Compositions comprising an Anti-mir-126 nucleic acid and BCL-2 homology 3 (BH3) mimetic and methods of use

Abstract

Provided herein are, inter alia, methods for treating cancer using anti-miR-126 compounds and BH3 mimetic compounds. In embodiments, the anti-miR-126 compounds are CpG oligodeoxynucleotide (CpG-ODN) or phosphorothioate CpG-ODN conjugated to an anti-miR-126 nucleic acid sequence, or an unconjugated anti-miR-126 nucleic acid sequence. Further provided are pharmaceutical compositions and pharmaceutical kits including anti-miR-126 compounds and BH3 mimetic compounds.

Description

Compositions Comprising an Anti-miR-126 Nucleic Acid and Bcl-2 Homology 3 (BH3) Mimetic and Methods of Use CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63 / 686,557, filed August 23, 2024, which is hereby incorporated by reference in its entirety and for all purposes. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (048440- 201001WO_Sequence_Listing_ST26.xml; Size: 81,920 bytes; and Date of Creation: August 22, 2025) are hereby incorporated by reference in their entirety. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0003] This invention was made with government support under R01 CA205247 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND

[0004] Leukemic stem cells (LSCs), a subset of leukemic cells, demonstrate distinct metabolic characteristics compared to hematopoietic stem cells (HSCs), particularly in mitochondrial functions and dynamics. These cells are also highly treatment refractory and therefore are often indicated as the root-cause of therapy failure in AML patients. Thus, targeting and depleting LSCs is an essential step to achieve a cure in AML. Chemotherapy and BH3-mimetic compounds are often used as treatments for leukemia. However, despite initial treatment success, overcoming resistance to chemotherapy and BH3-mimetic resistance remains an obstacle.

[0005] Provided herein, inter alia, are solutions to these and other problems in the art. BRIEF SUMMARY

[0006] Provided herein, inter alia, are methods and compositions effective for treating cancer. The methods and compositions provided herein include a an anti-microRNA-126 (miR-126) compound,where the an anti-miR-126 compound includes a phosphorothioated CpG oligodeoxynucleotide (CpG-ODN) or a CpG-ODN conjugated to an anti- miR-126 nucleic acid sequence.

[0007] In an aspect is provided a method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of an anti-microRNA-126 (miR- 126) compound and a Bcl-2 homology 3 (BH3) mimetic compound.

[0008] In another aspect is provided a pharmaceutical composition including an anti-microRNA- 126 (miR-126) compound and a Bcl-2 homology 3 (BH3) mimetic compound.

[0009] In another aspect is provided a kit including an anti-microRNA-126 (miR-126) compound and a Bcl-2 homology 3 (BH3) mimetic compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG.s 1A-1I. miR-126 depletion in CM-AML cells downregulates fatty acid metabolism and disrupts OXPHOS dynamics. (FIG.1A) Enrichment plot for fatty acid metabolism and oxidative phosphorylation pathways in RNA-seq data from preleukemic CM / miR-126Δ / ΔLin-Sca1+cKit+ cells (LSK) vs. CM-LSK. (FIG. 1B) Unsupervised hierarchical clustering showingsignificant changes in metabolite abundances (absolute log2FC>1, p<0.01) in preleukemic CM / miR- 126Δ / ΔLSK (n=4) compared with CM-LSK (n=6). (FIG.1C) Top 25 enriched pathway ofdownregulated metabolites in preleukemic CM / miR-126Δ / Δ LSK vs. CM-LSK. (FIG. 1D) Relativelevel of miR-126 as measured by Q-PCR in preleukemic LSKs (CM / miR-126Δ / Δ, n=5; CM, n=6). (FIG.1E) Relative levels of fatty acid oxidation (FAO) in CM / miR-126Δ / Δand CM LSKs, measured by the oxidation rate of 3H-palmitic acid (each, n=3). (FIG.1F) Levels of oxygen consumption rate (OCR, indicating OXPHOS) and extracellular acidification rate (ECAR, indicating glycolysis) measured by Seahorse assay in CM / miR-126Δ / Δand CM LSKs (each, n=3). (FIG.1G) Relative levels of reactive oxygen species (ROS) measured by flow cytometry (each, n=6). (FIG.1H) Represented transmission electron microscope (TEM) images of mitochondria morphology in CM / miR-126Δ / Δand CM LSKs. Scale bar, 1000 nm. (FIG.1I) Quantification of mitochondria length in CM / miR-126Δ / Δand CM LSKs (each, n=30).

[0011] FIG.s 1J-1K. Metabolic profile between CM leukemic Lin-cKit+ cells compared with control. (FIG.1J) Unsupervised hierarchical clustering showing significant changes in metabolite abundances in Lin-cKit+ cells from CM compared with control (each group, n=3). Top 50 annotatedmetabolites showed differential abundance in CM vs normal (p<0.05). (FIG.1K) Enrichment analysis of significantly increased metabolites in Lin-cKit+ cells from CM compared to control.

[0012] FIG.s 2A-2L. miR-126 inhibition by miRisten disrupts mitochondrial metabolism and dynamics, leading to a homing defect in inv(16) AML cells. A-H Primary CD34+CD38- inv(16) AML cells (LSCs, n=3) were treated with SCR control or miRisten (2 µM) for 24 hrs. (FIG.2A) Relative level of miR-126 was measured by Q-PCR. (FIG.2B) Relative levels of FAO were measured by the oxidation rate of 3H-palmitic acid. (FIG.2C) Levels of OCR (left, indicating OXPHOS) and ECAR (right, indicating glycolysis) measured by Seahorse assay. (FIG.2D) Represented images of JC1 probes staining in SCR or miRisten treated cells. The decrease in MMP levels in miRisten treated cells is indicated by the ratio of the lower ratio of polymer to monomer JC-1 fluorescence. Scale bar, 10 µm. (FIG.2E) Levels of ROS measured by immunostaining with hydrogen peroxide / peroxidase (left) and flow cytometry (right). (FIG.2F) Representative TEM images of mitochondria morphology in SCR or miRisten treated cells. Scale bar, 1000 nm. (FIG. 2G) Quantification of mitochondria length in SCR or miRisten treated cells (each, n=30). (FIG.2H) Effects of miRisten on proliferation (left) and apoptosis (right) of inv(16) LSCs. I-J GFP+CD34+ inv(16) AML cells were pre-treated with SCR control or miRisten (2 µM) ex vivo for 24 hrs and injected into NSGS mice. (FIG.2I) Representative confocal images of bone section staining with Osteopontin (OPN) antibody. Scale bar, 500 nm. Magnified images. Scale bar, 100 nm. (FIG.2J) Percentage of CD34+ AML cells homing to bone marrow (BM) niche measured by flow cytometry. (FIG.2K) Leukemia burden was determined by the percentage of hCD45+ in bone marrow of mice. (FIG.2L) Kaplan-Meier survival curve of treated leukemic mice [median survival (ms); miRisten 147.5 days vs. SCR 90 days; p=0.034].

[0013] FIG.s 2M-2W. Mitochondrial metabolism and dynamics in CM-AML and inv(16) AMLcells. (FIG.s 2M-2R) Differential expression of miR-126 and mitochondrial metabolism anddynamics in CM-LSK compared to control (CON) LSK. (FIG.2M) Relative level of miR-126 was measured by Q-PCR. (FIG.2N) Relative levels of FAO were measured by the oxidation rate of 3H- palmitic acid. (FIG.2O) Levels of OCR (left, indicating OXPHOS) and ECAR (right, indicating glycolysis) measured by Seahorse assay. (FIG.2P) Relative levels of reactive oxygen species (ROS) were measured by flow cytometry. (FIG.2Q) Representative TEM images of mitochondria morphology in CM-LSK and CON-LSK. Scale bar, 1000 nm. (FIG.2R) Quantification ofmitochondria length (each, n=30). (FIG.s 2S-2W) Differential expression of miR-126 and mitochondrial metabolism and dynamics in primary CD34+CD38- inv(16) AML cells and normal CD34+CD38- cells from healthy controls. (FIG.2S) Relative level of miR-126 was measured by Q- PCR. (FIG.2T) Relative levels of FAO were measured by the oxidation rate of 3H-palmitic acid. I Levels of OCR and ECAR measured by Seahorse assay. (FIG.2U) Changes in OCR and ECAR. (FIG.2V) Relative levels of ROS were measured by flow cytometry. (FIG.2W) Representative TEM images of mitochondria morphology in inv(16) AML and healthy controls. Scale bar, 1000 nm. (FIG.2X) Quantification of mitochondria length (each, n=30).

[0014] FIG.s 3A-3J. miR-126 upregulates BCL-2 expression via ERK signaling and modulatesBCL-2-CPT1B and BCL-2-NRF2 pathways. (FIG. 3A) Immunoblot analysis of indicated proteinsin LSKs from control (CON) and CM mice (left), and primary CD34+CD38- cells from normalhealthy controls (CON) and inv(16) AML patients (right). (FIG.3B) Effects of miR-126 overexpression (OE) on SPRED1 / ERK / BCL-2 signaling. miR-126lowCD34+CD38- AML cells [n=5, excluded inv(16)] were treated with SCR control or miR-126 mimic (126 OE, 2 µM) for 24 hrs. Cell lysate was immunoblotted with indicated antibodies. (FIG.3C) Inhibition of ERK signaling by MAPK inhibitor (PD98058) and MAPK siRNA (siMAPK) reverses miR-126-enhanced BCL-2 expression. miR-126lowCD34+CD38- AML cells [n=5, excluded inv(16)] were treated with miR-126 mimic (126 OE, 2 µM) in the presence of SCR control, PD98058 (10 µM), or siMAPK (20nM) for 24 hrs. Lysate was immunoblotted with indicated antibodies. (FIG. 3D) Representativeconfocal images of BCL-2 and CPT1B colocalization in primary CD34+CD38- inv(16) AML cells.Scale bar, 10 µm. (FIG.3E) miR-126 enhances BCL-2 and CPT1B levels and promotes BCL-2 binding with CPT1B. Increased BCL-2 and CPT1B levels, along with enhanced BCL-2 / CPT1B interaction, in murine CM cells compared to normal controls (left, n=4, each) and in human primary CD34+CD38− inv(16) AML cells compared to normal controls (right, n=3, each). (FIG.3F) Effectsof miRisten on BCL-2-CPT1B and BCL-2-NRF2 signaling. Primary CD34+CD38- inv(16) AMLcells (n=3) were treated with SCR control or miRisten (2 µM) for 24 hrs and immunoblotted with indicated antibodies. (FIG.3G) Effects of miRisten on DRP1-regulated mitofission. Representative immuno-transmission electron microscopy (IM-TEM) images showing DRP1 expression (black dots) and mitochondrial morphology in primary CD34+CD38− inv(16) AML cells (n=3) treated with SCR control or miRisten (2 µM) for 24 hrs. Scale bar, 200 nm. (FIG.3H) miR-126-OE enhances BCL-2 / NRF2 binding while inhibiting KEAP1 / NRF2 interaction, leading to reduce NRF2ubiquitination. miR-126lowCD34+CD38- AML cells [n=5, excluded inv(16)] were treated with SCR control or miR-126 mimic (126 OE, 2 µM) for 24 hrs. Left, cell lysates were immunoprecipitated with anti-NRF2 antibody and immunoblotted with anti-BCL-2, anti-KEAP1, and anti-NRF2 antibodies. Input loading controls are shown. Right, cell lysates were immunoprecipitated with anti- NRF2 antibodies and immunoblotted with anti-ubiquitin (Ub) antibodies. (FIG.3I) miR-126-OE increases NRF2 nuclear translocation, leading to reduced ROS levels. miR-126lowCD34+CD38- AML cells [n=5, excluded inv(16)] were treated with SCR control or miR-126 mimic (126 OE, 2 µM) for 24 hrs. Left, treated cells were fractionated into cytoplasmic and nuclear components, and lysates were immunoblotted with the indicated antibodies. Right, relative ROS levels in miR-126-OE cells compared to SCR control. (FIG. 3J) Schematic model illustrating miR-126 regulation ofBCL-2 expression via SPRED1 / p-ERK signaling and its impact on mitochondrial metabolism and dynamics through BCL-2-mediated CPT1B and NRF2 signaling.

[0015] FIG.s 3K-3O. miR-126 enhances BCL-2 interaction with CPT1B and promotes CPT1B stabilization. (FIG.s 3K-3L) miR-126lowCD34+CD38- AML cells [n=5, excluded inv(16)] were treated with SCR control or miR-126 mimic (126 OE, 2 μM) for 24 hrs. (FIG.3K) Relative level of miR-126 was measured by Q-PCR. (FIG.3L) Cell lysates were immunoprecipitated with anti-BCL- 2 antibody and immunoblotted with anti-BCL-2 and anti-CPT1B antibodies. Input loading controls are shown. (FIG.3M) miR-126lowCD34+CD38- AML cells [n=5, excluded inv(16)] were treated with SCR control or miR-126 mimic (126 OE, 2 μM) for 12 hrs followed by cycloheximide (CHX)treatment over time. Cell lysates were immunoblotted with indicated antibodies. (FIG.s 3N-3O)Inhibition of MAPK by PD98058 disrupts miR-126-regulated BCL-2 and CPT1B localization and reduces FAO levels. miR-126lowCD34+CD38- AML cells [n=5, excluded inv(16)] were treated with miR-126 mimic (126 OE, 2 μM) in the presence of either DMSO control or PD98058 (10 μM) for 24 hrs. (FIG.3N) Treated cells were fractionated into cytoplasmic and mitochondrial fractions. Celllysates were immunoblotted with indicated antibodies. (FIG. 3O) FAO levels were measured.

[0016] FIG.s 4A-4K. Synergistic effects of miRisten and venetoclax on mitochondria metabolismand dynamics. (FIG.s 4A-4H) Inv(16) primary CD34+CD38- AML cells (n=4) were treated withSCR control, venetoclax (VEN, 20 nM), miRisten (2 µM), or a combination of VEN and miRisten for 24 hrs. (FIG.4A) Relative level of FAO in treated cells. (FIG.4B) Levels of OCR (left, indicating OXPHOS) and ECAR (right, indicating glycolysis) measured by Seahorse assay. (FIG.4C) Relative levels of ROS in treated cells. (FIG.4D) Representative TEM images of mitochondria morphology in treated cells. Scale bar, 1000 nm. (FIG.4E) Quantification of mitochondria length in treated cells (each, n=30). (FIG.4F) Apoptosis defined by Annexin V+ percentage in treated cells.(FIG. 4G) Levels of DNA fragmentation in treated cells. (FIG. 4H) Immunoblots of PARPcleavage, BCL-2, NRF2 and CPT1B. (FIG.s 4I-4K) GFP+CD34+ inv(16) AML cells were pre- treated with SCR control, venetoclax (VEN, 20 nM), miRisten (2 µM), or a combination of VEN and miRisten for 24 hrs before injection into NSGS mice. Half of the mice were sacrificed after 16 hrs to assess homing, while the remaining mice were kept to isolate hCD45+ cells. (FIG.4I) The percentage of CD34+ AML cells homing to the bone marrow niche was measured by flow cytometry. (FIG.4J) Levels of OCR (indicating OXPHOS) in hCD45+ AML cells isolated from treated mice. (FIG.4K) Quantification of mitochondrial length (each, n=30) in hCD45+ AML cells isolated from treated mice.

[0017] FIG.s 4L-4R. Effects of miRisten and venetoclax combination treatment on normal HSCs and AML LSCs. (FIG.4L) Synergistic effect of miRisten and venetoclax (VEN) on LSCs. Inv(16)primary CD34+CD38- AML cells (1×105 cells / mL, n=3) were treated with the indicatedconcentration of miRisten and VEN. Cell viability was evaluated, and the synergy score of the drug combination was calculated using SynergyFinder. The HSA synergy score of 13.042 was observed.(FIG.s 4M-4Q) Primary CD34+CD38- cells were isolated from normal mononuclear cells (MNC)(NOR, n=3) or AML (n=3) and treated with vehicle control or combination of VEN (20 nM) and miRisten (2 μM) for 24 hrs. (FIG.4M) Relative levels of FAO. (FIG.4N) Relative levels of ROS.(FIG. 4O) Levels of OCR (up, indicating OXPHOS) and ECAR (down, indicating glycolysis) innormal MNC. (FIG.4P) Levels of OCR (up, indicating OXPHOS) and ECAR (down, indicating glycolysis) in AML. (FIG.4Q) Percentage of apoptosis defined by Annexin V+ cells (up) and DNA fragmentation (down). (FIG.4R) GFP-marked (GFP+)CD34+ inv(16) AML cells were pre-treated with SCR control, VEN (20 nM), miRisten (2 μM), or combination of VEN and miRisten for 24 hrs and injected into NSGS mice. Representative confocal images of bone section stained with OPN antibody. Scale bar, 500 nm.

