). In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NO: 38.

[0146] In one embodiment, the target region is H5A(+80+97). In another embodiment, the target region is H5A(+80+97). In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NO: 39.

[0147] In one embodiment, the target region is H5A(+82+99). In another embodiment, the target region is H5A(+82+99). In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NO: 40.

[0148] In further embodiments, the target region is H5A(+126+150). In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NO: 44.

[0149] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 153 to 173, measured from the 5' end of exon 5 (SEQ ID NO: 3) of the human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region contained in SEQ ID NO: 564. In a further embodiment, the target regions are H5A(+153+172) and H5A(+154+173). In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing SEQ ID NO: 46 or 47.

[0150] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region ranging from the 18th nucleotide of exon 5, measured from the 3' end of exon 5 of human UMOD gene pre-mRNA, to the 8th nucleotide of intron 5, measured from the 3' end of exon 5. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 160. In a further embodiment, the target region is selected from H5D(+18-2), H5D(+16-4), H5D(+14-6), H5D(+13-7), and H5D(+12-8). In yet another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 48 and 50-53.

[0151] In another embodiment, the target region is an intron / exon junction or an exon interior region of exon 6 (sequence number 4). In a particular embodiment, the target region of exon 6 is H6A(+1+25), H6A(+26+50), H6A(+48+67), H6A(+49+68), H6A(+50+69), H6A(+58+77), H6A(+59+78), H6A(+60+79), H6A(+76+100), H6A(+79+98), H6A(+101+125), H6A(+101+120), H6A(+110+129) The following sequences are selected from H6A(+111+130), H6A(+112+131), H6A(+113+132), H6A(+119+138), H6A(+120+139), H6A(+121+140), H6A(+122+141), H6A(+123+142), H6A(+124+143), H6A(+130+149), H6D(+24-1), H6D(+15-5), and H6D(+14-6). In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region of exon 6, and the targeting sequence includes a sequence selected from sequence numbers 56-81.

[0152] In a particular embodiment, the target region of exon 6 is H6A(+26+50), H6A(+48+67), H6A(+49+68), H6A(+58+77), H6A(+59+78), H6A(+76+100), H6A(+101+125), H6A(+101+120), H6A(+110+129), H6A(+111+130), H6A(+112 H6A(+131), H6A(+113+132), H6A(+119+138), H6A(+120+139), H6A(+121+140), H6A(+122+141), H6A(+123+142), H6A(+124+143), H6A(+130+149), H6D(+24-1), H6D(+15-5), and H6D(+14-6) are selected. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region of exon 6, and the targeting sequence is [ka] [ka] Includes an array selected from.

[0153] In some embodiments, the targeting sequence is sequence number 57. In some embodiments, the targeting sequence is sequence number 58. In some embodiments, the targeting sequence is sequence number 59. In some embodiments, the targeting sequence is sequence number 61. In some embodiments, the targeting sequence is sequence number 62. In some embodiments, the targeting sequence is sequence number 64. In some embodiments, the targeting sequence is sequence number 66. In some embodiments, the targeting sequence is sequence number 67. In some embodiments, the targeting sequence is sequence number 68. In some embodiments, the targeting sequence is sequence number 69. In some embodiments, the targeting sequence is sequence number 70. In some embodiments, the targeting sequence is sequence number 71. In some embodiments, the targeting sequence is sequence number 72. In some embodiments, the targeting sequence is sequence number 73. In some embodiments, the targeting sequence is sequence number 74. In some embodiments, the targeting sequence is sequence number 75. In some embodiments, the targeting sequence is sequence number 76. In some embodiments, the targeting sequence is sequence number 77. In some embodiments, the targeting sequence is SEQ ID NO: 78. In some embodiments, the targeting sequence is SEQ ID NO: 79. In some embodiments, the targeting sequence is SEQ ID NO: 80. In some embodiments, the targeting sequence is SEQ ID NO: 81.

[0154] In some embodiments, the target region is H6A(+26+50). In some embodiments, the target region is H6A(+48+67). In some embodiments, the target region is H6A(+49+68). In some embodiments, the target region is H6A(+58+77). In some embodiments, the target region is H6A(+59+78). In some embodiments, the target region is H6A(+76+100). In some embodiments, the target region is H6A(+101+125). In some embodiments, the target region is H6A(+101+120). In some embodiments, the target region is H6A(+110+129). In some embodiments, the target region is H6A(+111+130). In some embodiments, the target region is H6A(+112+131). In some embodiments, the target region is H6A(+113+132). In some embodiments, the target region is H6A(+119+138). In some embodiments, the target region is H6A(+120+139). In some embodiments, the target region is H6A(+121+140). In some embodiments, the target region is H6A(+122+141). In some embodiments, the target region is H6A(+123+142). In some embodiments, the target region is H6A(+124+143). In some embodiments, the target region is H6A(+130+149). In some embodiments, the target region is H6D(+24-1). In some embodiments, the target region is H6D(+15-5). In some embodiments, the target region is H6D(+14-6).

[0155] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region H6A(+26+50). In a further embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NO: 57.

[0156] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 48 to 78, measured from the 5' end of exon 6 of the human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 161. In a further embodiment, the target region is selected from H6A(+48+67), H6A(+49+68), H6A(+58+77), and H6A(+59+78). In yet another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 58, 59, 61, and 62.

[0157] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 58 to 78, measured from the 5' end of exon 6 of human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 162. In a particular embodiment, the target region is H6A(+58+77) or H6A(+59+78). In one embodiment, the target region is H6A(+58+77). In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing SEQ ID NO: 61. In another embodiment, the target region is H6A(+59+78). In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing SEQ ID NO: 62.

[0158] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region H6A(+76+100). In a further embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region H6A(+26+50). In a particular embodiment, the targeting sequence includes SEQ ID NO: 64. In a particular embodiment, the targeting sequence includes SEQ ID NO: 57.

[0159] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 101 to 132, measured from the 5' end of exon 6 of human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 163. In a further embodiment, the target region is H6A(+101+125), H6A(+101+120), H6A(+110+129), H6A(+111+130), H6A(+112+131), or H6A(+113+132). In yet another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 66-71.

[0160] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 111 to 132, measured from the 5' end of exon 6 of human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 164. In a particular embodiment, the target region is H6A(+111+130), H6A(+112+131), or H6A(+113+132). In one embodiment, the target region is H6A(+111+130). In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing SEQ ID NO: 69. In another embodiment, the target region is H6A(+112+131). In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing SEQ ID NO: 70. In yet another embodiment, the target region is H6A(+113+132). In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NO: 71.

[0161] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 119 to 149, measured from the 5' end of exon 6 of the human UMOD gene pre-mRNA. In one particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 165. In another embodiment, the target region is H6A(+119+138), H6A(+120+139), H6A(+121+140), H6A(+122+141), H6A(+123+142), H6A(+124+143), or H6A(+130+149). In yet another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 72-78.

[0162] In further embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 119 to 141, measured from the 5' end of exon 6 of human UMOD gene pre-mRNA. In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region contained in SEQ ID NO: 166. In some embodiments, the target region is H6A(+119+138), H6A(+120+139), H6A(+121+140), or H6A(+122+141). In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 72-75.

[0163] In further embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 120 to 141, measured from the 5' end of exon 6 of human UMOD gene pre-mRNA. In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 167. In certain embodiments, the target region is H6A(+120+139), H6A(+121+140), or H6A(+122+141). In one embodiment, the target region is H6A(+120+139). In yet another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 73-75. In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing SEQ ID NO: 73. In another embodiment, the target region is H6A(+121+140). In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NO: 74. In yet another embodiment, the target region is H6A(+122+141). In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NO: 75.

[0164] In further embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 123 to 149, measured from the 5' end of exon 6 of the human UMOD gene pre-mRNA. In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 168. In certain embodiments, the target region is H6A(+123+142), H6A(+124+143), or H6A(+130+149). In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 76-78.

[0165] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region ranging from the 24th nucleotide of exon 6, measured from the 3' end of exon 6 of human UMOD gene pre-mRNA, to the 6th nucleotide of intron 6, measured from the 3' end of exon 6. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 169. In a further embodiment, the target region is selected from H6D(+24-1), H6D(+15-5), and H6D(+14-6). In yet another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 79-81.

[0166] In further embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region ranging from the 15th nucleotide of exon 6, measured from the 3' end of exon 6 of human UMOD gene pre-mRNA, to the 6th nucleotide of intron 6, measured from the 3' end of exon 6. In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 170. In some embodiments, the target region is selected from H6D(+15-5) and H6D(+14-6). In yet another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 80 and 81. In one embodiment, the target region is H6D(+15-5). In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing SEQ ID NO: 80. In another embodiment, the target region is H6D(+14-6). In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NO: 81.

[0167] In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region of exon 8. In yet another embodiment, the target region is an intron / exon junction or an internal exon region of exon 8 (SEQ ID NO: 5). In a particular embodiment, the target region of exon 8 is H8A(-2+23), H8A(+26+50), H8A(+51+75), H8A(+60+79), H8A(+61+80), H8A(+62+81), H8A(+63+82), H8A(+68+87), H8A(+69+88), H8A (+70+89), H8A(+76+95), H8A(+76+100), H8A(+77+96), H8A(+78+97), H8A(+79+9) 8), H8A(+80+99), H8A(+81+100), H8A(+82+101), H8A(+83+102), H8A(+86+105), H8A(+94+113), H8A(+95+114), H8A(+96+115), H8A(+101+125), H8A(+102+121), H8A(+103+122), H8A(+104+123), H8A(+105+124), H8A(+120+139), H8A(+121+14 The sequence is selected from H8A(+122+141), H8A(+126+150), H8A(+128+147), H8A(+129+148), H8A(+133+152), H8A(+134+153), H8A(+139+158), H8D(+19-1), and H8D(+12-13). In some embodiments, the targeting sequence includes a sequence selected from sequence numbers 82-120.

[0168] In a particular embodiment, the target region of exon 8 is H8A(-2+23), H8A(+51+75), H8A(+60+79), H8A(+61+80), H8A(+68+87), H8A(+69+88), H8A(+70+89), H8A(+76+95), H8A(+76+100), H8A(+77+96), H8A(+78+97), H8A(+79+98), H8A(+81+100), H8A(+82+101), H8A(+83+102), H8A(+86+10 5) Selected from H8A(+94+113), H8A(+95+114), H8A(+96+115), H8A(+101+125), H8A(+102+121), H8A(+103+122), H8A(+104+123), H8A(+105+124), H8A(+120+139), H8A(+121+140), H8A(+122+141), H8A(+126+150), H8A(+128+147), H8A(+129+148), and H8D(+12-13). In some embodiments, the targeting sequence is [ka] [ka] Includes an array selected from.

[0169] In some embodiments, the targeting sequence is sequence number 82. In some embodiments, the targeting sequence is sequence number 84. In some embodiments, the targeting sequence is sequence number 85. In some embodiments, the targeting sequence is sequence number 86. In some embodiments, the targeting sequence is sequence number 89. In some embodiments, the targeting sequence is sequence number 90. In some embodiments, the targeting sequence is sequence number 91. In some embodiments, the targeting sequence is sequence number 92. In some embodiments, the targeting sequence is sequence number 93. In some embodiments, the targeting sequence is sequence number 94. In some embodiments, the targeting sequence is sequence number 95. In some embodiments, the targeting sequence is sequence number 96. In some embodiments, the targeting sequence is sequence number 98. In some embodiments, the targeting sequence is sequence number 99. In some embodiments, the targeting sequence is sequence number 100. In some embodiments, the targeting sequence is sequence number 101. In some embodiments, the targeting sequence is sequence number 102. In some embodiments, the targeting sequence is sequence number 103. In some embodiments, the targeting sequence is sequence number 104. In some embodiments, the targeting sequence is sequence number 105. In some embodiments, the targeting sequence is sequence number 106. In some embodiments, the targeting sequence is sequence number 107. In some embodiments, the targeting sequence is sequence number 108. In some embodiments, the targeting sequence is sequence number 109. In some embodiments, the targeting sequence is sequence number 110. In some embodiments, the targeting sequence is sequence number 111. In some embodiments, the targeting sequence is sequence number 112. In some embodiments, the targeting sequence is sequence number 113. In some embodiments, the targeting sequence is sequence number 114. In some embodiments, the targeting sequence is sequence number 115. In some embodiments, the targeting sequence is sequence number 120.

