Compositions and methods for targeting insulin receptor isoform a (IR-a)

Abstract

Described herein are compounds, compositions, and methods for selectively targeting insulin receptor isoform A (IR-A). In some embodiments, the compounds, compositions, and methods comprise an antisense oligonucleotide (ASO) targeted to IR-A for treating or preventing diseases and conditions characterized by elevated IR-A expression. In some embodiments, the compounds, compositions, and methods selectively reduce an expression level of IR-A. In some embodiments, the ASO comprises a modified oligonucleotide comprising at least one modified internucleoside linkage and at least one modified sugar moiety. In some embodiments, the disease or condition comprises cancer, diabetes, or a combination thereof. Also described herein are compounds, compositions, and methods for inhibiting cancer cell growth or proliferation.

Description

[0001]COMPOSITIONS AND METHODS FOR TARGETING INSULIN RECEPTOR ISOFORM A (IR-A) CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No.63 / 612,639, filed on December 20, 2023, which is incorporated by reference herein in its entirety. REFERENCE TO SEQUENCE LISTING This application was filed with a Sequence Listing XML in ST.26 XML format in accordance with 37 C.F.R. § 1.831 and PCT Rule 13ter. The Sequence Listing XML file submitted in the USPTO Patent Center, “210953-0008-WO01_sequence_listing_xml_19-DEC-2024.xml,” was created on December 19, 2024, contains 26 sequences, has a file size of 56.0 kilobytes (57,344 bytes), and is incorporated by reference in its entirety into the specification. TECHNICAL FIELD This disclosure generally relates to compounds, compositions, and methods for targeting insulin receptor isoform A (IR-A) expression. BACKGROUND The insulin receptor (IR) is a transmembrane tyrosine kinase receptor implicated in the regulation of energy metabolism. Two IR isoforms exist, designated as insulin receptor isoform A (IR-A) and insulin receptor isoform B (IR-B), that are the result of alternative mRNA splicing. Specifically, IR-A is generated by an alternative splicing mechanism of the mRNA transcribed from the IR gene to skip exon 11, which is included in the mRNA of IR-B. Thus, IR-A and IR-B are structurally identical except for IR-A lacking a stretch of amino acid residues at the carboxy terminus of the IR α-subunit. While the expression profiles of the two isoforms are different, the isoforms are co- expressed in cells. The relative abundance of IR-A and IR-B is regulated by developmental stage- specific and tissue-specific factors. For example, IR-A is predominantly expressed in fetal cells and cancer cells, whereas IR-B is predominantly expressed in normal cells and differentiated insulin target cells. IR-A also has a higher affinity for insulin-like growth factors (IGFs) compared to IR-B, and IR-A is more mitogenic, meaning that it stimulates cell growth and division. What is needed are novel therapeutic compositions and methods for selectively targeting the expression of the two insulin receptor isoforms. Such compositions and methods would be useful in treating a variety of diseases and conditions including various cancers and diabetes. SUMMARY One embodiment described herein is a compound comprising a modified oligonucleotide having a nucleobase sequence comprising at least 14 contiguous nucleobases complementary to a target region of equal length of an insulin receptor isoform A (IR-A) mRNA transcript, wherein the target region comprises a target sequence overlapping with an exon 10-exon 12 splice junction region of the IR-A mRNA transcript. In one aspect, the modified oligonucleotide is single stranded. In another aspect, the modified oligonucleotide comprises DNA, RNA, or a combination thereof. In another aspect, the nucleobase sequence comprises at least 15 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In another aspect, the nucleobase sequence comprises at least 16 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In another aspect, the nucleobase sequence comprises at least 17 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In another aspect, the nucleobase sequence comprises at least 18 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In another aspect, the nucleobase sequence comprises at least 19 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In another aspect, the nucleobase sequence comprises at least 20 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In another aspect, the nucleobase sequence is at least 80% complementary to the target region of equal length of the IR-A mRNA transcript. In another aspect, the nucleobase sequence is at least 90% complementary to the target region of equal length of the IR-A mRNA transcript. In another aspect, the nucleobase sequence is at least 95% complementary to the target region of equal length of the IR-A mRNA transcript. In another aspect, the nucleobase sequence is 100% complementary to the target region of equal length of the IR-A mRNA transcript. In another aspect, the modified oligonucleotide comprises at least one modified internucleoside linkage and at least one modified sugar moiety. In another aspect, the at least one modified sugar moiety is a 2′-substituted sugar moiety or a bicyclic sugar moiety. In another aspect, the 2′-substituted sugar moiety is selected from the group consisting of a 2′-O- methyoxyethyl (2′-MOE), 2′-O-methyl (2′-OMe), and 2′-fluoro (2′-F) modified sugar. In another aspect, the 2′-substituted sugar moiety is a 2′-MOE modified sugar. In another aspect, the bicyclic sugar moiety is selected from the group consisting of a locked nucleic acid (LNA) nucleoside and a constrained ethyl (cEt) nucleoside. In another aspect, the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage. In another aspect, the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage and the at least one modified sugar moiety is a 2′-O-methyoxyethyl (2′-MOE) modified sugar. In another aspect, each nucleoside of the modified oligonucleotide is a modified nucleoside. In another aspect, each internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage. In another aspect, the modified oligonucleotide comprises a gapmer motif comprising: a central gap segment comprising linked deoxynucleosides; a 5′-wing segment comprising linked nucleosides; and a 3′-wing segment comprising linked nucleosides; wherein the central gap segment is positioned immediately adjacent to and between the 5′-wing segment and the 3′-wing segment, and wherein each nucleoside of each wing segment comprises a modified sugar moiety. In another aspect, each internucleoside linkage of the gapmer motif is a phosphorothioate internucleoside linkage. In another aspect, each nucleoside of each wing segment comprises a 2′-O-methyoxyethyl (2′-MOE) modified sugar. In another aspect, the central gap segment comprises DNA, the 5′-wing segment comprises RNA, and the 3′-wing segment comprises RNA. In another aspect, the nucleobase sequence of the modified oligonucleotide has at least 90–99% identity to any one of SEQ ID NO: 6–13 or 17–26. In another aspect, the nucleobase sequence of the modified oligonucleotide is any one of SEQ ID NO: 6–13 or 17–26. In another aspect, the compound selectively reduces an expression level of IR-A. In another aspect, the compound selectively reduces an expression level of IR-A without modulating an expression level of insulin receptor isoform B (IR-B). In another aspect, the compound reduces a ratio of the expression levels of IR-A to insulin receptor isoform B (IR-B). Another embodiment described herein is a pharmaceutical composition for treating or preventing a disease or condition characterized by elevated insulin receptor isoform A (IR-A) expression in a subject, the composition comprising a therapeutically effective amount of a compound as described herein, and at least one pharmaceutically acceptable carrier, excipient, or diluent. In one aspect, the at least one pharmaceutically acceptable carrier, excipient, or diluent comprises water, saline, a lipid-based vehicle, or combinations thereof. Another embodiment described herein is a method for treating or preventing a disease or condition characterized by elevated insulin receptor isoform A (IR-A) expression in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound as described herein, and at least one pharmaceutically acceptable carrier, excipient, or diluent. In one aspect, the at least one pharmaceutically acceptable carrier, excipient, or diluent comprises water, saline, a lipid-based vehicle, or combinations thereof. In another aspect, the subject is a human. In another aspect, the disease or condition characterized by elevated IR-A expression comprises cancer, diabetes, or a combination thereof. In another aspect, the subject has, or is at risk of developing, cancer, diabetes, or a combination thereof. In another aspect, the cancer is one or more of pancreatic cancer, breast cancer, lung cancer, brain cancer, neck cancer, ovarian cancer, cervical cancer, prostate cancer, kidney cancer, liver cancer, colon cancer, colorectal cancer, stomach cancer, esophageal cancer, skin cancer, endometrial cancer, bladder cancer, thyroid cancer, or osteosarcoma. In another aspect, the composition is administered parenterally by subcutaneous or intravenous administration. In another aspect, the method further comprises administering to the subject at least one additional therapy. In another aspect, the composition and the at least one additional therapy are administered concomitantly. In another aspect, the composition and the at least one additional therapy are administered consecutively. In another aspect, the at least one additional therapy comprises a chemotherapeutic agent or an antibody-based agent. Another embodiment described herein is a method for inhibiting cancer cell growth or proliferation, the method comprising contacting a cancer cell with a compound as described herein. In one aspect, the cancer cell is in vitro. In another aspect, the cancer cell is in an animal. In another aspect, the cancer cell is a human cancer cell. DESCRIPTION OF THE DRAWINGS FIG.1A shows an illustration of insulin receptor mRNA alternative splicing that generates an insulin receptor isoform B (IR-B) mRNA transcript and an insulin receptor isoform A (IR-A) mRNA transcript. IR-B mRNA includes exon 11, while IR-A mRNA does not as exon 11 is skipped through alternative splicing to create an exon 10-exon 12 splice junction region. FIG. 1B shows a schematic of an exemplary modified antisense oligonucleotide (ASO) selectively targeting the exon 10-exon 12 splice junction region of IR-A mRNA. The 20-nucleotide anti-IR-A ASO is a chimeric DNA / RNA oligo having a “5-10-5 gapmer” design with modified phosphorothioate internucleoside linkages and 2′-O-methyoxyethyl (2′-MOE) RNA sugars that confer enhanced stability, selectivity, and efficacy. The sequence shown in FIG. 1B is shown 5′→3′. FIG. 2A–F show the silencing efficacy and selectivity dose response curves for the exemplary anti-IR-A ASO shown in FIG.1B (denoted as “irarsen”) in MDA-MB-231 triple negative breast cancer (TNBC) cells. FIG.3A–E show that an anti-IR-A small interfering RNA (siRNA) having a nearly identical sequence to irarsen only modestly silenced IR-A levels in MDA-MB-231 TNBC cells relative to irarsen. FIG. 4A–C show that irarsen-mediated knockdown is stable for at least 72 hours post- transfection. FIG.5 shows western blot analysis of ganitumab dose-response in MDA-MB-231 TNBC cells. FIG.6 shows that irarsen (i1) reduces MDA-MB-231 cell number compared to a mock- treatment control (Lipofectamine alone with no ASO) over 48 hours. FIG.7A–C show the dose-response effect of another exemplary modified ASO (denoted as “i2”). FIG.8A–C show the results of an ASO microwalk experiment. FIG.9A–C show silencing efficacy and selectivity dose response curves of irarsen i1 (5- 10-5 gapmer), i5 (5-8-5 gapmer), and i7 (4-10-4 gapmer) ASO variants targeting the exon 10-12 junction of IR-A in MDA-MB-231 TNBC cells by RT-qPCR analysis as compared to a scramble- sequence control. IR-A mRNA (FIG.9A), IR-B mRNA (FIG.9B), and IR-A:IR-B mRNA (FIG.9C) were assessed post ASO knockdown using human IR isoform primers as previously described. See Flannery et al., Endocrinology 157(4): 1702–1708 (2016). N = 3 for all experiments. FIG. 10A–D show silencing efficacy and selectivity dose response curves of i7 and i12 (LNA-modified) ASO variants versus scramble-sequence controls in MDA-MB-231 TNBC cells. IR-A mRNA (FIG.10A), IR-B mRNA (FIG.10B), and IR-A:IR-B mRNA (FIG.10C) were assessed post ASO knockdown by RT-qPCR analysis using human IR isoform primers as previously described. See Flannery et al., Endocrinology 157(4): 1702–1708 (2016). FIG.10D shows bar plots of 1 µM i7 and i12 compared via one-way ANOVA to assess changes in IR-A mRNA, IR-B mRNA, and the IR-A:IR-B mRNA ratio. N = 3 for all experiments. FIG.11A–E show that further characterization of the anti-IR-A oligo variants in MDA-MB- 231 cells showed intolerance of target sequence mismatches for silencing efficacy and a capacity for gymnotic uptake at high concentrations of oligo. FIG.11A shows that 18-nucleotide-long i7 ASO variants bearing 1, 2, 3 or 4 sequence mismatches, represented in the figure by their respective percent complementarity to the target human IR-A mRNA, were tested to assess for silencing efficacy at 100 nM concentration. Oligos were transfected via RNAiMAX Lipofectamine. FIG.11B–E show that i7 and i12 ASO variants were delivered without Lipofectamine in complete growth medium to MDA-MB-231 cells to assess for gymnotic uptake and silencing efficacy against IR-A (FIG.11B–C), IR-B (FIG.11D), or the A:B ratio (FIG.11E) at either 100 nM (FIG.11B) or 5 µM (FIG.11C–E). RNA was isolated 24 hr post-transfection. mRNA expression was determined via RT-qPCR using human IR isoform primers as previously described. See Flannery et al., Endocrinology 157(4): 1702–1708 (2016). N = 3 for all experiments. FIG. 12A–F show silencing efficacy and selectivity of 100 nM i7 and i12 ASO variants versus scramble-sequence controls in Hs822.T human Ewing sarcoma cells (FIG.12A–C) and 22Rv1 prostate carcinoma cells (FIG.12D–F). For all experiments, oligos were transfected via RNAiMAX Lipofectamine and RNA was isolated 24 hr post-transfection. mRNA expression was determined via RT-qPCR using human IR isoform primers as previously described. See Flannery et al., Endocrinology 157(4): 1702–1708 (2016). IR-A mRNA (FIG.12A and 12D), IR-B mRNA (FIG.12B and 12E), and IR-A:IR-B mRNA (FIG.12C and 12F) were assessed post-knockdown. N = 3 for all experiments. FIG.13A–D show that i7 reduces total IR^ protein at 1 µM in MDA-MB-231 cells. FIG. 13A–B show a dose-response study of i7 (FIG.13A) and i12 (FIG.13B) with subsequent western blot analysis, probing for total IR^ protein and normalized to ^-tubulin. Cells were harvested 3 days post-transfection. 