[0018] FIG.s 5A-5J. Combined treatment with miRisten and venetoclax synergistically reduces AML burden and prolongs survival in both murine and inv(16) PDX AML model. (FIG.s 5A-5D) CM-AML mouse model (see schematic of experimental design in FIG.5K). (FIG.5A) Frequencyof cKit+ AML cells in the BM of mice treated of control (n=10, mean 59.95%), VEN (n=10, mean 56.23%), miRisten (n=10, mean 49.84%; miRisten vs. CON p=0.013), or VEN / miRisten combination (n=10, mean 33.64%; combination vs. CON p<0.0001; combination vs. VEN p=0.0011; combination vs. miRisten p=0.0014). (FIG.5B) Kaplan-Meier survival curve of primary transplant recipients with CM-AML treated with control (n=10, ms 91.0 days), VEN (n=10, ms 106.5 days; VEN vs. CON p=0.01), miRisten (n=9, ms 108 days; miRisten vs. CON p=0.0005), or VEN / miRisten combination (n=12, ms 125 days; combination vs. CON p<0.0001; combination vs. VEN p=0.039; combination vs. miRisten p=0.0049). The statistical significance was determined using Log-rank (Mantel-Cox) test. (FIG.5C) Frequency of cKit+ AML cells in the PB of mice from second transplant recipients treated with control (n=8, mean 71.19%), VEN (n=7, mean 31.7%; VEN vs. CON p<0.0001), miRisten (n=8, mean 15.88%; miRisten vs. CON p<0.0001), or VEN / miRisten combination (n=7, mean 14.25%; combination vs. CON p<0.0001; combination vs. VEN p=0.016), which were analyzed for engraftment at 4 weeks after transplantation. (FIG.5D) Kaplan-Meier survival curve of second transplant recipient mice treated with control (n=8; ms 45 days), VEN (n=7; ms 54 days; VEN vs. CON p=0.0048), miRisten (n=8; ms 70.5 days; miRisten vs. CON p=0.0002), or VEN / miRisten combination (n=7; ms 92 days; combination vs. CON p=0.0002; combination vs. VEN p=0.0059; combination vs. miRisten p=0.048). The statistical significance was determined using Log-rank (Mantel-Cox) test. (FIG.s 5E-5H) Inv(16) AML PDX model (seeschematic of experimental design in FIG. 5O). (FIG. 5E) Frequency of hCD45+ AML cells in BMof NSGS recipient mice treated with control (n=6, mean 68.57%), VEN (n=6, mean 25.32%; VEN vs. CON p=0.0001), miRisten (n=6, mean 27.88%; miRisten vs. CON p<0.0001), or VEN / miRisten combination (n=7, mean 33.64%; combination vs. CON p<0.0001; combination vs. VEN p=0.032;combination vs. miRisten p=0.0033). (FIG. 5F) Kaplan-Meier survival curve of NSGS recipientmice transplanted with inv(16) AML cells and treated with control (n=7; ms 101 days), VEN (n=7; ms 173 days; VEN vs. CON p=0.0029), miRisten (n=7; ms 183 days; miRisten vs. CON p=0.0048), or VEN / miRisten combination (n=8; ms 235 days; combination vs. CON p<0.0001; combination vs. VEN p=0.0092; combination vs. miRisten p=0.0015). The statistical significance was determinedusing Log-rank (Mantel-Cox) test. (FIG. 5G) Frequency of hCD45+ AML cells in the PB of micefrom second transplant recipients treated with control (n=7, mean 53.6%), VEN (n=6, mean 21.24%; VEN vs. CON p=0.0032), miRisten (n=8, mean 4.84%; miRisten vs. CON p<0.0001), or VEN / miRisten combination (n=7, mean 0.666%; combination vs. CON p<0.0001; combination vs.VEN p=0.0068; combination vs. miRisten p=0.039), which were analyzed for engraftment at 4 weeks after transplantation. (FIG.5H) Kaplan-Meier survival curve of second transplant recipients treated with control (n=7; ms 115 days), VEN (n=6; ms 166.5 days; VEN vs. CON p=0.0485), miRisten (n=8; ms 227 days; miRisten vs. CON p<0.0001), or VEN / miRisten combination (n=7; ms 247 days; combination vs. CON p=0.0002; combination vs. VEN p=0.0005; combination vs. miRisten p=0.0018). (FIG.5I) Kaplan-Meier survival curves of primary transplant recipients with CM AML cells treated with control (n=10, ms 79 days), miRisten (n=9, ms 89 days; miRisten vs. control, p=0.046), VEN / AZA (n=9, ms 89 days; VEN / AZA vs. CON, p=0.026), or VEN / AZA / miRisten combination (n=9, ms 106 days; VEN / AZA / miRisten vs. VEN / AZA, p=0.041; VEN / AZA / miRisten vs. miRisten, p=0.037). Statistical significance was determined using the log- rank (Mantel-Cox) test. (FIG.5J) Kaplan-Meier survival curves of primary transplant recipients with FLT3 WT AML treated with control (n=7, ms 20 days), miRisten (n=7, ms 25 days; miRisten vs. control, p=0.0002), VEN / AZA (n=7, ms 27 days; VEN / AZA vs. CON, p=0.0002), or VEN / AZA / miRisten combination (n=7, ms 35 days; VEN / AZA / miRisten vs. VEN / AZA, p=0.0011; VEN / AZA / miRisten vs. miRisten, p=0.0002). Statistical significance was determined using the log- rank (Mantel-Cox) test. Each dot in A, C, E, and G represents the result from an individual mouse.

[0019] FIG.s 5K-5T. Combination of miRisten and venetoclax reduces disease burden in CM-AML and inv(16) AML PDX model. A-D CM-AML mouse model. (FIG. 5K) Schematic ofexperimental design. CM-AML cells (1^106 / mouse) were transplanted into cohorts of wild-type syngeneic mice. After 4 weeks, mice were treated with SCR control or miRisten (20 mg / kg / dose, daily for 3 weeks), venetoclax (100 mg / kg / day, daily for 2 weeks), or a combination of miRisten and venetoclax. Half of mice were monitored for survival and others were sacrificed and analyzed AML engraftment at 3 days after the last dose of treatment and BM cells were transplanted into second recipients. (FIG.5L) Engraftment of cKit+ AML cells in the peripheral blood (PB) of mice treated with control (n=10, mean 70.07%), VEN (n=10, mean 51.97%), miRisten (n=10, mean 53.22%), or VEN / miRisten combination (n=10, mean 27.94%; combination vs. CON p<0.0001; combination vs. VEN p=0.011; combination vs. miRisten p=0.0075). (FIG.5M) Frequency of cKit+ AML cells in the spleen (SP) of mice treated with control ( n=10, mean 54.82%), VEN (n=10, mean 40.98%; VEN vs. CON p=0.028), miRisten (n=10, mean 42.79%), or VEN / miRisten combination (n=10, mean 29.06%; combination vs. CON p<0.0001; combination vs. VEN p=0.026; combination vs. miRisten p=0.029). (FIG.5N) Left, Representative images of spleens from recipients of control,VEN, miRisten, or VEN / miRisten combination group. Right, Spleen weight from treated recipients of control (n=10, mean 0.853 g), VEN (n=10, mean 0.479 g; VEN vs. CON p<0.0001), miRisten (n=10, mean 0.495 g; miRisten vs. CON p<0.0001), or VEN / miRisten combination (n=10, mean 0.228 g; combination vs. CON p<0.0001; combination vs. VEN p=0.0022; combination vs.miRisten p=0.0012). (FIG.s 5O-5R) Inv(16) AML PDX model. (FIG. 5O) Schematic ofexperimental design. Inv(16) AML PDX was established by directly injecting expanded AML cells (2^106cells / mouse) into irradiated NSGS via intravenous injection. When hCD45+% in peripheral blood (PB) reached detectable levels (5-10%), PDX mice were randomly assigned to treatment groups: SCR control, miRisten (20 mg / kg per dose, administered daily for 3 weeks), venetoclax (100 mg / kg per day, administered daily for 2 weeks), or a combination of miRisten and venetoclax and followed by assessment of human cell engraftment in BM and spleen. (FIG.5P) Frequency of hCD45+ AML in PB of NSGS recipient mice treated with control (n=6, mean 22.21%), VEN (n=6, mean 3.858%; VEN vs. CON p=0.013), miRisten (n=6, mean 5.092%; miRisten vs. CON p=0.022), or VEN / miRisten combination (n=7, mean 1.444%; combination vs. CON p=0.0038). (FIG.5Q) Frequency of hCD45+ AML in SP of NSGS recipient mice treated with control (n=6, mean 13.79%), VEN (n=6, mean 3.722%; VEN vs. CON p=0.042), miRisten (n=6, mean 4.102%), or VEN / miRisten combination (n=7, mean 1.067%; combination vs. CON p=0.0069; combination vs. VEN p=0.027; combination vs. miRisten p=0.021). (FIG.5R) Frequency of hCD34+CD45+ AML in BM of NSGS recipient mice treated with control (n=6, mean 36.45%), VEN (n=6, mean 12.68%; VEN vs. CON p<0.0001), miRisten (n=6, mean 14.42%; miRisten vs. CON p<0.0001), or VEN / miRisten combination (n=7, mean 6.291%; combination vs. CON p<0.0001; combination vs. VEN p=0.047; combination vs. miRisten p=0.01). Each dot in B, C, D, F, G, H represents result from an individual mouse. (FIG.s 5S-5T) Schematic of the experimental design for comparison of the effects of adding miRisten to VEN / Azacitidine (AZA) regimen on CM AML or FLT3 WT AMLmouse survival. (FIG. 5S) CM AML cells (1×10⁶ cells / mouse) were transplanted into cohorts ofC57BL / 6 mice. After 6 weeks, mice were treated with either SCR control, miRisten (20 mg / kg / dose, daily for 3 weeks), the combination of VEN (100 mg / kg / day, daily for 2 weeks) and AZA (2 mg / kg, every 3 days for 2 weeks), or the combination of miRisten and VEN / AZA. Treated mice were monitored for survival. (FIG.5T) FLT3-WT AML cells (1×10⁶ cells / mouse) were transplanted into cohorts of NSG mice. After 5 days, mice were treated with either SCR control, miRisten (20 mg / kg / dose, daily for 3 weeks), the combination of VEN (100 mg / kg / day, daily for 2 weeks) andAZA (2 mg / kg, every 3 days for 2 weeks), or the combination of miRisten and VEN / AZA. Treated mice were monitored for survival.

[0020] FIG.s 6A-6O. The combination of miRisten and venetoclax effectively targets venetoclax-resistant AML cells by disrupting mitochondrial metabolism and dynamics. (FIG. 6A) RelativemiR-126 expression in venetoclax-resistant (VEN-RES AML) and venetoclax-sensitive (VEN-SEN AML) samples (n=4 per group) was measured by Q-PCR. (FIG.6B) Relative level of FAO inprimary CD34+CD38- AML cells isolated from VEN-RES and VEN-SEN patients. (FIG. 6C)Levels of OCR (left, indicating OXPHOS) and ECAR (right, indicating glycolysis) measured by Seahorse assay. (FIG.6D) Represented TEM images of mitochondria morphology. Scale bar, 1000 nm. (FIG.6E) Quantification of mitochondria length in VEN-RES and VEN-SEN AML cells (each, n=30). (FIG.s 6F-J) Effects of miRisten and venetoclax combined treatment on VEN-RES-AMLcells in vitro. Primary CD34+CD38- AML cells were isolated from VEN-RES-AML (n=4) andtreated with SCR (2 µM), VEN (200 nM), miRisten (2 µM) or a combination of venetoclax and miRisten for 24 hrs. (FIG.6F) Relative levels of FAO. (FIG.6G) Relative levels of ROS. (FIG.6H) Quantification of mitochondria length (each, n=30). (FIG. 6I) Levels of OCR. (FIG. 6J)Percentage of apoptosis defined by Annexin V+ cells. (FIG.s 6K-O) Effects of combined miRisten and venetoclax treatment on the VEN-RES AML PDX model in vivo. hCD45+ BM VEN-RES- AML cells (1^106cells / mouse) were transplanted into NSGS mice to generate a cohort of VEN- RES-AML bearing PDX mice. These mice were treated with either vehicle control, venetoclax (100 mg / kg / day, daily for 2 weeks), miRisten (20 mg / kg / day, daily for 3 weeks) or combination (the same dose as single agents). (FIG.6K) Representative images of spleens from recipients of treated mice. (FIG.6L) Spleen weight from treated recipients of CON (n=7, mean 0.164g), VEN (n=7, mean 0.153g), miRisten (n=7, mean 0.09g; miRisten vs. CON p=0.0009), or VEN / miRisten combination (n=7, mean 0.0643g; VEN / miRisten vs. CON p<0.0001; VEN / miRisten vs. VEN p=0.0019; VEN / miRisten vs. miRisten p=0.0164). (FIG.6M) Frequency of hCD33+CD45+ AML cells in BM of NSGS recipient mice treated with control (n=7, mean 71.27%), VEN (n=7, mean 63.51%), miRisten (n=7, mean 52.07%; miRisten vs. CON p=0.0036), or VEN / miRisten combination (n=7, mean 36.24%; VEN / miRisten vs. CON p<0.0001; VEN / miRisten vs. VEN p=0.0198; VEN / miRisten vs. miRisten p=0.0132). (FIG.6N) Kaplan-Meier survival curve of primary transplant recipients with VEN-RES-AML treated with control (n=10, ms 31.5 days), VEN (n=11, ms 32 days), miRisten (n=10, ms 40 days, miRisten vs. CON, p<0.0001), VEN / miRisten(n=10, ms 48 days; VEN / miRisten vs. CON p<0.0001; VEN / miRisten vs. VEN p<0.0001; VEN / miRisten vs. miRsiten p=0.0124). The statistical significance was determined using Log-rank (Mantel-Cox) test. (FIG.6O) Kaplan-Meier survival curve of 2ndtransplant recipients with VEN- RES-AML from control (n=6, ms 29 days), VEN (n=6, ms 30 days), miRisten (n=6, ms 42.5 days, miRisten vs. CON, p=0.0005), VEN / miRisten (n=6, ms 50 days; VEN / miRisten vs. CON p=0.0005; VEN / miRisten vs. VEN p=0.0007; VEN / miRisten vs. miRsiten p=0.0036.

[0021] FIG.s 6P-6Z. Effects of miR-126 overexpression on VEN-inhibited mitochondrialmetabolism. (FIG. 6P) Cell viability curve and IC50 of Ven-Resistant (VEN-RES) and VEN-Sensitive (VEN-SEN) AML cells treated with venetoclax (VEN). (FIG.s 6Q-6V) miR-126lowCD34+CD38- AML cells [n=4, excluded inv(16)] were treated with SCR control or miR-126 mimic(126 OE, 2 μM) for 24 hrs in the presence of VEN. (FIG. 6Q) Relative level of miR-126 wasmeasured by Q-PCR. (FIG.6R) Relative levels of FAO were measured by the oxidation rate of 3H- palmitic acid. (FIG.6S) Levels of OCR (left, indicating OXPHOS) and ECAR (right, indicating glycolysis) measured by Seahorse assay. (FIG.6T) Relative levels of ROS were measured by flow cytometry. (FIG.6U) Quantification of mitochondria length (each, n=30). (FIG.6V) Levels ofDNA fragmentation. (FIG.s 6W-6Z) Effects of VEN / miRisten combined treatment in VEN-RESand VEN-SEN AML cells. Primary CD34+CD38- AML cells isolated from VEN-RES or VEN-SENpatients (n=4) were treated with combination of VEN (200 nM) and miRisten (2 μM) for 24 hrs.(FIG.s 6W-6X) Levels of OCR (FIG. 6W) and ECAR (FIG. 6X) in treated VEN-RES and VEN-SEN AML cells. (FIG.6Y) Relative levels of FAO were measured by the oxidation rate of3H-palmitic acid. (FIG. 6Z) Levels of DNA fragmentation.

[0022] FIG.7. Schematic of experimental design for study shown in FIG.s 6A-6Z. VEN-RES AML 356 PDXs were established by directly injecting human AML cells (1x106cells / mouse) into NSGS via intravenous injection. When hCD45+% in PB reached detectable levels (5-10%), PDX mice were randomly assigned to treatment groups: SCR control, miRisten (20 mg / kg per dose, administered daily for 3 weeks), VEN (100 mg / kg per day, administered daily for 2 weeks), or a combination of miRisten and VEN and followed by assessment of human cell engraftment in BM and spleen.

[0023] FIG.s 8A-8D. Effects of miRisten and venetoclax / azacitidine combination treatment onAML cells. Results show a synergistic effect of miRisten and Ven / Aza on AML cell lines andprimary AML cells. Evaluation of viable cells as measured by cell proliferation (top panel) andapoptosis (bottom panel). (FIG. 8A) Synergistic effect of miRisten and venetoclax / azacitidine(Ven / Aza) on MV4-11 AML cell line. The maximum synergy ZIP score of 23.538 (proliferation) and 31.721 (apoptosis) were observed. (FIG.8B) Synergistic effect of miRisten and Ven / Aza on Molm13 AML cell line. The maximum synergy ZIP score of 23.741 (proliferation) and 31.845(apoptosis) were observed. (FIG. 8C) Synergistic effect of miRisten and Ven / Aza on FLT3-WTprimary AML cells. The maximum synergy ZIP score of 23.741 (proliferation) and 31.845(apoptosis) were observed. (FIG. 8D) Synergistic effect of miRisten and Ven / Aza on INV16primary AML cells. The maximum synergy ZIP score of 11.227 (proliferation) and 16.421 (apoptosis) were observed. DETAILED DESCRIPTION

[0024] The following definitions are included for the purpose of understanding the present subject matter and for constructing the appended patent claims. Abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0025] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. See, e.g., Singleton et al.,DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons(New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL,Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of this disclosure. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

[0026] Throughout the description and claims of this specification the word “comprise” and other forms of the word, such as “comprising” and “comprises,” means including but not limited to, and is not intended to exclude, for example, other components.

[0027] The term “about” refers to any minimal alteration in the concentration or amount of an agent that does not change the efficacy of the agent in preparation of a formulation and in treatment of a disease or disorder. The term “about” with respect to concentration range of the agents (e.g., therapeutic / active agents) of the current disclosure also refers to any variation of a stated amount orrange which would be an effective amount or range. In embodiments, the term "about" means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about means the specified value.

[0028] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it is understood that the particular value forms another aspect. It is further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. It is also understood that throughout the application, data are provided in a number of different formats and that this data represent endpoints and starting points and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0029] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0030] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0031] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched non-cyclic carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl,ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4- pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).

[0032] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0033] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable non-cyclic straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and –CH2-O-Si(CH3)3.

[0034] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of thelinking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and / or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like.

