Antisense oligomer formulations

Abstract

Provided herein is a pharmaceutical formulation comprising an antisense oligomer (ASO), a kit, and a method for use thereof for treating a disease or condition by modulating the expression of NaV1.1 protein in the cells of a subject in need thereof, wherein the ASO modulates splicing of a nonsense-mediated mRNA decay-inducing exon from a pre-mRNA in the cells of the subject, thereby modulating the expression of NaV1.1 protein in the subject.

Description

WSGR Docket No.47991-744.601 ANTISENSE OLIGOMER FORMULATIONS CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 625,171, filed January 25, 2024, and U.S. Provisional Application No.63 / 484,890, filed February 14, 2023, which are incorporated herein by reference in their entireties. BACKGROUND

[0002] Nervous system disorders are often associated with channelopathy, characterized by the disturbed function of ion channels that mediate neuronal excitability, neuronal interactions, and brain functions at large. Mutations in the SCN1A gene, which is part of the SCN1A-SCN2A-SCN3A gene cluster that encodes alpha-pore forming subunits of the neuronal voltage gated sodium channel, can result in expression of NaV1.1 protein (also termed as “NaV1.1”) with reduced functions as compared to a wild- type NaV1.1 protein, reduced expression of NaV1.1, or both. Mutations in SCN1A gene are associated with development of numerous diseases and conditions, such as Dravet Syndrome (DS) (Miller, et al., 1993-2015, Gene Reviews, Eds. Pagon RA, et al. Seattle (WA): University of Washington, Seattle, Bookshelf ID: NBK1318, and Mulley, et al., 2005, Hum. Mutat.25: 535-542). SUMMARY

[0003] Alternative splicing events in SCN1A gene can lead to non-productive mRNA transcripts which in turn can lead to aberrant protein expression, and therapeutic agents which can target the alternative splicing events in SCN1A gene can modulate the expression level of functional proteins in Dravet Syndrome patients and / or inhibit aberrant protein expression. Such therapeutic agents can be used to treat a condition caused by SCN1A, SCN8A or SCN5A protein deficiency.

[0004] Selecting the right formulation, dose, dosing regimen and patient population for a drug is a crucial step in the development of pharmaceutical drugs. For example, without adequate information on dosage, it is not possible for doctors to prescribe a drug to patients. For example, if a dose or dose range cannot be identified that allows safe and predictable administration, the drug cannot be a medically useful or commercially viable pharmaceutical product. Therefore, determining the correct drug dosage is a key question that needs to be addressed in clinical practice. The discovery of therapeutically effective dosages and dosage regimens of a drug needs to balance patient compliance, therapeutic efficacy and side effects of the drug; which requires substantial skills. For example, suitable dosages and dosage regimens may be discovered through a clinical trial that forms part of the approval process, requires substantial input of intellectual and financial resources of different parties, and is not within the routine of a medical practitioner. For example, patient compliance can be crucial for optimal treatment of various conditions. The more doses required or the more difficult the treatment plan, the less likely a patient is to comply. Although medical agents have the ability to enhance patients’ quality of life (QOL), they can only do so if they are used correctly. Thus, it is clear that selecting the right dose, formulation, dosing regimen andWSGR Docket No.47991-744.601 patient population for a drug is complex and unpredictable. Structurally similar compounds significantly differ in their solubility, toxicity, activity, stability, and pharmacological properties. Also, there are significant physiological differences between animal models and human subjects. Therefore, translating pre-clinical information into clinically effective therapy is an unpredictable and challenging task.

[0005] Provided herein are suitable pharmaceutical formulations, dosages, dosing regimens and patient populations for treating or reducing the likelihood of developing a disease or condition characterized by a reduced expression or function of NaV1.1 protein in a human subject in need thereof.

[0006] Provided herein is a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: i) an antisense oligomer (ASO), and ii) a pharmaceutically acceptable diluent; wherein the liquid composition is not buffered by a buffering agent; and wherein: (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0007] Also provided herein is a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent, wherein (a) the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (b) the pharmaceutical formulation has a shelf life of a time period when stored at -20 °C or a temperature and relative humidity; (c) the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at - 20 °C or a temperature and relative humidity for a time period; (d) the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (e) the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (f) the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at - 20 °C or a temperature and relative humidity for a time period; (g) the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (h) the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; and / or (i) no observable particulate formation is observed after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period. In some embodiments, the temperature is 4 °C, 25 °C, 30 °C, 37 °C, or 40 °C. In some embodiments, the relative humidity is about 55%, 60%, 65%, 70% or 75%. In some embodiments, the time period is at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.WSGR Docket No.47991-744.601

[0008] In some embodiments, (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0009] Also provided herein is a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising:(i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition lacks Na2HPO4 and / or NaH2PO4; and wherein: (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0010] In some embodiments, the liquid composition lacks phosphate ions.

[0011] In some embodiments, the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion.

[0012] Also provided herein is a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent consisting of: a) NaCl, b) KCl, c) MgCl2or MgCl26H2O, and d) CaCl2or CaCl22H2O.

[0013] In some embodiments, the liquid composition comprises 0.1-50 mM CaCl2or CaCl22H2O.

[0014] In some embodiments, the liquid composition comprises 1-2 mM CaCl2or CaCl22H2O.

[0015] In some embodiments, the liquid composition comprises about 1.4 mM CaCl2or CaCl22H2O.

[0016] In some embodiments, the liquid composition comprises 0.1-50 mM MgCl2or MgCl26H2O.

[0017] In some embodiments, the liquid composition comprises 0.5-1.5 mM MgCl2or MgCl26H2O.

[0018] In some embodiments, the liquid composition comprises about 0.79 mM MgCl2or MgCl26H2O.

[0019] In some embodiments, the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1- 50 mM CaCl2or CaCl22H2O, and 0.1-50 mM MgCl2or MgCl26H2O.

[0020] Also provided herein is a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition lacks calcium ions and / or magnesium ions; and wherein: (a) the liquid composition comprises potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0021] In some embodiments, the liquid composition comprises a buffering agent.

[0022] In some embodiments, the buffering agent has a pKa at 25 °C of about 4.75; about 5.64; about 1.70, about 6.04 and about 9.09; about 3.1, about 4.7 and about 6.4; or about 6.50.

[0023] In some embodiments, the buffering agent is an effective buffer at a pH range of from about 3.6 to 5.6, from about 5.5 to 6.5, from about 5.5 to 7.4, from about 3.0 to 6.2, or from about 5.8 to 7.2.

[0024] In some embodiments, the buffering agent is selected from the group consisting of acetate, succinate, histidine, citrate, 2-[Bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol (Bis- Tris), and any combination thereof.WSGR Docket No.47991-744.601

[0025] In some embodiments, the liquid composition is formulated for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject.

[0026] In some embodiments, the liquid composition is formulated for administration into cerebrospinal fluid in a brain of a human subject.

[0027] In some embodiments, the ASO comprises at least one modified sugar moiety.

[0028] In some embodiments, each nucleotide of the antisense oligomer comprises a modified sugar moiety.

[0029] Also provided herein is a kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO, and wherein the liquid composition is not buffered by a buffering agent; and wherein: (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0030] In some embodiments, the kit comprises: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO, and wherein (a) the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (b) the pharmaceutical formulation has a shelf life of a time period when stored at -20 °C or a temperature and relative humidity; (c) the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (d)the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (e) the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (f) the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (g) the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (h) the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; and / or (i) no observable particulate formation is observed after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period. In some embodiments, the temperature is 4 °C, 25 °C, 30 °C, 37 °C, or 40 °C. In some embodiments, the relative humidity is about 55%, 60%, 65%, 70% or 75%. In someWSGR Docket No.47991-744.601 embodiments, the time period is at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0031] In some embodiments, (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0032] In some embodiments, the kit comprises: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO, wherein the liquid composition lacks Na2HPO4and / or NaH2PO4; and wherein: (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0033] In some embodiments, the liquid composition lacks phosphate ions.

[0034] In some embodiments, the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion.

[0035] In some embodiments, the kit comprises: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent consisting of: a) NaCl, b) KCl, c) MgCl2or MgCl26H2O, and d) CaCl2or CaCl22H2O, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO.

[0036] In some embodiments, the liquid composition comprises 0.1-50 mM CaCl2or CaCl22H2O.

[0037] In some embodiments, the liquid composition comprises 1-2 mM CaCl2or CaCl22H2O.

[0038] In some embodiments, the liquid composition comprises about 1.4 mM CaCl2or CaCl22H2O.

[0039] In some embodiments, the liquid composition comprises 0.1-50 mM MgCl2or MgCl26H2O.

[0040] In some embodiments, the liquid composition comprises 0.5-1.5 mM MgCl2or MgCl26H2O.

[0041] In some embodiments, the liquid composition comprises about 0.79 mM MgCl2or MgCl26H2O.

[0042] In some embodiments, the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1- 50 mM CaCl2 or CaCl22H2O, and 0.1-50 mM MgCl2 or MgCl26H2O.

[0043] Also provided herein is a kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO, wherein the liquid composition lacks calcium ions and / or magnesium ions; and wherein: (a) the liquid composition comprises potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space,WSGR Docket No.47991-744.601 cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0044] In some embodiments, the liquid composition comprises a buffering agent.

[0045] In some embodiments, the buffering agent has a pKa at 25 °C of about 4.75; about 5.64; about 1.70, about 6.04 and about 9.09; about 3.1, about 4.7 and about 6.4; or about 6.50.

[0046] In some embodiments, the buffering agent is an effective buffer at a pH range of from about 3.6 to 5.6, from about 5.5 to 6.5, from about 5.5 to 7.4, from about 3.0 to 6.2, or from about 5.8 to 7.2.

[0047] In some embodiments, the buffering agent is selected from the group consisting of acetate, succinate, histidine, citrate, 2-[Bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol (Bis- Tris), and any combination thereof.

[0048] In some embodiments, the liquid composition is formulated for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject.

[0049] In some embodiments, the liquid composition is formulated for administration into cerebrospinal fluid in a brain of a human subject.

[0050] In some embodiments, the ASO comprises at least one modified sugar moiety.

[0051] In some embodiments, each nucleotide of the antisense oligomer comprises a modified sugar moiety.

[0052] In some embodiments, the kit further comprises: (iii) instructions for diluting or solubilizing the ASO in the pharmaceutically acceptable diluent.

[0053] In some embodiments, the liquid composition comprises 25-250 mM NaCl.

[0054] In some embodiments, the liquid composition comprises 0.1-20 mM KCl.

[0055] In some embodiments, the liquid composition comprises 2-4 mM KCl.

[0056] In some embodiments, the liquid composition about 3 mM KCl.

[0057] In some embodiments, the liquid composition comprises 100-160 mM NaCl.

[0058] In some embodiments, the liquid composition comprises 125-145 mM NaCl.

[0059] In some embodiments, the liquid composition comprises about 130 mM NaCl.

[0060] In some embodiments, the liquid composition comprises a buffered (pH 6.6 – 7.6) solution.

[0061] In some embodiments, the liquid composition comprises 0.1-50 mM Na2HPO4.

[0062] In some embodiments, the liquid composition comprises 0.1-50 mM NaH2PO4.

[0063] In some embodiments, the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1- 50 mM Na2HPO4, and 0.1-50 mM NaH2PO4.

[0064] In some embodiments, the ASO is solubilized in the pharmaceutically acceptable diluent.

[0065] In some embodiments, the pharmaceutically acceptable diluent is an isotonic solution.

[0066] In some embodiments, the ASO is not substantially polydisperse.

[0067] In some embodiments, the liquid composition has an osmolality of less than 150 mM.

[0068] In some embodiments, the liquid composition has an osmolality of about 130 mM.

[0069] In some embodiments, the liquid composition further comprises a carbohydrate.

[0070] In some embodiments, the carbohydrate comprises D-glucose.WSGR Docket No.47991-744.601

[0071] In some embodiments, the liquid composition further comprises 1-100 mM D-glucose.

[0072] In some embodiments, the liquid composition further comprises an antioxidant.

[0073] In some embodiments, the antioxidant is t-butylhydroxyquinoline (TBHQ), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or any combination thereof.

[0074] In some embodiments, the liquid composition does not comprise a preservative.

[0075] In some embodiments, the liquid composition is packaged in a single-use vial.

[0076] In some embodiments, the liquid composition is formulated or suitable for administration (i) as a bolus injection; (ii) by infusion with a delivery pump; (iii) by intracerebroventricular injection; and / or (iv) by intrathecal injection.

[0077] In some embodiments, the ASO comprises T-methoxyethyl sugar moiety.

[0078] In some embodiments, the T-methoxyethyl sugar moiety is a T-2’-methoxyethyl sugar moiety.

[0079] In some embodiments, the ASO comprises a 2’-O-methoxyethyl moiety.

[0080] In some embodiments, the ASO comprises a thymidine comprising a 2’-O-methoxyethyl moiety.

[0081] In some embodiments, each nucleobase of the ASO comprises a 2’-O-methoxyethyl moiety.

[0082] In some embodiments, the ASO consists of from 8 to 50 nucleobases.

[0083] In some embodiments, the ASO consists of less than 35 nucleobases.

[0084] In some embodiments, the ASO consists of from 16 to 20 nucleobases.

[0085] In some embodiments, the ASO consists of from 12 to 20 nucleobases.

[0086] In some embodiments, the ASO consists of from 8 to 20 nucleobases.

[0087] In some embodiments, the ASO comprises a 5’-methylcytosine (5’-MeC).

[0088] In some embodiments, each cytosine of the ASO is a 5’-methylcytosine (5’-MeC).

[0089] In some embodiments, the ASO comprises a phosphorothioate linkage.

[0090] In some embodiments, each internucleoside linkage of the ASO is a phosphorothioate linkage.

[0091] In some embodiments, the ASO comprises a locked nucleic acid (LNA).