100 nM of either oligo did not reduce total IR^ protein, but 1 µM of i7 did reduce total IR^. FIG.13C–D show MDA-MB-231 cells transfected with 100 nM of i7 or i12 and incubated for 1 week prior to harvest and analysis by qPCR (FIG.13C) and western blot (FIG. 13D). N = 3 for all experiments. FIG.14 shows that 1 µM i7 reduces proliferation of 22Rv1 prostate carcinoma cells over the course of 72 hr, shown graphically (top) and quantified via area under the curve and subsequent two-tailed t-test (bottom). The 22Rv1 cell number, as quantified via cell index values through the Agilent RTCA analyzer, was nearly halved (.54-fold) by transfection with i7 versus the scramble-sequence control ASO. DETAILED DESCRIPTION Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are well known and commonly used in the art. In case of conflict, the present disclosure, including definitions, will control. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the embodiments and aspects described herein. As used herein, the terms such as “include,” “including,” “contain,” “containing,” “having,” and the like mean “comprising.” The present disclosure also contemplates other embodiments “comprising,” “consisting of,” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not. As used herein, the term “a,” “an,” “the” and similar terms used in the context of the disclosure (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. In addition, “a,” “an,” or “the” means “one or more” unless otherwise specified. As used herein, the term “or” can be conjunctive or disjunctive. As used herein, the term “substantially” means to a great or significant extent, but not completely. As used herein, the term “about” or “approximately” as applied to one or more values of interest, refers to a value that is similar to a stated reference value, or within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, such as the limitations of the measurement system. In one aspect, the term “about” refers to any values, including both integers and fractional components that are within a variation of up to ± 10% of the value modified by the term “about.” Alternatively, “about” can mean within 3 or more standard deviations, per the practice in the art. Alternatively, such as with respect to biological systems or processes, the term “about” can mean within an order of magnitude, in some embodiments within 5-fold, and in some embodiments within 2-fold, of a value. As used herein, the symbol “~” means “about” or “approximately.” All ranges disclosed herein include both points as discrete values as well as all integers and fractions specified within the range. For example, a range of 0.1–2.0 includes 0.1, 0.2, 0.3, 0.4...2.0. If the end points are modified by the term “about,” the range specified is expanded by a variation of up to ±10% of any value within the range or within 3 or more standard deviations, including the end points. As used herein, the terms “amino acid,” “gene,” “nucleic acid,” “nucleotide,” “polynucleotide,” “oligonucleotide,” “vector,” “polypeptide,” and “protein” have their common meanings as would be understood by a biochemist of ordinary skill in the art. Standard single letter nucleotides (A, C, G, T, U) and standard single letter amino acids (A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y) are used herein. Nucleic acids may be single stranded or double stranded or may contain portions of both double stranded and single stranded sequence. The nucleic acid may be DNA, both genomic and cDNA, RNA (e.g., mRNA), or a hybrid, where the nucleic acid may contain combinations of deoxyribo- and ribo-nucleotides, and combinations of bases including uracil, adenine, thymine, cytosine, guanine, inosine, xanthine, hypoxanthine, isocytosine, and isoguanine. Nucleic acids may be obtained by chemical synthesis methods or by recombinant methods. As used herein, “chemical modification” means a chemical difference in a compound when compared to a naturally occurring counterpart. In reference to an oligonucleotide, chemical modification does not only include differences in nucleobase sequence. Chemical modifications of oligonucleotides may include nucleoside modifications (including sugar moiety modifications and nucleobase modifications) and internucleoside linkage modifications. As used herein, “furanosyl” means a structure comprising a 5-membered ring comprising four carbon atoms and one oxygen atom. As used herein, “naturally occurring sugar moiety” means a ribofuranosyl as found in naturally occurring RNA or a deoxyribofuranosyl as found in naturally occurring DNA. As used herein, “sugar moiety” means a naturally occurring sugar moiety or a modified sugar moiety of a nucleoside. As used herein, “modified sugar moiety” means a substituted sugar moiety, a bicyclic or tricyclic sugar moiety, or a sugar surrogate. As used herein, “substituted sugar moiety” means a furanosyl comprising at least one substituent group that differs from that of a naturally occurring sugar moiety. Substituted sugar moieties include, but are not limited to, furanosyls comprising substituents at the 2′-position, the 3′-position, the 4′-position, and / or the 5′- position. As used herein, “2′-substituted sugar moiety” means a furanosyl comprising a substituent at the 2′-position other than H or OH. Unless otherwise indicated, a 2′-substituted sugar moiety is not a bicyclic sugar moiety (i.e., the 2′-substituent of a 2′-substituted sugar moiety does not form a bridge to another atom of the furanosyl ring). As used herein, “methyoxyethyl” or “MOE” means –OCH2CH2OCH3. As used herein, “bicyclic sugar moiety” means a modified sugar moiety comprising a 4 to 7 membered ring (including but not limited to a furanosyl) comprising a bridge connecting two atoms of the 4 to 7 membered ring to form a second ring, resulting in a bicyclic structure. In certain embodiments, the 4 to 7 membered ring is a sugar ring. In certain embodiments, the 4 to 7 membered ring is a furanosyl. In certain such embodiments, the bridge connects the 2′-carbon and the 4′-carbon of the furanosyl. As used herein, “sugar surrogate” means a structure that does not comprise a furanosyl and that is capable of replacing the naturally occurring sugar moiety of a nucleoside, such that the resulting nucleoside is capable of (1) incorporation into an oligonucleotide and (2) hybridization to a complementary nucleoside. Such structures include rings comprising a different number of atoms than furanosyl (e.g., 4, 6, or 7-membered rings); replacement of the oxygen of a furanosyl with a non-oxygen atom (e.g., carbon, sulfur, or nitrogen); or both a change in the number of atoms and a replacement of the oxygen. Such structures may also comprise substitutions corresponding to those described for substituted sugar moieties (e.g., 6-membered carbocyclic bicyclic sugar surrogates optionally comprising additional substituents). Sugar surrogates also include more complex sugar replacements (e.g., the non-ring systems of peptide nucleic acid). Sugar surrogates include without limitation morpholino, modified morpholinos, cyclohexenyls, and cyclohexitols. As used herein, “nucleoside” means a molecule comprising a nucleobase moiety and a sugar moiety. Nucleosides include, but are not limited to, naturally occurring nucleosides (as found in DNA and RNA) and modified nucleosides. Nucleosides may be linked to a phosphate moiety. As used herein, “nucleotide” means a nucleoside further comprising a phosphate linking group. As used herein, “linked nucleosides” may or may not be linked by phosphate linkages and thus include, but are not limited to, “linked nucleotides.” As used herein, “linked nucleosides” are nucleosides that are connected in a contiguous sequence (i.e., no additional nucleosides are present between those that are linked). As used herein, “nucleobase” means a group of atoms that can be linked to a sugar moiety to create a nucleoside that is capable of incorporation into an oligonucleotide, and wherein the group of atoms is capable of bonding with a complementary naturally occurring nucleobase of another oligonucleotide or nucleic acid. Nucleobases may be naturally occurring or may be modified. As used herein, the terms “unmodified nucleobase” or “naturally occurring nucleobase” means the naturally occurring heterocyclic nucleobases of RNA or DNA: the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) (including 5-methyl C), and uracil (U). As used herein, “modified nucleobase” means any nucleobase that is not a naturally occurring nucleobase. As used herein, “modified nucleoside” means a nucleoside comprising at least one chemical modification compared to naturally occurring RNA or DNA nucleosides. Modified nucleosides comprise a modified sugar moiety and / or a modified nucleobase. As used herein, “bicyclic nucleoside” means a nucleoside comprising a bicyclic sugar moiety. As used herein, “constrained ethyl nucleoside” or “cEt” means a nucleoside comprising a bicyclic sugar moiety comprising a 4′-CH(CH3)-O-2′ bridge. As used herein, “locked nucleic acid” or “LNA” means a nucleoside (e.g., DNA or RNA) comprising a bicyclic sugar moiety comprising a 4′-CH2-O-2′ (methylene) bridge. As used herein, the terms DNA and RNA include LNA nucleosides. As used herein, “2′-substituted nucleoside” means a nucleoside comprising a substituent at the 2′-position other than H or OH. Unless otherwise indicated, a 2′-substituted nucleoside is not a bicyclic nucleoside. As used herein, “2′-deoxynucleoside” means a nucleoside comprising 2′-H furanosyl sugar moiety, as found in naturally occurring deoxyribonucleosides (DNA). In certain embodiments, a 2′-deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (e.g., uracil). As used herein, “oligonucleotide” means a compound comprising a plurality of linked nucleosides. In certain embodiments, an oligonucleotide comprises one or more unmodified ribonucleosides (RNA) and / or one or more unmodified deoxyribonucleosides (DNA) and / or one or more modified nucleosides. As used herein, “oligonucleoside” means an oligonucleotide in which none of the internucleoside linkages contains a phosphorus atom. As used herein, oligonucleotides include oligonucleosides. As used herein, “modified oligonucleotide” means an oligonucleotide comprising at least one modified nucleoside and / or at least one modified internucleoside linkage. As used herein, “internucleoside linkage” means a covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein, “naturally occurring internucleoside linkage” means a 3′ to 5′ phosphodiester linkage. As used herein, “modified internucleoside linkage” means any internucleoside linkage other than a naturally occurring internucleoside linkage. In some embodiments, a modified internucleoside linkage may comprise a phosphorothioate (PS) internucleoside linkage. As used herein, “oligomeric compound” means a polymeric structure comprising two or more substructures. In certain embodiments, an oligomeric compound comprises or consists of an oligonucleotide. In certain embodiments, an oligomeric compound comprises one or more conjugate groups and / or terminal groups. As used herein, “antisense oligonucleotide” or “ASO” means a compound comprising or consisting of an oligonucleotide, at least a portion of which is partially or fully complementary to a target nucleic acid to which it is capable of hybridizing, resulting in at least one antisense activity. As used herein, “antisense activity” means any detectable and / or measurable change attributable to the hybridization of an ASO to its target nucleic acid. In certain embodiments, antisense activity refers to the modulation of gene expression. As used herein, “detecting” or “measuring” means that a test or assay for detecting or measuring is performed. Such detection and / or measuring may result in a value of zero. Thus, if a test for detection or measuring results in a finding of no activity (i.e., activity of zero), the step of detecting or measuring the activity has nevertheless been performed. As used herein, “detectable and / or measurable activity” means a statistically significant activity that is not zero. As used herein, “modulation” means a change of amount or quality of a molecule, function, or activity when compared to the amount or quality of a molecule, function, or activity prior to modulation. For example, modulation includes the change, either an increase (stimulation or induction) or a decrease (inhibition or reduction) in gene expression. As used herein, “essentially unchanged” means little or no change in a particular parameter, particularly relative to another parameter which changes much more. In certain embodiments, a parameter is essentially unchanged when it changes less than 10%. In certain embodiments, a parameter is essentially unchanged when it changes less