[0035] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic non-aromatic versions of “alkyl” and “heteroalkyl,” respectively, wherein the carbons making up the ring or rings do not necessarily need to be bonded to a hydrogen due to all carbon valencies participating in bonds with non-hydrogen atoms. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0036] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1- C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0037] The term “acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0038] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently (e.g., biphenyl). A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6- fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2- phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2- quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Non-limiting examples of heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthanyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl, or quinolyl.The examples above may be substituted or unsubstituted and divalent radicals of each heteroaryl example above are non-limiting examples of heteroarylene.

[0039] A fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substituents described herein.

[0040] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

[0041] The term “alkylsulfonyl,” as used herein, means a moiety having the formula -S(O2)-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' may have a specified number of carbons (e.g., “C1-C4 alkylsulfonyl”).

[0042] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0043] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'' , -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S( O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', ^NR'NR''R''', ^ONR'R'', ^NR'C=(O)NR''NR'''R'''', -CN, -NO2, in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includesmore than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0044] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O) NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=N R''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', ^NR'NR''R''', ^ONR'R'', ^NR'C=(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1- C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' groups when more than one of these groups is present.

[0045] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0046] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C''R''R''')d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0047] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0048] A “substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2Cl, -SO3H, -SO4H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC=(O)NHNH2, ^NHC=(O) NH2, -NHSO2H, -NHC= (O)H, - NHC(O)-OH, -NHOH, -OCF3, -OCHF2, ^NHSO2CH3, -N3, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: (i) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2Cl, -SO3H, - SO4H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC=(O)NHNH2, ^NHC=(O) NH2, -NHSO2H, - NHC= (O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, ^NHSO2CH3, -N3, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: (a) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2Cl, -SO3H, - SO4H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC=(O)NHNH2, ^NHC=(O) NH2, -NHSO2H, - NHC= (O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, ^NHSO2CH3, -N3, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, , and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2Cl, -SO3H, -SO4H, - SO2NH2, ^NHNH2, ^ONH2, ^NHC=(O)NHNH2, ^NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, ^NHSO2CH3, -N3, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.

[0049] A “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0050] A “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl,each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.

[0051] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0052] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0053] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section below.

[0054] As used herein, the term "conjugated” when referring to two moieties means the two moieties are bonded, wherein the bond or bonds connecting the two moieties may be covalent or non-covalent. In embodiments, the two moieties are covalently bonded to each other (e.g., directly or through a covalently bonded intermediary). In embodiments, the two moieties are non-covalently bonded (e.g., through ionic bond(s), van der waal’s bond(s) / interactions, hydrogen bond(s), polar bond(s), or combinations or mixtures thereof).

[0055] "Nucleic acid" refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof; or nucleosides (e.g., deoxyribonucleosides or ribonucleosides). In embodiments, “nucleic acid” does not include nucleosides. The terms “polynucleotide,” “oligonucleotide,” “oligo” or the like refer, in the usual and customary sense, to a linear sequence of nucleotides. The term “nucleoside” refers, in the usual and customary sense, to a glycosylamine including a nucleobase and a five-carbon sugar (ribose or deoxyribose). Non-limiting examples, of nucleosides include, cytidine, uridine, adenosine, guanosine, thymidine and inosine. The term “nucleotide” refers, in the usual and customary sense, to a single unit of a polynucleotide, i.e., a monomer. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof. Examples of polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA, and hybrid molecules having mixtures of single and double stranded DNA and RNA. Examples of nucleic acid, e.g. polynucleotides contemplated herein include any types of RNA, e.g. mRNA,siRNA, miRNA, and guide RNA and any types of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof. The term “duplex” in the context of polynucleotides refers, in the usual and customary sense, to double strandedness. Nucleic acids can be linear or branched. For example, nucleic acids can be a linear chain of nucleotides or the nucleic acids can be branched, e.g., such that the nucleic acids comprise one or more arms or branches of nucleotides. Optionally, the branched nucleic acids are repetitively branched to form higher ordered structures such as dendrimers and the like.

[0056] As may be used herein, the terms “nucleic acid,” “nucleic acid molecule,” “nucleic acid oligomer,” “oligonucleotide,” “nucleic acid sequence,” “nucleic acid fragment” and “polynucleotide” are used interchangeably and are intended to include, but are not limited to, a polymeric form of nucleotides covalently linked together that may have various lengths, either deoxyribonucleotides or ribonucleotides, or analogs, derivatives or modifications thereof. Different polynucleotides may have different three-dimensional structures, and may perform various functions, known or unknown. Non-limiting examples of polynucleotides include a gene, a gene fragment, an exon, an intron, intergenic DNA (including, without limitation, heterochromatic DNA), messenger RNA (mRNA), transfer RNA, ribosomal RNA, a ribozyme, cDNA, a recombinant polynucleotide, a branched polynucleotide, a plasmid, a vector, isolated DNA of a sequence, isolated RNA of a sequence, a nucleic acid probe, and a primer. For example, the nucleic acid provided herein may be part of a vector. For example, the nucleic acid provided herein may be part of an adenoviral vector, which may be transduced into a cell. Polynucleotides useful in the methods of the disclosure may comprise natural nucleic acid sequences and variants thereof, artificial nucleic acid sequences, or a combination of such sequences.

[0057] Nucleic acids, including e.g., nucleic acids with a phosphothioate backbone, can include one or more reactive moieties. As used herein, the term reactive moiety includes any group capable of reacting with another molecule, e.g., a nucleic acid or polypeptide through covalent, non-covalent or other interactions. By way of example, the nucleic acid can include an amino acid reactive moiety that reacts with an amio acid on a protein or polypeptide through a covalent, non-covalent or other interaction. In embodiments, a nucleic acid may include a covalent linker as provided herein, attaching a first nucleic acid (e.g. anti-miR126) to a second nucleic acid (e.g. CpG ODN).

[0058] The terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate), phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite linkages (see Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press) as well as modifications to the nucleotide bases such as in 5-methyl cytidine or pseudouridine.; and peptide nucleic acid backbones and linkages. Other analog nucleic acids include those with positive backbones; non-ionic backbones, modified sugars, and non-ribose backbones (e.g. phosphorodiamidate morpholino oligos or locked nucleic acids (LNA) as known in the art), including those described in U.S. Patent Nos.5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, CARBOHYDRATE MODIFICATIONS IN ANTISENSE RESEARCH, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made. In embodiments, the internucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both.

[0059] Nucleic acids can include nonspecific sequences. As used herein, the term "nonspecific sequence" refers to a nucleic acid sequence that contains a series of residues that are not designed to be complementary to or are only partially complementary to any other nucleic acid sequence. By way of example, a nonspecific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism.

[0060] A polynucleotide is typically composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); and thymine (T) (uracil (U) for thymine (T) when thepolynucleotide is RNA). Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule; alternatively, the term may be applied to the polynucleotide molecule itself. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. Polynucleotides may optionally include one or more non-standard nucleotide(s), nucleotide analog(s) and / or modified nucleotides.

[0061] Unless indicated otherwise, the following annotations are used in the nucleic acid sequences disclosed herein: * = phosphorothioate linkage; xxxxx = any linker described herein and in embodiments xxxxx may be = -(CH2)n-PO4-[(CH2)n-PO4]z-(CH2)n) bonded to phosphate groups at both ends except at the termini where terminal phosphates are optionally added and 5’x has an OH terminus and 3’ x has a -C6-NH2bonded to the final phosphate group, other linkages are phosphodiester; mN indicates a 2’OMe modified nucleotide; fN indicates a 2’fluoro modified nucleotide; and rN indicates a ribonucleotide.

[0062] As used herein, the term “anti-microRNA (anti-miR)” or “anti-microRNA (anti-miR) nucleic acid sequence” is used according to its plain and ordinary meaning and refers to RNA that is capable of suppressing or reducing expression and / or activity of a target microRNA. In embodiments, the anti-miR oligomer may be a single stranded oligomer of 20–30 bases. In embodiments, the anti-miR oligomer may be a double stranded oligomer of 20–30 bases. In embodiments, the anti-miR oligomer may be partially double stranded, with single stranded overhangs. In embodiments, the oligomer may have a 2’chemical modification. In embodiments, the oligomer may have serum stability-enhancing chemical modification, e.g., a phosphothioate internucleotide linkage, a 2’-O-methyl ribonucleotide, a 2’-deoxy-2’fluoro ribonucleotide, a 2’- deoxy ribonucleotide, a universal base nucleotide, a 5-C methyl nucleotide, an inverted deoxybasic residue incorporation, or a locked nucleic acid. In embodiments, an anti-miR sequence hybridizes to the corresponding miR sequence. Full complementarity is not necessarily required, provided there is sufficient complementarity to cause hybridization. In some embodiments, the degree of complementarity between an anti-miR sequence and its corresponding miR sequence, when optimally aligned using a suitable alignment algorithm, is about or more than about 50%, 60%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. Optimal alignment may be determined with the use of any suitable algorithm for aligning sequences, non-limitingexample of which include the Smith-Waterman algorithm, the Needleman-Wunsch algorithm, algorithms based on the Burrows-Wheeler Transform (e.g. the Burrows Wheeler Aligner), ClustalW, Clustal X, BLAT, Novoalign (Novocraft Technologies, ELAND (Illumina, San Diego, Calif.), SOAP (available at soap.genomics.org.cn), and Maq (available at maq.sourceforge.net). In embodiments, the anti-miR sequence has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the perfectly complementary sequence of the target miR sequence.

[0063] A “microRNA,” “microRNA nucleic acid sequence,” “miR,” “miRNA” as used herein, refers to a nucleic acid that functions in RNA silencing and post-transcriptional regulation of gene expression. The term includes all forms of a miRNA, such as the pri-, pre-, and mature forms of the miRNA. In embodiments, microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein- coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. In embodiments, a miRNA nucleic acid sequence described herein is about 10 to 80 nucleotides (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 nucleotides) in length. In embodiments, a miRNA nucleic acid sequence described herein is about 15 to 50 nucleotides (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 nucleotides) in length. In embodiments, a miRNA nucleic acid sequence described herein is about 18 to 25 nucleotides (e.g., 18, 19, 20, 21, 22, 23, 24, 25 nucleotides) in length.

[0064] As used herein, the term “miR-126”, “miR126” or “microRNA126” includes all forms of miR-126 including the pri-, pre-, and mature forms of miR-126, as well as variants, homologues, modifications, and derivatives thereof (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%,99% or 100% activity compared to the native miR-126). In embodiments, the variants or homologues or derivatives have at least 50%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity across the whole sequence or a portion of the sequence (e.g. a 10, 15, 20, 25, 30, 40, 45, 50, 55, 60, 65, 70, 75, or 80 continuous nucleotides portion) compared to a naturally occurring form. In embodiments, the miR-126 is the miRNA as identifiedby NCBI Reference Sequence: NR_029695.1 or SEQ ID NO:1. In embodiments, the miR-126 is themiRNA as identified by NCBI Reference Sequence: NR_029695.1. In embodiments, the miR-126 is the miRNA as identified by SEQ ID NO:1.

[0065] The term “anti-microRNA-126”, “anti-miR-126” or “anti-miR-126 nucleic acid sequence” refers to a sequence that has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a sequence perfectly complementary sequence to the target miR-126 nucleic acid as defined above.

[0066] The term “anti-microRNA126 compound” or “anti-miR-126 compound” refers to a nucleic acid including an anti-miR-126 nucleic acid sequence. As described herein, in embodiments, the anti-miR-126 compound includes a CpG oligodeoxynucleotide (CpG-ODN) covalently linked to an anti-miR-126 sequence. In embodiments, the anti-miR-126 compound includes a phosphorothioate CpG-ODN covalently linked to an anti-miR-126 nucleic acid sequence. In embodiments, the anti- miR-126 compound includes a CpG-ODN or phosphorothioate CpG-ODN attached to an anti-miR- 126 nucleic acid by a linker.

[0067] As used herein, the term “phosphorothioated oligodeoxynucleotide (ODN)” refers to a nucleic acid sequence, e.g., “CpG nucleic acid sequence” or “GpC nucleic acid sequence”, in which some or all the internucleotide linkages constitute a phosphorothioate linkage. In embodiments, phosphorothioated oligodeoxynucleotide (ODN) is 15 to 30 bases long, single-stranded, partly or completely phosphorothioated. The partly phosphorothioated ODN is an ODN in which 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28, internucleotide linkages constitute a phosphorothioate linkage.

[0068] Unless indicated otherwise, the following annotations are used in the nucleic acid sequences disclosed herein: * = phosphorothioate linkage; xxxxx = any linker described herein and in embodiments xxxxx may be = -(CH2)n-PO4-[(CH2)n-PO4]z-(CH2)n) bonded to phosphate groups atboth ends except at the termini where terminal phosphates are optionally added and 5’x has an OH terminus and 3’ x has a -C6-NH2bonded to the final phosphate group, other linkages are phosphodiester; mN indicates a 2’OMe modified nucleotide; fN indicates a 2’fluoro modified nucleotide; and rN indicates a ribonucleotide.

[0069] In embodiments, the term “CpG” or “CpG motif” in a nucleic acid refers to a nucleic acid in which a 5’ C nucleotide is connected to a 3’ G nucleotide through a phosphodiester internucleotide linkage or a phosphodiester derivative internucleotide linkage. In embodiments, the term “CpG” or “CpG motif” in a nucleic acid refers to a nucleic acid in which a 5’ G nucleotide connected to a 3’ C nucleotide through a phosphodiester internucleotide linkage or a phosphodiester derivative internucleotide linkage (aka, a “GpC nucleic acid sequence”). In embodiments, a CpG includes a phosphodiester internucleotide linkage. In embodiments, a CpG includes a phosphodiester derivative internucleotide linkage. In embodiments, a CpG includes a phosphorothioate linkage.

[0070] As used herein, the term "Class A CpG ODN” or “A-class CpG ODN” or “D-type CpG ODN” or “Class A CpG DNA sequence” is used in accordance with its common meaning in the biological and chemical sciences and refers to a CpG motif including oligodeoxynucleotide including one or more of poly-G sequence at the 5’, 3’, or both ends; an internal palindrome sequence including CpG motif; or one or more phosphodiester derivatives linking deoxynucleotides. In embodiments, a Class A CpG ODN includes poly-G sequence at the 5’, 3’, or both ends; an internal palindrome sequence including CpG motif; and one or more phosphodiester derivatives linking deoxynucleotides. In embodiments, the phosphodiester derivative is phosphorothioate. Examples of Class A CpG ODNs include ODN D19, ODN 1585, ODN 2216, and ODN 2336.

[0071] As used herein, the term "Class B CpG ODN” or “B-class CpG ODN” or “K-type CpG ODN” or “Class B CpG DNA sequence” is used in accordance with its common meaning in the biological and chemical sciences and refers to a CpG motif including oligodeoxynucleotide including one or more of a 6mer motif including a CpG motif; phosphodiester derivatives linking all deoxynucleotides. In embodiments, a 6mer motif comprises 5’-PuPyCGPyPu-3’, where Pu represents a purine containing nucleobase (e.g., A or G) and Py represents a pyrimidine containing nucleobase (e.g., T / U or C). In embodiments, a Class B CpG ODN includes one or more copies of a 6mer motif including a CpG motif and phosphodiester derivatives linking all deoxynucleotides. Inembodiments, the phosphodiester derivative is phosphorothioate. In embodiments, a Class B CpG ODN includes one 6mer motif including a CpG motif. In embodiments, a Class B CpG ODN includes two copies of a 6mer motif including a CpG motif. In embodiments, a Class B CpG ODN includes three copies of a 6mer motif including a CpG motif. In embodiments, a Class B CpG ODN includes four copies of a 6mer motif including a CpG motif. Examples of Class B CpG ODNs include ODN 1668, ODN 1826, ODN 2006, and ODN 2007.

[0072] As used herein, the term "Class C CpG ODN” or “C-class CpG ODN” ” or “C-type CpG DNA sequence” is used in accordance with its common meaning in the biological and chemical sciences and refers to an oligodeoxynucleotide including a palindrome sequence including a CpG motif and phosphodiester derivatives (phosphorothioate) linking all deoxynucleotides. Examples of Class C CpG ODNs include ODN 2395 and ODN M362.

[0073] A “label” or a “detectable moiety” is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, useful detectable moieties include32P, fluorescent dyes, electron- dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates, monochrystalline SPIO, monochrystalline SPIO aggregates, monochrystalline iron oxide nanoparticles, monochrystalline iron oxide, other nanoparticle contrast agents, liposomes or other delivery vehicles containing Gadolinium chelate ("Gd-chelate") molecules, Gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma ray emitting radionuclides, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., including microbubble shells including albumin, galactose, lipid, and / or polymers; microbubble gas core including air, heavy gas(es), perfluorcarbon, nitrogen, octafluoropropane, perflexane lipid microsphere, perflutren, etc.), iodinated contrast agents (e.g., iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibodyspecifically reactive with a target peptide. Detectable moieties also include any of the above compositions encapsulated in nanoparticles, particles, aggregates, coated with additional compositions, derivatized for binding to a targeting agent (e.g., compound described herein). Any method known in the art for conjugating an oligonucleotide or protein to the label may be employed, e.g., using methods described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego.

[0074] A "cell" as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaryotic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. In embodiments, the cell is a cancer cell. In embodiments, the cell is a leukemic stem cell (LSC). The term “cell” as used herein also refers to individual cells, cell lines, or cultures derived from such cells. A “culture” refers to a composition comprising isolated cells of the same or a different type.