[0092] In some embodiments, the liquid composition comprises 1 mL to 20 mL of the pharmaceutically acceptable diluent, 2 mL to 10 mL of the pharmaceutically acceptable diluent, or 1 mL to 5 mL of the pharmaceutically acceptable diluent.

[0093] In some embodiments, the liquid composition comprises from 0.1 mL to 50 mL of the pharmaceutically acceptable diluent.

[0094] In some embodiments, the liquid composition comprises about 0.1, 0.5, 1, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45 or 50 mL of the pharmaceutically acceptable diluent.

[0095] In some embodiments, the liquid composition comprises from about 0.5 milligrams to about 500 milligrams of the ASO.

[0096] In some embodiments, the liquid composition comprises 0.1, 0.5, 1, 2.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60, 62.5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102.5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127.5, 130, 132.5, 135, 137.5, 140, 142.5, 145, 147.5, 150, 152.5,WSGR Docket No.47991-744.601 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190, 192.5, 195, 197.5, 200, 202.5, 205, 207.5, 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5, 245, 247.5, or 250 mg of the ASO.

[0097] In some embodiments, the ASO is present in the liquid composition at a concentration of from 0.1-500 mg / mL.

[0098] In some embodiments, the ASO is present in the liquid composition at a concentration of from 0.1 mg / mL to 250 mg / mL.

[0099] In some embodiments, the ASO is present in the pharmaceutical formulation at a concentration of from 6.7 mg / mL to 188 mg / mL or from 6.8 mg / mL to 187 mg / mL.

[0100] In some embodiments, the ASO is present in the liquid composition at a concentration of about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, or 20 mg / mL.

[0101] In some embodiments, the ASO is present in the liquid composition at a concentration of 11 mg / mL, 22 mg / mL, 33 mg / mL, 44 mg / mL, 55 mg / mL, 66 mg / mL, 77 mg / mL, 88 mg / mL, 99 mg / mL, or 100 mg / mL.

[0102] In some embodiments, the ASO is present in the liquid composition at a concentration of about 22.5 mg / mL, 25 mg / mL, 27.5 mg / mL, 30 mg / mL, 32.5 mg / mL, 35 mg / mL, 37.5 mg / mL, 40 mg / mL, 42.5 mg / mL, 45 mg / mL, 47.5 mg / mL, 50 mg / mL, 52.5 mg / mL, 55 mg / mL, 57.5 mg / mL, 60 mg / mL, 62.5 mg / mL, 65 mg / mL, 67.5 mg / mL, 70 mg / mL, 72.5 mg / mL, 75 mg / mL, 77.5 mg / mL, 80 mg / mL, 82.5 mg / mL, 85 mg / mL, 87.5 mg / mL, 90 mg / mL, 92.5 mg / mL, 95 mg / mL, 97.5 mg / mL, 100 mg / mL, 102.5 mg / mL, 105 mg / mL, 107.5 mg / mL, 110 mg / mL, 112.5 mg / mL, 115 mg / mL, 117.5 mg / mL, 120 mg / mL, 122.5 mg / mL, 125 mg / mL, 127.5 mg / mL, 130 mg / mL, 132.5 mg / mL, 135 mg / mL, 137.5 mg / mL, 140 mg / mL, 142.5 mg / mL, 145 mg / mL, 147.5 mg / mL, 150 mg / mL, 152.5 mg / mL, 155 mg / mL, 157.5 mg / mL, 160 mg / mL, 162.5 mg / mL, 165 mg / mL, 167.5 mg / mL, 170 mg / mL, 172.5 mg / mL, 175 mg / mL, 177.5 mg / mL, 180 mg / mL, 182.5 mg / mL, 185 mg / mL, 187.5 mg / mL, 190 mg / mL, 192.5 mg / mL, 195 mg / mL, 197.5 mg / mL, 200 mg / mL, 202.5 mg / mL, 205 mg / mL, 207.5 mg / mL, 210 mg / mL, 212.5 mg / mL, 215 mg / mL, 217.5 mg / mL, 220 mg / mL, 222.5 mg / mL, 225 mg / mL, 227.5 mg / mL, 230 mg / mL, 232.5 mg / mL, 235 mg / mL, 237.5 mg / mL, 240 mg / mL, 242.5 mg / mL, 245 mg / mL, 247.5 mg / mL, or 250 mg / mL.

[0103] In some embodiments, the ASO comprises a sequence with at least 80% sequence identity to any one of SEQ ID NOs: 21-67, 210-256 or 304-1099.

[0104] In some embodiments, the ASO comprises a sequence with at least 83%, 88%, 94% or 100% sequence identity to any one of SEQ ID NOs: 21-67, 210-256 or 304-1099.

[0105] In some embodiments, the ASO consists of a sequence with at least 83%, 88%, 94% or 100% sequence identity to any one of SEQ ID NOs: 21-67, 210-256 or 304-1099.

[0106] In some embodiments, the ASO is a compound according to the following chemical structure:WSGR Docket No.47991-744.601(I), or a salt thereof.

[0107] In some embodiments, the ASO is a compound according to the following chemical structure:(II).WSGR Docket No.47991-744.601

[0108] In some aspects, provided herein is a liquid pharmaceutical formulation consisting essentially of: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound according to the following chemical structure:(I), or a salt thereof; (b) calcium chloride dihydrate (CaCl22H2O) at a concentration of about 0.1 mM to about 50 mM; (c) magnesium chloride hexahydrate (MgCl26H2O) at a concentration of about 0.1 mM to about 50 mM; (d) potassium chloride (KCl) at a concentration of about 0.1 mM to about 20 mM; (e) sodium chloride (NaCl) at a concentration of about 25 mM to about 250 mM; and (f) water.

[0109] In some aspects, the pharmaceutical formulation further comprises sodium hydroxide (NaOH) and / or hydrochloric acid (HCl) in amounts that provide a pH of the pharmaceutical formulation at 6.6 to 7.6. In some aspects, the pharmaceutical formulation further comprises sodium hydroxide (NaOH) at a concentration of about 0.1 mM to about 20 mM, and / or hydrochloric acid (HCl) at a concentration of about 0.1 mM to about 20 mM. In some aspects, provided herein is a liquid pharmaceutical formulation consisting essentially of: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound according to the following chemical structure:WSGR Docket No.47991-744.601(I), or a salt thereof; (b) calcium chloride dihydrate (CaCl22H2O) at a concentration of about 0.1 mM to about 50 mM; (c) magnesium chloride hexahydrate (MgCl26H2O) at a concentration of about 0.1 mM to about 50 mM; (d) potassium chloride (KCl) at a concentration of about 0.1 mM to about 20 mM; (e) sodium chloride (NaCl) at a concentration of about 25 mM to about 250 mM; (f) sodium hydroxide (NaOH) at a concentration of about 0.1 mM to about 20 mM, and / or hydrochloric acid (HCl) at a concentration of about 0.1 mM to about 20 mM; and (g) water.

[0110] In some aspects, the concentration of the ASO is about 0.1 mg / mL to about 250 mg / mL. In some aspects, the concentration of the ASO is from 6.7 mg / mL to 188 mg / mL, from 6.8 mg / mL to 187 mg / mL, from 3 mg / mL to 100 mg / mL, or from 3 mg / mL to 33 mg / mL. In some aspects, the concentration of the ASO is about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, or 33 mg / mL. In some aspects, the concentration of the ASO is 11 mg / mL, 22 mg / mL, 33 mg / mL, 44 mg / mL, 55 mg / mL, 66 mg / mL, 77 mg / mL, 88 mg / mL, 99 mg / mL, or 100 mg / mL. In some aspects, the concentration of the ASO is about 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22.5 mg / mL, 25 mg / mL, 27.5 mg / mL, 30 mg / mL, 32.5 mg / mL, 35 mg / mL, 37.5 mg / mL, 40 mg / mL, 42.5 mg / mL, 45 mg / mL, 47.5 mg / mL, 50 mg / mL, 52.5 mg / mL, 55 mg / mL, 57.5 mg / mL, 60 mg / mL, 62.5 mg / mL, 65 mg / mL, 67.5 mg / mL, 70 mg / mL, 72.5 mg / mL, 75 mg / mL, 77.5 mg / mL, 80 mg / mL, 82.5 mg / mL, 85 mg / mL, 87.5 mg / mL, 90 mg / mL, 92.5 mg / mL, 95 mg / mL, 97.5 mg / mL, 100 mg / mL, 102.5 mg / mL, 105 mg / mL, 107.5 mg / mL, 110 mg / mL,WSGR Docket No.47991-744.601 112.5 mg / mL, 115 mg / mL, 117.5 mg / mL, 120 mg / mL, 122.5 mg / mL, 125 mg / mL, 127.5 mg / mL, 130 mg / mL, 132.5 mg / mL, 135 mg / mL, 137.5 mg / mL, 140 mg / mL, 142.5 mg / mL, 145 mg / mL, 147.5 mg / mL, 150 mg / mL, 152.5 mg / mL, 155 mg / mL, 157.5 mg / mL, 160 mg / mL, 162.5 mg / mL, 165 mg / mL, 167.5 mg / mL, 170 mg / mL, 172.5 mg / mL, 175 mg / mL, 177.5 mg / mL, 180 mg / mL, 182.5 mg / mL, 185 mg / mL, 187.5 mg / mL, 190 mg / mL, 192.5 mg / mL, 195 mg / mL, 197.5 mg / mL, 200 mg / mL, 202.5 mg / mL, 205 mg / mL, 207.5 mg / mL, 210 mg / mL, 212.5 mg / mL, 215 mg / mL, 217.5 mg / mL, 220 mg / mL, 222.5 mg / mL, 225 mg / mL, 227.5 mg / mL, 230 mg / mL, 232.5 mg / mL, 235 mg / mL, 237.5 mg / mL, 240 mg / mL, 242.5 mg / mL, 245 mg / mL, 247.5 mg / mL, or 250 mg / mL.

[0111] In some aspects, the concentration of calcium chloride dihydrate is 0.2 mM to 25 mM, 0.5 mM to 10 mM, 0.75 mM to 5 mM, or 1 mM to 2 mM. In some aspects, the concentration of calcium chloride dihydrate is from about 1 mM to about 2 mM. In some aspects, the concentration of calcium chloride dihydrate is about 1.4 mM. In some aspects, the concentration of magnesium chloride hexahydrate is 0.2 mM to 25 mM, 0.3 mM to 15 mM, 0.4 mM to 5 mM, 0.5 mM to 1.5 mM, or 0.6 mM to 1 mM. In some aspects, the concentration of magnesium chloride hexahydrate is from about 0.6 mM to about 1 mM. In some aspects, the concentration of magnesium chloride hexahydrate is about 0.79 mM. In some aspects, the concentration of potassium chloride is 0.5 mM to 10 mM, 1 mM to 7.5 mM, or 2 mM to 5 mM. In some aspects, the concentration of potassium chloride is from about 2 mM to about 5 mM. In some aspects, the concentration of potassium chloride is about 3 mM. In some aspects, the concentration of sodium chloride is 25 mM to 250 mM, 100 mM to 160 mM, 110 mM to 140 mM, or 130 mM to 160 mM. In some aspects, the concentration of sodium chloride is from about 125 mM to 145 mM. In some aspects, the concentration of sodium chloride is about 130 mM. In some aspects, the concentration of sodium chloride is from about 140 mM to 160 mM. In some aspects, the concentration of sodium chloride is about 150 mM. In some aspects, the concentration of calcium chloride dihydrate is from about 0.5 mM to about 5 mM; the concentration of magnesium chloride hexahydrate is from about 0.3 mM to about 1.25 mM; the concentration of potassium chloride is from about 1 mM to about 10 mM; and the concentration of sodium chloride is from about 100 mM to 180 mM. In some aspects, the concentration of calcium chloride dihydrate is from about 1 mM to about 2 mM; the concentration of magnesium chloride hexahydrate is from about 0.6 mM to about 1 mM; the concentration of potassium chloride is from about 2 mM to about 5 mM; and the concentration of sodium chloride is from about 120 mM to 160 mM. In some aspects, the concentration of the ASO is about 3 mg / mL, about 4.5 mg / mL, about 7 mg / mL, or about 33 mg / mL; the concentration of calcium chloride dihydrate is about 1.4 mM; the concentration of magnesium chloride hexahydrate is about 0.79 mM; the concentration of potassium chloride is about 3 mM; and the concentration of sodium chloride is about 150 mM. In some aspects, the pH of the pharmaceutical composition is about 6.6 to about 7.6. In some aspects, the pH of the pharmaceutical composition is about 6.8 to about 7.2. In some aspects, the pH of the pharmaceutical composition is about 6.9 to about 7.1. In some aspects, the volume of the pharmaceutical composition is about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 12 mL, about 15 mL,WSGR Docket No.47991-744.601 about 20 mL, about 25 mL. In some aspects, the volume of the pharmaceutical composition is about 10 mL.

[0112] In some aspects, provided herein is a liquid pharmaceutical formulation consisting essentially of: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound according to the following chemical structure:(I), or a salt thereof; (b) calcium ion (Ca2+) at a concentration of about 0.1 mM to about 50 mM; (c) magnesium ion (Mg2+) at a concentration of about 0.1 mM to about 50 mM; (d) potassium ion (K+) at a concentration of about 0.1 mM to about 20 mM; (e) sodium ion (Na+) at a concentration of about 25 mM to about 250 mM; (f) chloride ion (Cl-) at a concentration of about 25 mM to about 250 mM; and (g) water.

[0113] In some aspects, provided herein is a liquid pharmaceutical formulation consisting essentially of: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound according to the following chemical structure:WSGR Docket No.47991-744.601(I), or a salt thereof; (b) calcium ion (Ca2+) at a concentration of about 1.4 mM; (c) magnesium ion (Mg2+) at a concentration of about 0.79 mM; (d) potassium ion (K+) at a concentration of about 3 mM; (e) sodium ion (Na+) at a concentration of about 160 mM; (f) chloride ion (Cl-) at a concentration of about 160 mM; and (g) water.