than 5%. In certain embodiments, a parameter is essentially unchanged when it changes less than 2.5%. For example, in certain embodiments, an antisense activity is a change in the amount of a target nucleic acid. In certain such embodiments, the amount of a non-target nucleic acid is essentially unchanged if it changes much less than the target nucleic acid does, but the change need not be zero. As used herein, “mRNA” means an RNA molecule that encodes a protein. As used herein, “transcript” means an RNA molecule transcribed from DNA. Transcripts include, but are not limited to, mRNA, pre-mRNA, and partially processed RNA. As used herein, “hybridization” means the pairing of complementary oligomeric compounds (e.g., an ASO and its target nucleic acid). While not limited to a particular mechanism, the most common mechanism of pairing involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases. As used herein, “specifically hybridizes” means the ability of an oligomeric compound to hybridize to one nucleic acid site with greater affinity than it hybridizes to another nucleic acid site. In certain embodiments, an ASO may specifically hybridize to only one target site. In certain embodiments, an ASO may specifically hybridize to more than one target site. As used herein, “expression” means the process by which a gene ultimately results in a protein. Expression includes, but is not limited to, transcription, post-transcriptional modification (e.g., splicing, polyadenylation, addition of 5′-cap), and translation. As used herein, “target nucleic acid” means a nucleic acid molecule to which an ASO hybridizes. As used herein, “target region” means a portion of a target nucleic acid containing a “target sequence” to which one or more compounds is targeted. In some embodiments, the target nucleic acid is an insulin receptor isoform A (IR-A) mRNA transcript. In some embodiments, the target region comprises a target sequence overlapping with an exon 10-exon 12 splice junction region of the IR-A mRNA transcript. As used herein, “non-complementary” in reference to nucleobases means a pair of nucleobases that do not form hydrogen bonds with one another. As used herein, “complementary” in reference to oligomeric compounds (e.g., linked nucleosides, oligonucleotides, or nucleic acids) means the capacity of such oligomeric compounds or regions thereof to hybridize to another oligomeric compound or region thereof through nucleobase complementarity under stringent conditions. Complementary oligomeric compounds need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated. In certain embodiments, complementary oligomeric compounds or regions are complementary at 70% of the nucleobases (70% complementary). In certain embodiments, complementary oligomeric compounds or regions are 75% complementary. In certain embodiments, complementary oligomeric compounds or regions are 80% complementary. In certain embodiments, complementary oligomeric compounds or regions are 85% complementary. In certain embodiments, complementary oligomeric compounds or regions are 90% complementary. In certain embodiments, complementary oligomeric compounds or regions are 95% complementary. In certain embodiments, complementary oligomeric compounds or regions are 100% or fully complementary. In certain embodiments, complementary oligomeric compounds or regions are, or are at least, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% complementary to a target nucleic acid. As used herein, “motif” means a pattern of chemical modifications in an oligomeric compound or a region thereof. Motifs may be defined by modifications at certain nucleosides and / or at certain linking groups of an oligomeric compound. In some embodiments, disclosed oligonucleotides may comprise a “gapmer motif” region comprising two external regions or “wing segments” (5′ and 3′) and an internal region or “central gap segment.” The three regions of a gapmer motif (the 5′-wing segment, the central gap segment, and the 3′-wing segment) form a contiguous sequence of nucleosides wherein at least some of the sugar moieties of the nucleosides of each of the wing segments differ from at least some of the sugar moieties of the nucleosides of the central gap segment. In certain embodiments, the sugar moieties within the central gap segment are the same as one another. In certain embodiments, the sugar moieties of the two wing segments are the same as one another (symmetric gapmer). In certain embodiments, the sugar moieties of the 5′-wing segment differ from the sugar moieties of the 3′-wing segment (asymmetric gapmer). In one nonlimiting exemplary embodiment, a modified oligonucleotide comprises a gapmer motif comprising: a central gap segment comprising linked deoxynucleosides; a 5′-wing segment comprising linked nucleosides; and a 3′-wing segment comprising linked nucleosides; wherein the central gap segment is positioned immediately adjacent to and between the 5′-wing segment and the 3′-wing segment, and wherein each nucleoside of each wing segment comprises a modified sugar moiety. In certain embodiments, the central gap segment comprises DNA, the 5′-wing segment comprises RNA, and the 3′-wing segment comprises RNA. In certain embodiments, the wing segments of a gapmer motif comprise 1–5 nucleosides, 2–5 nucleosides, 3–5 nucleosides, or 5 or more nucleosides. In certain embodiments, the central gap segment of a gapmer motif comprises 7–12 nucleosides, 7–10 nucleosides, 8–10 nucleosides, or 10 or more nucleosides. In one nonlimiting exemplary embodiment, a gapmer motif comprises a 5-10-5 gapmer design including a 5′-wing segment comprising 5 linked nucleosides, a central gap segment comprising 10 linked nucleosides, and a 3′-wing segment comprising 5 linked nucleosides, with the central gap segment being positioned immediately adjacent to and between the 5′-wing segment and the 3′-wing segment. In certain embodiments, the nucleosides of a gapmer motif are all modified nucleosides. In certain embodiments, the nucleosides of a gapmer motif include at least one modified nucleoside. In certain embodiments, each internucleoside linkage of the gapmer motif is a modified internucleoside linkage (e.g., phosphorothioate internucleoside linkage). In certain embodiments, one or more nucleosides of each wing segment comprises a 2′-MOE modified sugar. In certain embodiments, each nucleoside of each wing segment comprises a 2′-MOE modified sugar. In certain embodiments, one or more nucleosides of each wing segment comprises a LNA nucleoside. In certain embodiments, each nucleoside of each wing segment comprises a LNA nucleoside. In certain embodiments, one or more nucleosides of each wing segment comprises a different modified sugar moiety from another nucleoside of the same wing segment. For example, in certain embodiments, one or more nucleosides of each wing segment may comprise a 2′-MOE modified sugar, while one or more different nucleosides of the same wing segment may comprise a LNA nucleoside. In other words, the wing segments of the gapmer motif may comprise nucleosides having different modified sugar moieties from one another, such as a combination of nucleosides having a 2′-substituted sugar moiety (e.g., 2′-MOE) and nucleosides having a bicyclic sugar moiety (e.g., LNA nucleoside). In one nonlimiting exemplary embodiment, a modified oligonucleotide comprises a gapmer motif comprising 5′- and 3′-wing segments comprising two nucleosides having 2′-MOE modified sugars and three nucleosides having LNA bicyclic sugar moieties, where the two nucleosides of each wing segment having the 2′-MOE modified sugars are positioned immediately adjacent to the central gap segment. As used herein, “variants” can include, but are not limited to, those that include conservative amino acid (AA) substitution, SNP variants, degenerate variants, and biologically active portions of a gene. A “degenerate variant” as used herein refers to a variant that has a mutated nucleotide sequence, but still encodes the same polypeptide due to the redundancy of the genetic code. There are 20 naturally occurring amino acids; however, some of these share similar characteristics. For example, leucine and isoleucine are both aliphatic, branched, and hydrophobic. Similarly, aspartic acid and glutamic acid are both small and negatively charged. Conservative substitutions in proteins often have a smaller effect on function than non- conservative mutations. Although there are many ways to classify amino acids, they are often sorted into six main groups on the basis of their structure and the general chemical characteristics of their R groups. A mutation among the same class of amino acids is considered a conservative amino acid substitution. The term “functional” when used in conjunction with “variant” or “fragment” refers to an entity or molecule which possess a biological activity that is substantially similar to a biological activity of the entity or molecule of which it is a variant or fragment thereof. In accordance with the present disclosure, an antisense oligonucleotide (ASO) may be modified, for example, to facilitate or improve activity, stability, identification, expression, isolation, storage, efficacy, selectivity, and / or administration, so long as such modifications do not reduce its function to an unacceptable level. As used herein, "substantial identity" of polynucleotide sequences means that a polynucleotide comprises a sequence that has at least 25% sequence identity compared to a reference sequence as determined using programs known in the art (e.g., Basic Local Alignment Search Tool (BLAST)). In preferred embodiments, percent identity can be any integer from 25% to 100%. More preferred embodiments include polynucleotide sequences that have at least about: 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity compared to a reference sequence. These values can be appropriately adjusted to determine corresponding identity of proteins encoded by two nucleotide sequences by taking into account codon degeneracy, amino acid similarity, reading frame positioning, and the like. Accordingly, polynucleotides of the present disclosure encoding a protein or polypeptide of the present disclosure include nucleic acid sequences that have substantial identity to the nucleic acid sequences that encode the proteins or polypeptides of the present disclosure. Polynucleotides encoding a polypeptide comprising an amino acid sequence that has at least about: 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity compared to a reference polypeptide sequence are also preferred. As used herein, "substantial identity" of amino acid sequences (and of polypeptides having these amino acid sequences) means that an amino acid sequence comprises a sequence that has at least 25% sequence identity compared to a reference sequence as determined using programs known in the art (e.g., BLAST). In preferred embodiments, percent identity can be any integer from 25% to 100%. More preferred embodiments include amino acid or polypeptide sequences that have at least about: 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity compared to a reference sequence. Polypeptides that are "substantially identical" share amino acid sequences except that residue positions which are not identical may differ by one or more conservative amino acid changes, as described above. Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains. For example, a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur-containing side chains is cysteine and methionine. Exemplary conservative amino acid substitution groups include valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, aspartic acid-glutamic acid, and asparagine-glutamine. Accordingly, polypeptides or proteins, encoded by the polynucleotides of the present disclosure, include amino acid sequences that have substantial identity to the amino acid sequences of the reference polypeptide sequences. As used herein, the terms “active ingredient” or “active pharmaceutical ingredient” refer to a pharmaceutical agent, active ingredient, compound, cell, or substance, compositions, or mixtures thereof, that provide a pharmacological, therapeutic, often beneficial, effect. In some embodiments, disclosed compositions may further comprise one or more pharmaceutically acceptable carriers, excipients, or diluents. As used herein, “pharmaceutically acceptable carrier, excipient, or diluent” means any substance suitable for use in administering to an animal. In certain embodiments, a pharmaceutically acceptable carrier, excipient, or diluent is sterile saline. In certain embodiments, such sterile saline is pharmaceutical grade saline. In other embodiments, a pharmaceutically acceptable carrier, excipient, or diluent comprises water, saline, a lipid-based vehicle, or combinations thereof. Example carriers may include, but are not limited to, liposomes, polymeric micelles, microspheres, microparticles, dendrimers, or nanoparticles. As used herein, the terms “control,” or “reference” are used herein interchangeably. A “reference” or “control” level may be a predetermined value or range, which is employed as a baseline or benchmark against which to assess a measured result. “Control” also refers to control experiments or control cells. As used herein, the term “administering” refers to the placement of a compound or a composition as disclosed herein into a subject by a method or route which results in at least partial localization of the compound or composition at a desired site. “Route of administration” may refer to any administration pathway known in the art, including but not limited to oral, intravenous (IV), topical, aerosol, nasal, via inhalation, anal, intra-anal, peri-anal, transmucosal, transdermal, parenteral, enteral, or local. “Parenteral” refers to a route of administration that is generally associated with