[0075] The term “complement,” as used herein, refers to a nucleotide (e.g., RNA or DNA) or a sequence of nucleotides capable of base pairing with a complementary nucleotide or sequence of nucleotides. As described herein and commonly known in the art the complementary (matching) nucleotide of adenosine is thymidine and the complementary (matching) nucleotide of guanosine is cytosine. Thus, a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a second nucleic acid sequence. The nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence. Where the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid sequence. Where the nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence only some of the nucleotides of the complement form base pairs with nucleotides of the second nucleic acid sequence. Examples of complementary sequences include coding and a non-coding sequences, wherein the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence. Afurther example of complementary sequences are sense and antisense sequences, wherein the sense sequence contains complementary nucleotides to the antisense sequence and thus forms the complement of the antisense sequence.

[0076] As described herein the complementarity of sequences may be partial, in which only some of the nucleic acids match according to base pairing, or complete, where all the nucleic acids match according to base pairing. Thus, two sequences that are complementary to each other, may have a specified percentage of nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region). “Perfectly complementary” means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence. “Substantially complementary” as used herein refers to a degree of complementarity that is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%.97%, 98%, 99%, or 100% over a region of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, or more nucleotides, or refers to two nucleic acids that hybridize under stringent conditions.

[0077] As used herein, “stringent conditions” for hybridization refer to conditions under which a nucleic acid having complementarity to a target sequence predominantly hybridizes with the target sequence, and substantially does not hybridize to non-target sequences. Stringent conditions are generally sequence-dependent, and vary depending on a number of factors. In general, the longer the sequence, the higher the temperature at which the sequence specifically hybridizes to its target sequence. Non-limiting examples of stringent conditions are described in detail in Tijssen (1993), Laboratory Techniques In Biochemistry And Molecular Biology-Hybridization With Nucleic Acid Probes Part 1, Second Chapter “Overview of principles of hybridization and the strategy of nucleic acid probe assay”, Elsevier, N.Y.

[0078] “Hybridization” refers to a reaction in which one or more polynucleotides react to form a complex that is stabilized via hydrogen bonding between the bases of the nucleotide residues. The hydrogen bonding may occur by Watson Crick base pairing, Hoogstein binding, or in any other sequence specific manner. The complex may comprise two strands forming a duplex structure, three or more strands forming a multi stranded complex, a single self 17 hybridizing strand, or any combination of these. A hybridization reaction may constitute a step in a more extensive process,such as the initiation of PCR, or the cleavage of a polynucleotide by an enzyme. A sequence capable of hybridizing with a given sequence is referred to as the “complement” of the given sequence.

[0079] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, and O- phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0080] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0081] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. A "fusion protein" refers to a chimeric protein encoding two or more separate protein sequences that are recombinantly expressed as a single moiety.

[0082] An amino acid or nucleotide base "position" is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acidresidue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0083] The terms "numbered with reference to" or "corresponding to," when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. An amino acid residue in a protein "corresponds" to a given residue when it occupies the same essential structural position within the protein as the given residue. One skilled in the art will immediately recognize the identity and location of residues corresponding to a specific position in a protein (e.g., Blc-2) in other proteins with different numbering systems. For example, by performing a simple sequence alignment with a protein (e.g., Blc-2) the identity and location of residues corresponding to specific positions of the protein are identified in other protein sequences aligning to the protein. For example, a selected residue in a selected protein corresponds to glutamic acid at position 138 when the selected residue occupies the same essential spatial or other structural relationship as a glutamic acid at position 138. In some embodiments, where a selected protein is aligned for maximum homology with a protein, the position in the aligned selected protein aligning with glutamic acid 138 is the to correspond to glutamic acid 138. Instead of a primary sequence alignment, a three-dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the glutamic acid at position 138, and the overall structures compared. In this case, an amino acid that occupies the same essential position as glutamic acid 138 in the structural model is the to correspond to the glutamic acid 138 residue.

[0084] "Conservatively modified variants" applies to both amino acid and nucleic acid sequences.With respect to particular nucleic acid sequences, "conservatively modified variants" refers to those nucleic acids that encode identical or essentially identical amino acid sequences. Because of thedegeneracy of the genetic code, a number of nucleic acid sequences will encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence.

[0085] As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the disclosure.

[0086] The following eight groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M)(see, e.g., Creighton, Proteins (1984)).

[0087] The terms "identical" or percent "identity," in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site http: / / www.ncbi.nlm.nih.gov / BLAST / or the like). Such sequences are then said to be "substantially identical." This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and / or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps and the like. Preferably, identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50- 100 amino acids or nucleotides in length.

[0088] "Percentage of sequence identity" is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.

[0089] A "comparison window", as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of, e.g., a full length sequence or from 20 to 600, about 50 to about 200, or about 100 to about 150 amino acids or nucleotides in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can beconducted, e.g., by the local homology algorithm of Smith and Waterman (1970) Adv. Appl. Math. 2:482c, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity method of Pearson and Lipman (1988) Proc. Nat’l. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Ausubel et al., Current Protocols in Molecular Biology (1995 supplement)).

[0090] An example of an algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nuc. Acids Res.25:3389-3402, and Altschul et al. (1990) J. Mol. Biol.215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http: / / www.ncbi.nlm.nih.gov / ). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, an expectation (E) or 10, M=5, N=-4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word length of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915) alignments (B) of 50, expectation (E) of 10, M=5, N=-4, and a comparison of both strands.

[0091] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5787). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.

[0092] An indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the antibodies raised against the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, where the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules or their complements hybridize to each other under stringent conditions, as described below. Yet another indication that two nucleic acid sequences are substantially identical is that the same primers can be used to amplify the sequence.

[0093] The term “Bcl-2 protein” or “Bcl-2” as used herein includes any of the recombinant or naturally-occurring forms of Bcl-2 protein, also known as Apoptosis regulator Bcl-2, or variants or homologs thereof that maintain Bcl-2 activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to Bcl-2). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring Bcl-2 protein. In embodiments, the Bcl-2 protein is substantially identical to the protein identified by the UniProt reference number P10415 or a variant or homolog having substantial identity thereto.

[0094] The term “Bcl-XL protein" or “Bcl-XL” as used herein includes any of the recombinant or naturally-occurring forms of Bcl-XL protein, also known as Bcl-2-like protein 1, Apoptosis regulator Bcl-X or variants or homologs thereof that maintain Bcl-XL activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to Bcl-XL). In someaspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring Bcl-XL protein. In embodiments, the Bcl-XL protein is substantially identical to the protein identified by the UniProt reference number Q07817 or a variant or homolog having substantial identity thereto.

[0095] The term “Blc-W protein" or “Blc-W” as used herein includes any of the recombinant or naturally-occurring forms of Blc-W protein, also known as Bcl-2-like protein 2, Bcl2-L-2, Apoptosis regulator Bcl-W or variants or homologs thereof that maintain Blc-W activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to Blc-W). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring Blc-W protein. In embodiments, the Blc-W protein is substantially identical to the protein identified by the UniProt reference number Q92843 or a variant or homolog having substantial identity thereto.

[0096] The term “Mcl-1 protein" or “Mcl-1” as used herein includes any of the recombinant or naturally-occurring forms of Mcl-1 protein, also known as Induced myeloid leukemia cell differentiation protein Mcl-1, Bcl-2-like protein 3, Bcl2-L-3, Bcl-2-related protein EAT / mcl1, mcl1 / EAT or variants or homologs thereof that maintain Mcl-1 activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to Mcl-1). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring Mcl-1 protein. In embodiments, the Mcl-1 protein is substantially identical to the protein identified by the UniProt reference number Q07820 or a variant or homolog having substantial identity thereto.

[0097] “Patient,” “subject,” “patient in need thereof,” and “subject in need thereof” are herein used interchangeably and refer to a living organism suffering from or prone to a disease (e.g. cancer (e.g. lymphoma, leukemia)) or condition that can be treated by administration using the methods and compositions provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In someembodiments, a patient is human. Tissues, cells and their progeny of a biological entity obtained in vitro or cultured in vitro are also contemplated.

[0098] The terms “treating”, or “treatment” refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. The term "treating" and conjugations thereof, may include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing.

[0099] “Treating” or “treatment” as used herein (and as well-understood in the art) also broadly includes any approach for obtaining beneficial or desired results in a subject’s condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease’s transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, "treatment" as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease’s spread; relieve the disease’s symptoms, fully or partially remove the disease’s underlying cause, shorten a disease’s duration, or do a combination of these things. Thus in the disclosed method, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 90%, or 100% reduction in the severity of an established disease, condition, or symptom of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject as compared to a control. Thus, the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of thedisease or condition. Further, as used herein, references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 90% or greater as compared to a control level and such terms can include but do not necessarily include complete elimination. In embodiments, the treatment is a cancer-treating effect. In embodiments, the treatment can be assessed by cancer cell (e.g. LSC) death (e.g. apoptosis). In embodiments, the treatment is a decrease in cancer cells. In embodiments, the treatment is inhibition or slowing of cancer cell growth. In embodiments, the treatment is lack of progression of the cancer. In embodiments, the treatment is prolonged patient survival.

[0100] "Treating" and "treatment" as used herein include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient. In embodiments, the treating or treatment is not prophylactic treatment.

[0101] The term “prevent” refers to a decrease in the occurrence of disease symptoms in a patient. As indicated above, the prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment.

[0102] The term “inhibiting” also means reducing an effect (disease state or expression level of a gene / protein / mRNA) relative to the state in the absence of a compound or composition of the present disclosure.

[0103] “Control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects.In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).

[0104] “Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. In some instances, “disease” or “condition” refers to a “cancer”. In embodiments, the cancer is leukemia or lymphoma.

[0105] As used herein, the term "cancer" refers to all types of cancer, neoplasm, malignant or benign tumors found in mammals, including leukemia, carcinomas and sarcomas. In embodiments, the cancer is ovarian cancer, colon cancer, liver cancer, kidney cancer and pancreatic cancer. In embodiments, the cancer is leukemia (e.g,. acute myeloid leukemia (“AML”) or chronic myeloid leukemia (“CML”)), cancer of the brain, lung cancer, non-small cell lung cancer, melanoma, sarcomas, and prostate cancer, cervix cancers, stomach cancers, head & neck cancers, uterus cancers, mesothelioma, metastatic bone cancer, Medulloblastoma, Hodgkin's Disease, Non- Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine and exocrine pancreas.

[0106] The term "leukemia" refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, aleukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia,hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0107] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture. In some embodiments contacting includes allowing a compound described herein to interact with a protein (e.g. BH3 protein) or a nucleic acid (e.g. miR- 126).

[0108] The term "contacting" may include allowing two species to react, interact, or physically touch, wherein the two species may be, for example, a compound (e.g. an anti-miR-126 compound, BH3 mimetic compound, chemotherapy) as provided herein and a cell (e.g. a cancer cell). In embodiments contacting includes, for example, allowing a compound (e.g. an anti-miR-126 compound, BH3 mimetic compound, chemotherapy) as described herein to interact with a cell. In embodiments contacting includes, for example, allowing a composition (e.g. pharmaceutical composition) as described herein to interact with a cell. In embodiments, contacting includes, for example, allowing a composition provided herein to be delivered into the cell. Thus, in embodiments, contacting includes intracellular delivery of a composition (e.g. anti-miR-126 compound BH3 mimetic, chemotherapy) provided herein into a cell.

[0109] The terms “phenotype” and “phenotypic” as used herein refer to an organism’s observable characteristics such as onset or progression of disease symptoms, biochemical properties, or physiological properties.

[0110] The word "expression" or "expressed" as used herein in reference to a DNA nucleic acid sequence (e.g., a gene) means the transcriptional and / or translational product of that sequence. The level of expression of a DNA molecule in a cell may be determined on the basis of either the amount of corresponding mRNA that is present within the cell or the amount of protein encoded by that DNA produced by the cell (Sambrook et al., 1989 Molecular Cloning: A Laboratory Manual, 18.1- 18.88). When used in reference to polypeptides, expression includes any step involved in the production of a polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0111] The term "gene" means the segment of DNA involved in producing a protein; it includes regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons). The leader, the trailer as well as the introns include regulatory elements that are necessary during the transcription and the translation of a gene. Further, a "protein gene product" is a protein expressed from a particular gene.

[0112] The term “recombinant” when used with reference, e.g., to a cell, or nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, recombinant cells express genes that are not found within the native (non-recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all. Transgenic cells and animals are those that express a heterologous gene or coding sequence, typically as a result of recombinant methods.

[0113] The term “exogenous” refers to a molecule or substance (e.g., a compound, nucleic acid or protein) that originates from outside a given cell or organism. Conversely, the term “endogenous” refers to a molecule or substance that is native to, or originates within, a given cell or organism. In embodiments, the anti-miR-126 compound is exogenous to the cell. In embodiments, the BH3 mimetic compound is exogenous to the cell. In embodiments, the chemotherapy (e.g. hypomethylating agent) is exogenous to the cell.

[0114] "Analog," "analogue," or "derivative" is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical agent that is structurally similar to another agent (i.e., a so-called "reference" agent) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of a chiral center of the reference agent. In some embodiments, a derivative may be a conjugate with a pharmaceutically acceptable agent, for example, phosphate or phosphonate.

[0115] As used herein, the term "salt" refers to acid or base salts of the agents used herein. Illustrative but non-limiting examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, and the like) salts, and quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.

[0116] The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of thepresent disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present disclosure. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with buffer prior to use.

[0117] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art.

[0118] An “adjuvant” (from Latin, adiuvare: to aid) is a pharmacological and / or immunological agent that modifies the effect of other agents.

[0119] A “diluent” (also referred to as a filler, dilutant or thinner) is a diluting agent. Certain fluids are too viscous to be pumped easily or too dense to flow from one particular point to the other. This can be problematic, because it might not be economically feasible to transport such fluids in this state. To ease this restricted movement, diluents are added. This decreases the viscosity of the fluids, thereby also decreasing the pumping / transportation costs.

[0120] The terms “administration” or “administering” refer to the act of providing an agent of the current embodiments or pharmaceutical composition including an agent of the current embodiments to the individual in need of treatment.

[0121] By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of additional therapies. The compound or the composition of the disclosure can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). The preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation). For example, in embodiments, the anti-miR-126 compound and the BH3 mimetic (e.g. venetoclax) areco-administered. In embodiments, the BH3 mimetic (venetoclax) and the chemotherapy (azacitidine) are co-administered. In embodiments, the anti-miR-126 compound and the chemotherapy (azacitidine) are co-administered. In embodiments, the anti-miR-126 compound, the BH3 mimetic (venetoclax), and the chemotherapy (azacitidine) are co-administered.

[0122] As used herein, “sequential administration” includes that the administration of two agents (e.g., the compounds or compositions described herein) occurs separately on the same day or do not occur on a same day (e.g., occurs on consecutive days).

[0123] As used herein, “concurrent administration” includes overlapping in duration at least in part. For example, when two agents (e.g., any of the agents or class of agents described herein that has bioactivity) are administered concurrently, their administration occurs within a certain desired time. In embodiments, the agents’ administration may begin and end on the same day. In embodiments, the administration of one agent can also precede the administration of a second agent by day(s) as long as both agents are taken on the same day at least once. Similarly, in embodiments, the administration of one agent can extend beyond the administration of a second agent as long as both agents are taken on the same day at least once. The bioactive agents / agents do not have to be taken at the same time each day to include concurrent administration.

[0124] As used herein, “intermittent administration includes the administration of an agent for a period of time (which can be considered a “first period of administration”), followed by a time during which the agent is not taken or is taken at a lower maintenance dose (which can be considered “off-period”) followed by a period during which the agent is administered again (which can be considered a “second period of administration”). Generally, during the second phase of administration, the dosage level of the agent will match that administered during the first period of administration but can be increased or decreased as medically necessary.

[0125] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal,subcutaneous, intraperitoneal, intraventricular, and. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.

[0126] The compositions disclosed herein can be delivered transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. The compositions of the present disclosure may additionally include components to provide sustained release and / or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely- divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions disclosed herein can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Bioniater Sci. Polym. Ed.7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Phann. Res.12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Phann. Pharmacol.49:669-674, 1997).

[0127] A “effective amount,” as used herein, is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). In the methods described herein, an effective amount of an anti-microRNA-126 (miR-126) compound provided herein including embodiments thereof is combined with an effective amount of a Bcl-2 homology 3 (BH3) mimetic provided herein including embodiments thereof. In these methods, the effective amount of the anti-microRNA-126 compound is an amount effective to accomplish the stated purpose of the method in combination with an effective amount of a BH3 mimetic. Likewise, an effective amount of a BH3 mimetic is an amount effective to accomplish the stated purpose of the method in combination with an effective amount of the anti-microRNA-126 compound. In thiscontext, the effective amount of the anti-microRNA-126 compound and the effective amount of the BH3 mimetic may be referred to as a “combined effective amount” of the anti-microRNA-126 compound and the BH3 mimetic. As described herein, in embodiments, the effective amount of the anti-microRNA-126 compound and the effective amount of the BH3 mimetic is a combined synergistic amount of the anti-miR-126 compound and the BH3 mimetic compound. For the methods described herein, in embodiments, an effective amount of the anti-microRNA-126 compound is combined with an effective amount of the BH3 mimetic and an effective amount of a chemotherapy (e.g. hypomethylating agent). In these methods, the effective amount of the anti- microRNA-126 compound is an amount effective to accomplish the stated purpose of the method in combination with an effective amount of a BH3 mimetic and an effective amount of a chemotherapy (e.g. hypomethylating agent). Likewise, an effective amount of a BH3 mimetic is an amount effective to accomplish the stated purpose of the method in combination with an effective amount of an anti-microRNA-126 compound and effective amount of a chemotherapy (e.g. hypomethylating agent). Likewise, an effective amount of a chemotherapy (e.g. hypomethylating agent) is an amount effective to accomplish the stated purpose of the method in combination with an effective amount of anti-microRNA-126 compound and an effective amount of a BH3 mimetic. In this context, the effective amount of anti-microRNA-126 compound, the effective amount of BH3 mimetic, and the effective amount of chemotherapy (e.g. hypomethylating agent) may be referred to as a “combined effective amount” of anti-microRNA-126 compound, BH3 mimetic, and chemotherapy (e.g. hypomethylating agent). In embodiments, the effective amount of the anti-microRNA-126 compound, the effective amount of the BH3 mimetic, and the effective amount of the chemotherapy (e.g. hypomethylating agent) is a combined synergistic amount of the anti-miR-126 compound, the BH3 mimetic compound, and the chemotherapy (e.g. hypomethylating agent). An example of an “effective amount” or “combined effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount” or “therapeutically combined effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar,Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0128] The term “therapeutically effective amount,” as used herein, refers to that amount of the therapeutic agent sufficient to ameliorate the disorder, as described above. For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control. As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0129] A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist.