[0114] In some aspects, provided herein is a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: i) an active pharmaceutical ingredient (API), and ii) a pharmaceutically acceptable diluent; wherein the liquid composition is not buffered by a buffering agent; and wherein: (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, and / or (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject.

[0115] In some aspects, also provided herein is a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising:(i) an active pharmaceutical ingredient (API), and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition lacks Na2HPO4and / or NaH2PO4; and wherein: (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, and / or (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject. In some embodiments, the liquid composition lacks phosphate ions. In some embodiments, the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion.

[0116] In some aspects, also provided herein is a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an active pharmaceutical ingredient (API), and (ii) a pharmaceutically acceptable diluent consisting of: a) NaCl, b) KCl, c) MgCl2or MgCl2WSGR Docket No.47991-744.601 6H2O, and d) CaCl2 or CaCl22H2O. In some embodiments, the liquid composition lacks phosphate ions. In some embodiments, the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion.

[0117] In some embodiments, the pharmaceutically acceptable diluent provided herein is suitable for preparation of any pharmaceutical formulation intrathecal administration. For instance, any active pharmaceutical ingredient suitable for intrathecal administration may be formulated using the pharmaceutically acceptable diluent provided herein. The active pharmaceutical ingredient can be a small molecule or a biologic, such as an organic chemical compound, an antisense oligonucleotide, a DNA, an antibody or any other protein or polypeptide, a living organism such as bacterium or fungi, viral vector, or viral-like particle, or any combination thereof.

[0118] Also provided herein is a method of treating or reducing the likelihood of developing a disease or condition in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition disclosed herein.

[0119] In some embodiments, the subject is a human subject.

[0120] In some embodiments, the human subject is at most 18 years old at a first dose of the pharmaceutical composition.

[0121] In some embodiments, the method comprises administering the ASO at a first dose of from about 0.5 milligrams to about 500 milligrams.

[0122] In some embodiments, the method comprises administering multiple doses of the ASO.

[0123] In some embodiments, the disease or condition is characterized by a reduced expression or function of NaV1.1 protein in the subject.

[0124] In some embodiments, the disease or condition is Dravet Syndrome.

[0125] In some embodiments, the subject is characterized by having: a. seizure onset prior to 12 months of age with recurrent focal motor or hemiconvulsive or generalized tonic-clonic seizures, which are often prolonged and triggered by hyperthermia; b. no past history of causal magnetic resonance imaging lesion; c. no other known etiology of any diseases or conditions except Dravet Syndrome; d. normal development at seizure onset; e. a pathogenic variant, or variant of uncertain significance in an SCN1A gene; f. at least 2 prior treatments for epilepsy that either had lack of adequate seizure control; g. 4 or more convulsive seizures during the 28 days prior to administering, wherein the convulsive seizures are any one selected from Hemiclonic, Focal with Motor Signs, Focal to Bilateral Tonic Clonic Convulsion, Generalized Tonic Clonic Convulsion, Tonic, Tonic or Atonic (Drop Attacks), and Clonic; h. a current intervention for epilepsy or medication with at least one antiepileptic drug at a dose which has been stable for at least 4 weeks, wherein the interventions for epilepsy isWSGR Docket No.47991-744.601 a ketogenic diet, a vagal nerve stimulator, or a cannabinoid or marijuana-derived product; or i. any combination thereof.

[0126] In some embodiments, the subject is characterized by not having one or more of the following: a. one of the following mutations in the SCN1A gene: Thr226Met, Leu263Val, Val422Leu, Thr1174Ser, Trp1204Arg, Pro1345Ser, Gln1489Lys, Phe1499Leu, Arg1575Cys, Val1611Phe, Leu1624Pro, Arg1648Cys, Leu1649Gln, Leu1670Trp, Gly1674Arg, and Asp1866Tyr; b. a known pathogenic mutation in another gene that causes epilepsy, wherein the pathogenic mutation is homozygous in cases of known recessive disease; c. currently treated with a sodium channel blocker as maintenance treatment and an anticoagulant, wherein the sodium channel blocker is phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, or rufinamide, and wherein the anticoagulant is not an aspirin; d. clinically, significantly unstable medical conditions other than epilepsy; e. clinically, relevant symptoms or a clinically significant illness in the 4 weeks prior to administering, other than epilepsy; f. a history of brain or spinal cord disease other than epilepsy, Dravet Syndrome or a history of bacterial meningitis or brain malformation; g. a spinal deformity or other condition that alters the free flow of cerebrospinal fluid (CSF) or having an implanted CSF drainage shunt; h. clinically significant abnormal laboratory values prior to administering; i. aspartate aminotransferase or alanine aminotransferase >2.5-fold upper limit of normal, serum creatinine greater than an upper limit of normal or platelet count less than a lower limit of normal; j. clinically relevant abnormalities in the 12-lead electrocardiogram (ECG) measured at prior to administering; k. a psychiatric or behavioral disorder; l. currently or in the past 4 weeks, medication of an anticoagulant, wherein the anticoagulant is not aspirin; or m. any combination thereof.

[0127] In some embodiments, the subject is from 1 to 18, from 2 to 18, from 3 to 18, from 4 to 18, from 5 to 18, from 6 to 18, from 7 to 18, from 8 to 18, from 9 to 18, from 10 to 18, from 11 to 18, from 12 to 18, from 13 to 18, from 14 to 18, from 15 to 18, from 16 to 18, or from 17 to 18 years old.

[0128] In some embodiments, the subject is a human from 1 to 17, from 1 to 16, from 1 to 15, from 1 to 14, from 1 to 13, from 1 to 12, from 1 to 11, from 1 to 10, from 1 to 9, from 1 to 8, from 1 to 7, from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, or from 1 to 2 years old.WSGR Docket No.47991-744.601

[0129] In some embodiments, the subject is less than a year old or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years old.

[0130] In some embodiments, the pharmaceutical composition is administered into the intrathecal space of the subject.

[0131] In some embodiments, the pharmaceutical composition is administered into the cerebrospinal fluid of the subject.

[0132] In some embodiments, the pharmaceutical composition is administered into the brain of the subject.

[0133] In some embodiments, the pharmaceutical composition is administered into the cerebrospinal fluid in the brain of the subject.

[0134] In some embodiments, the pharmaceutical composition is administered as a bolus injection.

[0135] In some embodiments, the method comprises administering the pharmaceutical composition as a bolus injection over 1 to 60 minutes, 1 to 50 minutes, 1 to 40 minutes, 1 to 30 minutes, 1 to 20 minutes, 1 to 10 minutes, 1 to 5 minutes, or 1 to 3 minutes.

[0136] In some embodiments, the pharmaceutical composition is administered by infusion with a delivery pump.

[0137] In some embodiments, the pharmaceutical composition is administered by intracerebroventricular injection.

[0138] In some embodiments, the pharmaceutical composition is administered by intrathecal injection.

[0139] In some embodiments, the method reduces or ameliorates at least one symptom of Dravet Syndrome in the human subject.

[0140] In some embodiments, the symptom of Dravet Syndrome is a seizure.

[0141] In some embodiments, the administration reduces or ameliorates seizure frequency, seizure intensity, or seizure duration.

[0142] In some embodiments, the method further comprises assessing tolerability or effectiveness of the pharmaceutical composition.

[0143] In some embodiments, the method further comprises administering to the subject a pharmaceutical composition comprising the ASO at subsequent doses of from about 0.5 milligrams to about 500 milligrams.

[0144] In some embodiments, the subsequent dose is 0.1, 0.5, 1, 2.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60, 62.5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102.5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127.5, 130, 132.5, 135, 137.5, 140, 142.5, 145, 147.5, 150, 152.5, 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190, 192.5, 195, 197.5, 200, 202.5, 205, 207.5, 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5, 245, 247.5, or 250 mg.

[0145] In some embodiments, the subsequent dose is lower than the previous dose following an indication that administration of the previous dose is not tolerated.WSGR Docket No.47991-744.601

[0146] In some embodiments, the subsequent dose is the same as the previous dose following an indication that administration of the previous dose is tolerated.

[0147] In some embodiments, the subsequent dose is higher than the previous dose following an indication that administration of the previous dose is tolerated.

[0148] In some embodiments, the subsequent dose is the same as the previous dose following an indication that administration of the previous dose is effective.

[0149] In some embodiments, the subsequent dose is lower than the previous dose following an indication that administration of the previous dose is effective.

[0150] In some embodiments, the subsequent dose is higher than the previous dose following an indication that administration of the previous dose is not effective.

[0151] In some embodiments, the subsequent doses are administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after administration of the previous dose.

[0152] In some embodiments, dose frequency is maintained or reduced following an indication that the previous dose is effective.

[0153] In some embodiments, dose frequency is increased following an indication that the previous dose is not effective.

[0154] In some embodiments, the method further comprises administrating at least one additional therapeutic agent or therapy.

[0155] In some embodiments, the at least one additional therapeutic agent or therapy is administered at the same time as the dose.

[0156] In some embodiments, the at least one additional therapeutic agent or therapy is administered prior to administration of the dose.

[0157] In some embodiments, the at least one additional therapeutic agent or therapy is administered after administration of the dose.

[0158] In some embodiments, the reduced expression or function of NaV1.1 protein is associated with an altered splicing of a nonsense-mediated RNA decay-inducing exon from a pre-mRNA that contains the NMD exon and encodes NaV1.1 protein.

[0159] In some embodiments, the ASO promotes exclusion of the NMD exon from the pre-mRNA that contains the NMD exon and that encodes the NaV1.1 protein.

[0160] In some embodiments, the ASO binds to a targeted portion of a pre-mRNA that contains the NMD exon and that encodes the NaV1.1 protein.

[0161] In some embodiments, the ASO promotes exclusion of the NMD exon from the pre-mRNA that contains the NMD exon and that encodes the NaV1.1 protein.

[0162] In some embodiments, the ASO increases a level of processed mRNA encoding the NaV1.1 protein when the ASO is introduced into the cell.

[0163] In some embodiments, the ASO increases a level of the NaV1.1 protein when the ASO is introduced into the cell.

[0164] In some embodiments, the targeted portion is within an intron sequence flanking the NMD exon.WSGR Docket No.47991-744.601

[0165] In some embodiments, the targeted portion comprises at least one nucleotide of the NMD exon.

[0166] In some embodiments, the targeted portion is within the NMD exon.

[0167] Also provided herein is a method of making a pharmaceutical composition described herein, the method comprising diluting the antisense oligomer (ASO) in the pharmaceutically acceptable diluent, thereby making the liquid composition.

[0168] In some embodiments, the ASO is present in the liquid composition at a concentration of 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, 30 mg / mL, 44 mg / mL, 55 mg / mL, 66 mg / mL, 77 mg / mL, 88 mg / mL, 99 mg / mL, 100 mg / mL, 22.5 mg / mL, 25 mg / mL, 27.5 mg / mL, 30 mg / mL, 32.5 mg / mL, 35 mg / mL, 37.5 mg / mL, 40 mg / mL, 42.5 mg / mL, 45 mg / mL, 47.5 mg / mL, 50 mg / mL, 52.5 mg / mL, 55 mg / mL, 57.5 mg / mL, 60 mg / mL, 62.5 mg / mL, 65 mg / mL, 67.5 mg / mL, 70 mg / mL, 72.5 mg / mL, 75 mg / mL, 77.5 mg / mL, 80 mg / mL, 82.5 mg / mL, 85 mg / mL, 87.5 mg / mL, 90 mg / mL, 92.5 mg / mL, 95 mg / mL, 97.5 mg / mL, 100 mg / mL, 102.5 mg / mL, 105 mg / mL, 107.5 mg / mL, 110 mg / mL, 112.5 mg / mL, 115 mg / mL, 117.5 mg / mL, 120 mg / mL, 122.5 mg / mL, 125 mg / mL, 127.5 mg / mL, 130 mg / mL, 132.5 mg / mL, 135 mg / mL, 137.5 mg / mL, 140 mg / mL, 142.5 mg / mL, 145 mg / mL, 147.5 mg / mL, 150 mg / mL, 152.5 mg / mL, 155 mg / mL, 157.5 mg / mL, 160 mg / mL, 162.5 mg / mL, 165 mg / mL, 167.5 mg / mL, 170 mg / mL, 172.5 mg / mL, 175 mg / mL, 177.5 mg / mL, 180 mg / mL, 182.5 mg / mL, 185 mg / mL, 187.5 mg / mL, 190 mg / mL, 192.5 mg / mL, 195 mg / mL, 197.5 mg / mL, 200 mg / mL, 202.5 mg / mL, 205 mg / mL, 207.5 mg / mL, 210 mg / mL, 212.5 mg / mL, 215 mg / mL, 217.5 mg / mL, 220 mg / mL, 222.5 mg / mL, 225 mg / mL, 227.5 mg / mL, 230 mg / mL, 232.5 mg / mL, 235 mg / mL, 237.5 mg / mL, 240 mg / mL, 242.5 mg / mL, 245 mg / mL, 247.5 mg / mL, or 250 mg / mL.

[0169] In some embodiments, the method further comprises diluting the liquid composition with an additional volume of the pharmaceutically acceptable diluent, thereby making the liquid composition.

[0170] In some embodiments, the ASO is present in the liquid composition at a concentration of wherein the ASO is present in the liquid composition at a concentration of from 0.1-500 mg / mL, from 0.1 mg / mL to 250 mg / mL, from 6.7 mg / mL to 188 mg / mL, from 6.8 mg / mL to 187 mg / mL, from 3 mg / mL to 100 mg / mL, or from 3 mg / mL to 33 mg / mL, or about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, or 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, 30 mg / mL, or 33 mg / mL.

[0171] In some embodiments, the method further comprises filtering the liquid composition.

[0172] In some embodiments, filtering comprises filtering the liquid composition at least twice or through at least two membranes.