[0170] In some embodiments, the target region is H8A(-2+23), H8A(+51+75), H8A(+60+79), H8A(+61+80), H8A(+68+87), H8A(+69+88), H8A(+70+89), H8A(+76+95), H8A(+76+100), H8A(+77+96), H8A(+78+97), H8A(+79+98), H8A(+81+100), H8A(+82+101), H8A(+83+102), H8A(+86+105), H The following are selected: 8A(+94+113), H8A(+95+114), H8A(+96+115), H8A(+101+125), H8A(+102+121), H8A(+103+122), H8A(+104+123), H8A(+105+124), H8A(+120+139), H8A(+121+140), H8A(+122+141), H8A(+126+150), H8A(+128+147), H8A(+129+148), and H8D(+12-13).

[0171] In some embodiments, the target region is H8A(-2+23). In some embodiments, the target region is H8A(+51+75). In some embodiments, the target region is H8A(+60+79). In some embodiments, the target region is H8A(+61+80). In some embodiments, the target region is H8A(+68+87). In some embodiments, the target region is H8A(+69+88). In some embodiments, the target region is H8A(+70+89). In some embodiments, the target region is H8A(+76+95). In some embodiments, the target region is H8A(+76+100). In some embodiments, the target region is H8A(+77+96). In some embodiments, the target region is H8A(+78+97). In some embodiments, the target region is H8A(+79+98). In some embodiments, the target region is H8A(+81+100). In some embodiments, the target region is H8A(+82+101). In some embodiments, the target region is H8A(+83+102). In some embodiments, the target region is H8A(+86+105). In some embodiments, the target region is H8A(+94+113). In some embodiments, the target region is H8A(+95+114). In some embodiments, the target region is H8A(+96+115). In some embodiments, the target region is H8A(+101+125). In some embodiments, the target region is H8A(+102+121). In some embodiments, the target region is H8A(+103+122). In some embodiments, the target region is H8A(+104+123). In some embodiments, the target region is H8A(+105+124). In some embodiments, the target region is H8A(+120+139). In some embodiments, the target region is H8A(+121+140). In some embodiments, the target region is H8A(+122+141). In some embodiments, the target region is H8A(+126+150). In some embodiments, the target region is H8A(+128+147). In some embodiments, the target region is H8A(+129+148). In some embodiments, the target region is H8D(+12-13).

[0172] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region H8A(-2+23). In a further embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NO: 82.

[0173] In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 51 to 80, measured from the 5' end of exon 8 of the human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 171. In further embodiments, the target region is selected from H8A(+51+75), H8A(+60+79), and H8A(+61+80). In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 84-86.

[0174] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 68 to 100, measured from the 5' end of exon 8 of the human UMOD gene pre-mRNA. In one particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 172. In another embodiment, the target region is H8A(+68+87), H8A(+69+88), H8A(+70+89), H8A(+76+95), H8A(+76+100), H8A(+77+96), H8A(+78+97), or H8A(+79+98). In yet another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 89-96.

[0175] In further embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 76 to 100, measured from the 5' end of exon 8 of the human UMOD gene pre-mRNA. In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region contained in SEQ ID NO: 173. In some embodiments, the target region is H8A(+76+95), H8A(+77+96), H8A(+78+97), or H8A(+79+98). In other embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 92 and 94-96.

[0176] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 81 to 105, measured from the 5' end of exon 8 of human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 174. In a further embodiment, the target region is selected from H8A(+81+100), H8A(+82+101), H8A(+83+102), and H8A(+86+105). In yet another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 98-101.

[0177] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 94 to 124, measured from the 5' end of exon 8 of human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 175. In a further embodiment, the target region is selected from H8A(+94+113), H8A(+95+114), H8A(+96+115), H8A(+101+125), H8A(+102+121), H8A(+103+122), H8A(+104+123), and H8A(+105+124). In further embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising a sequence selected from SEQ ID NOs: 102-109.

[0178] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 120 to 148, measured from the 5' end of exon 8 of the human UMOD gene pre-mRNA. In a particular embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 176. In a further embodiment, the target region is selected from H8A(+120+139), H8A(+121+140), H8A(+122+141), H8A(+126+150), H8A(+128+147), and H8A(+129+148). In yet another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 110-115.

[0179] In further embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region in the range of nucleotides 126 to 148, measured from the 5' end of exon 8 of human UMOD gene pre-mRNA. In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 177. In certain embodiments, the target region is selected from H8A(+126+150), H8A(+128+147), and H8A(+129+148). In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing a sequence selected from SEQ ID NOs: 113-115. In one embodiment, the target region is H8A(+126+150). In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence containing SEQ ID NO: 113. In one embodiment, the target region is H8A(+128+147). In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence including SEQ ID NO: 114. In one embodiment, the target region is H8A(+129+148). In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence including SEQ ID NO: 115.

[0180] In one embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region H8D(+12-13). In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence including SEQ ID NO: 120.

[0181] In another embodiment, the target region is the intron / exon junction or internal exon region of exon 9 (sequence number 6). In some embodiments, the target region of exon 9 is selected from H9A(-5+20), H9A(+1+25), H9A(+51+75), and H9D(+7-18). In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region of exon 9. In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising a sequence selected from sequence numbers 121-124. In a particular embodiment, the targeting sequence is [ka] Includes an array selected from.

[0182] In some embodiments, the targeting sequence is sequence number 121. In some embodiments, the targeting sequence is sequence number 122. In some embodiments, the targeting sequence is sequence number 123. In some embodiments, the targeting sequence is sequence number 124.

[0183] In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to a target region within the range of the 5th nucleotide of intron 8 measured from the 5' end of exon 9 to the 25th nucleotide of exon 9 measured from the 5' end of exon 9 of human UMOD gene pre-mRNA. In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence complementary to the target region contained in SEQ ID NO: 178. In further embodiments, the target region is H9A(-5+20) or H9A(+1+25). In some embodiments, the target region is H9A(-5+20). In some embodiments, the target region is H9A(+1+25). In some embodiments, the target region is H9A(+51+75). In some embodiments, the target region is H9D(+7-18).

[0184] In further embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising a sequence selected from SEQ ID NOs: 121 and 122.

[0185] In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a target sequence complementary to the target region H9A(+51+75). In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence including SEQ ID NO: 123.

[0186] In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof has a target sequence complementary to the target region H9D(+7-18). In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence including SEQ ID NO: 124.

[0187] In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising a sequence selected from SEQ ID NOs: 37, 32, 70, 74, 62, 81, 114, and 120. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NOs: 37. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NOs: 32. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NOs: 70. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NOs: 74. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NOs: 62. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NOs: 81. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NOs: 114. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof has a targeting sequence comprising SEQ ID NO: 120.

[0188] In one embodiment, the targeting sequence is at least 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent complementary to the target region. In another embodiment, the targeting sequence is at least 84%, at least 88%, or at least 92% complementary to the target region. In yet another embodiment, the targeting sequence is at least 90% complementary to the target region. In yet another embodiment, the targeting sequence is at least 95% complementary to the target region. In yet another embodiment, the targeting sequence is 100% complementary to the target region.

[0189] The antisense oligomers or pharmaceutically acceptable salts thereof of this disclosure may have non-natural chemical skeletons described herein or known in the art. For example, the antisense oligomers or pharmaceutically acceptable salts thereof may be peptide nucleic acids (PNAs), locked nucleic acids, phosphorodiamidate morpholino oligomers, 2'-OMe phosphorothioate oligomers, or combinations thereof. In one embodiment, the antisense oligomer or pharmaceutically acceptable salt thereof is a phosphorodiamidate morpholino oligomer. In another embodiment, the antisense oligomer or pharmaceutically acceptable salt thereof is a peptide nucleic acid. In yet another embodiment, the antisense oligomer or pharmaceutically acceptable salt thereof is a locked nucleic acid. In yet another embodiment, the antisense oligomer or pharmaceutically acceptable salt thereof is a 2'-OMe phosphorothioate oligomer. In another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof is any combination of the above-mentioned oligomers or pharmaceutically acceptable salts thereof, having a non-natural chemical skeleton.

[0190] In some embodiments, an antisense oligomer or a pharmaceutically acceptable salt thereof is conjugated (e.g., covalently attached) or associated with a delivery agent, such as a cell-permeable peptide, an antibody, an antibody fragment, an antibody antigen fragment, at least one ligand, or a combination thereof, or a complex thereof.

[0191] In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof further comprises a cell-permeable peptide (CPP) (e.g., conjugated thereto). In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof is covalently linked to a delivery agent selected from a cell-permeable peptide, an antibody, a fragment of an antibody, an antigen conjugate, and a combination thereof. In some embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof further comprises a cell-permeable peptide covalently linked to the antisense oligomer or a pharmaceutically acceptable salt thereof. In certain embodiments, the antisense oligomer or a pharmaceutically acceptable salt thereof is covalently linked to the cell-permeable peptide via a direct linkage, or via a linker selected from glycine amino acids, proline amino acids, glutamic acid amino acids, or isoglutamine amino acids.

[0192] In another embodiment, an antisense oligomer or a pharmaceutically acceptable salt thereof is conjugated to a cell-permeable peptide, the cell-permeable peptide being rTAT (SEQ ID NO: 179), TAT (SEQ ID NO: 180), R9F2 (SEQ ID NO: 181), R5F2R4 (SEQ ID NO: 182), R4 (SEQ ID NO: 183), R5 (SEQ ID NO: 184), R6 (SEQ ID NO: 185), R7 (SEQ ID NO: 136), R8 (SEQ ID NO: 137), R9 (SEQ ID NO: 138), (RXR)4 (SEQ ID NO: 139), (RXR)5 (SEQ ID NO: 140), (RXRRB Selected from (R)2 (SEQ ID NO: 141), (RAR)4F2 (SEQ ID NO: 142), (RGR)4F2 (SEQ ID NO: 143), and RBRBYLIQFRBRRBR (SEQ ID NO: 144), where A represents alanine, B represents beta-alanine (also represented as β-Ala or β), F represents phenylalanine, G represents glycine, I represents isoleucine, L represents leucine, Q represents glutamine, R represents arginine, X represents 6-aminohexanoic acid (also represented as Ahx or α), and Y represents tyrosine. In yet another embodiment, the antisense oligomer or a pharmaceutically acceptable salt thereof is conjugated to an antibody, an antibody fragment, or an antigenic fragment of an antibody.