[0130] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

[0131] Pharmaceutical compositions may include compositions wherein the therapeutic drug (e.g., agents described herein, including embodiments or examples) is contained in a therapeuticallyeffective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. When administered in methods to treat a disease, such compositions will contain an amount of therapeutic drug effective to achieve the desired result, e.g., modulating the activity of a target molecule, and / or reducing, eliminating, or slowing the progression of disease symptoms.

[0132] The dosage and frequency (single or multiple doses) administered to a mammal can vary depending upon a variety of factors, for example, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated, kind of concurrent treatment, complications from the disease being treated or other health-related problems. Other therapeutic regimens or agents can be used in conjunction with the methods and agents of this disclosure. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the ability of those skilled in the art.

[0133] For any therapeutic agent described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of therapeutic drug(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

[0134] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring agent’s effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0135] Dosages may be varied depending upon the requirements of the patient and the therapeutic drug being employed. The dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the agent. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosageamounts and intervals can be adjusted individually to provide levels of the administered agent effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0136] A weight percent of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0137] “Excipient” is used herein to include any other agent that may be contained in or combined with a disclosed agent, in which the excipient is not a therapeutically or biologically active agent / agent. As such, an excipient should be pharmaceutically or biologically acceptable or relevant (for example, an excipient should generally be non-toxic to the individual). “Excipient” includes a single such agent and is also intended to include a plurality of excipients. For the purposes of the present disclosure the term “excipient” and “carrier” are used interchangeably in some embodiments of the present disclosure and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”

[0138] As defined herein, the term “activation”, “activate”, “activating” and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state. In embodiments, “activate” refers the activity or function of a BH3 protein (e.g. Bcl-2) relative to the activity or function of the protein in the presence of the composition provided herein (e.g. anti-miR-126 compound). Thus, in embodiments, in the absence of the composition provided herein, the activity or function of a BH3 protein is activated relative to the activity or function of the BH3 protein in the presence of the composition provided herein.

[0139] The terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist.

[0140] As defined herein, the term “inhibition”, “inhibit”, “inhibiting” and the like in reference to a protein-inhibitor interaction or a miRNA-inhibitor interaction means negatively affecting (e.g. decreasing) the activity or function of the protein or the miRNA relative to the activity or function of the protein or miRNA in the absence of the inhibitor. In embodiments inhibition means negativelyaffecting (e.g. decreasing) the concentration or levels of the protein (e.g. BH3 protein) or miRNA (e.g. miR-126) relative to the concentration or level of the protein or the miRNA in the absence of the inhibitor. In embodiments, inhibition refers to reduction of a disease or symptoms of disease. In embodiments, inhibition refers to a reduction in the activity of a particular protein target (e.g. BH3 protein). Thus, in embodiments, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down- regulating signal transduction or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g. an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation). In embodiments, inhibition refers to a reduction in the activity or function of an miRNA (e.g. miR-126). In embodiments, inhibition refers to a reduction in translational inhibition of an mRNA target of the miRNA (e.g. miR-126). In embodiments, inhibition refers to a reduction in destabilization of an mRNA target of the miRNA (e.g. miR-126).

[0141] The terms “inhibitor,” “repressor” or “antagonist” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene, nucleic acid (e.g. miRNA126), or protein (e.g. BH3 protein). The antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.

[0142] The term "expression" includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post- translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0143] The term “aberrant” as used herein refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity mayrefer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g. by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.

[0144] The term “signaling pathway” as used herein refers to a series of interactions between cellular and optionally extra-cellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propagated to other signaling pathway components. For example, binding of an enzyme with a compound as described herein may reduce the level of a product of the enzyme catalyzed reaction or the level of a downstream derivative of the product or binding may reduce the interactions between the enzyme or a reaction product and downstream effectors or signaling pathway components, resulting in changes in cell growth, proliferation, or survival. METHODS OF TREATMENT

[0145] Provided herein, inter alia, are methods for treating cancer in a subject in need thereof including administering to the subject an effective amount of an anti-microRNA-126 (miR-126) compound provided herein including embodiments thereof and a Bcl-2 homology 3 (BH3) mimetic compound provided herein including embodiments thereof. Applicant describes herein, including in the examples and figures, that miR-126 is associated with levels of fatty acid oxidation (FAO), oxidative phosphorylation (OXPHOS), and inhibits mitochondrial fission in leukemia stem cells (LSCs) through BCL-2 / NRF2-CPT1B signaling. Applicant demonstrates that inhibiting miR-126 with an anti-miR-126 compound (e.g. miRisten) disrupts FAO / OXPHOS and triggers mitochondrial fission. Applicant is the first to demonstrate that combining an anti-miR-126 compound with a Bcl-2 mimetic compound (e.g. venetoclax (VEN)) synergistically inhibits FAO / OXPHOS, induces mitochondrial fission, and diminishes LSC activity in cancer cells. In an aspect is provided a method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of an anti-microRNA-126 (miR-126) compound and a Bcl-2 homology 3 (BH3) mimetic compound.

[0146] BCL-2 family proteins include BCL-2 homology (BH) domains and are classified into anti- and pro-apoptotic members, which are further classified into multidomain proteins including four BH domains (BH1 to BH4), and BH3-only proteins. Pro-apoptotic BCl-2 family members,including BAX and BAK play a role in opening pores in the mitochondrial outer member, facilitating apoptosis. In embodiments, anti-apoptotic Bcl-2 family proteins inhibit pro-apoptotic activity through binding to BAX and BAK. BH3-only proteins function upstream of multidomain members, and in embodiments, activate Bax and Bak directly or indirectly. As used herein, “BH3 mimetic” or “BH3 mimetic compound” refer to antagonists of anti-apoptotic Bcl-2 family member proteins that function as competitive inhibitors by binding to the hydrophobic pocket of the anti- apoptotic Bcl-2 family protein, thereby inhibiting or displacing binding of a BH3 domain of a pro- apoptotic Bcl-2 family member protein (e.g. a multi-domain or BH3-only pro-apoptotic Bcl-2 protein). In embodiments, a BH3 mimetic compound inhibits or displaces binding of an amphipathic α-helix of a BH3 domain of a pro-apoptotic Bcl-2 family protein (e.g. Bax, Bak) to the hydrophobic cleft of the anti-apoptotic Bcl-2 protein. The hydrophobic cleft may be formed, for example, by the BH1-BH3 domains of the anti-apoptotic Bcl-2 family protein. In embodiments, the anti-apoptotic Bcl-2 family member protein is Bcl-2, Bcl-XL, Blc-W, or Mcl-1. In embodiments, the pro-apoptotic Blc-2 family member protein is BAX, BAK, BIM, PUMA, or NOXA. Thus, binding of a BH3 mimetic to an anti-apoptotic Bcl-2 family member results in release of pro-apoptotic BH3 proteins (e.g. BAX, BAK, BIM, PUMA, NOXA, etc.) from the binding pocket of the anti-apoptotic Bcl-2 family member protein, enabling downstream pro-apoptotic signaling. In embodiments, the BH3 mimetic compound opens pores in the mitochondrial out membrane, thereby facilitating mitochondrial-mediated apoptosis. In embodiments, the BH3 mimetic compound is exogenous to the cell. For example, in embodiments, the BH3 mimetic compound does not naturally occur in the cell.

[0147] In embodiments, the BH3 mimetic compound binds Bcl-2, Bcl-XL, Blc-W, Mcl-1, or a combination thereof. In embodiments, the BH3 mimetic compound binds Bcl-2. In embodiments, the BH3 mimetic compound binds Bcl-XL. In embodiments, the BH3 mimetic compound binds Blc- W. In embodiments, the BH3 mimetic compound binds Mcl-1. In embodiments, the BH3 mimetic compound is venetoclax, S63845, A1331852, obatoclax, ABT-263, S55746, AMG176, AZD5991, WEHI-539, ABT-737, or a combination thereof. In embodiments, the BH3 mimetic compound is venetoclax. In embodiments, the BH3 mimetic compound is S63845. In embodiments, the BH3 mimetic compound is A1331852. In embodiments, the BH3 mimetic compound is obatoclax. In embodiments, the BH3 mimetic compound is ABT-263. In embodiments, the BH3 mimetic compound is S55746. In embodiments, the BH3 mimetic compound is AMG176. In embodiments,the BH3 mimetic compound is AZD5991. In embodiments, the BH3 mimetic compound is WEHI- 539. In embodiments, the BH3 mimetic compound is ABT-737. BH3 mimetic compounds are described in further detail in Lasica, M.; Anderson, M.A. Review of Venetoclax in CLL, AML and Multiple Myeloma. J. Pers. Med.2021, 11, 463. https: / / doi.org / 10.3390 / jpm11060463.; Saraswathy, S.D.; Mirunalini, A.; Karthikeyan, K.; Premkumar, K. BH3 Mimetic Peptides: An Effective Strategy to Complement Anticancer Therapy, Current Protein & Peptide Science, 24:10, pages 853-864, 2023, issn 1389-2037 / 1875-5550, doi 10.2174 / 1389203724666230822100131.; Montero, J.; Haq R. Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics. Cancer Discov.2022 May 2;12(5):1217-1232. doi: 10.1158 / 2159-8290.CD-21-1334. PMID: 35491624; PMCID: PMC9306285.; and Parry, N., Wheadon, H. & Copland, M. The application of BH3 mimetics in myeloid leukemias. Cell Death Dis 12, 222 (2021). https: / / doi.org / 10.1038 / s41419-021-03500-6., which are incorporated herein in their entirety and for all purposes.

[0148] The term “venetoclax,” also known as VENCLEXTA®, VENCLYXTO®, GDC-0199, ABT-199, RG-7601, or the like, refers in the usual and customary sense, to 4-(4-{[2-(4- Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro- 2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (CAS Registry number 1257044-40-8), or a pharmaceutically acceptable salt thereof.

[0149] The term “S63845,” or the like, refers in the usual and customary sense, to (R)-2-((5-(3- chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(5-fluorofuran-2-yl)thieno[2,3- d]pyrimidin-4-yl)oxy)-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)propanoic acid (CAS Registry number 1799633-27-4), or a pharmaceutically acceptable salt thereof.

[0150] The term “A1331852,” or the like, refers in the usual and customary sense, to 3-[1-(1- adamantylmethyl)-5-methylpyrazol-4-yl]-6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H- isoquinolin-2-yl]pyridine-2-carboxylic acid (CAS Registry number 1430844-80-6), or a pharmaceutically acceptable salt thereof.

[0151] The term “obatoclax,” also known as GX15-070, GX 05-070, or the like, refers in the usual and customary sense, to 2-(2-((3,5-Dimethyl-1H-pyrrol-2-yl)methylene)-3-methoxy-2H-pyrrol-5- yl)-1H-indole (CAS Registry number 803712-67-6), or a pharmaceutically acceptable salt thereof.

[0152] The term “ABT-263,” also known as Navitoclax, or the like, refers in the usual and customary sense, to 4-(4-{[2-(4-Chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl}-1- piperazinyl)-N-[(4-{[(2R)-4-(4-morpholinyl)-1-(phenylsulfanyl)-2-butanyl]amino}-3- [(trifluoromethyl)sulfonyl]phenyl)sulfonyl]benzamide (CAS Registry number 923564-51-6), or a pharmaceutically acceptable salt thereof.

[0153] The term “S55746,” also known as BCL201, or the like, refers in the usual and customary sense, to N-(4-hydroxyphenyl)-3-[6-[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydro-1H-isoquinoline- 2-carbonyl]-1,3-benzodioxol-5-yl]-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide (CAS Registry number 1448584-12-0), or a pharmaceutically acceptable salt thereof.

[0154] The term “AMG176,” also known as tapotoclax, or the like, refers in the usual and customary sense, to (3'R,4S,6'R,7'S,8'E,11'S,12'R)-7-chloro-7'-methoxy-11',12'-dimethyl-13',13'- dioxospiro[2,3-dihydro-1H-naphthalene-4,22'-20-oxa-13λ6-thia-1,14- diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15'-one (CAS Registry number 1883727-34-1), or a pharmaceutically acceptable salt thereof.

[0155] The term “AZD5991,” or the like, refers in the usual and customary sense, to 17-Chloro- 5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22- pentaazaheptacyclo(27.7.1.14,7.011,15.016,21.020,24.030,35)octatriaconta- 1(36),4(38),6,11,14,16,18,20,23,29(37),30(35),31,33-tridecaene-23-carboxylic acid (CAS Registry number 2143061-81-6), or a pharmaceutically acceptable salt thereof.

[0156] The term “WEHI-539,” or the like, refers in the usual and customary sense, to (E)-5-(3-(4-(aminomethyl)phenoxy)propyl)-2-(8-(2-(benzo[d]thiazol-2-yl)hydrazono)-5,6,7,8- tetrahydronaphthalen-2-yl)thiazole-4-carboxylic acid (CAS Registry number 1431866-33-9), or a pharmaceutically acceptable salt thereof.

[0157] The term “ABT-737,” or the like, refers in the usual and customary sense, to 4-[4-[(4'- Chloro[1,1'-biphenyl]-2-yl)methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(dimethylamino)-1- [(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]benzamide (CAS Registry number 852808-04-9), or a pharmaceutically acceptable salt thereof.

[0158] In embodiments, the anti-miR-126 compound includes: i) a CpG oligodeoxynucleotide (CpG-ODN) or a phosphorothioate CpG-ODN conjugated to an anti-miR-126 nucleic acidsequence; or ii) an unconjugated anti-miR-126 nucleic acid sequence. In embodiments, the anti- miR-126 compound includes a CpG oligodeoxynucleotide (CpG-ODN) or a phosphorothioate CpG- ODN conjugated to an anti-miR-126 nucleic acid sequence. In embodiments, the anti-miR-126 compound includes a CpG-ODN conjugated to an anti-miR-126 nucleic acid sequence. In embodiments, the anti-miR-126 compound includes a phosphorothioate CpG-ODN conjugated to an anti-miR-126 nucleic acid sequence. In embodiments, the anti-miR-126 compound includes an unconjugated anti-miR-126 nucleic acid sequence. In embodiments, the unconjugated anti-miR126 nucleic acid sequence includes one or more phosphorothioate linkages and one or more chemically modified nucleotides.

[0159] In embodiments, the anti-miR-126 compound includes an anti-miR-126 nucleic acid sequence, where the anti-miR-126 nucleic acid sequence contains one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more) phosphorothioate linkages and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more) chemically modified nucleotides. In embodiments, a chemical modification is selected from the group consisting of a 2’ O-Methyl, 2’- deoxy-2’fluoro, 2’-deoxy, a universal base, 5-C-methyl, an inverted deoxy abasic residue incorporation, and a locked nucleic acid.

[0160] In embodiments, the anti-miR-126 nucleic acid sequence includes the sequence of SEQ ID NO:4 or SEQ ID NO:5. In embodiments, the anti-miR-126 nucleic acid sequence includes the sequence of SEQ ID NO:4. In embodiments, the anti-miR-126 nucleic acid sequence is the sequence of SEQ ID NO:4. In embodiments, the anti-miR-126 nucleic acid sequence includes the sequence of SEQ ID NO:5. In embodiments, the anti-miR-126 nucleic acid sequence is the sequence of SEQ ID NO:5.

[0161] In embodiments, the CpG-ODN has about 80%–100% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity with at least a 15 nucleobase continuous sequence of one of SEQ ID NOs:6-22. In embodiments, the CpG-ODN has about 80%– 100% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity with one of SEQ ID NOs:6-22. In embodiments, the CpG-ODN has about 80-85%, about 85-90%, about 90-95%, about 95%-100% sequence identity with at least a 15 nucleobase continuous sequence of one of SEQ ID NOs:6-22. In embodiments, the CpG-ODN has about 80-85%, about 85-90%, about 90-95%, about 95%-100% sequence identity with one of SEQ ID NOs:6-22. In embodiments, the CpG-ODN is a 15 to 30 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) bases long, single-stranded, partly or completely phosphorothioated oligonucleotide.

[0162] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:6. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:6. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:6. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:6. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:6. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:6. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:6. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:6. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:6. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:6. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:6. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:6. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:6. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:6. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:6. In embodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:6. In embodiments, the CpG-ODN includes the sequence of SEQ ID NO:6. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:6.

[0163] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:7. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:7. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:7. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:7. In embodiments, theCpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:7. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:7. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:7. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:7. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:7. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:7. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:7. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:7. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:7. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:7. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:7. Inembodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:7. Inembodiments, the CpG-ODN includes the sequence of SEQ ID NO:7. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:7.

[0164] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:8. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:8. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:8. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:8. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:8. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:8. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:8. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:8. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:8. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:8. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:8. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:8. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:8. Inembodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:8. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:8. In embodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:8. In embodiments, the CpG-ODN includes the sequence of SEQ ID NO:8. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:8.

[0165] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:9. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:9. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:9. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:9. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:9. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:9. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:9. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:9. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:9. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:9. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:9. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:9. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:9. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:9. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:9. In embodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:9. In embodiments, the CpG-ODN includes the sequence of SEQ ID NO:9. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:9.