[0173] In some embodiments, filtering comprises filtering the liquid composition through a 0.45-μm membrane and a 0.2-μm membrane.

[0174] In some embodiments, the at least two membranes, the 0.45-μm membrane, and / or the 0.2-μm membrane comprises a polyethersulfone membrane.WSGR Docket No.47991-744.601

[0175] In some embodiments, the method further comprises filling a vial with the liquid composition.

[0176] In some embodiments, the vial is sterilized and / or depyrogenated.

[0177] In some embodiments, the method further comprises fitting the vial with a stopper.

[0178] In some embodiments, the stopper is sterilized and / or depyrogenated.

[0179] In some embodiments, the method further comprises capping the vial with a seal.

[0180] In some embodiments, the seal is sterilized and / or depyrogenated.

[0181] In some embodiments, the method if performed aseptically.

[0182] In some embodiments, the method further comprises storing the vial for a time period at a temperature.

[0183] In some embodiments, the temperature is -20 ± 5 °C.

[0184] In some embodiments, the time period is no more than 36 months.

[0185] In some embodiments, the time period is no more than 24 months.

[0186] In some embodiments, the method further comprises administering the liquid composition to a human subject after the storing. INCORPORATION BY REFERENCE

[0187] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0188] The features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0189] FIGs.1A-1B depict a schematic representation of a target pre-mRNA that contains a nonsense- mediated RNA decay-inducing exon (NMD exon mRNA) and therapeutic agent-mediated exclusion of the nonsense-mediated mRNA decay-inducing exon from the pre-mRNA to increase expression of the full-length target protein or functional RNA. FIG.1A shows a cell divided into nuclear and cytoplasmic compartments. In the nucleus, a pre-mRNA transcript of a target gene undergoes splicing to generate processed mRNA, and this processed mRNA is exported to the cytoplasm and translated into target protein. For this target gene, some fraction of the processed mRNA contains a nonsense-mediated mRNA decay-inducing exon (NMD exon mRNA) that is degraded in the cytoplasm, thus leading to no target protein production. FIG.1B shows an example of the same cell divided into nuclear and cytoplasmic compartments. Treatment with a therapeutic agent, such as an antisense oligomer (ASO), promotes the exclusion of the nonsense-mediated mRNA decay-inducing exon from the pre-mRNA and results in an increase in processed mRNA, which is in turn translated into higher levels of target protein.

[0190] FIG.1C is a schematic representation of therapeutic ASO-mediated exclusion of a nonsense- mediated mRNA decay-inducing exon from a pre-mRNA, which decreases non-productive processedWSGR Docket No.47991-744.601 mRNA (e.g., with an NMD exon) and increases productive mRNA (e.g., without an NMD exon) and increases expression of the full-length target protein from the productive mRNA.

[0191] FIG.1D shows identification of an exemplary sequence in the SCN1A gene that encodes a nonsense-mediated mRNA decay (NMD)-inducing exon. The identification of the sequence in the SCN1A gene that encodes the NMD-inducing exon using comparative genomics is shown, visualized in the UCSC genome browser. The upper panel shows a graphic representation of the SCN1A gene to scale. The conservation level across 100 vertebrate species is shown as peaks. The highest peaks correspond to exons (black boxes), while no peaks are observed for the majority of the introns (lines with arrow heads). Peaks of conservation were identified in intron 20 (NM_006920), shown in the middle panel. Inspection of the conserved sequences identified an exon-like sequence of 64 bp (bottom panel, sequence highlighted in grey) flanked by 3′ and 5′ splice sites (underlined sequence). Inclusion of this exon leads to a frameshift and the introduction of a premature termination codon in exon 21, rendering the transcript a target of NMD.

[0192] FIG.2 shows a study design timeline for monitoring wild type (WT) and Dravet Syndrome (DS) mice as well as a Kaplan-Meier curve showing DS and WT littermate mice monitored to 14 weeks for survival.

[0193] FIG.3 shows an experimental design for the EEG seizure monitoring study in DS mice and their WT littermates.

[0194] FIGs.4A-4E show the results of monitoring seizures in mice administered with ASO-22 or phosphate buffered saline (PBS). FIG.4A shows exemplary EEG recordings in DS mice. FIG.4B shows the number of seizures occurring in various regions of the brain in the two mice groups. *Indicates p<0.05. FIG.4C summarizes the total number of spontaneous seizures (generalized and focal) recorded between P22 and P46 in DS mice dosed with PBS (n=21) or ASO-22 (n=21). *Indicates p<0.05. FIG.4D shows the number of mice that had a number of seizures in each group. FIG.4E shows the effect of ASO-22 on the latency to the first recorded seizure between P22 and P46 in DS mice dosed with PBS (n=21) or ASO-22 (n=21).

[0195] FIGs.5A-5G show that a single ICV injection of 20 µg ASO-22 at P2 results in reduced sudden unexpected death in epilepsy (SUDEP) incidence and increased NaV1.1 protein expression in DS mice. FIG.5A is a schematic for the experimental design. FIGs.5B, 5C, 5D, 5E, 5F, and 5G illustrate the concentration of ASO-22, fold change in Scn1a gene expression, and NaV1.1 expression in brain tissues at 7 weeks or 14 weeks after a single ICV injection of ASO-22 (20 μg) or PBS at P2, respectively.

[0196] FIGs.6A-6B show the percent survival of DS and WT mice after a single ICV injection of ASO- 22 (60 μg) or PBS at P14.

[0197] FIGs.7A-7F show the ASO-22 exposure, Scn1a expression, and NaV1.1 expression in brain tissues at P35 and P90 after a single ICV injection of ASO-22 (60 μg) or PBS on P14, respectively.

[0198] FIG.8 shows the experimental conditions and numbers of monkeys used per group.

[0199] FIGs.9A-9B show the levels of ASO-22 in various regions of cynomolgus monkey brain on study day 3 and day 29, respectively.WSGR Docket No.47991-744.601

[0200] FIGs.10A-10B show the levels of NaV1.1 protein in various regions of cynomolgus monkey brain on study day 3 and day 29, respectively.

[0201] FIGs.11A-11B show the percentages of productive SCN1A gene to total SCN1A gene as an evaluation of target engagement in cynomolgus monkeys on day 3 and day 29.

[0202] FIG.12A shows the plasma pharmacokinetics in cynomolgus monkey at various timepoints after intrathecal administration of ASO-22. FIG.12B shows the levels of ASO-22 in the cynomolgus monkey cerebrospinal fluid (CSF) on study day 3 and 29.

[0203] FIGs.13A-13D depict identification of an alternative splicing event in SCN1A that results in NMD. FIG.13A shows SCN1A splicing isoforms with or without inclusion of the alternative exon in ReNcells as demonstrated by RT-PCR. FIG.13B shows evaluation of the alternative splice event of the SCN1A gene in the cerebral cortex of four species. FIG.13C shows an image of a TBE PAGE gel of RT- PCR products corresponding to Scn1a productive (lower bands, 498 bp) and non-productive transcript (upper bands, 562 bp) amplified from total RNA extracted from WT C57BL / 6J mouse brains from P0 to P20 and at 10 months. Mouse Gapdh was used as a loading control. FIG.13D summarizes expression of Scn1a productive and non-productive transcript in postnatal mouse brains, calculated with optical densities of PCR products shown in FIG.13C.

[0204] FIGs.14A-14E illustrate that selected ASOs suppressed the NMD splicing event and increased the expression of productive SCN1A mRNA in ReNcells.

[0205] FIGs.15A-15C show dose-dependent effects of ASO-22 on splicing and expression of SCN1A mRNA in ReNcells.

[0206] FIGs.16A-16H illustrate that ASO-22 ICV injection causes dose-dependent and durable increases in productive Scn1a mRNA and NaV1.1 protein expression in mouse brain.

[0207] FIG.17 shows dose-dependent effects of ASO-22 on the expression of Scn1a mRNA in ICV- injected neonatal mouse brains (§ = nonproductive; * = productive).

[0208] FIG.18 shows dose-dependent effects of ASO-22 on the expression of NaV1.1 in ICV-injected neonatal mouse brains.

[0209] FIG.19 shows expression of Scn1a mRNA in mouse brains at different post-injection days (§ = nonproductive; * = productive).

[0210] FIG.20 shows expression of NaV1.1 in mouse brains at different post-injection days.

[0211] FIG.21 shows validation of the two anti-NaV1.1 antibodies used in the Examples. Specificity of the two anti-NaV1.1 antibodies, Alomone ASC-001 and NeuroMab 75-023, was tested using total protein prepared from a Scn1a- / -mouse brain (middle lane) and brains of two WT littermates (left and right lanes).

[0212] FIG.22 shows a schematic representation of clinical manifestations of Dravet Syndrome and their relative incidences according to age. AA: atypical absences; AE: acute encephalopathy; CG: crouching gait; CPS: complex partial seizures; DD: developmental delay; DS: Dravet syndrome; EEG: electroencephalogram; FSz: complex febrile seizures; GMS: generalized motor seizures; HS: hyperthermia sensitivity; m: month; MSz: myoclonic seizures; OS: obtundation status; SE: statusWSGR Docket No.47991-744.601 epilepticus; SUDEP: sudden unexpected death in epilepsy; y: years; * Moderate fever for 60%, mostly clonic generalized and unilateral motor seizures; ** Difficult to distinguish between AA and CPS without ictal EEG recording, so their precise incidence is unknown. See, e.g., Gataullina and Dulac, 2017, of which the entire content is incorporated herein by reference.

[0213] FIG.23 shows TANGO (Targeted Augmentation of Nuclear Gene Output) that may be used to treat Dravet syndrome.

[0214] FIG.24 shows the transformative potential of TANGO technology in Dravet syndrome.

[0215] FIG.25 shows the study design. Phase 1 / 2a open-label, two-part study conducted at approximately 20 sites in the United States.

[0216] FIG.26 shows a schematic representation of the study design.

[0217] FIG.27 shows patient inclusion and exclusion criteria.

[0218] FIG.28 shows study assessments.

[0219] FIG.29 shows the effect of phosphate on the pH of the ASO-1 formulation.

[0220] FIG.30 shows oligonucleotide self-buffering capacity vs pH for the titrations of ASO-1 at 33 mg / mL and 5 mg / mL.

[0221] FIG.31 shows the readout of Fourier-transform infrared spectroscopy (FTIR).

[0222] FIG.32 shows the Scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM- EDS).

[0223] FIG.33 is a representative photograph of fiber-like particles present in an ASO formulation at 1 and 3 months when stored at 25 °C. This exemplary formulation contains 4.58 mM ASO-1, 1.4 mM CaCl2, 0.79 mM MgCl2, 3 mM KCl, 150 mM NaCl, 0.70 mM Na2HPO4·2H2O, and 0.3 mM NaH2PO4,·2H2O at pH 7.0 to 7.5.

[0224] FIG.34 is a representative photograph of large, waxy-looking flakes that were observed in stability tests of formulations containing either 4.58 mM ASO-1, 1.4 mM CaCl2, 0.79 mM MgCl2, 3 mM KCl, 0.70 mM Na2HPO4·2H2O, and 0.3 mM NaH2PO4,·2H2O; or containing 4.58 mM ASO-1, 1.4 mM CaCl2, 0.79 mM MgCl2, 3 mM KCl, 150 mM NaCl, 0.70 mM Na2HPO4·2H2O, and 0.3 mM NaH2PO4,·2H2O but without pH adjustment. These large, waxy-looking flakes were present in all stability conditions (2-8 °C; 25 °C / 60% relative humidity; and 40 °C / 75% relative humidity). DETAILED DESCRIPTION

[0225] Certain specific details of this description are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments.

[0226] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. AlthoughWSGR Docket No.47991-744.601 methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods, and materials are described below. Definitions

[0227] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise.

[0228] It should be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise. The terms “and / or” and “any combination thereof” and their grammatical equivalents as used herein, can be used interchangeably. These terms can convey that any combination is specifically contemplated. Solely for illustrative purposes, the following phrases “A, B, and / or C” or “A, B, C, or any combination thereof” can mean “A individually; B individually; C individually; A and B; B and C; A and C; and A, B, and C.” The term “or” can be used conjunctively or disjunctively, unless the context specifically refers to a disjunctive use.

[0229] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated, the term “about” meaning within an acceptable error range for the particular value should be assumed.

[0230] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the present disclosure, and vice versa. Furthermore, compositions of the present disclosure can be used to achieve methods of the present disclosure.

[0231] Reference in the specification to “embodiments,” “some embodiments,” “an embodiment,” “one embodiment,” “certain embodiments,” or “other embodiments” means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the present disclosures. To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0232] The terms “oligonucleotide sequence,” “nucleic acid sequence,” “polynucleic acid sequence,” “nucleotide sequence,” and “nucleotide acid sequence” are used herein interchangeably in its broadest sense and have the identical meaning herein and refer to preferably DNA or RNA. A nucleic acid sequence is a polymer comprising or consisting of nucleotide monomers, which are covalently linked toWSGR Docket No.47991-744.601 each other by phosphodiester-bonds of a sugar / phosphate-backbone. The term “nucleic acid sequence” also encompasses modified nucleic acid sequences, such as base-modified, sugar-modified or backbone- modified, etc., DNA or RNA.

[0233] The term “fragment,” or “fragment of a sequence” which have the identical meaning herein is a shorter portion of a full-length sequence of e.g., a nucleic acid molecule like DNA or RNA or a protein. Accordingly, a fragment, typically, consists of a sequence that is identical to the corresponding stretch within the full-length sequence. A preferred fragment of a sequence in the context of the present invention consists of a continuous stretch of entities, such as nucleotides or amino acids corresponding to a continuous stretch of entities in the molecule the fragment is derived from, which represents at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, at least 99.5%, or even 100% of the total (i.e., full-length) molecule from which the fragment is derived. For example, a “fragment” or “functional fragment” of a polynucleotide or a polypeptide is a fragment of the polynucleotide or the polypeptide that is shorter than the full-length, immature, or mature nucleotide or polypeptide and has at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, at least 99.5%, or even 100% or more of the activity of the full-length mature reference polynucleotide or polypeptide. Fragments of interest can be made by recombinant, synthetic, or digestive methods.