injection, including intracranial, intraventricular, intrathecal, epidural, intradural, intraorbital, infusion, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal, intrauterine, intravascular, intravenous (IV), intraarterial, subarachnoid, subcapsular, subcutaneous, transmucosal, or transtracheal. Via the parenteral route, the compound or composition may be in the form of solutions or suspensions for IV infusion or IV injection, or as lyophilized powders. Via the enteral route, the compound or composition can be in the form of capsules, gel capsules, tablets, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid vesicles or polymer vesicles allowing controlled release. Via the topical route, the compound or composition can be in the form of aerosol, lotion, cream, gel, ointment, suspensions, solutions, or emulsions. In one embodiment, the compound or composition may be provided in a powder form and mixed with a liquid, such as water, to form a beverage. In accordance with the present disclosure, “administering” can be self-administering. For example, it is considered “administering” when a subject consumes a compound or composition as disclosed herein. As used herein, “contacting” refers to contacting a target cell (e.g., cancer cell) with an agent (e.g., modified ASO) using any method that is suitable for placing the agent on, in, or adjacent to the target cell. For example, when the cells are in vitro, contacting the cells with the agent can comprise adding the agent to culture medium containing the cells. For example, when the cells are in vivo, contacting the cells with the agent can comprise administering the agent to a subject. As used herein, the terms “effective amount” or “therapeutically effective amount,” refers to a substantially non-toxic, but sufficient amount of an action, agent, composition, or cell(s) being administered to a subject that will prevent, treat, or ameliorate to some extent one or more of the symptoms of the disease or condition being experienced or that the subject is susceptible to contracting. The result can be the reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An effective amount may be based on factors individual to each subject, including, but not limited to, the subject’s age, size, type or extent of disease, stage of the disease, route of administration, the type or extent of supplemental therapy used, ongoing disease process, and type of treatment desired. As used herein, the term “subject” refers to an animal. Typically, the subject is a mammal. A subject also refers to primates (e.g., humans, male or female; infant, adolescent, or adult), non- human primates, rats, mice, rabbits, pigs, cows, sheep, goats, horses, dogs, cats, fish, birds, and the like. In one embodiment, the subject is a primate. In one embodiment, the subject is a human. As used herein, a subject is “in need of treatment” if such subject would benefit biologically, medically, or in quality of life from such treatment. A subject in need of treatment does not necessarily present symptoms, particular in the case of preventative or prophylaxis treatments. In some embodiments of the present disclosure, a subject is in need of treatment if the subject is suffering from, or at risk of suffering from, a disease or condition characterized by elevated insulin receptor isoform A (IR-A) expression. As used herein, “elevated IR-A expression” means higher measured and / or detected levels of IR-A RNA and / or protein as compared to the measured and / or detected IR-A levels in normal healthy conditions (e.g., a healthy normal subject or healthy normal cell). As used herein, the term “dose” denotes any form of an active ingredient formulation or composition, including cells, that contains an amount sufficient to initiate or produce a therapeutic effect with at least one or more administrations. “Formulation” and “composition” are used interchangeably herein. In some embodiments, a subject may be administered a single dose of the disclosed compounds or pharmaceutical compositions. In other embodiments, a subject may be administered a plurality of doses over a period of time. For example, in various embodiments, a compound or pharmaceutical composition as described herein may be administered to a subject once a day (SID / QD), twice a day (BID), three times a day (TID), four times a day (QID), or more, so as to administer a therapeutically effective amount of the pharmaceutical composition to the subject, where the therapeutically effective amount is any one or more of the doses described herein. In some embodiments, a compound or pharmaceutical composition as described herein is administered to a subject 1–3 times per day, 1–7 times per week, 1–9 times per month, 1–12 times per year, or more. In other embodiments, a compound or pharmaceutical composition as described herein is administered for about 1–10 days, 10–20 days, 20–30 days, 30–40 days, 40– 50 days, 50–60 days, 60–70 days, 70–80 days, 80–90 days, 90–100 days, 1–6 months, 6–12 months, 1–5 years, or more. In various embodiments, a compound or pharmaceutical composition as described herein is administered at about 0.001–0.01, 0.01–0.1, 0.1–0.5, 0.5–5, 5–10, 10–20, 20–50, 50–100, 100–200, 200–300, 300–400, 400–500, 500–600, 600–700, 700– 800, 800–900, 900–1000 mg / kg, or a combination thereof. The actual dosing regimen can depend upon many factors, including but not limited to, the judgment of a trained physician, the overall condition of the subject, and the specific disease or condition of the subject. The actual dosage can also depend on the determined experimental effectiveness of the specific compound or pharmaceutical composition that is administered. For example, the dosage may be determined based on in vitro responsiveness of relevant cultured cells, or in vivo responses observed in appropriate animal models or human studies. As used herein, the term “endogenous” refers to any material from or produced inside an organism, cell, tissue, or system. As used herein, the term “exogenous” refers to any material introduced from or produced outside an organism, cell, tissue, or system. As used herein, the terms “inhibit,” “inhibition,” or “inhibiting” refer to the reduction or suppression of a given biological process, condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. As used herein, “treatment” or “treating” refers to prophylaxis of, preventing, suppressing, repressing, reversing, alleviating, ameliorating, or inhibiting the progress of biological process including a disorder or disease, or completely eliminating a disease. A treatment may be either performed in an acute or chronic manner. The term “treatment” also refers to reducing the severity of a disease or symptoms associated with such disease prior to affliction with the disease. “Repressing” or “ameliorating” a disease, disorder, or the symptoms thereof involves administering a cell, composition, or compound described herein to a subject after clinical appearance of such disease, disorder, or its symptoms. “Prophylaxis of” or “preventing” a disease, disorder, or the symptoms thereof involves administering a cell, composition, or compound described herein to a subject prior to onset of the disease, disorder, or the symptoms thereof. “Suppressing” a disease or disorder involves administering a cell, composition, or compound described herein to a subject after induction of the disease or disorder thereof but before its clinical appearance or symptoms thereof have manifest. As used herein, “target analyte,” “target biomarker,” “target antigen,” or “target cell” refers to a substance that is associated with a biological state or a biological process, such as a disease state or a diagnostic or prognostic indicator of a disease or disorder (e.g., an indicator identifying the likelihood of the existence or later development of a disease or disorder). The presence or absence of a biomarker, or the increase or decrease in the concentration of a biomarker, can be associated with and / or be indicative of a particular state or process. Biomarkers can include, but are not limited to, cells or cellular components (e.g., a viral cell, a bacterial cell, a fungal cell, a cancer cell, a tumor cell, etc.), small molecules, lipids, carbohydrates, nucleic acids, peptides, proteins, enzymes, antigens, and antibodies. A biomarker can be derived from an infectious agent, such as a bacterium, fungus, or virus, or can be an endogenous molecule that is found in greater or lesser abundance in a subject suffering from a disease or disorder as compared to a healthy individual (e.g., an increase or decrease in expression of a gene or gene product). As used herein, “sample” or “target sample” refers to any sample in which the presence and / or level of a target analyte or target biomarker is to be detected or determined. Samples may include liquids, solutions, emulsions, or suspensions. Samples may include a medical sample. Samples may include any biological fluid or tissue, such as blood, whole blood, fractions of blood such as plasma and serum, muscle, interstitial fluid, sweat, saliva, urine, tears, synovial fluid, bone marrow, cerebrospinal fluid, nasal secretions, sputum, amniotic fluid, bronchoalveolar lavage fluid, gastric lavage, emesis, fecal matter, lung tissue, peripheral blood mononuclear cells, total white blood cells, lymph node cells, spleen cells, tonsil cells, cancer cells, tumor cells, bile, digestive fluid, skin, or combinations thereof. In some embodiments, the sample comprises an aliquot. In other embodiments, the sample comprises a biological or bodily fluid. Samples can be obtained by any means known in the art. The sample can be used directly as obtained from a patient or can be pre-treated, such as by filtration, distillation, extraction, concentration, centrifugation, inactivation of interfering components, addition of reagents, and the like, to modify the character of the sample in some manner as discussed herein or otherwise as is known in the art. As used herein, the term “cancer” refers to a disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers include, but are not limited to, pancreatic cancer, breast cancer, lung cancer, brain cancer, neck cancer, ovarian cancer, cervical cancer, prostate cancer, kidney cancer, liver cancer, colon cancer, colorectal cancer, stomach cancer, esophageal cancer, skin cancer, endometrial cancer, bladder cancer, thyroid cancer, osteosarcoma, renal or kidney cancer, lymphoma, leukemia, myeloma, and the like. As used herein, the term “anti-cancer effect” refers to a biological effect which can be manifested by a decrease in cancer cell number or cancer cell proliferation, a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in activity of pro-tumor or oncogenic molecular signaling transduction, an increase in activity of tumor suppressive molecular signaling transduction, an increase in activity of pro-immune or pro-inflammatory molecular signaling transduction, a decrease in the number of metastases, an increase in life expectancy, amelioration of various physiological symptoms associated with a cancerous condition, and the like. An “anti-cancer effect” can also be manifested by the ability of the disclosed polypeptides, polynucleotides, cells, compounds, and pharmaceutical compositions of the present disclosure in the prevention of the occurrence of a cancer cell or tumor in the first place. Treating cancer can be described by a number of different parameters including, but not limited to, reduction in the size of a tumor in an animal having cancer, reduction in the growth or proliferation of a tumor in an animal having cancer, preventing metastasis, or reducing the extent of metastasis, and / or extending the survival of an animal having cancer. In some embodiments, the disclosed compounds and compositions comprising anti-IR-A modified oligonucleotides result in an anti- cancer effect by reducing the expression levels of IR-A in subjects and cells. As used herein, the term “cytotoxic” or “cytotoxicity” refers to killing or damaging cells. Certain embodiments disclosed herein provide compounds, compositions, and methods for selectively targeting IR-A expression. In some embodiments, the compounds are ASOs. In some embodiments, the compounds are modified oligonucleotides, which are ASOs having at least one chemical modification (e.g., at least one modified nucleoside and / or at least one modified internucleoside linkage). One embodiment described herein is a compound comprising a modified oligonucleotide having a nucleobase sequence comprising at least 14 contiguous nucleobases complementary to a target region of equal length of an IR-A mRNA transcript, wherein the target region comprises a target sequence overlapping with the exon 10-exon 12 splice junction region unique to the IR- A mRNA transcript and absent in the insulin receptor isoform B (IR-B) mRNA transcript. In some embodiments, the nucleobase sequence comprises at least 15 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence comprises at least 16 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence comprises at least 17 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence comprises at least 18 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence comprises at least 19 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence comprises at least 20 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the modified oligonucleotide is single stranded. In some embodiments, the modified oligonucleotide comprises DNA, RNA, or a combination thereof. In some embodiments, the modified oligonucleotide comprises a chimeric DNA / RNA oligonucleotide. In some embodiments, the modified oligonucleotide comprises a gapmer motif comprising: a central gap segment comprising linked deoxynucleosides; a 5′-wing segment comprising linked nucleosides; and a 3′-wing segment comprising