[0193] The antisense oligomers of this disclosure or pharmaceutically acceptable salts thereof may be conjugated to a delivery agent (e.g., by covalent bond) or associated with it (e.g., forming a complex with it). In some embodiments, the antisense oligomers of this disclosure or pharmaceutically acceptable salts thereof are conjugated to the delivery agent via a linker. In some embodiments, the linker is a direct conjugation (e.g., covalent bond) from the antisense oligomer or pharmaceutically acceptable salt thereof to the delivery agent. In other embodiments, the linker is an amino acid, for example, a glycine amino acid, a proline amino acid, or a glutamic acid amino acid. In certain embodiments, the linker is a glycine amino acid or a proline amino acid. In certain embodiments, the delivery agent comprises an antibody, an antibody fragment, an antigenic fragment of an antibody, at least one ligand, or a combination thereof. In yet another embodiment, the antisense oligomer or pharmaceutically acceptable salt thereof is conjugated to an antibody, an antibody fragment, or an antigenic fragment of an antibody. Equation (I)

[0194] In some embodiments, the antisense oligomer of structural formula (I): [ka] or a pharmaceutically acceptable salt thereof During the ceremony, A' is -OH, [ka] Selected from, R 5 is -C(O)(O-alkyl) x -OH, x is 3 to 10, and each alkyl group is independently C each time it appears. 2~6 - Is it alkyl? or R 5 H, -C(O)C 1~6 -alkyl, trityl, monomethoxytrityl, -(C 1~6 -alkyl)-R 6 ,-(C 1~6-heteroalkyl)-R 6 , -C 6~10 -Aryl-R 6 , 5-10 member heteroaryl-R 6 , -C(O)O-(C 1~6 -alkyl)-R 6 -C(O)O-aryl-R 6 -C(O)O-(5-10 member heteroaryl)-R 6 , and [ka] Selected from, R 6 The ion is selected from -OH, -SH, and -NH2, or R 6 These are O, S, or NH, each covalently bonded to a solid support. R 9 C 1~6 It is alkyl, Each R 1 These are independently -OH and -N(R 3 )(R 4 ) are selected from each R 3 and R 4 Each instance is independently either -H or -C 1~6 -It is alkyl, Each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeting sequence of 13-30 bases complementary to the target region within the pre-mRNA of the human uromodulin (UMOD) gene (SEQ ID NO: 1), and the target region is an intron / exon junction or an internal exon region of the human UMOD gene pre-mRNA. t is between 11 and 28. E' is -H, -C 1~6 -alkyl, -C(O)C 1~6 -alkyl, benzoyl, stearoyl, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl, [ka] Selected from, During the ceremony, Q is -C(O)(CH2)6C(O)- or -C(O)(CH2)2S2(CH2)2C(O)-, R 7 is -(CH2)2OC(O)N(R 8 )2, and R 8 This is -(CH2)6NHC(=NH)NH2, L is a linked amino acid, and L is covalently linked to the C-terminus of J by an amide bond. J is a cell-permeable peptide, G is -H, -C(O)C 1~6 - Selected from alkyl, benzoyl, and stearoyl, G is covalently linked to J. Antisense oligomers or pharmaceutically acceptable salts thereof are provided herein.

[0195] In some embodiments, t in formula (I) is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28.

[0196] In one embodiment, t in equation (I) is an integer between 11 and 28. In one embodiment, t in equation (IA) is at least 11. In one embodiment, t in equation (I) is at most 28.

[0197] In one embodiment, t is 11-28. In one embodiment, t is 11-27. In one embodiment, t is 11-26. In one embodiment, t is 11-25. In one embodiment, t is 11-24. In one embodiment, t is 11-23. In one embodiment, t is 11-22. In one embodiment, t is 11-21. In one embodiment, t is 11-20. In one embodiment, t is 11-19. In one embodiment, t is 11-18. In one embodiment, t is 11-17. In one embodiment, t is 11-16. In one embodiment, t is 11-15. In one embodiment, t is 11-14. In one embodiment, t is 11-13. In one embodiment, t is 11-12. In one embodiment, t is 12-28. In one embodiment, t is 12-27. In one embodiment, t is 12-26. In one embodiment, t is 12-25. In one embodiment, t is 12-24. In one embodiment, t is 12-23. In one embodiment, t is 12-22. In one embodiment, t is 12-21. In one embodiment, t is 12-20. In one embodiment, t is 12-19. In one embodiment, t is 12-18. In one embodiment, t is 12-17. In one embodiment, t is 12-16. In one embodiment, t is 12-15. In one embodiment, t is 12-14. In one embodiment, t is 12-13. In one embodiment, t is 13-28. In one embodiment, t is 13-27. In one embodiment, t is 13-26. In one embodiment, t is 13-25. In one embodiment, t is 13-24. In one embodiment, t is 13-23. In one embodiment, t is 13-22. In one embodiment, t is 13-21. In another embodiment, t is 13-20. In another embodiment, t is 13-19. In another embodiment, t is 13-18. In another embodiment, t is 13-17. In another embodiment, t is 13-16. In another embodiment, t is 13-15. In another embodiment, t is 13-14. In another embodiment, t is 14-28. In another embodiment, t is 14-27.In one embodiment, t is 14-26. In one embodiment, t is 14-25. In one embodiment, t is 14-24. In one embodiment, t is 14-23. In one embodiment, t is 14-22. In one embodiment, t is 14-21. In one embodiment, t is 14-20. In one embodiment, t is 14-19. In one embodiment, t is 14-18. In one embodiment, t is 14-17. In one embodiment, t is 14-16. In one embodiment, t is 14-15. In one embodiment, t is 15-28. In one embodiment, t is 15-27. In one embodiment, t is 15-26. In one embodiment, t is 15-25. In one embodiment, t is 15-24. In one embodiment, t is 15-23. In one embodiment, t is 15-22. In one embodiment, t is 15-21. In one embodiment, t is 15-20. In one embodiment, t is 15-19. In one embodiment, t is 15-18. In one embodiment, t is 15-17. In one embodiment, t is 15-16. In one embodiment, t is 16-28. In one embodiment, t is 16-27. In one embodiment, t is 16-26. In one embodiment, t is 16-25. In one embodiment, t is 16-24. In one embodiment, t is 16-23. In one embodiment, t is 16-22. In one embodiment, t is 16-21. In one embodiment, t is 16-20. In one embodiment, t is 16-19. In one embodiment, t is 16-18. In one embodiment, t is 16-17. In one embodiment, t is 17-28. In one embodiment, t is 17-27. In one embodiment, t is 17-26. In one embodiment, t is 17-25. In another embodiment, t is 17-24. In another embodiment, t is 17-23. In another embodiment, t is 17-22. In another embodiment, t is 17-21. In another embodiment, t is 17-20. In another embodiment, t is 17-19. In another embodiment, t is 17-18. In another embodiment, t is 18-28. In another embodiment, t is 18-27.In one embodiment, t is 18-26. In one embodiment, t is 18-25. In one embodiment, t is 18-24. In one embodiment, t is 18-23. In one embodiment, t is 18-22. In one embodiment, t is 18-21. In one embodiment, t is 18-20. In one embodiment, t is 18-19. In one embodiment, t is 19-28. In one embodiment, t is 19-27. In one embodiment, t is 19-26. In one embodiment, t is 19-25. In one embodiment, t is 19-24. In one embodiment, t is 19-23. In one embodiment, t is 19-22. In one embodiment, t is 19-21. In one embodiment, t is 19-20. In one embodiment, t is 20-28. In one embodiment, t is 20-27. In one embodiment, t is 20-26. In one embodiment, t is 20-25. In one embodiment, t is 20-24. In one embodiment, t is 20-23. In one embodiment, t is 20-22. In one embodiment, t is 20-21. In one embodiment, t is 21-28. In one embodiment, t is 21-27. In one embodiment, t is 21-26. In one embodiment, t is 21-25. In one embodiment, t is 21-24. In one embodiment, t is 21-23. In one embodiment, t is 21-22. In one embodiment, t is 22-28. In one embodiment, t is 22-27. In one embodiment, t is 22-26. In one embodiment, t is 22-25. In one embodiment, t is 22-24. In one embodiment, t is 22-23. In one embodiment, t is 23-28. In one embodiment, t is 23-27. In one embodiment, t is 23-26. In one embodiment, t is 23-25. In one embodiment, t is 23-24. In one embodiment, t is 24-28. In one embodiment, t is 24-27. In one embodiment, t is 24-26. In one embodiment, t is 24-25. In one embodiment, t is 25-28. In one embodiment, t is 25-27. In one embodiment, t is 25-26.In another embodiment, t is 26-30. In one embodiment, t is 26-29. In one embodiment, t is 26-28. In one embodiment, t is 26-27. In one embodiment, t is 27-28.

[0198] In one embodiment, t is 11. In one embodiment, t is 12. In one embodiment, t is 13. In one embodiment, t is 14. In one embodiment, t is 15. In one embodiment, t is 16. In one embodiment, t is 17. In one embodiment, t is 18. In one embodiment, t is 19. In one embodiment, t is 20. In one embodiment, t is 21. In one embodiment, t is 22. In one embodiment, t is 23. In one embodiment, t is 24. In one embodiment, t is 25. In one embodiment, t is 26. In one embodiment, t is 27. In one embodiment, t is 28.

[0199] In some embodiments, each R of formula (I) 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeting sequence of 13 to 30 bases in length that is complementary to the target region within the pre-mRNA of the human uromodulin (UMOD) gene (SEQ ID NO: 1), and the target region is an intron / exon junction or an internal exon region of the human UMOD gene pre-mRNA. Each R in formula (I) 2 Together, they form a targeting sequence of 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 bases. In some embodiments, each R of formula (I) 2 Together, they form a target sequence of 18 to 27 bases. In some embodiments, each R of formula (I) 2 Together, they form a target sequence of 20 to 25 bases.

[0200] In one embodiment, each R2 is independently selected from naturally occurring or non-naturally occurring nucleobases that, when taken together, form a targeting sequence 13 to 30 bases in length. In certain embodiments, each R 2 is independently selected from naturally occurring or non-naturally occurring nucleobases that, when taken together, form a targeting sequence at least 13 bases in length. In certain embodiments, each R 2 is independently selected from naturally occurring or non-naturally occurring nucleobases that, when taken together, form a targeting sequence up to 30 bases in length.

[0201] In certain embodiments, each R 2 is independently selected from naturally occurring or non-naturally occurring nucleobases that, when taken together, form a targeting sequence 13 to 29 bases in length. In certain embodiments, each R 2 is independently selected from naturally occurring or non-naturally occurring nucleobases that, when taken together, form a targeting sequence 13 to 28 bases in length. In certain embodiments, each R 2 is independently selected from naturally occurring or non-naturally occurring nucleobases that, when taken together, form a targeting sequence 13 to 27 bases in length. In certain embodiments, each R 2 is independently selected from naturally occurring or non-naturally occurring nucleobases that, when taken together, form a targeting sequence 13 to 26 bases in length. In certain embodiments, each R 2 is independently selected from naturally occurring or non-naturally occurring nucleobases that, when taken together, form a targeting sequence 13 to 25 bases in length. In certain embodiments, each R 2 is independently selected from naturally occurring or non-naturally occurring nucleobases that, when taken together, form a targeting sequence 13 to 24 bases in length. In certain embodiments, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 19 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 18 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 17 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 16 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 15 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13-14 base lengths.

[0202] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 22 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 19 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 18 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 17 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 16 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14-15 base lengths.

[0203] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 29 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15-20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 19 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 18 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 17 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15-16 base lengths.

[0204] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 25 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 19 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 18 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16-17 base lengths.

[0205] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 30 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 20 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17-19 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and when combined, form a targeted sequence of 17-18 base lengths.

[0206] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 24 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18-19 base lengths.

[0207] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 27 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19-20 base lengths.

[0208] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 29 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20-25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20-22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20-21 base lengths.

[0209] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 30 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21-22 base lengths.

[0210] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 30 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22-24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22-23 base lengths.

[0211] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 29 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23-24 base lengths.

[0212] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 to 27 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24-25 base lengths.

[0213] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25-30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25-29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25-28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25-27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25-26 base lengths.

[0214] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 26 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 26 to 29 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 26-28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 26-27 base lengths.

[0215] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 27-30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 27-29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 27-28 base lengths.

[0216] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 28-30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 28-29 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 28-30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 29-30 base lengths.

[0217] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence with a length of 13 bases.

[0218] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a 15-base-length targeted sequence. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a 20-base-length targeted sequence. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 base lengths. In another embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 26 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence with a length of 27 bases. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 28 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 29 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a 30-base-length targeted sequence.