[0234] The term “recombinant” when used with reference, for example, to a cell, a nucleic acid, a protein, or a vector, indicates that the cell, nucleic acid, protein, or vector has been modified by or is the result of laboratory methods. Thus, for example, the term “recombinant polynucleotide” can refer to a polynucleotide that is not naturally occurring and are synthesized or manipulated in vitro, such as polynucleotides produced by laboratory methods. A recombinant polynucleotide can be synthesized in a laboratory and / or can be prepared by using recombinant DNA technology by using enzymatic modification of DNA, such as enzymatic restriction digestion, ligation, and cloning. A recombinant polypeptide can be prepared by in vitro transcription of a recombinant DNA followed by in vitro translation of the produced messenger RNA (mRNA). Alternatively, under suitable conditions, a recombinant polynucleic acid or RNA can be incorporated into a cell and a recombinant polypeptide can be expressed within the cell. Recombinant proteins can include amino acid residues not found within the native (non-recombinant) form of the protein or can include amino acid residues that have been modified, e.g., labeled.

[0235] The term “isolated” means separated from constituents, cellular and otherwise, in which the polynucleotide, polypeptide, protein, or fragments thereof, are normally associated with in nature. For example, with respect to a polynucleotide, an isolated polynucleotide is one that is separated from the 5’WSGR Docket No.47991-744.601 and 3’ ends with which it is normally associated in the naturally occurring sequence. As is apparent to those of skill in the art, a non-naturally occurring polynucleotide, polypeptide, protein, or fragments thereof, does not require “isolation” to distinguish it from its naturally occurring counterpart. In addition, a “concentrated,” “separated,” or “diluted” polynucleotide, polypeptide, protein, or fragments thereof, is distinguishable from its naturally occurring counterpart in that the concentration or number of molecules per volume is greater than “concentrated,” or less than “separated” or “diluted,” than that of its naturally occurring counterpart.

[0236] As used herein, "nucleotide" means a nucleoside further comprising a phosphate linking group. As used herein, "linked nucleosides" may or may not be linked by phosphate linkages and thus includes, but is not limited to, "linked nucleotides." As used herein, "linked nucleosides" are nucleosides that are connected in a continuous sequence (i.e., no additional nucleosides are present between those that are linked).

[0237] As used herein, "nucleobase" means a group of atoms that can be linked to a sugar moiety to create a nucleoside that is capable of incorporation into an oligonucleotide, and wherein the group of atoms is capable of bonding with a complementary naturally occurring nucleobase of another oligonucleotide or nucleic acid. Nucleobases may be naturally occurring or may be modified.

[0238] As used herein, "nucleoside" means a compound comprising a nucleobase moiety and a sugar moiety. Nucleosides include, but are not limited to, naturally occurring nucleosides (as found in DNA and RNA) and modified nucleosides. Nucleosides may be linked to a phosphate moiety.

[0239] As used herein, "naturally occurring sugar moiety" means a ribofuranosyl as found in naturally occurring RNA or a deoxyribofuranosyl as found in naturally occurring DNA.

[0240] As used herein, "sugar moiety" means a naturally occurring sugar moiety or a modified sugar moiety of a nucleoside.

[0241] As used herein, "modified sugar moiety" means a substituted sugar moiety, a bicyclic or tricyclic sugar moiety, or a sugar surrogate.

[0242] The term “antisense oligonucleotide,” as used herein, refers to synthetic antinucleotide oligonucleotide (ASO) or antisense oligonucleotide analogs usually between 12 and 30 nucleotides in length that are designed to hybridize to RNA by Watson-Crick base pairing. ASOs can be designed to bind to protein coding RNAs (mRNAs) as well as noncoding RNAs such as microRNAs or large noncoding RNAs. After binding to the targeted RNA, the ASO can modulate the function of the targeted RNA by several different mechanisms, including degradation of the pre-mRNA in the nucleus or mature RNA in the cytoplasm by RNase H1, and degradation of RNA in the cytoplasm by the RISC complex (Ago2) or ribozymes or DNAzymes. ASOs can also modulate RNA function by nondegradative mechanisms such as splicing or polyadenylation modulation in the nucleus and modulate protein translation in the cytoplasm.

[0243] The term “to hybridize” means to form hydrogen bond, which may be via Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleoside or nucleotide bases. “Complementary,” as used herein, refers to the capacity for precise pairing between twoWSGR Docket No.47991-744.601 nucleotides. The oligonucleotide and the DNA or RNA are complementary to each other when a sufficient number of corresponding positions in each molecule are occupied by nucleotides which can hydrogen bond with each other.

[0244] 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 nucleotides or amino acid residues that are the same (i.e., 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100%identity over a specified region, e.g., of the entire polypeptide sequences of the invention or individual domains of the polypeptides of the invention), when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using a sequence comparison algorithm or by manual alignment and visual inspection. Such sequences that are at least about 80% identical are said to be “substantially identical.” In some embodiments, two sequences are 100% identical. In some embodiments, two sequences are 100% identical over the entire length of one of the sequences (e.g., the shorter of the two sequences where the sequences have different lengths). In various embodiments, identity may refer to the complement of a test sequence.

[0245] In some embodiments, the identity exists over a region that is at least about 2 to about 400 amino acids or nucleotides in length. In some embodiments, the identity exists over a region that is at least about 2 to about 390, at least about 2 to about 380, at least about 2 to about 370, at least about 2 to about 360, at least about 2 to about 350, at least about 2 to about 340, at least about 2 to about 330, at least about 2 to about 320, at least about 2 to about 310, at least about 2 to about 300, at least about 2 to about 290, at least about 2 to about 280, at least about 2 to about 270, at least about 2 to about 260, at least about 2 to about 250, at least about 2 to about 200, at least about 2 to about 150, at least about 2 to about 100 amino acids or nucleotides in length. In some embodiments, the identity exists over a region that is at least about 2 to about 90, at least about 2 to about 85, at least about 2 to about 80, at least about 2 to about 75, at least about 2 to about 70, at least about 2 to about 65, at least about 2 to about 60, at least about 2 to about 55, at least about 2 to about 50, at least about 2 to about 45, at least about 2 to about 40, at least about 2 to about 35, at least about 2 to about 30, at least about 2 to about 25, at least about 2 to about 20, at least about 2 to about 10, at least about 2 to about 5 amino acids or nucleotides in length.

[0246] In some embodiments, the identity exists over a region that is at least about 3 to about 400, about 4 to about 400, about 5 to about 400, about 6 to about 400, about 7 to about 400, about 8 to about 400, about 9 to about 400, about 10 to about 400, about 11 to about 400, about 12 to about 400, about 13 to about 400, about 14 to about 400, about 15 to about 400, about 16 to about 400, about 17 to about 400, about 18 to about 400, about 19 to about 400, about 20 to about 400, about 21 to about 400, about 22 to about 400, about 23 to about 400, about 24 to about 400, about 25 to about 400, about 26 to about 400, about 27 to about 400, about 28 to about 400, about 29 to about 400, about 30 to about 400, about 31 to about 400, about 32 to about 400, about 33 to about 400, about 34 to about 400, about 35 to about 400 amino acids or nucleotides in length. In some embodiments, the identity exists over a region that is at least about 40 to about 400, about 45 to about 400, about 50 to about 400, about 55 to about 400, aboutWSGR Docket No.47991-744.601 60 to about 400, about 61 to about 400, about 62 to about 400, about 63 to about 400, about 64 to about 400, about 65 to about 400, about 66 to about 400, about 67 to about 400, about 68 to about 400, about 69 to about 400, about 70, to about 400, about 71 to about 400, about 72 to about 400, about 73 to about 400, about 74 to about 400, about 75 to about 400, about 80 to about 400, about 85 to about 400, about 90 to about 400, about 100 to about 400, about 150 to about 400, about 200 to about 400, about 250 to about 400, about 300 to about 400, about 350 to about 400 amino acids or nucleotides in length.

[0247] In some embodiments, the identity exists over a region that is at least about 2 to about 343, about 3 to about 343, about 4 to about 343, about 7 to about 343, about 9 to about 343, about 11 to about 343, about 15 to about 343, about 16 to about 343, about 20 to about 343, about 25 to about 343, about 62 to about 343, about 2 to about 317, about 3 to about 317, about 4 to about 317, about 7 to about 317, about 9 to about 317, about 11 to about 317, about 15 to about 317, about 16 to about 317, about 20 to about 317, about 25 to about 317, about 62 to about 317, about 2 to about 300, about 3 to about 300, about 4 to about 300, about 7 to about 300, about 9 to about 300, about 11 to about 300, about 15 to about 300, about 16 to about 300, about 20 to about 300, about 25 to about 300, about 62 to about 300, about 2 to about 62, about 3 to about 62, about 4 to about 62, about 7 to about 62, about 9 to about 62, about 11 to about 62, about 15 to about 62, about 16 to about 62, about 20 to about 62, about 25 to about 62 amino acids or nucleotides in length.

[0248] The term “genetically modified” means containing and / or expressing a foreign gene or nucleic acid sequence which in turn, modifies the genotype or phenotype of the cell or its progeny. In other words, it refers to any addition, deletion, or disruption to a cell's endogenous nucleotides.

[0249] The term “operably linked” can refer to a functional relationship between two or more nucleic acid sequences, e.g., a functional relationship of a transcriptional regulatory or signal sequence to a transcribed sequence. For example, a target motif or a nucleic acid encoding a target motif is operably linked to a coding sequence if it is expressed as a preprotein that participates in targeting the polypeptide encoded by the coding sequence to a cell membrane, intracellular, or an extracellular compartment. For example, a signal peptide or a nucleic acid encoding a signal peptide is operably linked to a coding sequence if it is expressed as a preprotein that participates in the secretion of the polypeptide encoded by the coding sequence. For example, a promoter is operably linked if it stimulates or modulates the transcription of the coding sequence.

[0250] The term “subject” or “patient” encompasses vertebrates or mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human. The term “animal” as used herein comprises human beings and non-human animals. In one embodiment, a “non-human animal” is a mammal, for example, a rodent such as rat or a mouse. In one embodiment, a non-human animal is a mouse.WSGR Docket No.47991-744.601

[0251] A “control” is an alternative subject or sample used in an experiment for comparison purpose. A control can be “positive” or “negative.” Pharmaceutical compositions

[0252] In one aspect, provided herein is a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition is not buffered by a buffering agent; and wherein: (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0253] In some embodiments, the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent, wherein the ASO is stable in the pharmaceutical formulation for at least 1 or 2 years at 4 °C.

[0254] In some embodiments, (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0255] In another aspect, provided herein is a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition lacks Na2HPO4and / or NaH2PO4; and wherein: (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0256] In some embodiments, the liquid composition lacks phosphate ions.

[0257] In some embodiments, the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion.

[0258] In another aspect, provided herein is a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent consisting of: a) NaCl, b) KCl, c) MgCl2 or MgCl26H2O, and d) CaCl2 or CaCl22H2O.

[0259] In some embodiments, the liquid composition comprises 0.1-50 mM CaCl2 or CaCl22H2O.

[0260] In some embodiments, the liquid composition comprises 1-2 mM CaCl2 or CaCl22H2O.

[0261] In some embodiments, the liquid composition comprises about 1.4 mM CaCl2 or CaCl22H2O.

[0262] In some embodiments, the liquid composition comprises 0.1-50 mM MgCl2 or MgCl26H2O.

[0263] In some embodiments, the liquid composition comprises 0.5-1.5 mM MgCl2 or MgCl26H2O.

[0264] In some embodiments, the liquid composition comprises about 0.79 mM MgCl2 or MgCl26H2O.WSGR Docket No.47991-744.601

[0265] In some embodiments, the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1- 50 mM CaCl2 or CaCl22H2O, and 0.1-50 mM MgCl2 or MgCl26H2O.

[0266] In another aspect, provided herein is a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition lacks calcium ions and / or magnesium ions; and wherein: (a) the liquid composition comprises potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0267] In some embodiments, the liquid composition is formulated for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject.

[0268] In some embodiments, the liquid composition is formulated for administration into cerebrospinal fluid in a brain of a human subject.

[0269] In some embodiments, the ASO comprises at least one modified sugar moiety.

[0270] In some embodiments, each nucleotide of the antisense oligomer comprises a modified sugar moiety.

[0271] In another aspect, provided herein is a kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO, and wherein the liquid composition is not buffered by a buffering agent; and wherein: (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0272] In some embodiments, a kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO, and wherein the ASO is stable in the liquid composition for at least 1 or 2 years at 4 °C.

[0273] In some embodiments, (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0274] In some embodiments, a kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO, wherein the liquid composition lacks Na2HPO4 and / or NaH2PO4; and wherein: (a) the liquid composition comprises calcium ion, magnesiumWSGR Docket No.47991-744.601 ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0275] In some embodiments, the liquid composition lacks phosphate ions.

[0276] In some embodiments, the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion.

[0277] In some embodiments, a kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent consisting of: a) NaCl, b) KCl, c) MgCl2 or MgCl2 6H2O, and d) CaCl2 or CaCl22H2O, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO.

[0278] In some embodiments, a kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO, wherein the liquid composition lacks calcium ions and / or magnesium ions; and wherein: (a) the liquid composition comprises potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

[0279] In some embodiments, the liquid composition is formulated for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject.

[0280] In some embodiments, the liquid composition is formulated for administration into cerebrospinal fluid in a brain of a human subject.

[0281] In some embodiments, the ASO comprises at least one modified sugar moiety.

[0282] In some embodiments, each nucleotide of the antisense oligomer comprises a modified sugar moiety.