linked nucleosides; wherein the central gap segment is positioned immediately adjacent to and between the 5′-wing segment and the 3′-wing segment, and wherein each nucleoside of each wing segment comprises a modified sugar moiety. In some embodiments, each internucleoside linkage of the gapmer motif is a phosphorothioate internucleoside linkage. In some embodiments, each nucleoside of each wing segment comprises a 2′-O-methyoxyethyl (2′-MOE) modified sugar. In some embodiments, the central gap segment comprises DNA, the 5′-wing segment comprises RNA, and the 3′-wing segment comprises RNA. In some embodiments, the present disclosure provides oligomeric compounds including oligonucleotides of any of a variety of ranges of lengths. In some embodiments, the disclosure provides oligomeric compounds or oligonucleotides comprising or consisting of “X” to “Y” linked nucleosides, where X represents the fewest number of nucleosides in the range and Y represents the largest number of nucleosides in the range. In some such embodiments, X and Y are each independently selected from 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30 or greater, provided that X<Y. For example, in some embodiments, the disclosure provides modified oligonucleotides comprising or consisting of 8 to 9, 8 to 10, 8 to 11, 8 to 12, 8 to 13, 8 to 14, 8 to 15, 8 to 16, 8 to 17, 8 to 18, 8 to 19, 8 to 20, 8 to 21, 8 to 22, 8 to 23, 8 to 24, 8 to 25, 8 to 26, 8 to 27, 8 to 28, 8 to 29, 8 to 30, 9 to 10, 9 to 11, 9 to 12, 9 to 13, 9 to 14, 9 to 15, 9 to 16, 9 to 17, 9 to 18, 9 to 19, 9 to 20, 9 to 21, 9 to 22, 9 to 23, 9 to 24, 9 to 25, 9 to 26, 9 to 27, 9 to 28, 9 to 29, 9 to 30, 10 to 11, 10 to 12, 10 to 13, 10 to 14, 10 to 15, 10 to 16, 10 to 17, 10 to 18, 10 to 19, 10 to 20, 10 to 21, 10 to 22, 10 to 23, 10 to 24, 10 to 25, 10 to 26, 10 to 27, 10 to 28, 10 to 29, 10 to 30, 11 to 12, 11 to 13, 11 to 14, 11 to 15, 11 to 16, 11 to 17, 11 to 18, 11 to 19, 11 to 20, 11 to 21, 11 to 22, 11 to 23, 11 to 24, 11 to 25, 11 to 26, 11 to 27, 11 to 28, 11 to 29, 11 to 30, 12 to 13, 12 to 14, 12 to 15, 12 to 16, 12 to 17, 12 to 18, 12 to 19, 12 to 20, 12 to 21, 12 to 22, 12 to 23, 12 to 24, 12 to 25, 12 to 26, 12 to 27, 12 to 28, 12 to 29, 12 to 30, 13 to 14, 13 to 15, 13 to 16, 13 to 17, 13 to 18, 13 to 19, 13 to 20, 13 to 21, 13 to 22, 13 to 23, 13 to 24, 13 to 25, 13 to 26, 13 to 27, 13 to 28, 13 to 29, 13 to 30, 14 to 15, 14 to 16, 14 to 17, 14 to 18, 14 to 19, 14 to 20, 14 to 21, 14 to 22, 14 to 23, 14 to 24, 14 to 25, 14 to 26, 14 to 27, 14 to 28, 14 to 29, 14 to 30, 15 to 16, 15 to 17, 15 to 18, 15 to 19, 15 to 20, 15 to 21, 15 to 22, 15 to 23, 15 to 24, 15 to 25, 15 to 26, 15 to 27, 15 to 28, 15 to 29, 15 to 30, 16 to 17, 16 to 18, 16 to 19, 16 to 20, 16 to 21, 16 to 22, 16 to 23, 16 to 24, 16 to 25, 16 to 26, 16 to 27, 16 to 28, 16 to 29, 16 to 30, 17 to 18, 17 to 19, 17 to 20, 17 to 21, 17 to 22, 17 to 23, 17 to 24, 17 to 25, 17 to 26, 17 to 27, 17 to 28, 17 to 29, 17 to 30, 18 to 19, 18 to 20, 18 to 21, 18 to 22, 18 to 23, 18 to 24, 18 to 25, 18 to 26, 18 to 27, 18 to 28, 18 to 29, 18 to 30, 19 to 20, 19 to 21, 19 to 22, 19 to 23, 19 to 24, 19 to 25, 19 to 26, 19 to 29, 19 to 28, 19 to 29, 19 to 30, 20 to 21, 20 to 22, 20 to 23, 20 to 24, 20 to 25, 20 to 26, 20 to 27, 20 to 28, 20 to 29, 20 to 30, 21 to 22, 21 to 23, 21 to 24, 21 to 25, 21 to 26, 21 to 27, 21 to 28, 21 to 29, 21 to 30, 22 to 23, 22 to 24, 22 to 25, 22 to 26, 22 to 27, 22 to 28, 22 to 29, 22 to 30, 23 to 24, 23 to 25, 23 to 26, 23 to 27, 23 to 28, 23 to 29, 23 to 30, 24 to 25, 24 to 26, 24 to 27, 24 to 28, 24 to 29, 24 to 30, 25 to 26, 25 to 27, 25 to 28, 25 to 29, 25 to 30, 26 to 27, 26 to 28, 26 to 29, 26 to 30, 27 to 28, 27 to 29, 27 to 30, 28 to 29, 28 to 30, or 29 to 30 total linked nucleosides. In some embodiments, the nucleobase sequence may comprise less than 14 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence comprises at least 14 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence comprises at least 15 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence comprises at least 16 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence comprises at least 17 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence comprises at least 18 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence comprises at least 19 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence comprises at least 20 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence comprises more than 20 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence is at least 70% complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence is at least 75% complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence is at least 80% complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence is at least 85% complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence is at least 90% complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence is at least 95% complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the nucleobase sequence is 100% or fully complementary to the target region of equal length of the IR-A mRNA transcript. In some embodiments, the modified oligonucleotide comprises at least one modified internucleoside linkage and at least one modified sugar moiety. In some embodiments, the at least one modified sugar moiety is a 2′-substituted sugar moiety or a bicyclic sugar moiety. In some embodiments, the 2′-substituted sugar moiety is selected from the group consisting of a 2′- O-methyoxyethyl (2′-MOE), 2′-O-methyl (2′-OMe), and 2′-fluoro (2′-F) modified sugar. In some embodiments, the 2′-substituted sugar moiety is a 2′-MOE modified sugar. In some embodiments, the bicyclic sugar moiety is selected from the group consisting of a locked nucleic acid (LNA) nucleoside and a constrained ethyl (cEt) nucleoside. In some embodiments, the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage. In some embodiments, the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage and the at least one modified sugar moiety is a 2′-O-methyoxyethyl (2′- MOE) modified sugar. In some embodiments, each nucleoside of the modified oligonucleotide is a modified nucleoside. In some embodiments, each modified sugar moiety of the modified oligonucleotide is the same modified sugar moiety. In some embodiments, each modified sugar moiety of the modified oligonucleotide is a 2′-MOE modified sugar. In some embodiments, each internucleoside linkage of the modified oligonucleotide is the same internucleoside linkage. In some embodiments, each internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage. In some embodiments, the nucleobase sequence of the modified oligonucleotide has at least 75% identity to any one of SEQ ID NO: 6–13 or 17–26. In some embodiments, the nucleobase sequence of the modified oligonucleotide has at least 80% identity to any one of SEQ ID NO: 6–13 or 17–26. In some embodiments, the nucleobase sequence of the modified oligonucleotide has at least 85% identity to any one of SEQ ID NO: 6–13 or 17–26. In some embodiments, the nucleobase sequence of the modified oligonucleotide has at least 90% identity to any one of SEQ ID NO: 6–13 or 17–26. In some embodiments, the nucleobase sequence of the modified oligonucleotide has at least 95% identity to any one of SEQ ID NO: 6–13 or 17–26. In some embodiments, the nucleobase sequence of the modified oligonucleotide has at least 90– 99% identity to any one of SEQ ID NO: 6–13 or 17–26. In some embodiments, the nucleobase sequence of the modified oligonucleotide is any one of SEQ ID NO: 6–13 or 17–26. In some embodiments, the compound selectively reduces an expression level of IR-A. In some embodiments, the compound selectively reduces an expression level of IR-A, while the expression level of IR-B is essentially unchanged. In some embodiments, the compound selectively reduces an expression level of IR-A without modulating an expression level of IR-B. In some embodiments, the compound reduces a ratio of the expression levels of IR-A to IR-B. Another embodiment described herein is a pharmaceutical composition for treating or preventing a disease or condition characterized by elevated IR-A expression in a subject, the composition comprising a therapeutically effective amount of any of the oligomeric compounds described herein, and at least one pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the at least one pharmaceutically acceptable carrier, excipient, or diluent comprises water, saline, a lipid-based vehicle, or combinations thereof. In some embodiments, the disease or condition characterized by elevated IR-A expression comprises cancer, diabetes, or a combination thereof. In some embodiments, the subject has, or is at risk of developing, cancer, diabetes, or a combination thereof. In some embodiments, the cancer is one or more of pancreatic cancer, breast cancer, lung cancer, brain cancer, neck cancer, ovarian cancer, cervical cancer, prostate cancer, kidney cancer, liver cancer, colon cancer, colorectal cancer, stomach cancer, esophageal cancer, skin cancer, endometrial cancer, bladder cancer, thyroid cancer, or osteosarcoma. Another embodiment described herein is a method for treating or preventing a disease or condition characterized by elevated IR-A expression in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any of the oligomeric compounds described herein, and at least one pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the at least one pharmaceutically acceptable carrier, excipient, or diluent comprises water, saline, a lipid-based vehicle, or combinations thereof. In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the disease or condition characterized by elevated IR-A expression comprises cancer, diabetes, or a combination thereof. In some embodiments, the subject has, or is at risk of developing, cancer, diabetes, or a combination thereof. In some embodiments, the cancer is one or more of pancreatic cancer, breast cancer, lung cancer, brain cancer, neck cancer, ovarian cancer, cervical cancer, prostate cancer, kidney cancer, liver cancer, colon cancer, colorectal cancer, stomach cancer, esophageal cancer, skin cancer, endometrial cancer, bladder cancer, thyroid cancer, or osteosarcoma. In some embodiments, the composition is administered parenterally by subcutaneous or intravenous administration. In some embodiments, the method further comprises administering to the subject at least one additional therapy. In some embodiments, the composition and the at least one additional therapy are administered concomitantly. In some embodiments, the composition and the at least one additional therapy are administered consecutively. In some embodiments, the at least one additional therapy comprises a chemotherapeutic agent or an antibody-based agent. Another embodiment described herein is a method for inhibiting cancer cell growth or proliferation, the method comprising contacting a cancer cell with any of the oligomeric compounds described herein. In some embodiments, the cancer cell is in vitro. In some embodiments, the cancer cell is in an animal. In some embodiments, the cancer cell is a human cancer cell. It will be apparent to one of ordinary skill in the relevant art that suitable modifications and adaptations to the compositions, formulations, methods, processes, and applications described herein can be made without departing from the scope of any embodiments or aspects thereof. The compositions and methods provided are exemplary and are not intended to limit the scope of any of the specified embodiments. All of the various embodiments, aspects, and options disclosed herein can be combined in any variations or iterations. The scope of the compositions, formulations, methods, and processes described herein include all actual or potential combinations of embodiments, aspects, options, examples, and preferences herein described. The exemplary compositions and formulations described herein may omit any component, substitute any component disclosed herein, or include any component disclosed elsewhere herein. The ratios of the mass of any component of any of the compositions or formulations disclosed herein to the mass of any other component in the formulation or to the total mass of the other components in the formulation are hereby disclosed as if they were expressly disclosed. Should the meaning of any terms in any of the patents or publications incorporated by reference conflict with the meaning of the terms used in this disclosure, the meanings of the terms or phrases in this disclosure are controlling. Furthermore, the foregoing discussion discloses and describes merely exemplary embodiments. All patents and publications cited herein are incorporated by reference herein for the specific teachings thereof. Various embodiments and aspects of the inventions described herein are summarized by the following clauses: Clause 1. A compound comprising a modified oligonucleotide having a nucleobase sequence comprising at least 14 contiguous nucleobases complementary to a target region of equal length of an insulin receptor isoform A (IR-A) mRNA transcript, wherein the target region comprises a target sequence overlapping with an exon 10-exon 12 splice junction region of the IR-A mRNA transcript. Clause 2. The compound of clause 1, wherein the modified oligonucleotide is single stranded. Clause 3. The compound of clause 1 or 2, wherein the modified oligonucleotide comprises DNA, RNA, or a combination thereof. Clause 4. The compound of any one of clauses 1–3, wherein the nucleobase sequence comprises at least 15 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. Clause 5. The compound of any one of clauses 1–4, wherein the nucleobase sequence comprises at least 16 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. Clause 6. The compound of any one of clauses 1–5, wherein the nucleobase sequence