[0219] In one embodiment, E' in equation (I) is -H, -C 1~6 -alkyl, -C(O)C 1~6-alkyl, benzoyl, stearoyl, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl, and [ka] Selected from.

[0220] In further embodiments, E' in formula (I) is -H, -C(O)CH3, benzoyl, stearoyl, trityl, 4-methoxytrityl, and [ka] Selected from.

[0221] In one embodiment, A' in equation (I) is [ka] Selected from.

[0222] In one embodiment, at least one of the following is true for equation (I): A' [ka] (2) E' is [ka] Being.

[0223] In one embodiment of formula (I), A' is, [ka] Selected from, E' is, [ka] That is the case.

[0224] In one embodiment of formula (I), A' is, [ka] And, E' is selected from H, -C(O)CH3, trityl, 4-methoxytrityl, benzoyl, and stearoyl.

[0225] In one embodiment, each R in equation (I) 1 is -N(CH3)2. In some embodiments, L in formula (I) is glycine, proline, or β-alanine. In some embodiments, L in formula (I) is glycine. In some embodiments, L in formula (I) is proline. In some embodiments, L in formula (I) is β-alanine.

[0226] In one embodiment, J in formula (I) is selected from rTAT (sequence number 179), TAT (sequence number 180), R9F2 (sequence number 181), R5F2R4 (sequence number 182), R4 (sequence number 183), R5 (sequence number 184), R6 (sequence number 185), R7 (sequence number 136), R8 (sequence number 137), R9 (sequence number 138), (RXR)4 (sequence number 139), (RXR)5 (sequence number 140), (RXRRBR)2 (sequence number 141), (RAR)4F2 (sequence number 142), (RGR)4F2 (sequence number 143), and RBRBYLIQFRBRRBR (sequence number 144). (from), A represents alanine, B represents β-alanine (also represented as β-Ala or β), F represents phenylalanine, G represents glycine, R represents arginine, and X represents 6-aminohexanoic acid (also represented as Ahx or α).

[0227] In some embodiments, G in formula (I) is selected from H, -C(O)CH3, benzoyl, and stearoyl. In some embodiments, G in formula (I) is H or -C(O)CH3. In some embodiments, G in formula (I) is H. In some embodiments, G in formula (I) is -C(O)CH3. In certain embodiments of the antisense oligomer of structural formula (I) or a pharmaceutically acceptable salt thereof, the salt is an HCl salt. Formula (IA)

[0228] In some embodiments, the antisense oligomer of formula (I) is structural formula (IA): [ka] or a pharmaceutically acceptable salt thereof During the ceremony, A' is, [ka] It is the part selected from, Each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeting sequence of 13-30 bases complementary to the target region within the pre-mRNA of the human uromodulin (UMOD) gene (SEQ ID NO: 1), and the target region is an intron / exon junction or an internal exon region of the human UMOD gene pre-mRNA. R 9 C 1~6 It is alkyl, t is between 11 and 28. Antisense oligomers or pharmaceutically acceptable salts thereof are provided herein.

[0229] In some embodiments, t in formula (IA) is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28.

[0230] In some embodiments, t in equation (IA) is an integer between 11 and 28. In some embodiments, t in equation (IA) is at least 11. In some embodiments, t in equation (IA) is at most 28.

[0231] In one embodiment, t is 11-28. In one embodiment, t is 11-27. In one embodiment, t is 11-26. In one embodiment, t is 11-25. In one embodiment, t is 11-24. In one embodiment, t is 11-23. In one embodiment, t is 11-22. In one embodiment, t is 11-21. In one embodiment, t is 11-20. In one embodiment, t is 11-19. In one embodiment, t is 11-18. In one embodiment, t is 11-17. In one embodiment, t is 11-16. In one embodiment, t is 11-15. In one embodiment, t is 11-14. In one embodiment, t is 11-13. In one embodiment, t is 11-12. In one embodiment, t is 12-28. In one embodiment, t is 12-27. In one embodiment, t is 12-26. In one embodiment, t is 12-25. In one embodiment, t is 12-24. In one embodiment, t is 12-23. In one embodiment, t is 12-22. In one embodiment, t is 12-21. In one embodiment, t is 12-20. In one embodiment, t is 12-19. In one embodiment, t is 12-18. In one embodiment, t is 12-17. In one embodiment, t is 12-16. In one embodiment, t is 12-15. In one embodiment, t is 12-14. In one embodiment, t is 12-13. In one embodiment, t is 13-28. In one embodiment, t is 13-27. In one embodiment, t is 13-26. In one embodiment, t is 13-25. In one embodiment, t is 13-24. In one embodiment, t is 13-23. In one embodiment, t is 13-22. In one embodiment, t is 13-21. In another embodiment, t is 13-20. In another embodiment, t is 13-19. In another embodiment, t is 13-18. In another embodiment, t is 13-17. In another embodiment, t is 13-16. In another embodiment, t is 13-15. In another embodiment, t is 13-14. In another embodiment, t is 14-28. In another embodiment, t is 14-27.In one embodiment, t is 14-26. In one embodiment, t is 14-25. In one embodiment, t is 14-24. In one embodiment, t is 14-23. In one embodiment, t is 14-22. In one embodiment, t is 14-21. In one embodiment, t is 14-20. In one embodiment, t is 14-19. In one embodiment, t is 14-18. In one embodiment, t is 14-17. In one embodiment, t is 14-16. In one embodiment, t is 14-15. In one embodiment, t is 15-28. In one embodiment, t is 15-27. In one embodiment, t is 15-26. In one embodiment, t is 15-25. In one embodiment, t is 15-24. In one embodiment, t is 15-23. In one embodiment, t is 15-22. In one embodiment, t is 15-21. In one embodiment, t is 15-20. In one embodiment, t is 15-19. In one embodiment, t is 15-18. In one embodiment, t is 15-17. In one embodiment, t is 15-16. In one embodiment, t is 16-28. In one embodiment, t is 16-27. In one embodiment, t is 16-26. In one embodiment, t is 16-25. In one embodiment, t is 16-24. In one embodiment, t is 16-23. In one embodiment, t is 16-22. In one embodiment, t is 16-21. In one embodiment, t is 16-20. In one embodiment, t is 16-19. In one embodiment, t is 16-18. In one embodiment, t is 16-17. In one embodiment, t is 17-28. In one embodiment, t is 17-27. In one embodiment, t is 17-26. In one embodiment, t is 17-25. In another embodiment, t is 17-24. In another embodiment, t is 17-23. In another embodiment, t is 17-22. In another embodiment, t is 17-21. In another embodiment, t is 17-20. In another embodiment, t is 17-19. In another embodiment, t is 17-18. In another embodiment, t is 18-28. In another embodiment, t is 18-27.In one embodiment, t is 18-26. In one embodiment, t is 18-25. In one embodiment, t is 18-24. In one embodiment, t is 18-23. In one embodiment, t is 18-22. In one embodiment, t is 18-21. In one embodiment, t is 18-20. In one embodiment, t is 18-19. In one embodiment, t is 19-28. In one embodiment, t is 19-27. In one embodiment, t is 19-26. In one embodiment, t is 19-25. In one embodiment, t is 19-24. In one embodiment, t is 19-23. In one embodiment, t is 19-22. In one embodiment, t is 19-21. In one embodiment, t is 19-20. In one embodiment, t is 20-28. In one embodiment, t is 20-27. In one embodiment, t is 20-26. In one embodiment, t is 20-25. In one embodiment, t is 20-24. In one embodiment, t is 20-23. In one embodiment, t is 20-22. In one embodiment, t is 20-21. In one embodiment, t is 21-28. In one embodiment, t is 21-27. In one embodiment, t is 21-26. In one embodiment, t is 21-25. In one embodiment, t is 21-24. In one embodiment, t is 21-23. In one embodiment, t is 21-22. In one embodiment, t is 22-28. In one embodiment, t is 22-27. In one embodiment, t is 22-26. In one embodiment, t is 22-25. In one embodiment, t is 22-24. In one embodiment, t is 22-23. In one embodiment, t is 23-28. In one embodiment, t is 23-27. In one embodiment, t is 23-26. In one embodiment, t is 23-25. In one embodiment, t is 23-24. In one embodiment, t is 24-28. In one embodiment, t is 24-27. In one embodiment, t is 24-26. In one embodiment, t is 24-25. In one embodiment, t is 25-28. In one embodiment, t is 25-27. In one embodiment, t is 25-26.In another embodiment, t is 26-30. In one embodiment, t is 26-29. In one embodiment, t is 26-28. In one embodiment, t is 26-27. In one embodiment, t is 27-28.

[0232] In one embodiment, t is 11. In one embodiment, t is 12. In one embodiment, t is 13. In one embodiment, t is 14. In one embodiment, t is 15. In one embodiment, t is 16. In one embodiment, t is 17. In one embodiment, t is 18. In one embodiment, t is 19. In one embodiment, t is 20. In one embodiment, t is 21. In one embodiment, t is 22. In one embodiment, t is 23. In one embodiment, t is 24. In one embodiment, t is 25. In one embodiment, t is 26. In one embodiment, t is 27. In one embodiment, t is 28.

[0233] In some embodiments, each R of formula (IA) 2 Together, they form a targeting sequence of 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 bases. In some embodiments, each R of formula (IA) 2 Together, they form a targeting sequence of 18 to 27 bases. In some embodiments, each R of formula (IA) 2 Together, they form a target sequence of 20 to 25 bases.

[0234] In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 30 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of at least 13 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence up to 30 base lengths in length.

[0235] In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 23 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 19 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 18 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 17 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 16 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 15 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13-14 base lengths.

[0236] In another embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 21 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 19 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 18 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 17 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 16 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14-15 base lengths.

[0237] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 28 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15-20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 19 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 18 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 17 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15-16 base lengths.

[0238] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 24 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 19 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 18 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16-17 base lengths.

[0239] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 29 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17-19 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and when combined, form a targeted sequence of 17-18 base lengths.

[0240] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 23 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18-19 base lengths.

[0241] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 26 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19-20 base lengths.

[0242] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 28 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20-25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20-22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20-21 base lengths.

[0243] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 29 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21-22 base lengths.

[0244] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 29 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22-24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22-23 base lengths.

[0245] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 28 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23-24 base lengths.

[0246] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 to 26 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24-25 base lengths.

[0247] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25-30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25-29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25-28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25-27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25-26 base lengths.

[0248] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 26 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 26 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 26-28 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 26-27 base lengths.

[0249] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 27-30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 27-29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 27-28 base lengths.

[0250] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 28-30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 28-29 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 28-30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 29-30 base lengths.

[0251] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence with a length of 13 bases.

[0252] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a 15-base-length targeted sequence. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a 20-base-length targeted sequence. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 base lengths. In another embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 26 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence with a length of 27 bases. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 28 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 29 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a 30-base-length targeted sequence. In certain embodiments of the antisense oligomer of structural formula (IA) or its pharmaceutically acceptable salt, the salt is an HCl salt. Formula (II)

[0253] In some embodiments, the antisense oligomer of formula (I) is an oligomer of formula (II): [ka] or a pharmaceutically acceptable salt thereof During the ceremony, Each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeting sequence of 13-30 bases complementary to the target region within the pre-mRNA of the human uromodulin (UMOD) gene (SEQ ID NO: 1), and the target region is an intron / exon junction or an internal exon region of the human UMOD gene pre-mRNA. t is between 11 and 28. G is selected from -H, -C(O)C1~6-alkyl, benzoyl, and stearoyl. Antisense oligomers or pharmaceutically acceptable salts thereof are provided herein.