[0283] In some embodiments, the kit further comprises (iii) instructions for diluting or solubilizing the ASO in the pharmaceutically acceptable diluent.

[0284] In some embodiments, the liquid composition comprises 25-250 mM NaCl.

[0285] In some embodiments, the liquid composition comprises 0.1-20 mM KCl.

[0286] In some embodiments, the liquid composition comprises 2-4 mM KCl.

[0287] In some embodiments, the liquid composition about 3 mM KCl.

[0288] In some embodiments, the liquid composition comprises 100-160 mM NaCl.

[0289] In some embodiments, the liquid composition comprises 125-145 mM NaCl.

[0290] In some embodiments, the liquid composition comprises about 130 mM NaCl.

[0291] In some embodiments, the liquid composition comprises a buffered (pH 6.6 – 7.6) solution.

[0292] In some embodiments, the liquid composition comprises 0.1-50 mM Na2HPO4.

[0293] In some embodiments, the liquid composition comprises 0.1-50 mM NaH2PO4.WSGR Docket No.47991-744.601

[0294] In some embodiments, the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1- 50 mM Na2HPO4, and 0.1-50 mM NaH2PO4.

[0295] In some embodiments, the ASO is solubilized in the pharmaceutically acceptable diluent.

[0296] In some embodiments, the pharmaceutically acceptable diluent is an isotonic solution.

[0297] In some embodiments, the ASO is not substantially polydisperse.

[0298] In some embodiments, the liquid composition has an osmolality of less than 150 mM.

[0299] In some embodiments, the liquid composition has an osmolality of about 130 mM.

[0300] In some embodiments, the liquid composition further comprises a carbohydrate.

[0301] In some embodiments, the carbohydrate comprises D-glucose.

[0302] In some embodiments, the liquid composition further comprises 1-100 mM D-glucose.

[0303] In some embodiments, the liquid composition further comprises an antioxidant.

[0304] In some embodiments, the antioxidant is t-butylhydroxyquinoline (TBHQ), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or any combination thereof.

[0305] In some embodiments, the ASO as described herein is solubilized or diluted in an artificial cerebral spinal fluid (aCSF) solution. In some embodiments, the ASO as described herein is solubilized or diluted in an isotonic solution.

[0306] The term “artificial cerebrospinal fluid (aCSF),” as used herein, refers to a biological buffer solution that is commonly used as a vehicle solution for administration of agents to the central nervous system (CNS). aCSF, for instance, closely matches the electrolyte concentrations and physiological compatibility of endogenous CSF to enable a vital environment for neuronal tissue by maintaining the homeostasis, osmolarity, and pH at physiological levels.

[0307] The term “isotonic solution,” as used herein, refers to a solution that contains an electrolyte balance similar to plasma in the bloodstream. Administration of an isotonic solution to a subject or patient may increase the fluid volume of the subject or patient without a fluid shift. Exemplary isotonic solutions include, but are not limited to 0.9% normal saline, lactated Ringer’s solution, Ringer’s solution, plasma-lyte, and 5% Dextrose in water (D5W).

[0308] The term “hypotonic solution,” as used herein, refers to a solution that has a lower concentration of electrolytes than plasma. Administration of a hypotonic solution, for example, via an intravenous route, may lead to shifting fluid out of the bloodstream to the area of higher concentration in the interstitial and intracellular spaces. Exemplary hypotonic solutions include, but are not limited to, 0.45% normal saline (half normal saline), 0.33% NaCl solution, 0.225% NaCl solution, and 2.5% Dextrose in water (D2.5W).

[0309] The term “hypertonic solution,” as used herein, refers to a solution that has a higher concentration of electrolytes than plasma. Administration of a hypertonic solution, for example, via an intravenous route, may shift fluid from the interstitial and intracellular spaces into the bloodstream to dilute the electrolytes. Exemplary hypertonic solutions include, but are not limited to, 3% NaCl solution, 5% Dextrose in 0.45% NaCl (D5 ½ NS), 5% Dextrose in 0.9% normal saline (D5NS), 5% Dextrose inWSGR Docket No.47991-744.601 lactated Ringer’s solution (D5LR), 10% Dextrose in water (D10W), 20% Dextrose in water (D20W), and 50% Dextrose in water (D50W).

[0310] In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate- buffered (pH 6.6-7.6) solution. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered (pH 6.0-8.0) solution. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered (pH 5.0-8.0) solution. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 4.5-8.5, pH 4.6-8.5, pH 4.7-8.5, pH 4.8-8.5, pH 4.9-8.5, pH5.0-8.5, pH 5.1-8.5, pH5.2-8.5, pH 5.3-8.5, pH5.4-8.5, pH 5.5-8.5, pH5.6-8.5, pH 5.7-8.5, pH 5.8-8.5, H 5.9-8.5, pH 6.0-8.5, pH 6.1-8.5, pH 6.2-8.5, pH 6.3-8.5, pH 6.4-8.5, pH 6.5-8.5, pH 6.6-8.5, pH 6.7-8.5, pH 6.8-8.5, pH 6.9-8.5, pH 7.0-8.5, pH 7.1-8.5, pH 7.2-8.5, pH 7.3-8.5, pH 7.4-8.5, pH 7.5-8.5, pH 7.6-8.5, pH 7.7-8.5, pH 7.8-8.5, pH 7.9-8.5, pH 8.0-8.5, pH 8.1- 8.5, pH 8.2-8.5, pH 8.3-8.5, or pH 8.4-8.5. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 4.5-8.3, pH 4.5-8.2, pH 4.5-8.1, pH 4.5- 8.0, pH 4.5-7.9, pH 4.5-7.8, pH 4.5-7.7, pH 4.5-7.6, pH 4.5-7.5, pH 4.5-7.4, pH 4.5-7.3, pH 4.5-7.2, pH 4.5-7.1, pH 4.5-7.0, pH 4.5-6.9, pH 4.5-6.8, pH 4.5-6.7, pH 4.5-6.6, pH 4.5-6.5, pH 4.5-6.4, pH 4.5-6.3, pH 4.5-6.2, pH 4.5-6.1, pH 4.5-6.0, pH 4.5-5.9, pH 4.5-5.8, pH 4.5-5.7, pH 4.5-5.6, pH 4.5-5.5, pH 4.5- 5.4, pH 4.5-5.3, pH 4.5-5.2, pH 4.5-5.1, pH 4.5-5.0, pH 4.5-4.9, pH 4.5-4.8, pH 4.5-4.7, or pH 4.5-4.6. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 6.0-7.6, pH 6.1-7.6, pH 6.2-7.6, pH 6.3-7.6, pH 6.4-7.6, pH 6.5-7.6, pH 6.6-7.6, pH 6.7- 7.6, pH 6.8-7.6, pH 6.9-7.6, pH 7.0-7.6, pH 7.1-7.6, pH 7.2-7.6, pH 7.3-7.6, pH 7.4-7.6, or pH 7.5-7.6. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 6.6-8.0, pH 6.6-7.9, pH 6.6-7.8, pH 6.6-7.7, pH 6.6-7.6, pH 6.6-7.5, pH 6.6-7.4, pH 6.6- 7.3, pH 6.6-7.2, pH 6.6-7.1, pH 6.6-7.0, pH 6.6-6.9, pH 6.6-6.8, or pH 6.6-6.7. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 6.0-8.0, pH 6.1-8.0, pH 6.2-8.0, pH 6.3-8.0, pH 6.4-8.0, pH 6.5-8.0, pH 6.6-8.0, pH 6.7-8.0, pH 6.8-8.0, pH 6.9-8.0, pH 7.0-8.0, pH 7.1-8.0, pH 7.2-8.0, pH 7.3-8.0, pH 7.4-8.0, pH 7.5-8.0, pH 7.6-8.0, pH 7.7-8.0, pH 7.8- 8.0, or pH 7.9-8.0. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 6.0-7.9, pH 6.0-7.8, pH 6.0-7.7, pH 6.0-7.6, pH 6.0-7.5, pH 6.0-7.4, pH 6.0-7.3, pH 6.0-7.2, pH 6.0-7.1, pH 6.0-7.0, pH 6.0-6.9, pH 6.0-6.8, pH 6.0-6.7, pH 6.0-6.6, pH 6.0- 6.5, pH 6.0-6.4, pH 6.0-6.3, pH 6.0-6.2, or pH 6.0-6.1. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 5.7-8.5, 5.8-8.4, 5.9-8.3, 6.0-8.2, 6.1-8.1, 6.2-8.0, 6.3-7.9, 6.4-7.8, 6.5-7.7, or 6.6-7.6. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH about 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, or 8.0. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 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, or 8.0.WSGR Docket No.47991-744.601

[0311] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 25-250 mM NaCl.

[0312] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 25-250, 30-250, 35-250, 40-250, 45-250, 50-250, 55-250, 60-250, 65-250, 70-250, 75-250, 80-250, 85-250, 90-250, 95-250, 100-250, 105-250, 110-250, 115-250, 120-250, 125-250, 130-250, 135- 250, 140-250, 145-250, 150-250, 155-250, 160-250, 165-250, 170-250, 175-250, 180-250, 185-250, 190- 250, 195-250, 200-250, 205-250, 210-250, 215-250, 220-250, 225-250, 230-250, 235-250, 240-250, or 245-250 mM NaCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 25-245, 25-240, 25-235, 25-230, 25-225, 25-220, 25-215, 25-210, 25-205, 25-200, 25- 195, 25-190, 25-185, 25-180, 25-175, 25-170, 25-165, 25-160, 25-155, 25-150, 25-145, 25-140, 25-135, 25-130, 25-125, 25-120, 25-115, 25-110, 25-105, 25-110, 25-105, 25-100, 25-95, 25-90, 25-85, 25-80, 25-75, 25-70, 25-65, 25-60, 25-55, 25-50, 25-45, 25-40, 25-35, or 25-30 mM NaCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 30-245, 35- 240, 40-235, 45-230, 50-225, 55-220, 60-215, 65-210, 70-205, 75-200, 80-195, 85-190, 90-185, 95-180, 100-175, 105-170, 110-165, 115-160, 120-155, 125-150, 130-145 or 135-140 mM NaCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 100-140, 101- 140, 102-140, 103-140, 104-140, 105-140, 106-140, 107-140, 108-140, 109-140, 110-140, 111-140, 112- 140, 113-140, 114-140, 115-140, 116-140, 117-140, 118-140, 119-140, 120-140, 121-140, 122-140, 123- 140, 124-140, 125-140, 126-140, 127-140, 128-140, 129-140, 130-140, 131-140, 132-140, 133-140, 134- 140, 135-140, 136-140, 137-140, 138-140, or 139-140 mM NaCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 100-139, 100-138, 100-137, 100-136, 100-135, 100-134, 100-133, 100-132, 100-131, 100-130, 100-129, 100-128, 100-127, 100-126, 100-125, 100-124, 100-123, 100-122, 100-121, 100-120, 100-119, 100-118, 100-117, 100-116, 100-115, 100-114, 100-113, 100-112, 100-111, 100-110, 100-109, 100-108, 100-107, 100-106, 100-105, 100-104, 100-103, 100-102, or 100-101 mM NaCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 mM NaCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 mM NaCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 mM NaCl.

[0313] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-20 mM KCl.WSGR Docket No.47991-744.601

[0314] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-40, 0.1-39, 0.1-38, 0.1-37, 0.1-36, 0.1-35, 0.1-34, 0.1-33, 0.1-32, 0.1-31, 0.1-30, 0.1-29, 0.1-28, 0.1-27, 0.1-26, 0.1-25, 0.1-24, 0.1-23, 0.1-22, 0.1-21, 0.1-20, 0.1-19, 0.1-18, 0.1-17, 0.1-16, 0.1- 15, 0.1-14, 0.1-13, 0.1-12, 0.1-10, 0.1-9, 0.1-8, 0.1-7, 0.1-6, 0.1-5, 0.1-4, 0.1-3, 0.1-2, or 0.1-1 mM KCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.2- 40, 0.3-40, 0.4-40, 0.5-40, 0.6-40, 0.7-40, 0.8-40, 0.9-40, 1-40, 2-40, 3-40, 4-40, 5-40, 6-40, 7-40, 8-40, 9-40, 10-40, 11-40, 12-40, 13-40, 14-40, 15-40, 16-40, 17-40, 18-40, 19-40, 20-40, 21-40, 22-40, 23-40, 24-40, 25-40, 26-40, 27-40, 28-40, 29-40, 30-40, 31-40, 32-40, 33-40, 34-40, 35-40, 36-40, 37-40, 38-40, or 39-40 mM KCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-3.5, 0.2-3.5, 0.3-3.5, 0.4-3.5, 0.5-3.5, 0.6-3.5, 0.7-3.5, 0.8-3.5, 0.9-3.5, 1.0-3.5, 1.1-3.5, 1.2-3.5, 1.3-3.5, 1.4-3.5, 1.5-3.5, 1.6-3.5, 1.7-3.5, 1.8-3.5, 1.9-3.5, 2.0-3.5, 2.1-3.5, 2.2-3.5, 2.3- 3.5, 2.4-3.5, 2.5-3.5, 2.6-3.5, 2.7-3.5, 2.8-3.5, 2.9-3.5, 3.0-3.5, 3.1-3.5, 3.2-3.5, 3.3-3.5, or 3.4-3.5 mM KCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-3.4, 0.1-3.3, 0.1-3.2, 0.1-3.1, 0.1-3.0, 0.1-2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1- 2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8, 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM KCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 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, or 3.5 mM KCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 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, or 3.5 mM KCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 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, or 3.5 mM KCl.

[0315] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-50 mM Na2HPO4.