comprises at least 17 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. Clause 7. The compound of any one of clauses 1–6, wherein the nucleobase sequence comprises at least 18 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. Clause 8. The compound of any one of clauses 1–7, wherein the nucleobase sequence comprises at least 19 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. Clause 9. The compound of any one of clauses 1–8, wherein the nucleobase sequence comprises at least 20 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript. Clause 10. The compound of any one of clauses 1–9, wherein the nucleobase sequence is at least 80% complementary to the target region of equal length of the IR-A mRNA transcript. Clause 11. The compound of any one of clauses 1–10, wherein the nucleobase sequence is at least 90% complementary to the target region of equal length of the IR-A mRNA transcript. Clause 12. The compound of any one of clauses 1–11, wherein the nucleobase sequence is at least 95% complementary to the target region of equal length of the IR-A mRNA transcript. Clause 13. The compound of any one of clauses 1–12, wherein the nucleobase sequence is 100% complementary to the target region of equal length of the IR-A mRNA transcript. Clause 14. The compound of any one of clauses 1–13, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage and at least one modified sugar moiety. Clause 15. The compound of any one of clauses 1–14, wherein the at least one modified sugar moiety is a 2′-substituted sugar moiety or a bicyclic sugar moiety. Clause 16. The compound of any one of clauses 1–15, wherein the 2′-substituted sugar moiety is selected from the group consisting of a 2′-O-methyoxyethyl (2′-MOE), 2′-O-methyl (2′- OMe), and 2′-fluoro (2′-F) modified sugar. Clause 17. The compound of any one of clauses 1–16, wherein the 2′-substituted sugar moiety is a 2′-MOE modified sugar. Clause 18. The compound of any one of clauses 1–17, wherein the bicyclic sugar moiety is selected from the group consisting of a locked nucleic acid (LNA) nucleoside and a constrained ethyl (cEt) nucleoside. Clause 19. The compound of any one of clauses 1–18, wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage. Clause 20. The compound of any one of clauses 1–19, wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage and the at least one modified sugar moiety is a 2′-O-methyoxyethyl (2′-MOE) modified sugar. Clause 21. The compound of any one of clauses 1–20, wherein each nucleoside of the modified oligonucleotide is a modified nucleoside. Clause 22. The compound of any one of clauses 1–21, wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage. Clause 23. The compound of any one of clauses 1–22, wherein the modified oligonucleotide comprises a gapmer motif comprising: a central gap segment comprising linked deoxynucleosides; a 5′-wing segment comprising linked nucleosides; and a 3′-wing segment comprising linked nucleosides; wherein the central gap segment is positioned immediately adjacent to and between the 5′-wing segment and the 3′-wing segment, and wherein each nucleoside of each wing segment comprises a modified sugar moiety. Clause 24. The compound of any one of clauses 1–23, wherein each internucleoside linkage of the gapmer motif is a phosphorothioate internucleoside linkage. Clause 25. The compound of any one of clauses 1–24, wherein each nucleoside of each wing segment comprises a 2′-O-methyoxyethyl (2′-MOE) modified sugar. Clause 26. The compound of any one of clauses 1–25, wherein the central gap segment comprises DNA, the 5′-wing segment comprises RNA, and the 3′-wing segment comprises RNA. Clause 27. The compound of any one of clauses 1–26, wherein the nucleobase sequence of the modified oligonucleotide has at least 90–99% identity to any one of SEQ ID NO: 6–13 or 17–26. Clause 28. The compound of any one of clauses 1–27, wherein the nucleobase sequence of the modified oligonucleotide is any one of SEQ ID NO: 6–13 or 17–26. Clause 29. The compound of any one of clauses 1–28, wherein the compound selectively reduces an expression level of IR-A. Clause 30. The compound of any one of clauses 1–29, wherein the compound selectively reduces an expression level of IR-A without modulating an expression level of insulin receptor isoform B (IR-B). Clause 31. The compound of any one of clauses 1–30, wherein the compound reduces a ratio of the expression levels of IR-A to insulin receptor isoform B (IR-B). Clause 32. A pharmaceutical composition for treating or preventing a disease or condition characterized by elevated insulin receptor isoform A (IR-A) expression in a subject, the composition comprising a therapeutically effective amount of a compound of any one of clauses 1–31, and at least one pharmaceutically acceptable carrier, excipient, or diluent. Clause 33. The composition of clause 32, wherein the at least one pharmaceutically acceptable carrier, excipient, or diluent comprises water, saline, a lipid-based vehicle, or combinations thereof. Clause 34. A method for treating or preventing a disease or condition characterized by elevated insulin receptor isoform A (IR-A) expression in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of clauses 1–31, and at least one pharmaceutically acceptable carrier, excipient, or diluent. Clause 35. The method of clause 34, wherein the at least one pharmaceutically acceptable carrier, excipient, or diluent comprises water, saline, a lipid-based vehicle, or combinations thereof. Clause 36. The method of clause 34 or 35, wherein the subject is a human. Clause 37. The method of any one of clauses 34–36, wherein the disease or condition characterized by elevated IR-A expression comprises cancer, diabetes, or a combination thereof. Clause 38. The method of any one of clauses 34–37, wherein the subject has, or is at risk of developing, cancer, diabetes, or a combination thereof. Clause 39. The method of any one of clauses 34–38, wherein the cancer is one or more of pancreatic cancer, breast cancer, lung cancer, brain cancer, neck cancer, ovarian cancer, cervical cancer, prostate cancer, kidney cancer, liver cancer, colon cancer, colorectal cancer, stomach cancer, esophageal cancer, skin cancer, endometrial cancer, bladder cancer, thyroid cancer, or osteosarcoma. Clause 40. The method of any one of clauses 34–39, wherein the composition is administered parenterally by subcutaneous or intravenous administration. Clause 41. The method of any one of clauses 34–40, further comprising administering to the subject at least one additional therapy. Clause 42. The method of any one of clauses 34–41, wherein the composition and the at least one additional therapy are administered concomitantly. Clause 43. The method of any one of clauses 34–42, wherein the composition and the at least one additional therapy are administered consecutively. Clause 44. The method of any one of clauses 34–43, wherein the at least one additional therapy comprises a chemotherapeutic agent or an antibody-based agent. Clause 45. A method for inhibiting cancer cell growth or proliferation, the method comprising contacting a cancer cell with a compound of any one of clauses 1–31. Clause 46. The method of clause 45, wherein the cancer cell is in vitro. Clause 47. The method of clause 45 or 46, wherein the cancer cell is in an animal. Clause 48. The method of any one of clauses 45–47, wherein the cancer cell is a human cancer cell. EXAMPLES Example 1 Materials and Methods Cell Culture and Transfection MDA-MB-231 triple negative breast cancer (TNBC) and Hs822.T Ewing’s sarcoma cells were maintained in DMEM media (Thermo Fisher) with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin. 22Rv1 cells were maintained in RPMI 1640 (ATCC) with 10% FBS and 1% penicillin / streptomycin. Media changes or cell passages were performed 2-3 times per week. Cells were seeded at a density of 5 × 105cells per well in 6-well plates or 1–2 × 105cells per well in 12-well plates the day prior to transfection. ASOs or siRNA targeted to IR-A were transfected at the indicated concentrations via Lipofectamine RNAiMAX reagent (Thermo Fisher 13778030) per the manufacturer’s instructions. Cells were analyzed or collected for lysis at the indicated timepoints. For gymnosis experiments, on the day after seeding in the 12-well plate format, cell media was aspirated and replaced with 1 mL media containing the indicated concentrations of oligo with no Lipofectamine or other delivery vehicle. RNA was then isolated 24 hr later. RNA Isolation and Quantitative RT-PCR (qRT-PCR) Cell plates were placed on ice immediately prior to cell lysis. Cells were washed with 1× PBS and then incubated in RLT lysis buffer from the Qiagen RNeasy Mini Kit (#74106) for 5 minutes on ice. Cells were then scraped and collected, and RNA isolation was performed per the manufacturer’s instructions. RNA concentration and quality were assessed via the NanoDrop ND-1000 spectrophotometer (Thermo Fisher). 300 ng or 500 ng of RNA was used for cDNA synthesis via the iScript cDNA Synthesis Kit (BioRad #1708891). cDNA was diluted 1:5 in nuclease-free water. qPCR was performed using iTaq™ Universal SYBR® Green Supermix (BioRad 1725124) and the primers listed in Table 1 via the BioRad CFX96 real-time PCR machine. Relative expression values were calculated via the Q-Gene software from BioTechniques Software Library using ^-tubulin as the reference gene. Final values were multiplied by 103to increase numbers above decimal fractions. Table 1. Primers and Oligonucleotide Reagents Exon Primer or Oligo SEQ ID Source Sequence (5′^3′) or C Target Reagent atalog # NO (Primers) Human IR-A Forward PrimerIDTTTTTCGTCCCCAGGCCATCN / A 1Human IR-B Forward PrimerIDTCCCCAGAAAAACCTCTTCAGGN / A 2Human IR Reverse PrimerIDTGTCACATTCCCAACATCGCCN / A 3Human ^-tubulin IDT #NM_178014 1-2 - Human INSR IDT #NM_000208 21-22 - Negative Control Thermo AM4611 N / A - No.1 siRNA Fisher Negative Control Thermo AM4613 N / A - No.2 siRNA Fisher Custom anti-IR-A Thermo siRNA Sense Strand FisherCGUCCCCAGGCCAUCUCGGAAN / A 4Custom anti-IR-A Thermo siRNA Antisense FisherCCGAGAUGGCCUGGGGACGAAN / A 5Strand rC*rC*rG*rA*rG*A*T*G*G*C*C*T Irarsen (i1) IDT*G*G*G*rG*rA*rC*rG*rAN / A 6rG*rA*rG*rA*T*G*G*C*C*T*G*G* i2 IDTrG*rG*rA*rCN / A 7r - denotes 2′-MOE-modified ribonucleotides * - denotes phosphorothioate internucleotide linkages Protein Isolation, SDS-PAGE, and Western Blot For protein isolation and western blotting, 2 × 105cells per well were plated in a 12-well plate. For FIG.13, cells were collected in complete growth medium without additional treatment. For FIG. 5, cells were serum starved in the presence or absence of ganitumab at the concentrations indicated in FIG.5 (0, 5, 10, 25, or 50 nM ganitumab) the day after seeding. Cells were then stimulated with either 10 nM insulin or 10 nM IGF1 as indicated in FIG.5 for 10 minutes prior to lysis. After ligand stimulation or transfection, cell plates were placed immediately on ice and washed with 1× PBS. Cells were incubated for 5 minutes in Pierce RIPA Lysis and Extraction Buffer (Thermo Fisher 89901) supplemented with Halt™ Protease Inhibitor Cocktail (Thermo Fisher 1861281) before cell scraping and collection. Protein concentration was measured via the BioRad DC Protein Assay Reagent A (#5000113) and Reagent B (#5000114) per the manufacturer’s instructions. 5–35 µg of protein were loaded with 4x Laemmli buffer (BioRad) and separated via SDS-PAGE. Primary antibodies used included anti-IGF1R^ (Cell Signaling #3027), anti-pIGF1R^ / pIR^ (Cell Signaling #3024), anti-IR^ (Cell Signaling #3025), and anti-^-tubulin (Cell Signaling #2146). Primary antibodies were diluted 1:1000 in 5% BSA / TBS-T and incubated at either 4^C overnight or room temperature for 1 hour. Secondary antibodies (Gt anti-Rb, Jackson ImmunoResearch, #111-035-003) were diluted 1:5000 in 5% milk / TBS-T and incubated with membranes for 1 hour at room temperature. Cell Number Assay At 2 days post-transfection, cells were detached via accutase (Sigma-Aldrich), collected in complete growth medium, and seeded into xCELLigence E-plates (Agilent #300600890) in technical quadruplicate at a density of 3 × 104cells per well. Just prior to plating, 25 nM ganitumab (MedChemExpress #HY-P99294) was administered to the treatment groups in FIG. 6. Plates were loaded into the xCELLigence RTCA DP analyzer (Agilent) and measurements were taken every 15 minutes over the indicated time course. Statistics Experiments comparing 2 groups were assessed for significance via two-tailed t-test. Experiments comparing more than 2 groups were assessed for significance using a one-way ANOVA and post-hoc Tukey’s or Dunnett’s multiple comparisons test with alpha set to .05. Example 2 Dose Response of Irarsen in Breast Cancer Cells FIG. 2A–F show the silencing efficacy and selectivity dose response curves for the exemplary anti-IR-A ASO shown in FIG.1B (denoted as “irarsen”) in MDA-MB-231 triple negative breast cancer (TNBC) cells. The sequence for irarsen is provided in Table 1 and shown in FIG. 1B. Irarsen, which is a 20-nucleotide anti-IR-A ASO, is a chimeric DNA / RNA oligo having a 5-10- 5 gapmer design with modified phosphorothioate internucleoside linkages and 2′-O- methyoxyethyl (2′-MOE) RNA sugars that confer enhanced stability, selectivity, and efficacy. For all experiments, irarsen was transfected via RNAiMAX lipofectamine and RNA was isolated 24 hours post-transfection. mRNA expression was determined via RT-qPCR using previously described human IR isoform primers. Irarsen was found to selectively reduce IR-A mRNA levels (FIG.2A and 2D) with a slight effect on IR-B mRNA levels (FIG.2B and 2E). Irarsen also reduced the IR-A:IR-B mRNA ratio at all doses (FIG. 2C and 2F). At the higher doses (FIG. 2A–C), irarsen reduced the IR-A:IR-B mRNA ratio greater than three-fold (FIG.2C), but also resulted in a higher level of off-target