[0254] In some embodiments, t in formula (II) is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28. In some embodiments, each R in formula (II) 2 Together, they form a targeting sequence of 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 bases. In some embodiments, each R of formula (II) 2 Together, they form a target sequence of 18 to 27 bases. In some embodiments, each R of formula (II) 2 Together, they form a targeting sequence of 20 to 25 bases. In certain embodiments of formula (II), the pharmaceutically acceptable salt is the HCl salt.

[0255] In one embodiment, t in equation (II) is an integer between 11 and 28. In one embodiment, t in equation (II) is at least 11. In one embodiment, t in equation (II) is at most 28.

[0256] In one embodiment, t is 11-28. In one embodiment, t is 11-27. In one embodiment, t is 11-26. In one embodiment, t is 11-25. In one embodiment, t is 11-24. In one embodiment, t is 11-23. In one embodiment, t is 11-22. In one embodiment, t is 11-21. In one embodiment, t is 11-20. In one embodiment, t is 11-19. In one embodiment, t is 11-18. In one embodiment, t is 11-17. In one embodiment, t is 11-16. In one embodiment, t is 11-15. In one embodiment, t is 11-14. In one embodiment, t is 11-13. In one embodiment, t is 11-12. In one embodiment, t is 12-28. In one embodiment, t is 12-27. In one embodiment, t is 12-26. In one embodiment, t is 12-25. In one embodiment, t is 12-24. In one embodiment, t is 12-23. In one embodiment, t is 12-22. In one embodiment, t is 12-21. In one embodiment, t is 12-20. In one embodiment, t is 12-19. In one embodiment, t is 12-18. In one embodiment, t is 12-17. In one embodiment, t is 12-16. In one embodiment, t is 12-15. In one embodiment, t is 12-14. In one embodiment, t is 12-13. In one embodiment, t is 13-28. In one embodiment, t is 13-27. In one embodiment, t is 13-26. In one embodiment, t is 13-25. In one embodiment, t is 13-24. In one embodiment, t is 13-23. In one embodiment, t is 13-22. In one embodiment, t is 13-21. In another embodiment, t is 13-20. In another embodiment, t is 13-19. In another embodiment, t is 13-18. In another embodiment, t is 13-17. In another embodiment, t is 13-16. In another embodiment, t is 13-15. In another embodiment, t is 13-14. In another embodiment, t is 14-28. In another embodiment, t is 14-27.In one embodiment, t is 14-26. In one embodiment, t is 14-25. In one embodiment, t is 14-24. In one embodiment, t is 14-23. In one embodiment, t is 14-22. In one embodiment, t is 14-21. In one embodiment, t is 14-20. In one embodiment, t is 14-19. In one embodiment, t is 14-18. In one embodiment, t is 14-17. In one embodiment, t is 14-16. In one embodiment, t is 14-15. In one embodiment, t is 15-28. In one embodiment, t is 15-27. In one embodiment, t is 15-26. In one embodiment, t is 15-25. In one embodiment, t is 15-24. In one embodiment, t is 15-23. In one embodiment, t is 15-22. In one embodiment, t is 15-21. In one embodiment, t is 15-20. In one embodiment, t is 15-19. In one embodiment, t is 15-18. In one embodiment, t is 15-17. In one embodiment, t is 15-16. In one embodiment, t is 16-28. In one embodiment, t is 16-27. In one embodiment, t is 16-26. In one embodiment, t is 16-25. In one embodiment, t is 16-24. In one embodiment, t is 16-23. In one embodiment, t is 16-22. In one embodiment, t is 16-21. In one embodiment, t is 16-20. In one embodiment, t is 16-19. In one embodiment, t is 16-18. In one embodiment, t is 16-17. In one embodiment, t is 17-28. In one embodiment, t is 17-27. In one embodiment, t is 17-26. In one embodiment, t is 17-25. In another embodiment, t is 17-24. In another embodiment, t is 17-23. In another embodiment, t is 17-22. In another embodiment, t is 17-21. In another embodiment, t is 17-20. In another embodiment, t is 17-19. In another embodiment, t is 17-18. In another embodiment, t is 18-28. In another embodiment, t is 18-27.In one embodiment, t is 18-26. In one embodiment, t is 18-25. In one embodiment, t is 18-24. In one embodiment, t is 18-23. In one embodiment, t is 18-22. In one embodiment, t is 18-21. In one embodiment, t is 18-20. In one embodiment, t is 18-19. In one embodiment, t is 19-28. In one embodiment, t is 19-27. In one embodiment, t is 19-26. In one embodiment, t is 19-25. In one embodiment, t is 19-24. In one embodiment, t is 19-23. In one embodiment, t is 19-22. In one embodiment, t is 19-21. In one embodiment, t is 19-20. In one embodiment, t is 20-28. In one embodiment, t is 20-27. In one embodiment, t is 20-26. In one embodiment, t is 20-25. In one embodiment, t is 20-24. In one embodiment, t is 20-23. In one embodiment, t is 20-22. In one embodiment, t is 20-21. In one embodiment, t is 21-28. In one embodiment, t is 21-27. In one embodiment, t is 21-26. In one embodiment, t is 21-25. In one embodiment, t is 21-24. In one embodiment, t is 21-23. In one embodiment, t is 21-22. In one embodiment, t is 22-28. In one embodiment, t is 22-27. In one embodiment, t is 22-26. In one embodiment, t is 22-25. In one embodiment, t is 22-24. In one embodiment, t is 22-23. In one embodiment, t is 23-28. In one embodiment, t is 23-27. In one embodiment, t is 23-26. In one embodiment, t is 23-25. In one embodiment, t is 23-24. In one embodiment, t is 24-28. In one embodiment, t is 24-27. In one embodiment, t is 24-26. In one embodiment, t is 24-25. In one embodiment, t is 25-28. In one embodiment, t is 25-27. In one embodiment, t is 25-26.In another embodiment, t is 26-30. In one embodiment, t is 26-29. In one embodiment, t is 26-28. In one embodiment, t is 26-27. In one embodiment, t is 27-28.

[0257] In one embodiment, t is 11. In one embodiment, t is 12. In one embodiment, t is 13. In one embodiment, t is 14. In one embodiment, t is 15. In one embodiment, t is 16. In one embodiment, t is 17. In one embodiment, t is 18. In one embodiment, t is 19. In one embodiment, t is 20. In one embodiment, t is 21. In one embodiment, t is 22. In one embodiment, t is 23. In one embodiment, t is 24. In one embodiment, t is 25. In one embodiment, t is 26. In one embodiment, t is 27. In one embodiment, t is 28. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of at least 13 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence up to 30 base lengths in length.

[0258] In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 29 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 19 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 18 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 17 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 16 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 15 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13-14 base lengths.

[0259] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 27 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 19 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 18 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 17 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 16 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14-15 base lengths.

[0260] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 24 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15-20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 19 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 18 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15 to 17 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 15-16 base lengths.

[0261] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 30 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 20 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 19 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 to 18 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16-17 base lengths.

[0262] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 25 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 to 20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17-19 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and when combined, form a targeted sequence of 17-18 base lengths.

[0263] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 29 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 to 20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18-19 base lengths.

[0264] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 22 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19-20 base lengths.

[0265] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20-25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 24 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20-22 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 20-21 base lengths.

[0266] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 25 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21-22 base lengths.

[0267] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 to 25 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22-24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22-23 base lengths.

[0268] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23-24 base lengths.

[0269] In another embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24-25 base lengths.

[0270] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25-30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25-29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25-28 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25-27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25-26 base lengths.

[0271] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 26 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 26 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 26-28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 26-27 base lengths.

[0272] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 27-30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 27-29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 27-28 base lengths.

[0273] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 28-30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 28-29 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 28-30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 29-30 base lengths.

[0274] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence with a length of 13 bases.

[0275] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a 15-base-length targeted sequence. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 16 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 17 base lengths. In another embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 18 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 19 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a 20-base-length targeted sequence. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 21 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 22 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 23 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 24 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 25 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 26 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence with a length of 27 bases. In another embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 28 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 29 base lengths. In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a 30-base-length targeted sequence. In certain embodiments of the antisense oligomer of structural formula (II) or its pharmaceutically acceptable salt, the salt is an HCl salt. Formula (III)

[0276] In some embodiments, an antisense oligomer structural Formula (III): [ka] or a pharmaceutically acceptable salt thereof During the ceremony, Each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeting sequence of 13-30 bases complementary to the target region within the pre-mRNA of the human uromodulin (UMOD) gene (SEQ ID NO: 1), and the target region is an intron / exon junction or an internal exon region of the human UMOD gene pre-mRNA. n is between 11 and 28. Antisense oligomers or pharmaceutically acceptable salts thereof are provided herein.

[0277] In some embodiments, n in formula (III) is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28. In some embodiments, each R in formula (III) 2Together, they form a targeting sequence of 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 bases. In some embodiments, each R of formula (III) 2 Together, they form a targeting sequence of 18 to 27 bases. In some embodiments, each R of formula (III) 2 Together, they form a target sequence of 20 to 25 bases.

[0278] In some embodiments, n is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28. In some embodiments, each R 2 Together, they form a targeting sequence of 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 bases. In some embodiments, each R 2 Together, they form a target sequence of 18 to 27 bases. In some embodiments, each R 2 Together, they form a target sequence of 20 to 25 bases.