[0316] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.01-100, 0.02-100, 0.03-100, 0.04-100, 0.05-100, 0.06-100, 0.07-100, 0.08-100, 0.09-100, 0.1-100, 0.2-100, 0.3-100, 0.4-100, 0.5-100, 0.6-100, 0.7-100, 0.8-100, 0.9-100, 1-100, 2-100, 3-100, 4- 100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45- 100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM Na2HPO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.01- 95, 0.01-90, 0.01-85, 0.01-80, 0.01-75, 0.01-70, 0.01-65, 0.01-60, 0.01-55, 0.01-50, 0.01-45, 0.01-40, 0.01-35, 0.01-30, 0.01-25, 0.01-20, 0.01-15, 0.01-10, 0.01-9, 0.01-8, 0.01-7, 0.01-6, 0.01-5, 0.01-4, 0.01- 3, 0.01-2, 0.01-1, 0.01-0.9, 0.01-0.8, 0.01-0.7, 0.01-0.6, 0.01-0.5, 0.01-0.4, 0.01-0.3, 0.01-0.2, 0.01-0.1, 0.01-0.09, 0.01-0.08, 0.01-0.07, 0.01-0.06, 0.01-0.05, 0.01-0.04, 0.01-0.03, or 0.01-0.02 mM Na2HPO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1- 3.0, 0.1-2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1-2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8,WSGR Docket No.47991-744.601 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1- 0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM Na2HPO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-3.0, 0.2-3.0, 0.3-3.0, 0.4-3.0, 0.5-3.0, 0.6-3.0, 0.7-3.0, 0.8-3.0, 0.9-3.0, 1.0-3.0, 1.2-3.0, 1.3-3.0, 1.4-3.0, 1.5-3.0, 1.6-3.0, 1.7-3.0, 1.8-3.0, 1.9-3.0, 2.0-3.0, 2.1- 3.0, 2.2-3.0, 2.3-3.0, 2.4-3.0, 2.5-3.0, 2.6-3.0, 2.7-3.0, 2.8-3.0, or 2.9-3.0 mM Na2HPO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 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, or 3.0 mM Na2HPO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 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, or 3.0 mM Na2HPO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 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, or 3.0 mM Na2HPO4.

[0317] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-50 mM NaH2PO4.

[0318] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.01-100, 0.02-100, 0.03-100, 0.04-100, 0.05-100, 0.06-100, 0.07-100, 0.08-100, 0.09-100, 0.1-100, 0.2-100, 0.3-100, 0.4-100, 0.5-100, 0.6-100, 0.7-100, 0.8-100, 0.9-100, 1-100, 2-100, 3-100, 4- 100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45- 100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.01- 95, 0.01-90, 0.01-85, 0.01-80, 0.01-75, 0.01-70, 0.01-65, 0.01-60, 0.01-55, 0.01-50, 0.01-45, 0.01-40, 0.01-35, 0.01-30, 0.01-25, 0.01-20, 0.01-15, 0.01-10, 0.01-9, 0.01-8, 0.01-7, 0.01-6, 0.01-5, 0.01-4, 0.01- 3, 0.01-2, 0.01-1, 0.01-0.9, 0.01-0.8, 0.01-0.7, 0.01-0.6, 0.01-0.5, 0.01-0.4, 0.01-0.3, 0.01-0.2, 0.01-0.1, 0.01-0.09, 0.01-0.08, 0.01-0.07, 0.01-0.06, 0.01-0.05, 0.01-0.04, 0.01-0.03, or 0.01-0.02 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1- 3.0, 0.1-2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1-2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8, 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1- 0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-3.0, 0.2-3.0, 0.3-3.0, 0.4-3.0, 0.5-3.0, 0.6-3.0, 0.7-3.0, 0.8-3.0, 0.9-3.0, 1.0-3.0, 1.2-3.0, 1.3-3.0, 1.4-3.0, 1.5-3.0, 1.6-3.0, 1.7-3.0, 1.8-3.0, 1.9-3.0, 2.0-3.0, 2.1- 3.0, 2.2-3.0, 2.3-3.0, 2.4-3.0, 2.5-3.0, 2.6-3.0, 2.7-3.0, 2.8-3.0, or 2.9-3.0 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 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, or 3.0 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 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, or 3.0 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1, 0.2, 0.3,WSGR Docket No.47991-744.601 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, or 3.0 mM NaH2PO4.

[0319] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-50 mM CaCl2.

[0320] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-50, 0.2-50, 0.3-50, 0.4-50, 0.5-50, 0.6-50, 0.7-50, 0.8-50, 0.9-50, 1.0-50, -50, 1.1-50, 1.2- 50, 1.3-50, 1.4-50, 1.5-50, 1.6-50, 1.7-50, 1.8-50, 1.9-50, 2.0-50, 2.1-50, 2.2-50, 2.3-50, 2.4-50, 2.5-50, 2.6-50, 2.7-50, 2.8-50, 2.9-50, 3.0-50, 3.1-50, 3.2-50, 3.3-50, 3.4-50, 3.5-50, 3.6-50, 3.7-50, 3.8-50, 3.9- 50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 15-50, 20-50, 25-50, 130-50, 35-50, 40-50, or 45-50 mM CaCl2. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-45, 0.1-40, 0.1-35, 0.1-30, 0.1-25, 0.1-20, 0.1-15, 0.1-10, 0.1-5, 0.1-4, 0.1-4.9, 0.1-4.8, 0.1-4.7, 0.1-4.6, 0.1-4.5, 0.1-4.4, 0.1-4.3, 0.1-4.2, 0.1-4.1, 0.1-4.0, 0.1-3.9, 0.1-3.8, 0.1-3.7, 0.1-3.6, 0.1- 3.5, 0.1-3.4, 0.1-3.3, 0.1-3.2, 0.1-3.1, 0.1-3.0, 0.1-2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1-2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8, 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1- 1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM CaCl2. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 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, or 4.0 mM CaCl2. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 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, or 4.0 mM CaCl2. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 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, or 4.0 mM CaCl2.

[0321] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-50 mM MgCl2.

[0322] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-50, 0.2-50, 0.3-50, 0.4-50, 0.5-50, 0.6-50, 0.7-50, 0.8-50, 0.9-50, 1.0-50, -50, 1.1-50, 1.2- 50, 1.3-50, 1.4-50, 1.5-50, 1.6-50, 1.7-50, 1.8-50, 1.9-50, 2.0-50, 2.1-50, 2.2-50, 2.3-50, 2.4-50, 2.5-50, 2.6-50, 2.7-50, 2.8-50, 2.9-50, 3.0-50, 3.1-50, 3.2-50, 3.3-50, 3.4-50, 3.5-50, 3.6-50, 3.7-50, 3.8-50, 3.9- 50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 15-50, 20-50, 25-50, 130-50, 35-50, 40-50, or 45-50 mM MgCl2. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-45, 0.1-40, 0.1-35, 0.1-30, 0.1-25, 0.1-20, 0.1-15, 0.1-10, 0.1-5, 0.1-4, 0.1-4.9, 0.1-4.8, 0.1-4.7, 0.1-4.6, 0.1-4.5, 0.1-4.4, 0.1-4.3, 0.1-4.2, 0.1-4.1, 0.1-4.0, 0.1-3.9, 0.1-3.8, 0.1-3.7, 0.1-3.6, 0.1- 3.5, 0.1-3.4, 0.1-3.3, 0.1-3.2, 0.1-3.1, 0.1-3.0, 0.1-2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1-2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8, 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1- 1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM MgCl2. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 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,WSGR Docket No.47991-744.601 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, or 4.0 mM MgCl2. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 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, or 4.0 mM MgCl2. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 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, or 4.0 mM MgCl2.

[0323] In some embodiments, the ASO is solubilized or diluted in a buffer further comprising 1-100 mM NaHCO3, 1-100 mM KHCO3, or a combination thereof.

[0324] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 1-100 mM NaHCO3.

[0325] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 1-99, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mM NaHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 2-100, 3-100, 4-100, 5-100, 6-100, 7- 100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60- 100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM NaHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 24.0-28.0, 24.0-27.9, 24.0- 27.8, 24.0-27.7, 24.0-27.6, 24.0-27.5, 24.0-27.4, 24.0-27.3, 24.0-27.2, 24.0-27.1, 24.0-27.0, 24.0-26.9, 24.0-26.8, 24.0-26.7, 24.0-26.6, 24.0-26.5, 24.0-26.4, 24.0-26.3, 24.0-26.2, 24.0-26.1, 24.0-26.0, 24.0- 25.9, 4.0-25.8, 24.0-25.7, 24.0-25.6, 24.0-25.5, 24.0-25.4, 24.0-25.3, 24.0-25.2, 24.0-25.1, 24.0-25.0, 24.0-24.9, 24.0-24.8, 24.0-24.7, 24.0-24.6, 24.0-24.5, 24.0-24.4, 24.0-24.3, 24.0-24.2, or 24.0-24.1 mM NaHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 24.1-28.0, 24.2-28.0, 24.3-28.0, 24.4-28.0, 24.5-28.0, 24.6-28.0, 24.7-28.0, 24.8-28.0, 24.9- 28.0, 25.0-28.0, 25.1-28.0, 25.2-28.0, 25.3-28.0, 25.4-28.0, 25.5-28.0, 25.6-28.0, 25.7-28.0, 25.8-28.0, 25.9-28.0, 26.0-28.0, 26.1-28.0, 26.2-28.0, 26.3-28.0, 26.4-28.0, 26.5-28.0, 26.6-28.0, 26.7-28.0, 26.8- 28.0, 26.9-28.0, 27.0-28.0, 27.1-28.0, 27.2-28.0, 27.3-28.0, 27.4-28.0, 27.5-28.0, 27.6-28.0, 27.7-28.0, 27.8-28.0, or 27.9-28.0 mM NaHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM NaHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM NaHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM NaHCO3.WSGR Docket No.47991-744.601

[0326] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 1-100 mM KHCO3.

[0327] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 1-99, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mM KHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 2-100, 3-100, 4-100, 5-100, 6-100, 7- 100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60- 100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM KHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 24.0-28.0, 24.0-27.9, 24.0-27.8, 24.0-27.7, 24.0-27.6, 24.0-27.5, 24.0-27.4, 24.0-27.3, 24.0-27.2, 24.0-27.1, 24.0-27.0, 24.0-26.9, 24.0- 26.8, 24.0-26.7, 24.0-26.6, 24.0-26.5, 24.0-26.4, 24.0-26.3, 24.0-26.2, 24.0-26.1, 24.0-26.0, 24.0-25.9, 4.0-25.8, 24.0-25.7, 24.0-25.6, 24.0-25.5, 24.0-25.4, 24.0-25.3, 24.0-25.2, 24.0-25.1, 24.0-25.0, 24.0- 24.9, 24.0-24.8, 24.0-24.7, 24.0-24.6, 24.0-24.5, 24.0-24.4, 24.0-24.3, 24.0-24.2, or 24.0-24.1 mM KHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 24.1-28.0, 24.2-28.0, 24.3-28.0, 24.4-28.0, 24.5-28.0, 24.6-28.0, 24.7-28.0, 24.8-28.0, 24.9- 28.0, 25.0-28.0, 25.1-28.0, 25.2-28.0, 25.3-28.0, 25.4-28.0, 25.5-28.0, 25.6-28.0, 25.7-28.0, 25.8-28.0, 25.9-28.0, 26.0-28.0, 26.1-28.0, 26.2-28.0, 26.3-28.0, 26.4-28.0, 26.5-28.0, 26.6-28.0, 26.7-28.0, 26.8- 28.0, 26.9-28.0, 27.0-28.0, 27.1-28.0, 27.2-28.0, 27.3-28.0, 27.4-28.0, 27.5-28.0, 27.6-28.0, 27.7-28.0, 27.8-28.0, or 27.9-28.0 mM KHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM KHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM KHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM KHCO3.

[0328] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-50 mM KH2PO4.

[0329] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-100, 0.01-100, 0.02-100, 0.03-100, 0.04-100, 0.05-100, 0.06-100, 0.07-100, 0.08-100, 0.09- 100, 0.1-100, 0.2-100, 0.3-100, 0.4-100, 0.5-100, 0.6-100, 0.7-100, 0.8-100, 0.9-100, 1-100, 2-100, 3- 100, 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-95, 0-90, 0-85, 0-80, 0-75, 0-70, 0-65, 0-60, 0-55, 0-50, 0-45, 0-40, 0-35, 0-30, 0-25, 0-20,WSGR Docket No.47991-744.601 0-15, 0-10, 0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0-1, 0-0.9, 0-0.8, 0-0.7, 0-0.6, 0-0.5, 0-0.4, 0-0.3, 0-0.2, 0-0.1, 0-0.09, 0-0.08, 0-0.07, 0-0.06, 0-0.05, 0-0.04, 0-0.03, or 0-0.02 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.01-95, 0.01- 90, 0.01-85, 0.01-80, 0.01-75, 0.01-70, 0.01-65, 0.01-60, 0.01-55, 0.01-50, 0.01-45, 0.01-40, 0.01-35, 0.01-30, 0.01-25, 0.01-20, 0.01-15, 0.01-10, 0.01-9, 0.01-8, 0.01-7, 0.01-6, 0.01-5, 0.01-4, 0.01-3, 0.01-2, 0.01-1, 0.01-0.9, 0.01-0.8, 0.01-0.7, 0.01-0.6, 0.01-0.5, 0.01-0.4, 0.01-0.3, 0.01-0.2, 0.01-0.1, 0.01-0.09, 0.01-0.08, 0.01-0.07, 0.01-0.06, 0.01-0.05, 0.01-0.04, 0.01-0.03, or 0.01-0.02 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-3.0, 0-2.9, 0-2.8, 0-2.7, 0-2.6, 0-2.5, 0-2.4, 0-2.3, 0-2.2, 0-2.1, 0-2.0, 0-1.9, 0-1.8, 0-1.7, 0-1.6, 0-1.5, 0-1.4, 0-1.3, 0- 1.2, 0-1.1, 0-1.0, 0-0.9, 0-0.8, 0-0.7, 0-0.6, 0-0.5, 0-0.4, 0-0.3, or 0-0.2 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-3.0, 0.1- 2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1-2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8, 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1- 0.4, 0.1-0.3, or 0.1-0.2 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-3.0, 0.1-3.0, 0.2-3.0, 0.3-3.0, 0.4-3.0, 0.5-3.0, 0.6-3.0, 0.7-3.0, 0.8-3.0, 0.9-3.0, 1.0-3.0, 1.2-3.0, 1.3-3.0, 1.4-3.0, 1.5-3.0, 1.6-3.0, 1.7-3.0, 1.8-3.0, 1.9-3.0, 2.0-3.0, 2.1-3.0, 2.2- 3.0, 2.3-3.0, 2.4-3.0, 2.5-3.0, 2.6-3.0, 2.7-3.0, 2.8-3.0, or 2.9-3.0 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 0, 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, or 3.0 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 0, 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, or 3.0 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 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, or 3.0 mM KH2PO4.