[0166] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:10. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:10. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobasecontinuous sequence of SEQ ID NO:10. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:10. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:10. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:10. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:10. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:10. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:10. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:10. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:10. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:10. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:10. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:10. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:10. In embodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:10. In embodiments, the CpG-ODN includes the sequence of SEQ ID NO:10. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:10.

[0167] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:11. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:11. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:11. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:11. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:11. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:11. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:11. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:11. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:11. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:11. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQID NO:11. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:11. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:11. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:11. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:11. Inembodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:11. Inembodiments, the CpG-ODN includes the sequence of SEQ ID NO:11. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:11.

[0168] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:12. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:12. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:12. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:12. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:12. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:12. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:12. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:12. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:12. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:12. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:12. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:12. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:12. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:12. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:12. Inembodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:12. Inembodiments, the CpG-ODN includes the sequence of SEQ ID NO:12. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:12.

[0169] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:13. In embodiments, the CpG-ODN has at least85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:13. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:13. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:13. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:13. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:13. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:13. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:13. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:13. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:13. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:13. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:13. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:13. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:13. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:13. Inembodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:13. Inembodiments, the CpG-ODN includes the sequence of SEQ ID NO:13. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:13.

[0170] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:14. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:14. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:14. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:14. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:14. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:14. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:14. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:14. In embodiments, the CpG-ODN has at least 80% sequenceidentity with SEQ ID NO:14. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:14. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:14. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:14. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:14. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:14. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:14. Inembodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:14. Inembodiments, the CpG-ODN includes the sequence of SEQ ID NO:14. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:14.

[0171] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:15. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:15. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:15. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:15. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:15. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:15. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:15. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:15. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:15. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:15. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:15. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:15. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:15. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:15. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:15. In embodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:15. In embodiments, the CpG-ODN includes the sequence of SEQ ID NO:15. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:15.

[0172] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:16. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:16. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:16. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:16. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:16. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:16. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:16. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:16. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:16. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:16. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:16. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:16. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:16. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:16. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:16. In embodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:16. In embodiments, the CpG-ODN includes the sequence of SEQ ID NO:16. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:16.

[0173] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:17. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:17. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:17. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:17. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:17. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:17. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:17. Inembodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:17. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:17. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:17. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:17. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:17. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:17. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:17. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:17. Inembodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:17. Inembodiments, the CpG-ODN includes the sequence of SEQ ID NO:17. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:17.

[0174] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:18. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:18. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:18. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:18. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:18. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:18. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:18. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:18. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:18. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:18. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:18. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:18. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:18. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:18. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:18. Inembodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:18. Inembodiments, the CpG-ODN includes the sequence of SEQ ID NO:18. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:18.

[0175] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:19. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:19. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:19. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:19. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:19. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:19. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:19. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:19. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:19. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:19. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:19. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:19. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:19. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:19. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:19. Inembodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:19. Inembodiments, the CpG-ODN includes the sequence of SEQ ID NO:19. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:19.

[0176] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:20. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:20. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:20. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:20. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence ofSEQ ID NO:20. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:20. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:20. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:20. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:20. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:20. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:20. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:20. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:20. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:20. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:20. Inembodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:20. Inembodiments, the CpG-ODN includes the sequence of SEQ ID NO:20. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:20.

[0177] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:21. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:21. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:21. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:21. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:21. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:21. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:21. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:21. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:21. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:21. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:21. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:21. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:21. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:21. Inembodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:21. Inembodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:21. Inembodiments, the CpG-ODN includes the sequence of SEQ ID NO:21. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:21.

[0178] In embodiments, the CpG-ODN has at least 80% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:22. In embodiments, the CpG-ODN has at least 85% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:22. In embodiments, the CpG-ODN has at least 90% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:22. In embodiments, the CpG-ODN has at least 91% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:22. In embodiments, the CpG-ODN has at least 92% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:22. In embodiments, the CpG-ODN has at least 93% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:22. In embodiments, the CpG-ODN has at least 94% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:22. In embodiments, the CpG-ODN has at least 95% sequence identity with at least a 15 nucleobase continuous sequence of SEQ ID NO:22. In embodiments, the CpG-ODN has at least 80% sequence identity with SEQ ID NO:22. In embodiments, the CpG-ODN has at least 85% sequence identity with SEQ ID NO:22. In embodiments, the CpG-ODN has at least 90% sequence identity with SEQ ID NO:22. In embodiments, the CpG-ODN has at least 91% sequence identity with SEQ ID NO:22. In embodiments, the CpG-ODN has at least 92% sequence identity with SEQ ID NO:22. In embodiments, the CpG-ODN has at least 93% sequence identity with SEQ ID NO:22. In embodiments, the CpG-ODN has at least 94% sequence identity with SEQ ID NO:22. Inembodiments, the CpG-ODN has at least 95% sequence identity with SEQ ID NO:22. Inembodiments, the CpG-ODN includes the sequence of SEQ ID NO:22. In embodiments, the CpG- ODN is the sequence of SEQ ID NO:22.

[0179] In embodiments, the anti-miR-126 compound further includes a covalent linker between the CpG-ODN or phosphorothioate CpG-ODN and the anti-miR-126 nucleic acid sequence. In embodiments, the linker is a substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene. In embodiments, the linker is a substituted or unsubstituted C1-C40 alkylene, substituted or unsubstituted 2 to 40 membered heteroalkylene, substituted or unsubstituted C3-C8cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted C6-C10 arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene. In embodiments, the linker is an unsubstituted C1-C40alkylene, unsubstituted 2 to 40 membered heteroalkylene, unsubstituted C3-C8 cycloalkylene, unsubstituted 3 to 8 membered heterocycloalkylene, unsubstituted C6-C10 arylene, or unsubstituted 5 to 10 membered heteroarylene. In embodiments, the linker is a substituted 2 to 40 membered heteroalkylene.

[0180] In embodiments, the anti-miR-126 nucleic acid sequence includes one or more phosphorothioate linkages. In embodiments, the anti-miR-126 nucleic acid sequence includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more), phosphorothioate linkages and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more) chemically modified nucleotides. In embodiments, the anti-miR-126 nucleic acid sequence includes one or more chemically modified nucleotides. In embodiments, the anti-miR-126 nucleic acid includes a chemical modification selected from the group consisting of a 2’ O-Methyl, 2’-deoxy-2’fluoro, 2’- deoxy, a universal base, 5-C-methyl, an inverted deoxy abasic residue incorporation, and a locked nucleic acid. In embodiments, the modification is positioned at the terminal nucleobase of the anti- miR-126 nucleic acid. In embodiments, the modification is not positioned at the terminal nucleobase of the anti-miR-126 nucleic acid. In embodiments, the modification protects against serum-derived nucleases. In embodiments, the anti-miR-126 nucleic acid sequence includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more) chemically modified nucleotides. In embodiments, the anti-miR-126 nucleic acid sequence includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more), phosphorothioate linkages and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more) chemically modified nucleotides.

[0181] In embodiments, the linker represented by “xxxxx” or the like described herein is a bond,substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted alkylene, substituted (e.g. substituted with a substituent group,size-limited substituent group or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g. replaced with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted arylene, substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted cyclo- heteroalkylene or -(CH2)n-PO4-[(CH2)n-PO4]z-(CH2)n,in which the symbol n is an integer from 1 to 5 (e.g., 3) and the symbol z is an integer from 0 to 50 (e.g. from 0 to 25, 0 to 10, or 0 to 5). In embodiments, n is 3 and z is 0 to 5 or 1 to 5. In embodiments, n is 3 and z is 0 to 4 or 1 to 4. In embodiments, n is 3 and z is 0 to 3 or 1 to 3. In embodiments, n is 3 and z is 3. 2’OMe (2’-O- Methylnucleoside; Hydroxyl in 2’-position replaced with 2’-OMethyl); PS is phoshorothioation. One none-bridging oxygen replaced with sulfur; PS+3 represents three phosphates in the sequence modified, had one none-bridging oxygen replaced with sulfur; PS+5 represents five phosphates in the sequence modified, had one none-bridging oxygen replaced with sulfur.

[0182] For example, as shown below, in embodiments, nucleobases in the phosphorothioated oligonucleotide of the present disclosure sequence may include a phosphorothioate internucleotide linkage. A portion of such a phosphorothioated oligonucleotide is shown below..

[0183] The below formula represents a portion of a CpG-ODN linked at the 3’-OH end with a (CH2)3linker (also referred to herein as the C3 linker), which links to the 5’-phosphate of the anti- sense RNA.

[0184] The linker may be a bond, substituted (e.g. substituted with a substituent group, size- limited substituent group or lower substituent group) or unsubstituted alkylene, substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g. substituted with a substituent group, size-limitedsubstituent group or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0185] In embodiments, the anti-miR-126 compound includes a CpG-ODN conjugated to an anti- miR-126 nucleic acid sequence, with one or more linkers described herein.

[0186] In embodiments, the linker is a covalent linker (i.e. a linker that covalently attaches at least two (e.g.2) portions of a compound). In embodiments, the linker is or includes a substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted alkylene or heteroalkylene linker. In embodiments, the nucleic acid conjugated to anti-miRs and miRNA mimics includes more than one substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted heteroalkylene linkers. Linkers may be added during the synthesis in sequence. In embodiments, heteroalkylene linkers are connected to each other with an intervening phosphate bond. In embodiments, the covalent linker is a substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted heteroalkylene linker.

[0187] In embodiments, the linker is a substituted (e.g. substituted with a substituent group, size- limited substituent group or lower substituent group) or unsubstituted heteroalkylene or substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted cyclo-heteroalkylene. A “cyclo-heteroalkylene,” as used herein is a heteroalkylene having a one or more divalent cyclic moieties within the heteroalkylene chain. The cyclic moiety may be a substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted cycloalklylene, substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted arylene or substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted heteroarylene. In embodiments, the cyclic moiety is a substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted ribose (e.g., anucleoside). In embodiments, the cyclic moiety serves as a branch point of the linker thereby forming a branched linker. The cyclic moiety branch point may be used to attach additional functional moieties to the conjugates provided herein, such as detectable moieties, drug moieties or biomolecule. As explained in more detail below, the additional functional moieties may be connected using click chemistry techniques as known in the art.

[0188] For example, the linker may have the structure below, where the linker connects with the 3’ phosphate of the guanine on one end and the 5’ phosphate of the thymidine on the other end: .

[0189] In embodiments, the guanidine above is connected to CpG-ODN or a phosphorothioate CpG-ODN, and the thymidine is connected to an anti-miR-126.

[0190] In embodiments, the CpG-ODN conjugated to the anti-miR-126 nucleic acid sequence has a terminal moiety. A terminal moiety is a chemically reactive moiety, detectable moiety, therapeutic moiety (e.g. anti-cancer agent or anti-viral agent), nucleic acid sequence, DNA sequence, substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted alkyl, substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g. substituted with asubstituent group, size-limited substituent group or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted aryl, or substituted (e.g. substituted with a substituent group, size-limited substituent group or lower substituent group) or unsubstituted heteroaryl.

[0191] In embodiments, a terminal moiety is a chemically reactive moiety, detectable moiety, therapeutic moiety (e.g. anti-cancer agent or anti-viral agent), nucleic acid sequence, DNA sequence, nucleic acid analogs, R1-substituted or unsubstituted alkyl, R1-substituted or unsubstituted heteroalkyl, R1-substituted or unsubstituted cycloalkyl, R1-substituted or unsubstituted heterocycloalkyl, R1-substituted or unsubstituted aryl, or R1-substituted or unsubstituted heteroaryl.

[0192] In embodiments, a CpG-ODN nucleic acid sequence conjugated to the anti-miR-126 nucleic acid sequence includes a terminal moiety, wherein the terminal moiety is a detectable moiety. In embodiments, the CpG-ODN conjugated to an anti-miR or miRNA-mimic includes a terminal detectable moiety such as, a fluorescent dye, electron-dense reagent, enzyme, biotin, digoxigenin, paramagnetic molecule, paramagnetic nanoparticle, contrast agent, magnetic resonance contrast agent, X-ray contrast agent, Gadolinium, radioisotope, radionuclide, fluorodeoxyglucose, gamma ray emitting radionuclide, positron-emitting radionuclide, biocolloid, microbubble, iodinated contrast agent, barium sulfate, thorium dioxide, gold, gold nanoparticle, gold nanoparticle aggregate, fluorophore, two-photon fluorophore, hapten, protein, or fluorescent moiety. In embodiments, the CpG-ODN conjugated to an anti-miR or miRNA-mimic includes a terminal moiety, which is a therapeutic moiety (e.g., anti-cancer agent).

[0193] In embodiments, the compound includes CpG-ODN, in which C and G are nucleotides connected by a phosphodiester internucleotide linkage. In embodiments, the compound includes CpG, wherein C and G are nucleotides connected by a phosphodiester derivative internucleotide linkage. In embodiments, the CpG motif is unmethylated. In embodiments, C and G are connected as 5’C-G 3’. In embodiments, C and G are connected as 5’G-C 3’.

[0194] In embodiments, the compound includes a phosphodiester derivative linkage (e.g., phosphoramidate, phosphorodiamidate, phosphorothioate, phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate,boron phosphonate, or O-methylphosphoroamidite linkages). In embodiments, the compound includes a plurality of phosphodiester derivative linkages (e.g., phosphoramidate, phosphorodiamidate, phosphorothioate, phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, O-methylphosphoroamidite linkages, or combinations thereof).

[0195] In embodiments, the phosphodiester derivative linkage in the compound may be a phosphoramidate linkage, phosphorodiamidate linkage, phosphorothioate linkage, phosphorodithioate linkage, phosphonocarboxylic acid linkage, phosphonocarboxylate linkage, phosphonoacetic acid linkage, phosphonoformic acid linkage, methyl phosphonate linkage, boron phosphonate linkage, or O-methylphosphoroamidite linkage.

[0196] In embodiments, the anti-miR-126 compound includes a CpG-ODN including the sequence of SEQ ID NO:6 conjugated to an anti-miR-126 nucleic acid sequence including the sequence of SEQ ID NO:5. In embodiments, the anti-miR-126 compound includes the sequence of SEQ ID NO:2. In embodiments, the anti-miR-126 compound is the sequence of SEQ ID NO:2. In embodiments, the anti-miR-126 compound of SEQ ID NO:2 may be referred to as “miRisten”. Anti- miRNA compounds targeting miR-126 (e.g. anti-miR-126 compounds) and methods of making the same are described in WO 2017 / 066639 and US 2020 / 0281982, which are incorporated herein in their entirety and for all purposes.

[0197] For the method provided herein, in embodiments, the anti-miR-126 compound may be administered with an effective dose between about 0.001 mg / kg to about 100 mg / kg of the agent (e.g., 0.001, 0.005, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 mg / kg). In embodiments, an effective dose of an anti-miR-126 compound is administered to a subject in need thereof for treating a disease (e.g., cancer). In embodiments, the anti-miR-126 compound suppresses expression / activity of a miR-126 in a cell.

[0198] The anti-miR-126 compound may be administered to a subject in need thereof, at a dose between about 0.001 mg / kg to about 0.01 mg / kg of the compound, between about 0.01 mg / kg to about 0.1 mg / kg of the compound, between about 0.1 mg / kg to about 1.0 mg / kg of the compound,between about 1.0 mg / kg to about 5.0 mg / kg of the compound, between about 5.0 mg / kg to about 10 mg / kg of the compound, between about 10 mg / kg to about 15 mg / kg of the compound, between about 15 mg / kg to about 20 mg / kg of the compound, between about 20 mg / kg to about 25 mg / kg of the compound, between about 25 mg / kg to about 30 mg / kg of the compound, between about 30 mg / kg to about 35 mg / kg of the compound, between about 35 mg / kg to about 40 mg / kg of the compound, between about 40 mg / kg to about 45 mg / kg of the compound, between about 45 mg / kg to about 50 mg / kg of the compound, between about 50 mg / kg to about 55 mg / kg of the compound, between about 55 mg / kg to about 60 mg / kg of the compound, between about 60 mg / kg to about 65 mg / kg of the compound, between about 65 mg / kg to about 70 mg / kg of the compound, between about 70 mg / kg to about 75 mg / kg of the compound, between about 75 mg / kg to about 80 mg / kg of the compound, between about 80 mg / kg to about 85 mg / kg of the compound, between about 85 mg / kg to about 90 mg / kg of the compound, between about 90 mg / kg to about 95 mg / kg of the compound, or between about 95 mg / kg to about 100 mg / kg of the compound.

[0199] In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 10 mg / kg to about 80 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 15 mg / kg to about 80 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 20 mg / kg to about 80 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 25 mg / kg to about 80 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 30 mg / kg to about 80 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 35 mg / kg to about 80 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 40 mg / kg to about 80 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 45 mg / kg to about 80 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 50 mg / kg to about 80 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 55 mg / kg to about 80 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 60 mg / kg to about 80 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 65 mg / kg to about 80 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dosebetween about 70 mg / kg to about 80 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 75 mg / kg to about 80 mg / kg.

[0200] In embodiments, the anti-miR-126 compound is administered with an effective dose between about 10 mg / kg to about 75 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 10 mg / kg to about 70 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 10 mg / kg to about 65 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 10 mg / kg to about 60 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 10 mg / kg to about 55 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 10 mg / kg to about 50 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 10 mg / kg to about 45 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 10 mg / kg to about 40 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 10 mg / kg to about 35 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 10 mg / kg to about 30 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 10 mg / kg to about 25 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 10 mg / kg to about 20 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 10 mg / kg to about 15 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose of about 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75mg / kg, or 80 mg / kg. In embodiments, the anti-miR-126 compound compound is administered at an effective dose of about 20 mg / kg.