IR-B knockdown (FIG.2B). Example 3 Efficacy of anti-IR-A siRNA in Breast Cancer Cells No current RNA-targeting knockdown methods exist for selectively reducing expression levels of IR-A. IR-A is a particularly difficult target as it is only differentiable from IR-B by the exon 10-exon 12 splice junction region that exists in IR-A mRNA but not IR-B through alternative splicing (FIG.1A). FIG.3A–E show that an anti-IR-A small interfering RNA (siRNA) having a nearly identical sequence to irarsen only modestly silenced IR-A levels in MDA-MB-231 TNBC cells relative to irarsen. Specifically, IR-A mRNA was modestly reduced using 10 nM of the siRNA after 24 hours post-lipofectamine transfection (FIG. 3A), but IR-B mRNA was not (FIG. 3B), resulting in a reduced IR-A:IR-B mRNA ratio (FIG.3C). At 48 hours post-lipofectamine transfection (FIG.3D), the knockdown of IR-A mRNA levels and the effect on the IR-A:IR-B mRNA ratio was reduced. By 72 hours post-lipofectamine transfection (FIG.3E), the knockdown of IR-A mRNA levels was diminished. These results indicate that anti-IR-A ASOs such as irarsen offer a more effective approach for silencing IR-A expression compared to anti-IR-A siRNAs. These findings were both surprising and unexpected as IR-A mRNA likely forms secondary structures (e.g., hairpins, stems, and / or loops), making it difficult for any type of RNA-targeting approach to hybridize with the structured IR-A mRNA transcript target and effectively reduce IR-A expression levels. Example 4 Time Course Treatment of Irarsen in Breast Cancer Cells FIG. 4A–C show that irarsen-mediated knockdown is stable for at least 72 hours post- transfection. IR-A mRNA levels (FIG.4A), IR-B mRNA levels (FIG.4B), and the IR-A:IR-B mRNA ratio (FIG.4C) were assessed via RT-qPCR at 24 hours, 48 hours, and 72 hours post-transfection of either 15 nM or 30 nM irarsen in MDA-MB-231 TNBC cells. Example 5 Dose Response of Ganitumab in Breast Cancer Cells FIG.5 shows western blot analysis of ganitumab dose-response in MDA-MB-231 TNBC cells. Ganitumab efficacy against IGF1R phosphorylation peaked at 25 nM. Ganitumab did not cross react with IR up to 50 nM. These results indicate that any biological effect resulting from the treatment of MDA-MB- 231 TNBC cells with 25 nM ganitumab are attributable to IGF1R inhibition and not IR inhibition. In combination with the results shown in FIG.6, these data indicate that aggressive TNBCs are likely sensitive to IR-A inhibition and not IGF1R inhibition, since a selective dose of irarsen (30 nM) reduced MDA-MB-231 cell number, while a selective dose of ganitumab (25 nM) produced no effect. Example 6 Irarsen Effects on Cell Number and Proliferation FIG. 6 shows that irarsen reduces MDA-MB-231 cell number compared to a mock- treatment control (Lipofectamine alone with no ASO) over 48 hours. Irarsen treatment reduced MDA-MB-231 cell number both with and without ganitumab, which is a selective IGF1R antagonist. Ganitumab and irarsen combination treatment did not significantly reduce the cell number compared to irarsen treatment alone, and ganitumab treatment alone did not significantly affect cell number compared to mock-treatment control. These results indicate that reducing IR- A expression in cancer cells using the disclosed ASOs exhibits an anti-cancer effect of reduced cell number and proliferation. Example 7 Dose Response of i2 in Breast Cancer Cells FIG.7A–C show the dose-response effect of another exemplary modified ASO (denoted as “i2”). The sequence for i2 is provided in Table 1. This i2 ASO has a truncated 4-8-4 gapmer motif design (16-nucleotide ASO) with modified phosphorothioate internucleoside linkages and 2′-MOE RNA sugars. IR-A mRNA levels (FIG.7A), IR-B mRNA levels (FIG.7B), and the IR-A:IR- B mRNA ratio (FIG.7C) were assessed via RT-qPCR at 72 hours post-transfection of 0–80 nM i2 in MDA-MB-231 TNBC cells. These results indicate that the truncation of irarsen to generate i2 abrogated the IR-A mRNA silencing efficacy, and demonstrate that modulating the specific length and / or gapmer structure of the disclosed anti-IR-A ASO sequences can significantly alter the silencing efficacy for IR-A expression. Example 8 IR-A ASO Microwalk An ASO microwalk centered on the sequence of irarsen (denoted as “i1”) was performed to generate a series of additional ASO variants for IR-A knockdown. Overlapping 20-nucleotide ASOs were designed in 1-nucleotide steps (+1, +2, +3, −1, −2, −3) based on the sequence of irarsen (i1). The sequences of the ASO microwalk variants are provided in Table 2, shown 5′→3′. Each of the ASO microwalk variants selectively targets the exon 10-exon 12 splice junction region of the IR-A mRNA transcript. Similar to irarsen, the 20-nucleotide ASO microwalk variants are chimeric DNA / RNA oligos having a 5-10-5 gapmer design with modified phosphorothioate internucleoside linkages and 2′-MOE RNA sugars that confer enhanced stability, selectivity, and efficacy. Experiments were performed to test the efficacy of the anti-IR-A ASO microwalk variants in selectively silencing IR-A expression. MDA-MB-231 TNBC cells were transfected with 30 nM of each ASO microwalk variant via Lipofectamine RNAiMAX reagent and cell lysates were collected 24 hours post-transfection. mRNA levels of IR-A (FIG.8A), IR-B (FIG.8B), and the IR- A:IR-B mRNA ratio (FIG.8C) were assessed via RT-qPCR. The data of FIG.8A–C demonstrate that the original irarsen (i1) sequence design was more potent than all of the microwalk variants tested in reducing IR-A expression and the IR-A:IR-B ratio, assessed via one-way ANOVA and subsequent Tukey test. Statistical comparisons of each variant to mock control (Lipofectamine alone with no ASO) were nonsignificant unless otherwise indicated in each figure. These results also demonstrate that modulating / shifting the specific targeting region within the exon 10-exon 12 splice junction region of IR-A mRNA by only one nucleobase can significantly alter the IR-A silencing efficacy for the disclosed anti-IR-A ASOs. Table 2. ASO Microwalk Variants with 5-10-5 Gapmer Design ASO Variant Sequence (5′^3′) SEQ ID NO Irarsen (i1) +1rT*rC*rC*rG*rA*G*A*T*G*G*C*C*T*G*G*rG*rG*rA*rC*rG8Irarsen (i1) +2 Irarsen (i1) +3rT*rT*rT*rC*rC*G*A*G*A*T*G*G*C*C*T*rG*rG*rG*rG*rA10Irarsen (i1) −1rC*rG*rA*rG*rA*T*G*G*C*C*T*G*G*G*G*rA*rC*rG*rA*rA11Irarsen (i1) −2rG*rA*rG*rA*rT*G*G*C*C*T*G*G*G*G*A*rC*rG*rA*rA*rA12Irarsen (i1) −3rA*rG*rA*rT*rG*G*C*C*T*G*G*G*G*A*C*rG*rA*rA*rA*rA13r - denotes 2′- * - denotes Example 9 Additional ASO Variants Although the i1 IR-A ASO exhibited a high level of potency against IR-A, there was a significant off-target effect on IR-B that prompted further testing of oligo variants to improve the selectivity of the design. Therefore, additional IR-A ASO variants were tested for silencing efficacy and selectivity in cancer cells. The sequences of these additional ASO variants are provided in Table 3. Table 3. Additional ASO Variants SEQ ASO Variant Sequence (5′^3′) ID NO Scramble (Scr) rG*rG*rT*rG*C*G*A*A*C*T*G*G*A*C*G*A*rC*rG*rC*rG 14 i1 Control rG*rA*rG*rT*G*G*T*C*G*G*C*A*G*C*rG*rC*rG*rA 15Scr i12 Control rA*lG*T*G*G*A*C*G*G*A*G*T*lC*rG 16 i1.v2rC*rC*rG*rA*G*A*T*G*G*C*C*T*G*G*G*G*rA*rC*rG*rA17i5 rC*rG*rA*rG*rA*T*G*G*C*C*T*G*G*rG*rG*rA*rC*rG 18 i7rC*rG*rA*rG*A*T*G*G*C*C*T*G*G*G*rG*rA*rC*rG19i794% (1 rC*rG*rA*rA*A*T*G*G*C*C*T*G*G*G*rG*rA*rC*rG 20 mismatch) i789% (2 rC*rG*rA*rA*A*T*G*G*A*C*T*G*G*G*rG*rA*rC*rG 21 mismatches) i783% (3 rC*rG*rA*rA*A*T*G*G*A*A*T*G*G*G*rG*rA*rC*rG 22 mismatches) i778% (4 rC*rG*rA*rA*A*T*G*G*A*A*T*G*G*G*rA*rA*rC*rG 23 mismatches) i11rG*rA*lG*A*T*G*G*C*C*T*G*G*G*lG*rA*rC24i12rA*lG*A*T*G*G*C*C*T*G*G*G*lG*rA25i13lG*A*T*G*G*C*C*T*G*G*G*lG26 - Two ASO variants with truncated 18-nucleotide sequences, i5 and i7 (SEQ ID NO: 18 and 19), were found to have a minimal impact on IR-B mRNA levels up to 1 µM, while significantly reducing IR-A mRNA levels and the IR-A:IR-B ratio past 100 nM (FIG.9A–C). In addition, longer ASO variants of 22 nucleotides were found to be highly nonspecific. IR-A protein knockdown was not able to be assessed specifically due to the high homology between the A and B isoforms, and no established protocol for detecting IR-A protein currently exists. However, variant i7 exhibited significant knockdown of total IR^ protein, which includes both IR-A and IR-B isoforms, at 1000 nM 3 days post-transfection in a dose-dependent study (FIG.13A). Because variant i5 did not seem to affect total IR protein, this design was not further pursued. To determine if longer incubation times are required for more robust protein knockdown at lower doses, MDA-MB-231 cells were incubated for 1 week post-transfection with 100 nM i7 and i12 prior to qPCR and western blot analysis (FIG.13). At the 1-week timepoint, i7 maintained both IR-A and IR-A:IR-B mRNA ratio knockdown with no effect on IR-B mRNA levels (FIG.13C). Although a 1-week incubation improved protein reduction via i7 versus a 3-day incubation, the protein knockdown was not statistically significant (p = .0682). Thus, a longer incubation time with high-dose oligo may produce a more robust level of protein knockdown. In addition, the continued knockdown of IR-A mRNA after 1 week of incubation suggests that i7 is highly stable and resistant to nuclease degradation. Locked nucleic acid (LNA) modified oligos were also tested, as LNA greatly improves oligo affinity to target sequences as well as construct stability. Oligos bearing 3 LNA nucleotides in both RNA flanks were found to be highly nonselective and knocked down IR-B. Oligos with single LNA nucleotide modifications in each RNA flank were then tested, named i11–i13 (SEQ ID NO: 24–26). i12 exhibited a similar potency to i7 compared to i11 and i13 (FIG. 10A–C); i11 was nonselective and i13 was inefficacious. In a dose-response curve of i7 and i12 versus their respective scramble-sequence control oligos, i7 and i12 were both highly selective with minimal off-target effects on IR-B up to 1 µM (FIG.10A–C). i12 was less efficacious than i7 at reducing IR-A mRNA and the A:B ratio up to 1 µM; however, further tests were run on i12 due to its short, 14-nucleotide sequence. Oligos that are 16 nucleotides and shorter have been shown to exhibit unassisted, “gymnotic” uptake into cells, and it was expected that i12 could also be delivered to cells unassisted. To test if the oligo variants could tolerate any mismatched base pairing to target mRNA, four variants of i7 with either 1, 2, 3, or 4 nucleotide substitutions were developed and tested. G or C nucleotides were replaced with A nucleotides throughout the oligo. It was found that i7 could not tolerate a single mismatch in base pairing (FIG.11A). This indicated that checking for target sequence conservation in test samples is important to ensure oligo efficacy. Further, the oligos’ capacity for gymnotic uptake into cells was tested without the use of Lipofectamine. At 100 nM, which induces a significant reduction in IR-A mRNA when i7 is delivered via Lipofectamine, no gymnosis was observed (FIG.11B). However, when oligo concentrations were increased to 5 µM, a robust reduction in both IR-A mRNA and the A:B ratio was observed with no effect on IR-B mRNA from both i7 and i12 (FIG.11C–E). Notably, i7 appeared to exhibit gymnotic uptake at high doses despite its longer 18-nucleotide sequence. This suggested that i7 may be the most suitable candidate oligo for IR-A knockdown, since it has greater efficacy than i12 while still being highly selective and deliverable. The oligos were then tested for efficacy against IR-A in other cancers. It was found that both i7 and i12 reduced the A:B ratio with no IR-B mRNA knockdown in Hs822.T Ewing sarcoma cells and 22Rv1 prostate carcinoma cells (FIG. 12A–F). i7 significantly reduced Hs822.T and 22Rv1 IR-A mRNA. i12 did not significantly reduce IR-A mRNA, and this may be due to variability in IR-A and IR-B baseline expression levels between replicates as well as lower efficacy in comparison to i7. It should also be noted that the dosing for i7 and i12 was not optimized for other cell lines, and as a result, other cancers may require higher or lower levels of oligo depending on their expression profile. Thus, these data suggest that the i7 and i12 oligos are both suitable candidates for selective knockdown of IR-A, with i7 being the best likely candidate. Table 4 provides a summary of knockdown efficacy for the different variants that were tested. Table 4. Summary of Knockdown Efficacy for Additional anti-IR-A ASO Variants ASO Variant IR-A Knockdown (KD) Efficacy Scramble (Scr) i1 Control Control Scr i7 Control Control Scr i12 Control Control i1.v2 High efficacy; partly selective i5 Moderate efficacy; highly selective; no protein KD i7 High efficacy; highly selective; reduced protein i794% (1 mismatch) Abolished mRNA KD i789% (2 mismatches) Abolished mRNA KD i783% (3 mismatches) Abolished mRNA KD i778% (4 mismatches) Abolished mRNA KD i11 High efficacy; partly selective i12 Moderate efficacy; highly selective; no protein KD i13 Inefficacious Example 10 i7 Effects on Cell Proliferation To test for a biological effect of i7-mediated IR-A knockdown on cancer cells, an xCELLigence proliferation study was performed on 22Rv1 human prostate carcinoma cells, similar to the experiment performed on MDA-MB-231 TNBC cells shown in FIG. 6. Over the course of 72 hr, 1 µM i7 significantly reduced 22Rv1 cell proliferation as compared to a scramble- sequence control ASO (FIG.14). IR-A is predominantly known for its mitogenic and tumorigenic effects. IR-B primarily mediates metabolic effects in the cell and has been proposed to reduce cell proliferation, as induced expression of IR-B limited cell replication in colorectal cancer cells. These data provide evidence for a selective and robust inhibition of IR-A via i7-mediated knockdown, with a resultant biological effect of reduced cell proliferation.