[0279] In some embodiments, n is an integer between 11 and 28. In some embodiments, n is at least 11. In some embodiments, n is at most 28. In some embodiments, n is between 11 and 28. In some embodiments, n is between 11 and 27. In some embodiments, n is between 11 and 26. In some embodiments, n is between 11 and 25. In some embodiments, n is between 11 and 24. In some embodiments, n is between 11 and 23. In some embodiments, n is between 11 and 22. In some embodiments, n is between 11 and 21. In some embodiments, n is between 11 and 20. In some embodiments, n is between 11 and 19. In some embodiments, n is between 11 and 18. In some embodiments, n is between 11 and 17. In some embodiments, n is between 11 and 16. In some embodiments, n is between 11 and 15. In some embodiments, n is between 11 and 14. In some embodiments, n is between 11 and 13. In one embodiment, n is 11-12. In one embodiment, n is 12-28. In one embodiment, n is 12-27. In one embodiment, n is 12-26. In one embodiment, n is 12-25. In one embodiment, n is 12-24. In one embodiment, n is 12-23. In one embodiment, n is 12-22. In one embodiment, n is 12-21. In one embodiment, n is 12-20. In one embodiment, n is 12-19. In one embodiment, n is 12-18. In one embodiment, n is 12-17. In one embodiment, n is 12-16. In one embodiment, n is 12-15. In one embodiment, n is 12-14. In one embodiment, n is 12-13. In one embodiment, n is 13-28. In one embodiment, n is 13 to 27. In one embodiment, n is 13 to 26. In one embodiment, n is 13 to 25. In one embodiment, n is 13 to 24. In one embodiment, n is 13 to 23. In one embodiment, n is 13 to 22. In one embodiment, n is 13 to 21. In one embodiment, n is 13 to 20. In one embodiment, n is 13 to 19. In one embodiment, n is 13 to 18.In one embodiment, n is 13-17. In one embodiment, n is 13-16. In one embodiment, n is 13-15. In one embodiment, n is 13-14. In one embodiment, n is 14-28. In one embodiment, n is 14-27. In one embodiment, n is 14-26. In one embodiment, n is 14-25. In one embodiment, n is 14-24. In one embodiment, n is 14-23. In one embodiment, n is 14-22. In one embodiment, n is 14-21. In one embodiment, n is 14-20. In one embodiment, n is 14-19. In one embodiment, n is 14-18. In one embodiment, n is 14-17. In one embodiment, n is 14-16. In one embodiment, n is 14-15. In one embodiment, n is 15-28. In one embodiment, n is 15-27. In one embodiment, n is 15-26. In one embodiment, n is 15-25. In one embodiment, n is 15-24. In one embodiment, n is 15-23. In one embodiment, n is 15-22. In one embodiment, n is 15-21. In one embodiment, n is 15-20. In one embodiment, n is 15-19. In one embodiment, n is 15-18. In one embodiment, n is 15-17. In one embodiment, n is 15-16. In one embodiment, n is 16-28. In one embodiment, n is 16-27. In one embodiment, n is 16-26. In one embodiment, n is 16-25. In one embodiment, n is 16-24. In one embodiment, n is 16-23. In one embodiment, n is 16-22. In one embodiment, n is 16-21. In one embodiment, n is 16-20. In one embodiment, n is 16-19. In one embodiment, n is 16-18. In one embodiment, n is 16-17. In one embodiment, n is 17-28. In one embodiment, n is 17-27. In one embodiment, n is 17-26. In one embodiment, n is 17-25.In one embodiment, n is 17-24. In one embodiment, n is 17-23. In one embodiment, n is 17-22. In one embodiment, n is 17-21. In one embodiment, n is 17-20. In one embodiment, n is 17-19. In one embodiment, n is 17-18. In one embodiment, n is 18-28. In one embodiment, n is 18-27. In one embodiment, n is 18-26. In one embodiment, n is 18-25. In one embodiment, n is 18-24. In one embodiment, n is 18-23. In one embodiment, n is 18-22. In one embodiment, n is 18-21. In one embodiment, n is 18-20. In one embodiment, n is 18-19. In one embodiment, n is 19-28. In one embodiment, n is 19-27. In one embodiment, n is 19-26. In one embodiment, n is 19-25. In one embodiment, n is 19-24. In one embodiment, n is 19-23. In one embodiment, n is 19-22. In one embodiment, n is 19-21. In one embodiment, n is 19-20. In one embodiment, n is 20-28. In one embodiment, n is 20-27. In one embodiment, n is 20-26. In one embodiment, n is 20-25. In one embodiment, n is 20-24. In one embodiment, n is 20-23. In one embodiment, n is 20-22. In one embodiment, n is 20-21. In one embodiment, n is 21-28. In one embodiment, n is 21-27. In one embodiment, n is 21-26. In one embodiment, n is 21-25. In one embodiment, n is 21-24. In one embodiment, n is 21-23. In one embodiment, n is 21-22. In one embodiment, n is 22-28. In one embodiment, n is 22-27. In one embodiment, n is 22-26. In one embodiment, n is 22-25. In one embodiment, n is 22-24. In one embodiment, n is 22-23.In one embodiment, n is 23-28. In one embodiment, n is 23-27. In one embodiment, n is 23-26. In one embodiment, n is 23-25. In one embodiment, n is 23-24. In one embodiment, n is 24-28. In one embodiment, n is 24-27. In one embodiment, n is 24-26. In one embodiment, n is 24-25. In one embodiment, n is 25-28. In one embodiment, n is 25-27. In one embodiment, n is 25-26. In another embodiment, n is 26-30. In one embodiment, n is 26-29. In one embodiment, n is 26-28. In one embodiment, n is 26-27. In one embodiment, n is 27-28.

[0280] In one embodiment, n is 11. In one embodiment, n is 12. In one embodiment, n is 13. In one embodiment, n is 14. In one embodiment, n is 15. In one embodiment, n is 16. In one embodiment, n is 17. In one embodiment, n is 18. In one embodiment, n is 19. In one embodiment, n is 20. In one embodiment, n is 21. In one embodiment, n is 22. In one embodiment, n is 23. In one embodiment, n is 24. In one embodiment, n is 25. In one embodiment, n is 26. In one embodiment, n is 27. In one embodiment, n is 28.

[0281] In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 30 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of at least 13 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence up to 30 base lengths in length.

[0282] In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 27 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 26 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 25 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 24 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 23 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 22 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 21 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 20 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 19 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 18 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 17 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 16 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13 to 15 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 13-14 base lengths.

[0283] In another embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 30 base lengths. In one embodiment, each R 2These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 29 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a targeted sequence of 14 to 28 base lengths. In one embodiment, each R 2 These are selected from naturally occurring or non-naturally occurring nucleic acid bases that, independently and together, form a...

Claims

1. An antisense oligomer or a pharmaceutically acceptable salt thereof comprising a non-natural chemical skeleton and a targeting sequence of 13 to 30 bases in length that is complementary to a target region in the pre-mRNA of the human uromodulin (UMOD) gene represented by Sequence ID No. 1, wherein the target region is an intron / exon junction or an internal exon region of the human UMOD gene pre-mRNA.

2. The antisense oligomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the target region is an intron / exon junction or internal exon sequence of exon 2 (SEQ ID NO: 2), exon 5 (SEQ ID NO: 3), exon 6 (SEQ ID NO: 4), exon 8 (SEQ ID NO: 5), or exon 9 (SEQ ID NO: 6).

3. The antisense oligomer or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the target region is an intron / exon junction or an internal exon region of exon 2 (SEQ ID NO: 2).

4. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the target region is selected from H2A(-15+10), H2A(+1+25), H2A(+26+50), H2A(+51+75), H2A(+85+104), H2A(+86+105), H2A(+95+119), H2A(+101+125), H2A(+110+129), H2A(+118+137), H2A(+126+150), and H2A(+151+175).

5. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the targeted sequence comprises a sequence selected from sequence numbers 11 to 17, 20, 23, and 26 to 28.

6. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the target region is within the range from the 51st to the 119th nucleotide from the 5' end of exon 2 (SEQ ID NO: 2) of the human UMOD gene pre-mRNA.

7. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or 6, wherein the target region is within the range from the 51st to the 105th nucleotide from the 5' end of exon 2 (SEQ ID NO: 2) of the human UMOD gene pre-mRNA.

8. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, 6, or 7, wherein the target region is H2A(+51+75).

9. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or 6 to 8, wherein the targeted sequence comprises SEQ ID NO:

14.

10. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the target region is within the range from nucleotide 85 to nucleotide 119 from the 5' end of exon 2 (SEQ ID NO: 2) of the human UMOD gene pre-mRNA.

11. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or 10, wherein the target region is selected from H2A(+85+104), H2A(+86+105), and H2A(+95+119).

12. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, 10, or 11, wherein the targeted sequence comprises a sequence selected from sequence numbers 15 to 17.

13. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the target region is within the range from the 15th nucleotide of intron 1 measured from the 5' end of exon 2 (sequence number 2) to the 25th nucleotide of exon 2 measured from the 5' end of exon 2 (sequence number 2).

14. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or 13, wherein the target region is selected from H2A(-15+10) and H2A(+1+25).

15. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or 13 to 14, wherein the targeted sequence comprises sequence number 12 or 13.

16. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the target region is within the range from the 118th to the 150th nucleotide of exon 2, measured from the 5' end of exon 2 (sequence number 2).

17. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or 16, wherein the target region is selected from H2A(+118+137) and H2A(+126+150).

18. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or 16 to 17, wherein the targeted sequence comprises a sequence selected from sequence numbers 26 and 27.

19. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the target region is selected from H2A(+101+125), H2A(+110+129), and H2A(+151+175).

20. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or 19, wherein the targeted sequence comprises a sequence selected from sequence numbers 20, 21, and 28.

21. The antisense oligomer or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the target region is an intron / exon junction or an internal exon region of exon 5 (SEQ ID NO: 3).

22. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 21, wherein the target region is selected from H5A(-15+5), H5A(-14+6), H5A(-11+9), H5A(-10+10), H5A(+51+75), H5A(+76+100), H5A(+78+95), H5A(+80+97), H5A(+82+99), H5A(+126+150), H5A(+153+172), H5A(+154+173), H5D(+18-2), H5D(+16-4), H5D(+14-6), H5D(+13-7), and H5D(+12-8).

23. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 21 to 22, wherein the targeted sequence comprises a sequence selected from SEQ ID NOs: 30 to 33, 35, 37 to 40, 44, 46 to 48, and 50 to 53.

24. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 21, wherein the target region is within the range from the 15th nucleotide of intron 4 measured from the 5' end of exon 5 (sequence number 3) of the human UMOD gene pre-mRNA to the 10th nucleotide of exon 5 measured from the 5' end of exon 5 (sequence number 3).

25. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 21 to 22, or 24, wherein the target region is selected from H5A(-15+5), H5A(-14+6), H5A(-11+9), and H5A(-10+10).

26. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 21 to 22, or 24 to 25, wherein the target region is H5A(-15+5).

27. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 21-22, or 24-26, wherein the targeted sequence comprises SEQ ID NO:

30.

28. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 21 to 22, or 24 to 25, wherein the target region is H5A(-14+6).

29. The antisense oligomer according to 1-2, 21-22, 24-25, or 29, wherein the targeted sequence includes SEQ ID NO: 31, or a pharmaceutically acceptable salt thereof.

30. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 21 to 22, or 24 to 25, wherein the target region is H5A(-11+9).

31. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 21-22, 24-25, or 30, wherein the targeted sequence comprises SEQ ID NO:

32.

32. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 21 to 22, or 24 to 25, wherein the target region is H5A(-10+10).

33. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 21-22, 24-25, or 32, wherein the targeted sequence comprises SEQ ID NO:

33.

34. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 21 to 22, wherein the target region is H5A (+51+75).

35. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 21 to 22, or 34, wherein the targeted sequence comprises SEQ ID NO:

35.

36. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 21, wherein the target region is within the range of 76 to 100 nucleotides measured from the 5' end of exon 5 (SEQ ID NO: 3) of the human UMOD gene pre-mRNA.

37. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 21 to 22, or 36, wherein the target region is selected from H5A(+76+100), H5A(+78+95), H5A(+80+97), and H5A(+82+99).

38. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 21 to 22, or 36 to 37, wherein the target region is H5A (+76+100).

39. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 21-22, or 36-38, wherein the targeted sequence comprises SEQ ID NO:

37.

40. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 21-22, or 36-37, wherein the target region is H5A (+78+95).

41. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 21-22, 36-37, or 40, wherein the targeted sequence comprises SEQ ID NO:

38.

42. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 21-22, or 36-37, wherein the target region is H5A (+80+97).

43. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 21-22, 36-37, or 42, wherein the targeted sequence comprises SEQ ID NO:

39.

44. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 21 to 22, or 36 to 37, wherein the target region is H5A (+82+99).

45. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 21-22, 36-37, or 44, wherein the targeted sequence comprises SEQ ID NO:

40.

46. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 21 to 22, wherein the target region is H5A (+126+150).

47. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 21-22, or 46, wherein the targeted sequence comprises SEQ ID NO:

44.

48. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 21, wherein the target region is within the range of nucleotides 153 to 173 measured from the 5' end of exon 5 (SEQ ID NO: 3) of the human UMOD gene pre-mRNA.

49. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 21 to 22, or 48, wherein the target region is selected from H5A(+153+172) and H5A(+154+173).

50. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 21-22, or 48-49, wherein the targeted sequence comprises a sequence selected from sequence numbers 46 and 47.

51. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 21, wherein the target region is within the range from the 18th nucleotide of exon 5 measured from the 3' end of exon 5 (sequence number 3) to the 8th nucleotide of intron 5 measured from the 3' end of exon 5 (sequence number 3).

52. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 21 to 22, or 51, wherein the target region is selected from H5D(+18-2), H5D(+16-4), H5D(+14-6), H5D(+13-7), and H5D(+12-8).

53. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 21-22, or 51-52, wherein the targeted sequence comprises a sequence selected from sequence numbers 48 and 50-53.

54. The antisense oligomer or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the target region is an intron / exon junction or an internal exon region of exon 6 (SEQ ID NO: 4).

55. The target region is H6A(+26+50), H6A(+48+67), H6A(+49+68), H6A(+58+77), H6A(+59+78), H6A(+76+100), H6A(+101+125), H6A(+101+120), H6A(+110+129), H6A(+111+130), H6A(+112+131), H6A(+113+132), H6A(+119+138) An antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 54, selected from H6A(+120+139), H6A(+121+140), H6A(+122+141), H6A(+123+142), H6A(+124+143), H6A(+130+149), H6D(+24-1), H6D(+15-5), and H6D(+14-6).

56. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 54 to 55, wherein the targeted sequence comprises a sequence selected from sequence numbers 57 to 59, 61, 62, 64, and 66 to 81.

57. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 54 to 55, wherein the target region is H6A (+26+50).

58. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 54 to 57, wherein the targeted sequence comprises sequence number 57.

59. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 54, wherein the target region is within the range of 48 to 78 nucleotides measured from the 5' end of exon 6 (SEQ ID NO: 4) of the human UMOD gene pre-mRNA.

60. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 59, wherein the target region is selected from H6A(+48+67), H6A(+49+68), H6A(+58+77), and H6A(+59+78).

61. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 54-55, or 59-60, wherein the targeted sequence comprises a sequence selected from sequence numbers 58, 59, 61, and 62.

62. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 54, wherein the target region is within the range of nucleotides 58 to 78 measured from the 5' end of exon 6 (SEQ ID NO: 4) of the human UMOD gene pre-mRNA.

63. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 62, wherein the target region is selected from H6A(+58+77) and H6A(+59+78).

64. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 62 to 63, wherein the target region is H6A (+58+77).

65. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 62 to 64, wherein the targeted sequence comprises SEQ ID NO:

61.

66. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 62 to 63, wherein the target region is H6A (+59+78).

67. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54, 62 to 63, or 66, wherein the targeted sequence comprises SEQ ID NO:

62.

68. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 54 to 55, wherein the target region is H6A (+76+100).

69. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 68, wherein the targeted sequence comprises sequence number 64.

70. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 54, wherein the target region is within the range of nucleotides 101 to 132 measured from the 5' end of exon 6 (SEQ ID NO: 4) of the human UMOD gene pre-mRNA.

71. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 70, wherein the target region is selected from H6A(+101+125), H6A(+101+120), H6A(+110+129), H6A(+111+130), H6A(+112+131), and H6A(+113+132).

72. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 54-55, or 70-71, wherein the targeted sequence comprises a sequence selected from sequence numbers 66-71.

73. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 54, wherein the target region is within the range of nucleotides 111 to 132 measured from the 5' end of exon 6 (SEQ ID NO: 4) of the human UMOD gene pre-mRNA.

74. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 73, wherein the target region is selected from H6A(+111+130), H6A(+112+131), and H6A(+113+132).

75. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 73 to 74, wherein the target region is H6A (+111+130).

76. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 54-55, or 73-75, wherein the targeted sequence comprises SEQ ID NO:

69.

77. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 73 to 74, wherein the target region is H6A (+112+131).

78. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 54-55, 73-74, or 77, wherein the targeted sequence comprises SEQ ID NO:

70.

79. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 73 to 74, wherein the target region is H6A (+113+132).

80. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, 73 to 74, or 79, wherein the targeted sequence comprises SEQ ID NO:

71.

81. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 54, wherein the target region is within the range of nucleotides 119 to 149 measured from the 5' end of exon 6 (SEQ ID NO: 4) of the human UMOD gene pre-mRNA.

82. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 81, wherein the target region is selected from H6A(+119+138), H6A(+120+139), H6A(+121+140), H6A(+122+141), H6A(+123+142), H6A(+124+143), and H6A(+130+149).

83. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 54-55, or 81-82, wherein the targeted sequence includes a sequence selected from sequence numbers 72-78.

84. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 54, wherein the target region is within the range of nucleotides 119 to 141 measured from the 5' end of exon 6 (SEQ ID NO: 4) of the human UMOD gene pre-mRNA.

85. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 84, wherein the target region is selected from H6A(+119+138), H6A(+120+139), H6A(+121+140), and H6A(+122+141).

86. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 54-55, or 84-85, wherein the targeted sequence comprises a sequence selected from sequence numbers 72-75.

87. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 54, wherein the target region is within the range of nucleotides 120 to 141 measured from the 5' end of exon 6 (SEQ ID NO: 4) of the human UMOD gene pre-mRNA.

88. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 87, wherein the target region is selected from H6A(+120+139), H6A(+121+140), and H6A(+122+141).

89. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 87 to 88, wherein the target region is H6A (+120+139).

90. The targeting sequence comprises the antisense oligomers according to 1-2, 54-55, or 87-89, or a pharmaceutically acceptable salt thereof.

91. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 87 to 88, wherein the target region is H6A (+121+140).

92. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 54-55, 87-88, or 91, wherein the targeted sequence comprises sequence number 74.

93. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 87 to 88, wherein the target region is H6A (+122+141).

94. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 54-55, 87-88, or 93, wherein the targeted sequence comprises SEQ ID NO:

75.

95. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 54, wherein the target region is within the range of nucleotides 123 to 149 measured from the 5' end of exon 6 (SEQ ID NO: 4) of the human UMOD gene pre-mRNA.

96. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 95, wherein the target region is selected from H6A(+123+142), H6A(+124+143), and H6A(+130+149).

97. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 54-55, or 95-96, wherein the targeted sequence comprises a sequence selected from sequence numbers 76-78.

98. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 54, wherein the target is within the range from the 24th nucleotide of exon 6 (SEQ ID NO: 4), measured from the 3' end of exon 6 (SEQ ID NO: 4) of the human UMOD gene pre-mRNA, to the 6th nucleotide of intron 6, measured from the 3' end of exon 6 (SEQ ID NO: 4).

99. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 98, wherein the target region is selected from H6D(+24-1), H6D(+15-5), and H6D(+14-6).

100. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 54-55, or 98-99, wherein the targeted sequence comprises a sequence selected from sequence numbers 79-81.

101. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 54, wherein the target region is within the range from the 15th nucleotide of exon 6 (SEQ ID NO: 4), measured from the 3' end of exon 6 (SEQ ID NO: 4) of the human UMOD gene pre-mRNA, to the 6th nucleotide of intron 6, measured from the 3' end of exon 6 (SEQ ID NO: 4).

102. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 101, wherein the target region is selected from H6D(+15-5) and H6D(+14-6).

103. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 101 to 102, wherein the target region is H6A (+15-5).

104. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 101 to 103, wherein the targeted sequence comprises sequence number 80.

105. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54 to 55, or 101 to 102, wherein the target region is H6A (+14-6).

106. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 54, 101 to 102, or 105, wherein the targeted sequence comprises sequence number 81.

107. The antisense oligomer or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the target region is an intron / exon junction or an internal exon region of exon 8 (SEQ ID NO: 5).

108. The aforementioned target region is H8A(-2+23), H8A(+51+75), H8A(+60+79), H8A(+61+80), H8A(+68+87), H8A(+69+88), H8A(+70+89), H8A(+76+95), H8A(+76+100), H8A(+77+96), H8A(+78+97), H8A(+79+98), H8A(+81+100), H8A(+82+101), H8A(+83+102), H8A(+86+105), H8A(+94+113), H8A(+95+114), H8A( An antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 107, selected from H8A(+96+115), H8A(+101+125), H8A(+102+121), H8A(+103+122), H8A(+104+123), H8A(+105+124), H8A(+120+139), H8A(+121+140), H8A(+122+141), H8A(+126+150), H8A(+128+147), H8A(+129+148), and H8D(+12-13).

109. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 107 to 108, wherein the targeted sequence comprises a sequence selected from SEQ ID NOs. 82, 84 to 86, 89 to 96, 98 to 115, and 120.

110. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 107 to 108, wherein the target region is H8A(-2+23).

111. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 107 to 109, wherein the targeted sequence comprises SEQ ID NO:

82.

112. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 107, wherein the target region is within the range of nucleotides 51 to 80 measured from the 5' end of exon 8 (SEQ ID NO: 5) of the human UMOD gene pre-mRNA.

113. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 107 to 108, or 112, wherein the target region is selected from H8A(+51+75), H8A(+60+79), and H8A(+61+80).

114. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 107-108, or 112-113, wherein the targeted sequence includes a sequence selected from sequence numbers 84-86.

115. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 107, wherein the target region is within the range of 68 to 100 nucleotides measured from the 5' end of exon 8 (SEQ ID NO: 5) of the human UMOD gene pre-mRNA.

116. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 107 to 108, or 115, wherein the target region is selected from H8A(+68+87), H8A(+69+88), H8A(+70+89), H8A(+76+95), H8A(+76+100), H8A(+77+96), H8A(+78+97), and H8A(+79+98).

117. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 107 to 108, or 115 to 116, wherein the targeted sequence includes a sequence selected from sequence numbers 89 to 96.

118. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 107, wherein the target region is within the range of nucleotides 76 and 100 measured from the 5' end of exon 8 (SEQ ID NO: 5) of the human UMOD gene pre-mRNA.

119. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 107-108, or 118, wherein the target region is selected from H8A(+76+95), H8A(+77+96), H8A(+78+97), and H8A(+79+98).

120. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 107-108, or 118-119, wherein the targeted sequence comprises a sequence selected from sequence numbers 92 and 94-96.

121. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 107, wherein the target region is within the range of nucleotides 81 to 105 measured from the 5' end of exon 8 (SEQ ID NO: 5) of the human UMOD gene pre-mRNA.

122. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 107-108, or 121, wherein the target region is selected from H8A(+81+100), H8A(+82+101), H8A(+83+102), and H8A(+86+105).

123. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 107-108, or 121-122, wherein the targeted sequence includes a sequence selected from sequence numbers 98-101.

124. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 107, wherein the target region is within the range of nucleotides 94 to 124 measured from the 5' end of exon 8 (SEQ ID NO: 5) of the human UMOD gene pre-mRNA.

125. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 107-108, or 124, wherein the target region is selected from H8A(+94+113), H8A(+95+114), H8A(+96+115), H8A(+101+125), H8A(+102+121), H8A(+103+122), H8A(+104+123), and H8A(+105+124).

126. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 107-108, or 124-125, wherein the targeted sequence includes a sequence selected from sequence numbers 102-109.

127. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 107, wherein the target region is within the range of nucleotides 120 to 148 measured from the 5' end of exon 8 (SEQ ID NO: 5) of the human UMOD gene pre-mRNA.

128. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 107-108, or 127, wherein the target region is selected from H8A(+120+139), H8A(+121+140), H8A(+122+141), H8A(+126+150), H8A(+128+147), and H8A(+129+148).

129. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 107 to 108, or 127 to 128, wherein the targeted sequence includes a sequence selected from sequence numbers 110 to 115.

130. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 107, wherein the target region is within the range of nucleotides 126 to 148 measured from the 5' end of exon 8 (SEQ ID NO: 5) of the human UMOD gene pre-mRNA.

131. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 107 to 108, or 130, wherein the target region is selected from H8A(+126+150), H8A(+128+147), and H8A(+129+148).

132. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 107 to 108, or 130 to 131, wherein the target region is H8A (+126+150).

133. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 107 to 108, or 130 to 132, wherein the targeted sequence comprises sequence number 113.

134. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 107 to 108, or 130 to 131, wherein the target region is H8A (+128+147).

135. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 107-108, 130-131, or 134, wherein the targeted sequence comprises sequence number 114.

136. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 107 to 108, or 130 to 131, wherein the target region is H8A (+129+148).

137. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 107-108, 130-131, or 136, wherein the targeted sequence comprises sequence number 115.

138. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 107 to 108, wherein the target region is H8D (+12-13).

139. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 107 to 108, or 138, wherein the targeted sequence comprises sequence number 120.

140. The antisense oligomer or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the target region is an intron / exon junction or an internal exon region of exon 9 (SEQ ID NO: 6).

141. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 140, wherein the target region is selected from H9A(-5+20), H9A(+1+25), H9A(+51+75), and H9D(+7-18).

142. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 140 to 141, wherein the targeted sequence comprises a sequence selected from sequence numbers 121 to 124.

143. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 142, wherein the target region is within the range of the 5th nucleotide of intron 8 measured from the 5' end of exon 9 (sequence number 6) of the human UMOD gene pre-mRNA and the 25th nucleotide of exon 9 measured from the 5' end of exon 9 (sequence number 6).

144. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 140 to 141, or 143, wherein the target region is selected from H9A(-5+20) and H9A(+1+25).

145. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 140 to 141, or 143 to 144, wherein the targeted sequence comprises a sequence selected from sequence numbers 121 and 122.

146. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 140 to 141, wherein the target region is H9A (+51+75).

147. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 140 to 141, or 146, wherein the targeted sequence comprises sequence number 123.

148. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 140 to 141, wherein the target region is H9D (+7-18).

149. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 140 to 141, or 148, wherein the targeted sequence comprises sequence number 124.

150. An antisense oligomer according to any one of claims 1 to 149, selected from peptide nucleic acids, locked nucleic acids, phosphorodiamidate morpholino oligomers, 2'-OMe phosphorothioate oligomers, or combinations thereof, or a pharmaceutically acceptable salt thereof.

151. An antisense oligomer according to any one of claims 1 to 150, which is a phosphorodiamidate morpholino oligomer (PMO), or a pharmaceutically acceptable salt thereof.

152. An antisense oligomer according to any one of claims 1 to 151, further comprising a cell-permeable peptide, an antibody, a fragment of an antibody, an antigen-binding agent, at least one ligand, and a delivery agent selected from a combination thereof, or a pharmaceutically acceptable salt thereof.

153. An antisense oligomer according to any one of claims 1 to 152, covalently linked to a cell-permeable peptide, or a pharmaceutically acceptable salt thereof.

154. The antisense oligomer or a pharmaceutically acceptable salt thereof according to claim 153, which is covalently linked to the cell-permeable peptide by direct linkage, or via a linker selected from glycine amino acids, proline amino acids, glutamic acid amino acids, or isoglutamine amino acids.

155. The cell-permeable peptide is selected from rTAT (SEQ ID NO: 179), TAT (SEQ ID NO: 180), R ９ F ２ (SEQ ID NO: 181), R ５ F ２ R ４ (SEQ ID NO: 182), R ４ (SEQ ID NO: 183), R ５ (SEQ ID NO: 184), R ６ (SEQ ID NO: 185), R ７ (SEQ ID NO: 136), R ８ (SEQ ID NO: 137), R ９ (SEQ ID NO: 138), (RXR) ４ (SEQ ID NO: 139), (RXR) ５ (SEQ ID NO: 140), (RXRRBR) ２ (SEQ ID NO: 141), (RAR) ４ F ２ (SEQ ID NO: 142), (RGR) ４ F ２ (SEQ ID NO: 143), and RBRBYLIQFRBRRBR (SEQ ID NO: 144), where B represents beta-alanine (also represented as β-Ala or β), F represents phenylalanine, G represents glycine, L represents leucine, Q represents glutamine, R represents arginine, X represents 6-aminohexanoic acid (also represented as Ahx or α), and Y represents tyrosine, The antisense oligomer according to claim 153 or 154, or a pharmaceutically acceptable salt thereof.

156. Structure of equation (I): 【Chemistry 191】 It has, During the ceremony, A' is -OH, 【Chemistry 192】 Selected from, R ５ is -C(O)(O-alkyl) ｘ It is -OH, x is 3 to 10, and each alkyl group is independently C each time it appears. ２～６ - Is it alkyl? or R ５ H, -C(O)C １～６ -Alkyl, trityl, monomethoxytrityl, -(C １～６ -alkyl)-R ６ , - (C １～６ -heteroalkyl)-R ６ , -C ６～１０ -Aryl-R ６ , 5-10 member heteroaryl-R ６ , -C(O)O-(C １～６ -alkyl)-R ６ ,-C(O)O-aryl-R ６ ,-C(O)O-(5-10 member heteroaryl)-R ６ , and 【Chemistry 193】 Selected from, R ６ Mrityl, trimethoxytrityl 【Chemistry 194】 And, During the ceremony, Q is -C(O)(CH ２ ) ６ C(O)- or -C(O)(CH ２ ) ２ S ２ (CH ２ ) ２ C(O)-, R ７ is, -(CH ２ ) ２ OC(O)N(R) ８ ) ２ And R ８ is, -(CH ２ ) ６ NHC (=NH)NH ２ And, L is a linked amino acid, and L is covalently linked to the C-terminus of J by an amide bond. J is a cell-permeable peptide, G is -H, -C(O)C １～６ - Selected from alkyl, benzoyl, and stearoyl, G is covalently linked to J. An antisense oligomer according to any one of claims 1 to 155 or a pharmaceutically acceptable salt thereof.

157. E' is -H, -C １～６ -Alkyl, -C(O)C １～６ -alkyl, benzoyl, stearoyl, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl, and 【Chemistry 195】 An antisense oligomer according to claim 156, selected from the above, or a pharmaceutically acceptable salt thereof.

158. E' is -H, -C(O)CH ３ , benzoyl, stearoyl, trityl, 4-methoxytrityl, and 【Chemistry 196】 An antisense oligomer according to claim 156 or 157, selected from the above, or a pharmaceutically acceptable salt thereof.

159. A' is, 【Chemistry 197】 An antisense oligomer according to any one of claims 156 to 158, selected from the above, or a pharmaceutically acceptable salt thereof.

160. below: (1) A' 【Chemistry 198】 (2) E' is 【Chemistry 199】 An antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 156 to 159, wherein at least one of the following is true.

161. A' is, 【Chemistry 200】 Selected from, E' is, 【Chemical Engineering 201】 The antisense oligomer according to any one of claims 156 to 160 or a pharmaceutically acceptable salt thereof.

162. A' is, 【Chemical Engineering 202】 And, E' is H, -C(O)CH ３ Selected from trityl, 4-methoxytrityl, benzoyl, and stearoyl, An antisense oligomer according to any one of claims 156 to 160 or a pharmaceutically acceptable salt thereof.

163. Each R １ However, -N(CH ３ ) ２ The antisense oligomer according to any one of claims 156 to 162 or a pharmaceutically acceptable salt thereof.

164. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 156 to 163, wherein L is glycine, proline, or β-alanine.

165. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 156 to 164, wherein L is glycine.

166. An antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 156 to 164, wherein L is proline.

167. The antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 156 to 164, wherein L is β-alanine.

168. J is rTAT (SEQ ID NO: 179), TAT (SEQ ID NO: 180), R ９ F ２ (Sequence ID 181), R ５ F ２ R ４ (Sequence ID 182), R ４ (Sequence ID 183), R ５ (Sequence ID 184), R ６ (Sequence ID 185), R ７ (Sequence ID 136), R ８ (Sequence ID 137), R ９ (Sequence ID 138), (RXR) ４ (Sequence ID 139), (RXR) ５ (Sequence ID 140), (RXRRBR) ２ (Sequence ID 141), (RAR) ４ F ２ (Sequence ID 142), (RGR) ４ F ２ Selected from (SEQ ID NO: 143) and RBRBYLIQFRBRRRBR (SEQ ID NO: 144), where B represents beta-alanine (also represented as β-Ala or β), F represents phenylalanine, G represents glycine, L represents leucine, Q represents glutamine, R represents arginine, X represents 6-aminohexanoic acid (also represented as Ahx or α), and Y represents tyrosine. An antisense oligomer according to any one of claims 156 to 167 or a pharmaceutically acceptable salt thereof.

169. G is -H, -C(O)CH ３ An antisense oligomer according to any one of claims 156 to 168, selected from benzoyl and stearoyl, or a pharmaceutically acceptable salt thereof.

170. G is -H or -C(O)CH ３ The antisense oligomer according to any one of claims 156 to 169 or a pharmaceutically acceptable salt thereof.

171. An antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 156 to 170, wherein G is -H.

172. G is -C(O)CH ３ The antisense oligomer according to any one of claims 156 to 170 or a pharmaceutically acceptable salt thereof.

173. Structural formula (IA): 【Chemical 203】 (In the formula, A' is, 【Chemical 204】 (This is the part that is selected from) An antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 156 to 172.

174. Structural formula (II): 【Chemical 205】 An antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 156 to 172.

175. Structural formula (III): 【Chemical 206】 An antisense oligomer or a pharmaceutically acceptable salt thereof according to any one of claims 156 to 172 of the formula (wherein n is 11 to 28).

176. Structural formula (IV): 【Chemical 207】 (In the formula, n is between 11 and 28.) The antisense oligomer according to any one of claims 156 to 172.

177. Each R ２ The antisense oligomer or a pharmaceutically acceptable salt thereof according to claim 175 or 176, wherein together they form a targeted sequence having sequence number 37.

178. Each R ２ The antisense oligomer or a pharmaceutically acceptable salt thereof according to claim 175 or 176, wherein together they form a targeted sequence having sequence number 32.

179. Each R ２ The antisense oligomer or a pharmaceutically acceptable salt thereof according to claim 175 or 176, wherein together they form a targeted sequence having sequence number 70.

180. Each R ２ The antisense oligomer or a pharmaceutically acceptable salt thereof according to claim 175 or 176, wherein together they form a targeted sequence having sequence number 74.

181. Each R ２ The antisense oligomer or a pharmaceutically acceptable salt thereof according to claim 175 or 176, wherein together they form a targeted sequence having sequence number 62.

182. Each R ２ The antisense oligomer or a pharmaceutically acceptable salt thereof according to claim 175 or 176, wherein together they form a targeted sequence having sequence number 81.

183. Each R ２ The antisense oligomer or a pharmaceutically acceptable salt thereof according to claim 175 or 176, wherein together they form a targeted sequence having sequence number 114.

184. Each R ２ The antisense oligomer or a pharmaceutically acceptable salt thereof according to claim 175 or 176, wherein together they form a targeted sequence having sequence number 120. 【Request Item 185】 【Chemistry 208】 【Chemical Engineering 209】 【Chemical 210】 【Chemistry 211】 【Chemical Engineering 212】 【Chemistry 213】 【Chemical 214】 Antisense oligomers selected from the above. 【Request Item 186】 【Chemistry 215】 The antisense oligomer according to claim 185. 【Request Item 187】 【Chemistry 216】 The antisense oligomer according to claim 185. 【Request Item 188】 【Chemistry 217】 The antisense oligomer according to claim 185. 【Request Item 189】 【Chemistry 218】 The antisense oligomer according to claim 185. 【Request Item 190】 【Chemistry 219】 The antisense oligomer according to claim 185. 【Request Item 191】 【Chemistry 220】 The antisense oligomer according to claim 185. 【Request Item 192】 【Chemistry 221】 The antisense oligomer according to claim 185.

193. A pharmaceutical composition comprising an antisense oligomer according to any one of claims 1 to 192 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

194. A method for treating chronic kidney disease (CKD), comprising administering to a subject in need of such treatment a therapeutically effective amount of an antisense oligomer according to any one of claims 1 to 192 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 193.

195. A method for treating a disease associated with abnormal expression of uromodulin protein, comprising administering to a subject in need of such treatment a therapeutically effective amount of an antisense oligomer according to any one of claims 1 to 192 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 193.

196. A method for treating uromodulin-related kidney disease, comprising administering to a subject in need of such treatment a therapeutically effective amount of an antisense oligomer according to any one of claims 1 to 192 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 193.

197. The method according to any one of claims 194 to 196, wherein the disease is autosomal dominant kidney disorder.

198. The method according to claim 197, wherein the autosomal dominant kidney disorder is autosomal dominant tubulointerstitial kidney disease (ADTKD).

199. The method according to any one of claims 194 to 196, wherein the disease is autosomal dominant tubulointerstitial kidney disease - uromodulin (ADTKD-UMOD).

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