[0201] In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.4 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.6 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.8 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound isadministered with an effective dose between about 1 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 1.2 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 1.4 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 1.6 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 1.8 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 2 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 2.2 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 2.4 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 2.6 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 2.8 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 3 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 3.2 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 3.4 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 3.6 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 3.8 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 4 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 4.2 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 4.4 mg / kg to about 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 4.6 mg / kg to about 4.8 mg / kg.

[0202] In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 4.6 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 4.4 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 4.2 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 4 mg / kg. In embodiments, the anti-miR-126 compound isadministered with an effective dose between about 0.2 mg / kg to about 3.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 3.6 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 3.4 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 3.2 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 3 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 2.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 2.6 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 2.4 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 2.2 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 2 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 1.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 1.6 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 1.4 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 1.2 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 1 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 0.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 0.6 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose between about 0.2 mg / kg to about 0.4 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose of about 0.2 mg / kg, 0.4 mg / kg, 0.6 mg / kg, 0.8 mg / kg, 1 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.6 mg / kg, 2.8 mg / kg, 3 mg / kg, 3.2 mg / kg, 3.4 mg / kg, 3.6 mg / kg, 3.8 mg / kg, 4 mg / kg, 4.2 mg / kg, 4.4 mg / kg, 4.6 mg / kg, or 4.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose of about 0.2 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose of about 0.4 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose of about 0.6 mg / kg. In embodiments, the anti-miR-126 compound is administeredwith an effective dose of about 0.8 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose of about 1.2 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose of about 1.6 mg / kg. In embodiments, the anti-miR- 126 compound is administered with an effective dose of about 2.4 mg / kg. In embodiments, the anti- miR-126 compound is administered with an effective dose of about 3.2 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose of about 4.0 mg / kg. In embodiments, the anti-miR-126 compound is administered with an effective dose of about 4.8 mg / kg.

[0203] In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 2 µM to about 30 µM. In embodiments, the anti- miR-126 compound may be administered with an effective dose between about 3 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 4 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 5 µM to about 30 µM. In embodiments, the anti- miR-126 compound may be administered with an effective dose between about 6 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 7 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 8 µM to about 30 µM. In embodiments, the anti- miR-126 compound may be administered with an effective dose between about 9 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 10 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 11 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 12 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 13 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 14 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 15 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 16 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 17 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 18 µM to about30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 19 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 20 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 21 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 22 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 23 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 24 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 25 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 26 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 27 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 28 µM to about 30 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 29 µM to about 30 µM.

[0204] In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 29 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 28 µM. In embodiments, the anti- miR-126 compound may be administered with an effective dose between about 1 µM to about 27 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 26 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 25 µM. In embodiments, the anti- miR-126 compound may be administered with an effective dose between about 1 µM to about 24 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 23 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 22 µM. In embodiments, the anti- miR-126 compound may be administered with an effective dose between about 1 µM to about 21 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 20 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 19 µM. In embodiments, the anti- miR-126 compound may be administered with an effective dose between about 1 µM to about 18µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 17 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 16 µM. In embodiments, the anti- miR-126 compound may be administered with an effective dose between about 1 µM to about 15 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 14 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 13 µM. In embodiments, the anti- miR-126 compound may be administered with an effective dose between about 1 µM to about 12 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 11 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 10 µM. In embodiments, the anti- miR-126 compound may be administered with an effective dose between about 1 µM to about 9 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 8 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 7 µM. In embodiments, the anti- miR-126 compound may be administered with an effective dose between about 1 µM to about 6 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 5 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 4 µM. In embodiments, the anti- miR-126 compound may be administered with an effective dose between about 1 µM to about 3 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM to about 2 µM. In embodiments, the anti-miR-126 compound may be administered with an effective dose between about 1 µM, 2 µM, 3 µM, 4 µM, 5 µM, 6 µM, 7 µM, 8 µM, 9 µM, 10 µM, 11 µM, 12 µM, 13 µM, 14 µM, 15 µM, 16 µM, 17 µM, 18 µM, 19 µM, 20 µM, 21 µM, 22 µM, 23 µM, 24 µM, 25 µM, 26 µM, 27 µM, 28 µM, 29 µM, or 30 µM.

[0205] In embodiments, the present disclosure includes compositions with an effective dose of an anti-miR-126 compound between about 0.1% to about 20% w / v of the composition.

[0206] For example, the effective dose of the anti-miR-126 compound may be between about 0.001% - about 0.01%, between about 0.01% - about 0.1%, between about 0.1% - about 1.0%, between about 1.0% - about 2.0%, between about 2.0% - about 3.0%, between about 3.0% - about4.0%, between about 4.0% - about 5.0%, between about 5.0% - about 6.0%, between about 6.0% - about 7.0%, between about 7.0% - about 8.0%, between about 8.0% - about 9.0%, between about 9.0% - about 10%, between about 10% - about 11%, between about 11% - about 12%, between about 12% - about 13%, between about 13% - about 14%, between about 14% - about 15%, between about 15% - about 16%, between about 16% - about 17%, between about 17% - about 18%, between about 18% - about 19%, or between about 19% - about 20% w / v of the composition.

[0207] In embodiments, the anti-miR-126 compound is administered once a day. In embodiments, the anti-miR-126 compound is administered two times a day. In embodiments, the anti-miR-126 compound is administered three times a day. In embodiments, the anti-miR-126 compound is administered four times a day.

[0208] In embodiments, the anti-miR-126 compound is administered to the subject for a duration of about 10 days to about 40 days. In embodiments, the anti-miR-126 compound is administered to the subject for a duration of about 15 days to about 40 days. In embodiments, the anti-miR-126 compound is administered to the subject for a duration of about 20 days to about 40 days. In embodiments, the anti-miR-126 compound is administered to the subject for a duration of about 25 days to about 40 days. In embodiments, the anti-miR-126 compound is administered to the subject for a duration of about 30 days to about 40 days. In embodiments, the anti-miR-126 compound is administered to the subject for a duration of about 35 days to about 40 days.

[0209] In embodiments, the anti-miR-126 compound is administered to the subject for a duration of about 10 days to about 35 days. In embodiments, the anti-miR-126 compound is administered to the subject for a duration of about 10 days to about 30 days. In embodiments, the anti-miR-126 compound is administered to the subject for a duration of about 10 days to about 25 days. In embodiments, the anti-miR-126 compound is administered to the subject for a duration of about 10 days to about 20 days. In embodiments, the anti-miR-126 compound is administered to the subject for a duration of about 10 days to about 15 days. In embodiments, the anti-miR-126 compound is administered to the subject for a duration of about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 days. In embodiments, the anti-miR-126 compound is administered for a duration of about 28 days. In embodiments,

[0210] In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 24 months. In embodiments, the anti-miR-126 compound is administered to thesubject for about 2 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 3 months to about 24 months. In embodiments, the anti-miR- 126 compound is administered to the subject for about 4 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 5 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 6 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 7 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 8 months to about 24 months. In embodiments, the anti-miR- 126 compound is administered to the subject for about 9 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 10 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 11 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 12 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 13 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 14 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 15 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 16 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 17 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 18 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 19 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 20 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 21 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 22 months to about 24 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 23 months to about 24 months.

[0211] In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 23 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 22 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 21 months. In embodiments, the anti-miR- 126 compound is administered to the subject for about 1 month to about 20 months. Inembodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 19 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 18 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 17 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 16 months. In embodiments, the anti-miR- 126 compound is administered to the subject for about 1 month to about 15 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 14 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 13 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 12 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 11 months. In embodiments, the anti-miR- 126 compound is administered to the subject for about 1 month to about 10 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 9 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 8 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 7 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 6 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 5 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 4 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 3 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1 month to about 2 months. In embodiments, the anti-miR-126 compound is administered to the subject for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months. In embodiments, the anti-miR-126 compound is administered to the subject until a desired or beneficial clinical result is observed.

[0212] In embodiments, the anti-miR-126 compound is administered for multiple treatment cycles. A treatment cycle refers to a period of time where the anti-miR-126 compound is administered. In embodiments, a treatment cycle may include intermittent administration. For example, in embodiments, within a treatment cycle the anti-miR-126 compound may be administered for a period of time (e.g.1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days), followed by a time during which the agent is not administered (e.g.1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days). A treatment cycle maybe followed by a period of time where the anti-miR-126 compound is not administered (e.g. rest period). Thus, in embodiments, the anti-miR-126 compound may be administered for a period of time (e.g. a treatment cycle) followed by a period of time where the anti-miR-126 compound is not administered (e.g. rest period). An anti-miR126 compound treatment course may include multiple treatment cycles interspersed with periods of time where the anti-miR-126 compound is not administered (rest period). In embodiments, the anti-miR-126 compound treatment course includes about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 treatment cycles.

[0213] In embodiments, the anti-miR-126 compound is administered to the subject by intravenous infusion.

[0214] For the method provided herein, in embodiments, the BH3-mimetic compound may be administered with an effective dose between about 1 mg / kg to about 500 mg / kg of the agent (e.g., 1, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg / kg). In embodiments, the BH3-mimetic compound may be administered with an effective dose between about 1 mg / kg to about 150 mg / kg of the agent (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 101, 101, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, or 150 mg / kg). In embodiments, an effective dose of an BH3-mimetic compound is administered to a subject in need thereof for treating a disease (e.g., cancer). In embodiments, the BH3-mimetic suppresses expression / activity of an anti-Bcl-2 family member protein in a cell.

[0215] In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 20 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 40 mg to about 500 mg per day In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 60 mg to about 500 mg per day. Inembodiments, the BH3- mimetic compound may be administered with an effective dosage between about 80 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 100 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 120 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 140 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 160 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 180 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 200 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 220 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 240 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 260 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 280 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 300 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 320 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 340 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 360 mg to about 500 mg per day In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 380 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 400 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 420 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 440 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 460 mg to about 500 mg per day. Inembodiments, the BH3- mimetic compound may be administered with an effective dosage between about 480 mg to about 500 mg per day.

[0216] In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 480 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 460 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 440 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 420 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 400 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 380 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 360 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 340 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 320 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 300 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 280 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 260 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 240 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 220 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 200 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 180 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 160 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 140 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 120 mg per day. In embodiments, the BH3- mimetic compound may beadministered with an effective dosage between about 1 mg to about 100 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 80 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 60 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 40 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 1 mg to about 20 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage of about 1, 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, or 500 mg per day.

[0217] In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 50 mg to about 800 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 100 mg to about 800 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 150 mg to about 800 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 200 mg to about 800 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 250 mg to about 800 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 300 mg to about 800 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 350 mg to about 800 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 400 mg to about 800 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 450 mg to about 800 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 500 mg to about 800 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 550 mg to about 800 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 600 mg to about 800 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 650 mg to about 800 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 700 mg to about 800 mgper day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 750 mg to about 800 mg per day.

[0218] In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 50 mg to about 750 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 50 mg to about 700 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 50 mg to about 650 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 50 mg to about 600 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 50 mg to about 550 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 50 mg to about 500 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 50 mg to about 450 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 50 mg to about 400 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 50 mg to about 350 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 50 mg to about 300 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 50 mg to about 250 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 50 mg to about 200 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 50 mg to about 150 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage between about 50 mg to about 100 mg per day. In embodiments, the BH3- mimetic compound may be administered with an effective dosage of about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, or 800 mg per day.

[0219] In embodiments, the BH3- mimetic compound may be administered to a subject in need thereof, at an effective dosage between about 1 mg / m2to about 50 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 5 mg / m2to about 50 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 10 mg / m2to about 50 mg / m2. In embodiments, the BH3- mimetic compound isadministered with an effective dose between about 15 mg / m2to about 50 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 20 mg / m2to about 50 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 25 mg / m2to about 50 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 30 mg / m2to about 50 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 35 mg / m2to about 50 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 40 mg / m2to about 50 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 45 mg / m2to about 50 mg / m2.

[0220] In embodiments, the BH3- mimetic compound is administered with an effective dose between about 1 mg / m2to about 45 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 1 mg / m2to about 40 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 1 mg / m2to about 35 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 1 mg / m2to about 30 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 1 mg / m2to about 25 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 1 mg / m2to about 20 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 1 mg / m2to about 15 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 1 mg / m2to about 10 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose between about 1 mg / m2to about 5 mg / m2. In embodiments, the BH3- mimetic compound is administered with an effective dose of about 1 mg / m2, 5 mg / m2, 10 mg / m2, 15 mg / m2, 20 mg / m2, 25 mg / m2, 30 mg / m2, 35 mg / m2, 40 mg / m2, 45 mg / m2, or 50 mg / m2.

[0221] In embodiments, the BH3 mimetic compound is administered once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, or once every 7 days. In embodiments, the BH3 mimetic compound is administered once a day. In embodiments, the BH3 mimetic compound is administered two times a day.

[0222] In embodiments, the BH3 mimetic compound is administered to the subject for a duration of about 5 days to about 40 days. In embodiments, the BH3 mimetic compound is administered tothe subject for a duration of about 10 days to about 40 days. In embodiments, the BH3 mimetic compound is administered to the subject for a duration of about 15 days to about 40 days. In embodiments, the BH3 mimetic compound is administered to the subject for a duration of about 20 days to about 40 days. In embodiments, the BH3 mimetic compound is administered to the subject for a duration of about 25 days to about 40 days. In embodiments, the BH3 mimetic compound is administered to the subject for a duration of about 30 days to about 40 days. In embodiments, the BH3 mimetic compound is administered to the subject for a duration of about 35 days to about 40 days.

[0223] In embodiments, the BH3 mimetic compound is administered to the subject for a duration of about 5 days to about 35 days. In embodiments, the BH3 mimetic compound is administered to the subject for a duration of about 5 days to about 30 days. In embodiments, the BH3 mimetic compound is administered to the subject for a duration of about 5 days to about 25 days. In embodiments, the BH3 mimetic compound is administered to the subject for a duration of about 5 days to about 20 days. In embodiments, the BH3 mimetic compound is administered to the subject for a duration of about 5 days to about 15 days. In embodiments, the BH3 mimetic compound is administered to the subject for a duration of about 5 days to about 10 days. In embodiments, the BH3 mimetic compound is administered to the subject for a duration of about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 days. In embodiments, the BH3 mimetic compound is administered for a duration of about 7 days. In embodiments, the BH3 mimetic compound is administered for a duration of about 14 days. In embodiments, the BH3 mimetic compound is administered for a duration of about 21 days. In embodiments, the BH3 mimetic compound is administered for a duration of about 28 days.

[0224] In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 2 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 3 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 4 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 5 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 6 months to about 24 months. In embodiments, the BH3 mimetic compound is administered tothe subject for about 7 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 8 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 9 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 10 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 11 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 12 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 13 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 14 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 15 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 16 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 17 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 18 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 19 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 20 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 21 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 22 months to about 24 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 23 months to about 24 months.

[0225] In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 23 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 22 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 21 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 20 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 19 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 18 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 17 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 16 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 15 months. Inembodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 14 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 13 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 12 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 11 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 10 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 9 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 8 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 7 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 6 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 5 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 4 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 3 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1 month to about 2 months. In embodiments, the BH3 mimetic compound is administered to the subject for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months. In embodiments, the BH3 mimetic compound is administered to the subject until a desired or beneficial clinical result is observed.

[0226] In embodiments, the BH3 mimetic compound is administered for multiple treatment cycles. A treatment cycle refers to a period of time where the BH3 mimetic compound is administered. In embodiments, a treatment cycle may include intermittent administration. For example, in embodiments, within a treatment cycle the BH3 mimetic compound may be administered for a period of time (e.g.1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days), followed by a time during which the agent is not administered (e.g.1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days). In embodiments, a BH3 mimetic compound treatment cycle is about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 days. A treatment cycle may be followed by a period of time where the BH3 mimetic compound is not administered (e.g. rest period). Thus, in embodiments, the BH3 mimetic compound may be administered for a period of time (e.g. a treatment cycle) followed by a period of time where the BH3 mimetic compound is not administered (e.g. rest period). A BH3 mimetic compound treatment course may includemultiple treatment cycles interspersed with periods of time where the BH3 mimetic compound is not administered (rest period). In embodiments, the BH3 mimetic compound treatment course includes about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 treatment cycles.

[0227] In embodiments, the anti-miR-126 compound is administered to the subject by intravenous infusion or orally.

[0228] In embodiments, the effective amount is a combined synergistic amount of said anti-miR- 126 nucleic acid and said BH3 mimetic compound. A "combined synergistic amount" as used herein refers to the sum of a first amount (e.g., an amount of an anti-microRNA126 (miR-126) compound) and a second amount (e.g., an amount of a BH3 mimetic compound) that results in a synergistic effect (i.e. an effect greater than an additive effect). Therefore, the terms "synergy", "synergism", "synergistic", "combined synergistic amount", and "synergistic therapeutic effect" which are used herein interchangeably, refer to a measured effect of compounds administered in combination where the measured effect is greater than the sum of the individual effects of each of the compounds administered alone as a single agent.

[0229] In embodiments, a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of the anti-microRNA126 (miR-126) compound when used separately from the BH3 mimetic compound. In embodiments, a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of the BH3 mimetic compound when used separately from the anti-microRNA126 (miR- 126) compound.

[0230] The synergistic effect may be a miR-126 activity decreasing effect and / or an anti-apoptotic Blc-2 family protein activity decreasing effect. In embodiments, synergy between the anti- microRNA126 (miR-126) compound and the BH3 mimetic compound may result in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease (e.g., decrease of miR-126 activity or decrease of anti-apoptotic Blc-2 family protein activity) than the sum of the decrease of the anti-microRNA126 (miR-126) compound or the BH3 mimetic compound when used individually and separately. In embodiments, synergy between the anti-microRNA126 (miR-126) compound and the BH3 mimetic compound may result in 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater inhibition of miR-126 activity and / or anti-apoptotic Blc-2 family protein than the sum of the inhibition of the anti-microRNA126 (miR-126) compound or the BH3 mimetic compound when used individually and separately.