Claims

CLAIMS What is claimed:

1. A compound comprising a modified oligonucleotide having a nucleobase sequence comprising at least 14 contiguous nucleobases complementary to a target region of equal length of an insulin receptor isoform A (IR-A) mRNA transcript, wherein the target region comprises a target sequence overlapping with an exon 10-exon 12 splice junction region of the IR-A mRNA transcript.

2. The compound of claim 1, wherein the modified oligonucleotide is single stranded.

3. The compound of claim 1, wherein the modified oligonucleotide comprises DNA, RNA, or a combination thereof.

4. The compound of claim 1, wherein the nucleobase sequence comprises at least 15 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript.

5. The compound of claim 1, wherein the nucleobase sequence comprises at least 16 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript.

6. The compound of claim 1, wherein the nucleobase sequence comprises at least 17 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript.

7. The compound of claim 1, wherein the nucleobase sequence comprises at least 18 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript.

8. The compound of claim 1, wherein the nucleobase sequence comprises at least 19 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript.

9. The compound of claim 1, wherein the nucleobase sequence comprises at least 20 contiguous nucleobases complementary to the target region of equal length of the IR-A mRNA transcript.

10. The compound of claim 1, wherein the nucleobase sequence is at least 80% complementary to the target region of equal length of the IR-A mRNA transcript.

11. The compound of claim 1, wherein the nucleobase sequence is at least 90% complementary to the target region of equal length of the IR-A mRNA transcript.

12. The compound of claim 1, wherein the nucleobase sequence is at least 95% complementary to the target region of equal length of the IR-A mRNA transcript.

13. The compound of claim 1, wherein the nucleobase sequence is 100% complementary to the target region of equal length of the IR-A mRNA transcript.

14. The compound of claim 1, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage and at least one modified sugar moiety.

15. The compound of claim 14, wherein the at least one modified sugar moiety is a 2′- substituted sugar moiety or a bicyclic sugar moiety.

16. The compound of claim 15, wherein the 2′-substituted sugar moiety is selected from the group consisting of a 2′-O-methyoxyethyl (2′-MOE), 2′-O-methyl (2′-OMe), and 2′-fluoro (2′-F) modified sugar.

17. The compound of claim 16, wherein the 2′-substituted sugar moiety is a 2′-MOE modified sugar.

18. The compound of claim 15, wherein the bicyclic sugar moiety is selected from the group consisting of a locked nucleic acid (LNA) nucleoside and a constrained ethyl (cEt) nucleoside.

19. The compound of claim 14, wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

20. The compound of claim 14, wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage and the at least one modified sugar moiety is a 2′-O-methyoxyethyl (2′-MOE) modified sugar.

21. The compound of claim 1, wherein each nucleoside of the modified oligonucleotide is a modified nucleoside.

22. The compound of claim 1, wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage.

23. The compound of claim 1, wherein the modified oligonucleotide comprises a gapmer motif comprising: a central gap segment comprising linked deoxynucleosides; a 5′-wing segment comprising linked nucleosides; and a 3′-wing segment comprising linked nucleosides; wherein the central gap segment is positioned immediately adjacent to and between the 5′-wing segment and the 3′-wing segment, and wherein each nucleoside of each wing segment comprises a modified sugar moiety.

24. The compound of claim 23, wherein each internucleoside linkage of the gapmer motif is a phosphorothioate internucleoside linkage.

25. The compound of claim 23, wherein each nucleoside of each wing segment comprises a 2′-O-methyoxyethyl (2′-MOE) modified sugar.

26. The compound of claim 23, wherein the central gap segment comprises DNA, the 5′-wing segment comprises RNA, and the 3′-wing segment comprises RNA.

27. The compound of claim 1, wherein the nucleobase sequence of the modified oligonucleotide has at least 90–99% identity to any one of SEQ ID NO: 6–13 or 17–26.

28. The compound of claim 1, wherein the nucleobase sequence of the modified oligonucleotide is any one of SEQ ID NO: 6–13 or 17–26.

29. The compound of claim 1, wherein the compound selectively reduces an expression level of IR-A.

30. The compound of claim 1, wherein the compound selectively reduces an expression level of IR-A without modulating an expression level of insulin receptor isoform B (IR-B).

31. The compound of claim 1, wherein the compound reduces a ratio of the expression levels of IR-A to insulin receptor isoform B (IR-B).

32. A pharmaceutical composition for treating or preventing a disease or condition characterized by elevated insulin receptor isoform A (IR-A) expression in a subject, the composition comprising a therapeutically effective amount of a compound of any one of claims 1–31, and at least one pharmaceutically acceptable carrier, excipient, or diluent.

33. The composition of claim 32, wherein the at least one pharmaceutically acceptable carrier, excipient, or diluent comprises water, saline, a lipid-based vehicle, or combinations thereof.

34. A method for treating or preventing a disease or condition characterized by elevated insulin receptor isoform A (IR-A) expression in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1–31, and at least one pharmaceutically acceptable carrier, excipient, or diluent.

35. The method of claim 34, wherein the at least one pharmaceutically acceptable carrier, excipient, or diluent comprises water, saline, a lipid-based vehicle, or combinations thereof.

36. The method of claim 34, wherein the subject is a human.

37. The method of claim 34, wherein the disease or condition characterized by elevated IR-A expression comprises cancer, diabetes, or a combination thereof.

38. The method of claim 37, wherein the subject has, or is at risk of developing, cancer, diabetes, or a combination thereof.

39. The method of claim 37, wherein the cancer is one or more of pancreatic cancer, breast cancer, lung cancer, brain cancer, neck cancer, ovarian cancer, cervical cancer, prostate cancer, kidney cancer, liver cancer, colon cancer, colorectal cancer, stomach cancer, esophageal cancer, skin cancer, endometrial cancer, bladder cancer, thyroid cancer, or osteosarcoma.

40. The method of claim 34, wherein the composition is administered parenterally by subcutaneous or intravenous administration.

41. The method of claim 34, further comprising administering to the subject at least one additional therapy.

42. The method of claim 41, wherein the composition and the at least one additional therapy are administered concomitantly.

43. The method of claim 41, wherein the composition and the at least one additional therapy are administered consecutively.

44. The method of claim 41, wherein the at least one additional therapy comprises a chemotherapeutic agent or an antibody-based agent.

45. A method for inhibiting cancer cell growth or proliferation, the method comprising contacting a cancer cell with a compound of any one of claims 1–31.

46. The method of claim 45, wherein the cancer cell is in vitro.

47. The method of claim 45, wherein the cancer cell is in an animal.

48. The method of claim 45, wherein the cancer cell is a human cancer cell.

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