[0231] The synergistic effect may be a cancer-treating effect, including leukemia treating effect (i.e. leukemia treating synergistic effect) or lymphoma treating effect (i.e. lymphoma treating synergistic effect). In embodiments, the synergistic effect is acute myeloid leukemia (AML) treating effect (i.e. AML treating synergistic effect), chronic lymphocytic leukemia (CLL) treating effect (i.e. CLL treating synergistic effect), chronic myelogenous leukemia (CML) treating effect (i.e. CML treating synergistic effect), acute lymphocytic leukemia (ALL) treating effect (i.e. ALL treating synergistic effect), or small lymphocytic lymphoma (SLL) treating effect (i.e. SLL treating synergistic effect). In embodiments, the synergistic effect is myelodysplastic syndrome (MDS) treating effect (i.e. MDS treating synergistic effect). In embodiments, the cancer-treating effect may be measured by, for example, cancer cell death, decrease in cancer cells, inhibition or slowing of cancer cell growth, lack of progression of the cancer, prolonged survival, or desired or beneficial clinical results.

[0232] In embodiments, the cancer-treating effect of a therapeutic including the anti- microRNA126 (miR-126) compound and the BH3 mimetic compound is increased by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% , 90%, or 100% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 10% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 20% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 30% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 40% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 50% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of atherapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 60% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 70% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 10% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 80% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 90% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 91% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 92% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 93% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 94% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 95% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound isincreased by at least about 96% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 97% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 98% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including the anti-microRNA126 compound and the BH3 mimetic compound is increased by at least about 99% compared to a therapeutic including a BH3 mimetic compound without the anti-microRNA126 compound.

[0233] In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 0.1-fold, 0.2- fold, 0.4-fold, 0.6-fold, 0.8-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 100-fold, 150-fold, or 200-fold compared to a therapeutic including a BH3 mimetic compound without the anti- microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-microRNA126 compound and a BH3 mimetic compound is increased by at least about 0.1-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 0.2-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 0.3-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 0.4-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 0.5-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 0.6-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 0.7-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 0.8-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 0.9-fold compared to a therapeutic including a BH3 mimetic compound without anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 1-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 2-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 3-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 4-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 5-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 6-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-microRNA126 compound and a BH3 mimetic compound is increased by at least about 7-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 8-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 9-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 10-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 15-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 20-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 25-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 30-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 35-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 40-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 45-foldcompared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 50-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 100-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 150-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 compound and a BH3 mimetic compound is increased by at least about 200-fold compared to a therapeutic including the BH3 mimetic compound without the anti-microRNA126 compound.

[0234] In embodiments, the anti-miR-126 compound and the BH3 mimetic compound are administered simultaneously or sequentially. In embodiments, the anti-miR-126 compound and the BH3 mimetic compound are administered simultaneously. In embodiments, the anti-miR-126 compound and the BH3 mimetic compound are administered sequentially.

[0235] The anti-microRNA126 (miR-126) compound and the BH3 mimetic compound may be administered in combination either simultaneously (e.g., as a mixture), separately but simultaneously (e.g., via separate intravenous lines) or sequentially (e.g., one agent is administered first followed by administration of the second agent). Thus, in embodiments, the term combination is used to refer to concomitant, simultaneous or sequential administration of the anti-microRNA126 (miR-126) compound and the BH3 mimetic compound.

[0236] In embodiments, the anti-microRNA126 (miR-126) compound and the BH3 mimetic compound are administered simultaneously or sequentially. In embodiments, the anti- microRNA126 (miR-126) compound and the BH3 mimetic compound are administered simultaneously. In embodiments, the anti-microRNA126 (miR-126) compound and the BH3 mimetic compound are administered sequentially. During the course of treatment, the anti-microRNA126 (miR-126) compound and BH3 mimetic compound may at times be administered sequentially and at other times be administered simultaneously.

[0237] In embodiments, where the anti-microRNA126 (miR-126) compound and the BH3 mimetic compound are administered sequentially, the BH3 mimetic compound is administered at a first time point and the anti-microRNA126 (miR-126) compound is administered at a second time point, wherein the first time point precedes the second time point. Alternatively, in embodiments, where the anti-microRNA126 (miR-126) compound and the BH3 mimetic compound are administered sequentially, the anti-microRNA126 (miR-126) compound is administered at a first time point and the BH3 mimetic compound is administered at a second time point, wherein the first time point precedes the second time point.

[0238] The course of treatment is best determined on an individual basis depending on the particular characteristics of the subject and the type of treatment selected. The treatment, such as those disclosed herein, can be administered to the subject on a daily, twice daily, bi-weekly, monthly or any applicable basis that is therapeutically effective. The treatment can be administered alone or in combination with any other treatment disclosed herein or known in the art. The additional treatment can be administered simultaneously with the first treatment, at a different time, or on an entirely different therapeutic schedule (e.g., the first treatment can be daily, while the additional treatment is weekly).

[0239] In instances where the anti-microRNA126 (miR-126) compound and BH3 mimeticcompound are administered simultaneously, the anti-microRNA126 (miR-126) compound and BH3 mimetic compound may be administered as a mixture. Thus, in embodiments, the anti- microRNA126 (miR-126) compound and the BH3 mimetic compound are admixed prior to administration.

[0240] As described throughout the specification, a combination therapy including an anti- microRNA126 (miR-126) compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is effective for the treatment of cancer (e.g. leukemia). Applicant found that the addition of an anti-miR-126 compound to combination therapies including a BH3 mimetic compound and a chemotherapy (e.g. hypomethylating agent) increases or potentiates the cancer- treating effect of the therapy. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR-126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylatingagent) is increased by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to a therapeutic including a BH3 mimetic compound and a chemotherapy (e.g. hypomethylating agent) without an anti-miR-126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR-126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 10% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR-126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR-126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 20% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR- 126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR- 126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 30% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR-126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR-126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 40% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR-126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR-126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 50% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR-126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR-126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 60% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR- 126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR- 126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 70% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR-126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR-126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 80%compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR-126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR-126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 90% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR-126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR-126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 91% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR- 126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR- 126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 92% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR-126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR-126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 93% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR-126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR-126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 94% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR-126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR-126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 95% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR- 126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR- 126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 96% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR-126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR-126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 97% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g.hypomethylating agent) without an anti-miR-126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR-126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 98% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR-126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-miR-126 compound, BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 99% compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-miR- 126 compound.

[0241] In embodiments, the cancer-treating effect of a therapeutic including an anti- microRNA126 (miR-126) compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9- fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 100-fold, 150- fold, or 200-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 0.1-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 0.2-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 0.3-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 0.4-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g.hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 0.5-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 0.6-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 0.7-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 0.8-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 0.9-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 1-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 2-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 3-foldcompared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 4-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 5-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 6-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 7-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 8-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 9-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 10-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimeticcompound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 15-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 20-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 25-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 30-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 35-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 40-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 45-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 50-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer-treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 100-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 150-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound. In embodiments, the cancer- treating effect of a therapeutic including an anti-microRNA126 compound, a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) is increased by at least about 200-fold compared to a therapeutic including a BH3 mimetic compound, and a chemotherapy (e.g. hypomethylating agent) without an anti-microRNA126 compound.

[0242] Thus, in embodiments, the method further includes administering an effective amount of a chemotherapy. The chemotherapy agent may precede, or follow administration of a compound (e.g. the anti-microRNA126 (miR-126) compound and BH3 mimetic compound) or composition of the present disclosure or may be given simultaneously therewith. Preparation and dosing schedules for chemotherapy are also described in Chemotherapy Service Ed., M. C. Perry, Williams & Wilkins, Baltimore, Md. (1992).

[0243] In embodiments, the anti-miR-126 compound, the BH3 mimetic compound, and the chemotherapy (e.g. hypomethylating agent) are administered simultaneously or sequentially. In embodiments, the anti-miR-126 compound, the BH3 mimetic compound, and the chemotherapy (e.g. hypomethylating agent) are administered simultaneously. In embodiments, the anti-miR-126 compound, the BH3 mimetic compound, and the chemotherapy (e.g. hypomethylating agent) are administered sequentially. During the course of treatment, the anti-microRNA126 (miR-126) compound, the BH3 mimetic compound, and the chemotherapy (e.g. hypomethylating agent) may at times be administered sequentially and at other times be administered simultaneously.

[0244] The anti-miR-126 compound, the BH3 mimetic compound, and the chemotherapy (e.g. hypomethylating agent) may be administered in combination either simultaneously (e.g., as a mixture), separately but simultaneously (e.g., via separate intravenous lines, via different administration routes) or sequentially (e.g., one agent is administered first followed byadministration of the second agent and third agent, one agent is administered first followed by administration of the second agent followed by administration of the third agent).

[0245] In embodiments, a first agent is administered, followed by administration of the second agent and third agent simultaneously. In embodiments, a first agent and a second agent are administered simultaneously, followed by administration of a third agent. In embodiments, a first agent is administered, followed by administration of a second agent, followed by administration of a third agent. Thus, in embodiments, the term combination is used to refer to concomitant, simultaneous or sequential administration of the anti-microRNA126 (miR-126) compound, the BH3 mimetic compound, and the chemotherapy (e.g. hypomethylating agent).

[0246] In embodiments, where the anti-miR-126 compound, the BH3 mimetic compound, and the chemotherapy (e.g. hypomethylating agent) are administered sequentially, one of the agents is administered at a first time point, the second agent is administered at a second time point, and the third agent is administered at a third time point, wherein the first time point precedes the second time point and the second time point precedes the third time point. In embodiments, the anti-miR- 126 compound is administered at a first time point, and the BH3 mimetic compound and the chemotherapy are administered at a second time point, wherein the first time point precedes the second time point. Alternatively, in embodiments, the BH3 mimetic compound and the chemotherapy (e.g. hypomethylating agent) are administered at a first time point and the anti-miR- 126 compound is administered at a second time point, wherein the first time point precedes the second time point.

[0247] For the method provided herein, in embodiments, the chemotherapy (e.g. hypomethylating agent) may be administered with an effective dose between about 1 mg / kg to about 500 mg / kg of the agent (e.g., 1, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg / kg). In embodiments, an effective dose of n chemotherapy (e.g. hypomethylating agent) is administered to a subject in need thereof for treating a disease (e.g., cancer).

[0248] In embodiments, the chemotherapy (e.g. hypomethylating agent) may be administered to a subject in need thereof with an effective dose between about 1 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 20 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 40 mg / kg to about 500 mg / kg. In embodiments, thechemotherapy (e.g. hypomethylating agent) is administered at a dose between about 60 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 80 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 100 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 120 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 140 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 160 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 180 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 200 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 220 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 240 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 260 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 280 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 300 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 320 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 340 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 360 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 380 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is administered at a dose between about 400 mg / kg to about 500 mg / kg. In embodiments, the chemotherapy (e.g. hypomethylating agent) is admi...

Claims

1. WHAT IS CLAIMED IS:

1. A method of treating cancer in a subject in need thereof, the method comprising administering to said subject an effective amount of an anti-microRNA126 (miR-126) compound and a Bcl-2 homology 3 (BH3) mimetic compound.

2. The method of claim 1, wherein the BH3 mimetic compound binds Bcl-2, Bcl-XL, Blc-W, Mcl-1, or a combination thereof.

3. The method of claim 1, wherein the BH3 mimetic compound is venetoclax, S63845, A1331852, obatoclax, ABT-263, S55746, AMG176, AZD5991, WEHI-539, ABT-737, or a combination thereof.

4. The method of claim 3, wherein the BH3 mimetic compound is venetoclax.

5. The method of claim 1 wherein said anti-miR-126 compound comprises: i) a CpG oligodeoxynucleotide (CpG-ODN) or a phosphorothioate CpG-ODNconjugated to an anti-miR-126 nucleic acid sequence; or ii) an unconjugated anti-miR-126 nucleic acid sequence.

6. The method of claim 5, wherein said anti-miR-126 nucleic acid sequence comprises one or more phosphorothioate linkages.

7. The method claim 5, wherein said anti-miR-126 nucleic acid sequence comprises one or more chemically modified nucleotides.

8. The method of claim 1, wherein said anti-miR-126 compound comprises the sequence of SEQ ID NO:

2.

9. The method of claim 1, wherein said effective amount is a combined synergistic amount of said anti-miR-126 compound and said BH3 mimetic compound.

10. The method of claim 1, wherein said anti-miR-126 compound and said BH3 mimetic compound are administered simultaneously or sequentially.

11. The method of claim 1, wherein the method further comprises administering an effective amount of a chemotherapy.

12. The method of claim 11, wherein the chemotherapy is a hypomethylating agent.

13. The method of claim 12, wherein the hypomethylating agent is azacitidine, decitabine, or guadecitabine.

14. The method of claim 13, wherein the hypomethylating agent is azacitidine.

15. The method of claim 11, wherein said effective amount is a combined synergistic amount of said anti-miR-126 compound, said BH3 mimetic compound, and said chemotherapy.

16. The method of claim 1, wherein the cancer is leukemia or lymphoma.

17. The method of claim 16, wherein the leukemia is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), or acute lymphocytic leukemia (ALL).

18. The method of claim 16, wherein the lymphoma is small lymphocytic lymphoma (SLL).

19. The method of claim 1, wherein the cancer is myelodysplastic syndrome (MDS).

20. The method of claim 1, wherein the subject has a relapsed cancer, a BH3 mimetic resistant cancer, a chemotherapy resistant cancer, or a combination thereof.

21. The method of claim 20, wherein said BH3 mimetic resistant cancer is a venetoclax-resistant cancer.

22. A pharmaceutical composition comprising an anti-microRNA126 (miR-126) compound and a Bcl-2 homology 3 (BH3) mimetic compound.

23. The pharmaceutical composition of claim 22, wherein the BH3 mimetic compound binds Bcl-2, Bcl-XL, Blc-W, Mcl-1, or a combination thereof.

24. The pharmaceutical composition of claim 22, wherein the BH3 mimetic compound is venetoclax, S63845, A1331852, obatoclax, ABT-263, S55746, AMG176, AZD5991, WEHI-539, ABT-737, or a combination thereof.

25. The pharmaceutical composition of claim 24, wherein the BH3 mimetic compound is venetoclax.

26. The pharmaceutical composition of claim 22, wherein said anti-miR-126 compound comprises: i) a CpG oligodeoxynucleotide (CpG-ODN) or a phosphorothioate CpG-ODNconjugated to an anti-miR-126 nucleic acid sequence; or ii) an unconjugated anti-miR-126 nucleic acid sequence.

27. The pharmaceutical composition of claim 26, wherein said anti-miR-126 nucleic acid sequence comprises one or more phosphorothioate linkages.

28. The pharmaceutical composition of claim 26, wherein said anti-miR-126 nucleic acid sequence comprises one or more chemically modified nucleotides.

29. The pharmaceutical composition of claim 22, wherein said anti-miR-126 compound comprises the sequence of SEQ ID NO:

2.

30. The pharmaceutical composition of claim 22, wherein said pharmaceutical composition comprises a first amount of said anti-miR-126 compound and a second amount of said BH3 mimetic compound, wherein said first amount and said second amount provide a combined synergistic amount.

31. The pharmaceutical composition of claim 22, wherein the pharmaceutical composition further comprises a chemotherapy.

32. The pharmaceutical composition of claim 31, wherein the chemotherapy is a hypomethylating agent.

33. The pharmaceutical composition of claim 32, wherein the hypomethylating agent is azacitidine, decitabine, or guadecitabine.

34. The pharmaceutical composition of claim 33, wherein the hypomethylating agent is azacitidine.

35. The pharmaceutical composition of claim 31, wherein said pharmaceutical composition comprises a third amount of said chemotherapy, wherein said first amount, said second amount, and said third amount provide a combined synergistic amount.

36. A kit comprising an anti-microRNA126 (miR-126) compound and a Bcl-2 homology 3 (BH3) mimetic compound.

37. The kit of claim 36, wherein the BH3 mimetic compound binds Bcl-2, Bcl- XL, Blc-W, Mcl-1, or a combination thereof.

38. The kit of claim 36, wherein the BH3 mimetic compound is venetoclax, S63845, A1331852, obatoclax, ABT-263, S55746, AMG176, AZD5991, WEHI-539, ABT-737, or a combination thereof.

39. The kit of claim 38, wherein the BH3 mimetic compound is venetoclax.

40. The kit of claim 36, wherein said anti-miR-126 compound comprises: i) a CpG oligodeoxynucleotide (CpG-ODN) or a phosphorothioate CpG-ODNconjugated to an anti-miR-126 nucleic acid sequence; or ii) an unconjugated anti-miR-126 nucleic acid sequence.

41. The kit of claim 40, wherein said anti-miR-126 nucleic acid sequence comprises one or more phosphorothioate linkages.

42. The kit of claim 40, wherein said anti-miR-126 nucleic acid sequence comprises one or more chemically modified nucleotides.

43. The kit of claim 36, wherein said anti-miR-126 compound comprises the sequence of SEQ ID NO:

2.

44. The kit of claim 36, wherein said kit comprises a first amount of said anti- miR-126 compound and a second amount of said BH3 mimetic compound, wherein said first amount and said second amount provide a combined synergistic amount.

45. The kit of claim 36, wherein the kit further comprises a chemotherapy.

46. The kit of claim 45, wherein the chemotherapy is a hypomethylating agent.

47. The kit of claim 46, wherein the hypomethylating agent is azacitidine, decitabine, or guadecitabine.

48. The kit of claim 47, wherein the hypomethylating agent is azacitidine.

49. The kit of claim 45, wherein said kit comprises a third amount of said chemotherapy, wherein said first amount, said second amount, and said third amount provide a combined synergistic amount.

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