[0330] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-50 mM NaH2PO4.

[0331] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-50, 0-45, 0-40, 0-35, 0-30, 0-25, 0-20, 0-19, 0-18, 0-17, 0-16, 0-15, 0-14, 0-13, 0-12, 0-11, 0-10, 0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0-1, 0-0.9, 0-0.8, 0-0.7, 0-0.6, 0-0.5, 0-0.4, 0-0.3, or 0-0.2 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-50, 0.1-45, 0.1-40, 0.1-35, 0.1-30, 0.1-25, 0.1-20, 0.1-19, 0.1-18, 0.1-17, 0.1-16, 0.1-15, 0.1-14, 0.1-13, 0.1-12, 0.1-11, 0.1-10, 0.1-9, 0.1-8, 0.1-7, 0.1-6, 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-50, 0.1-50, 0.2-50, 0.3-50, 0.4- 50, 0.5-50, 0.6-50, 0.7-50, 0.8-50, 0.9-50, 1-50, 2-50, 3-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 1-50, 11- 50, 12-50, 13-50, 14-50, 15-50, 16-50, 17-50, 18-50, 19-50, 20-50, 25-50, 30-50, 35-50, 40-50, or 45-50 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a bufferWSGR Docket No.47991-744.601 comprising 0-20, 0.1-20, 0.2-20, 0.3-20, 0.4-20, 0.5-20, 0.6-20, 0.7-20, 0.8-20, 0.9-20, 1-20, 2-20, 3-20, 4-20, 5-20, 6-20, 7-20, 8-20, 9-20, 10-20, 11-20, 12-20, 13-20, 14-20, 15-20, 16-20, 17-20, 18-20, or 19- 20 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 0, 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, or 20 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 0, 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, or 20 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0, 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, or 20 mM NaH2PO4.

[0332] In some embodiments, the ASO is solubilized in the liquid composition that is not buffered by a buffering agent. A buffering agent in a liquid formulation described herein is an agent other than the active pharmaceutical ingredient (e.g., an ASO described herein) in the formulation that buffers the pH of the formulation.

[0333] In some embodiments, the ASO is solubilized in the liquid composition that comprises a buffering agent. In some embodiments, the buffering agent has a pKa at 25 °C of about 4.75; about 5.64; about 1.70, about 6.04 and about 9.09; about 3.1, about 4.7 and about 6.4; or about 6.50. In some embodiments, the buffering agent is an effective buffer at a pH range of from about 3.6 to 5.6, from about 5.5 to 6.5, from about 5.5 to 7.4, from about 3.0 to 6.2, or from about 5.8 to 7.2. In some embodiments, the buffering agent is selected from the group consisting of acetate, succinate, histidine, citrate, 2-[Bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol (Bis-Tris), and any combination thereof.

[0334] In some embodiments, the ASO is stable in the pharmaceutical formulation for at least 1 or 2 or 3 years at -20 °C. In some embodiments, the ASO is stable in the pharmaceutical formulation for at least 1 or 2 or 3 years at 4 °C. In some embodiments, the ASO is stable in the pharmaceutical formulation for at least 1 or 2 or 3 years at 25 °C. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at -20 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at -20 °C for at least 12 months. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at -20 °C for at least 24 months. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at -20 °C for at least 36 months. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at 4 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of theWSGR Docket No.47991-744.601 pharmaceutical formulation at 25 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at 30 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at 37 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at 40 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at 4 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at 25 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at 30 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at 37 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at 40 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the ASO is stable in the pharmaceuticalWSGR Docket No.47991-744.601 formulation according to identification of a molecule with a molecular weight of 7197.2 ± 4.0 Da according to LC / MS.

[0335] In some embodiments, the pharmaceutical formulation has a shelf life of at least 1 or 2 or 3 years when stored at -20 °C. In some embodiments, the pharmaceutical formulation has a shelf life of at least 1 or 2 or 3 years when stored at 4 °C. In some embodiments, the pharmaceutical formulation has a shelf life of at least 1 or 2 or 3 years when stored at 25 °C. In some embodiments, the pharmaceutical formulation has a shelf life of at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at -20 °C. In some embodiments, the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at -20 °C for at least 12 months. In some embodiments, the pharmaceutical formulation has a shelf life of at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 4 °C. In some embodiments, the pharmaceutical formulation has a shelf life of at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 25 °C. In some embodiments, the pharmaceutical formulation has a shelf life of at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 30 °C. In some embodiments, the pharmaceutical formulation has a shelf life of at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 37 °C. In some embodiments, the pharmaceutical formulation has a shelf life of at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 40 °C. In some embodiments, the pharmaceutical formulation has a shelf life of at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 4 °C at 55%, 60%, 65%, 70% or 75% relative humidity. In some embodiments, the pharmaceutical formulation has a shelf life of at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 25 °C at 55%, 60%, 65%, 70% or 75% relative humidity. In some embodiments, the pharmaceutical formulation has a shelf life of at least 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,WSGR Docket No.47991-744.601 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 30 °C at 55%, 60%, 65%, 70% or 75% relative humidity. In some embodiments, the pharmaceutical formulation has a shelf life of at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 37 °C at 55%, 60%, 65%, 70% or 75% relative humidity. In some embodiments, the pharmaceutical formulation has a shelf life of at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years when stored at 40 °C at 55%, 60%, 65%, 70% or 75% relative humidity.

[0336] In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at -20 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at -20 °C for at least 12 months. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at -20 °C for at least 24 months. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at -20 °C for at least 36 months. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at 4 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at 25 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at 30 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLCWSGR Docket No.47991-744.601 relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at 37 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at 40 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at 4 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at 25 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at 30 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at 37 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at 40 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0337] In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at -20 °C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,WSGR Docket No.47991-744.601 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at -20 °C for at least 12 months. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at -20 °C for at least 24 months. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at -20 °C for at least 36 months. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at 4 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at 25 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at 30 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at 37 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at 40 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at 4 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in theWSGR Docket No.47991-744.601 pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at 25 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at 30 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at 37 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at 40 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0338] In some embodiments, the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at -20 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at -20 °C for at least 12 months. In some embodiments, the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at -20 °C for at least 24 months. In some embodiments, the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at -20 °C for at least 36 months. In some embodiments, the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at 4 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurities in the pharmaceutical formulation according toWSGR Docket No.47991-744.601 HPLC is not more than 1.8% after storage of the pharmaceutical formulation at 25 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at 30 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at 37 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at 40 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at 4 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at 25 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at 30 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at 37 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of any unspecified impurities in the pharmaceuticalWSGR Docket No.47991-744.601 formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at 40 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0339] In some embodiments, the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at -20 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at -20 °C for at least 12 months. In some embodiments, the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at -20 °C for at least 24 months. In some embodiments, the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at -20 °C for at least 36 months. In some embodiments, the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at 4 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at 25 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at 30 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at 37 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at 40 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In someWSGR Docket No.47991-744.601 embodiments, the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at 4 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at 25 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at 30 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at 37 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at 40 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0340] In some embodiments, the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at -20 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at -20 °C for at least 12 months. In some embodiments, the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at -20 °C for at least 24 months. In some embodiments, the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at -20 °C for at least 36 months. In some embodiments, the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at 4 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. InWSGR Docket No.47991-744.601 some embodiments, the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at 25 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at 30 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at 37 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at 40 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at 4 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at 25 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at 30 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at 37 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at 40 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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,WSGR Docket No.47991-744.601 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0341] In some embodiments, the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at -20 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at -20 °C for at least 12 months. In some embodiments, the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at -20 °C for at least 24 months. In some embodiments, the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at -20 °C for at least 36 months. In some embodiments, the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at 4 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at 25 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at 30 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at 37 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at 40 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at 4 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is fromWSGR Docket No.47991-744.601 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at 25 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at 30 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at 37 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at 40 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0342] In some embodiments, no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at -20 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at -20 °C for at least 12 months. In some embodiments, no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at -20 °C for at least 24 months. In some embodiments, no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at -20 °C for at least 36 months. In some embodiments, no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at 4 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at 25 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2,WSGR Docket No.47991-744.601 3, 4, or 5 years. In some embodiments, no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at 30 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at 37 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at 40 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at 4 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at 25 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at 30 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at 37 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at 40 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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,WSGR Docket No.47991-744.601 46, 47, 48, 49, 50, 51, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0343] In some embodiments, no observable particulate formation is observed after storage of the pharmaceutical formulation at -20 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation is observed after storage of the pharmaceutical formulation at -20 °C for at least 12 months. In some embodiments, no observable particulate formation is observed after storage of the pharmaceutical formulation at -20 °C for at least 24 months. In some embodiments, no observable particulate formation is observed after storage of the pharmaceutical formulation at -20 °C for at least 36 months. In some embodiments, no observable particulate formation is observed after storage of the pharmaceutical formulation at 4 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation is observed after storage of the pharmaceutical formulation at 25 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation is observed after storage of the pharmaceutical formulation at 30 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation is observed after storage of the pharmaceutical formulation at 37 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation is observed after storage of the pharmaceutical formulation at 40 °C for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation is observed after storage of the pharmaceutical formulation at 4 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation is observed after storage of the pharmaceutical formulation at 25 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52WSGR Docket No.47991-744.601 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation is observed after storage of the pharmaceutical formulation at 30 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation is observed after storage of the pharmaceutical formulation at 37 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years. In some embodiments, no observable particulate formation is observed after storage of the pharmaceutical formulation at 40 °C at 55%, 60%, 65%, 70% or 75% relative humidity for at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

[0344] In some embodiments, the ASO is solubilized in a buffer without Na2HPO4and / or NaH2PO4.

[0345] In some embodiments, the ASO is solubilized or diluted in a buffer further comprising carbohydrates. In some embodiments, the carbohydrates comprise D-glucose. In some embodiments, the ASO is solubilized or diluted in a buffer further comprising 1-100 mM D-glucose.

[0346] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 1-100 mM D-glucose.

[0347] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 1-100, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mM D-glucose. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 2-100, 3-100, 4-100, 5-100, 6-100, 7-100, 8-100, 9- 100, 10-100, 11-100, 12-100, 13-100, 14-100, 15-100, 16-100, 17-100, 18-100, 19-100, 20-100, 21-100, 22-100, 23-100, 24-100, 25-100, 26-100, 29-100, 28-100, 29-100, 30-100, 35-100, 40-100, 45-100, 50- 100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM D-glucose. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 2-30, 3- 30, 4-30, 5-30, 6-30, 7-30, 8-30, 9-30, 10-30, 11-30, 12-30, 13-30, 14-30, 15-30, 16-30, 17-30, 18-30, 19- 30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, or 29-30 mM D-glucose. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 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, or 30 mM D- glucose. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 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, or 30 mM D-glucose. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 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, or 30 mM D-glucose.WSGR Docket No.47991-744.601

[0348] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 1-100, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mM glucose. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 2-100, 3-100, 4-100, 5-100, 6-100, 7-100, 8-100, 9- 100, 10-100, 11-100, 12-100, 13-100, 14-100, 15-100, 16-100, 17-100, 18-100, 19-100, 20-100, 21-100, 22-100, 23-100, 24-100, 25-100, 26-100, 29-100, 28-100, 29-100, 30-100, 35-100, 40-100, 45-100, 50- 100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM glucose. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 2-30, 3-30, 4- 30, 5-30, 6-30, 7-30, 8-30, 9-30, 10-30, 11-30, 12-30, 13-30, 14-30, 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, or 29-30 mM glucose. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 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, or 30 mM glucose. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 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, or 30 mM glucose. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 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, or 30 mM glucose.

[0349] In some embodiments, the ASO is solubilized or diluted in a buffer comprising 25-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM Na2HPO4, 0.1-50 mM NaH2PO4, 0.1-50 mM CaCl2, and 0.1-50 mM MgCl2.

[0350] In some embodiments, the ASO is solubilized or diluted in a buffer comprising 150 mM NaCl, 3.0 mM KCl, 0.7 mM Na2HPO4, 0.3 mM NaH2PO4, 0.79 mM MgCl2, and 1.4 mM CaCl2.

[0351] In some embodiments, the ASO is solubilized or diluted in a buffer further comprising an antioxidant. In some embodiments, the antioxidant is t-butylhydroxyquinoline (TBHQ), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or any combination thereof. In some embodiments, the ASO is solubilized or diluted in a buffer further comprising an antioxidant, wherein the antioxidant is ascorbic acid (vitamin C), glutathione, lipoic acid, uric acid, carotenes, α-tocopherol (vitamin E), ubiquinol (coenzyme Q), or any combination thereof.

[0352] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 25-250 mM NaCl, 0.1-20 mM KCl, 0-50 mM KH2PO4, 1-100 mM NaHCO3, 0-50 mM Na2HPO4, 1-100 mM D-glucose, 0.1-50 mM CaCl2, 0.1-50 mM MgCl2, or any combination thereof.

[0353] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 25-250 mM NaCl, 0.1-20 mM KCl, 0-50 mM KH2PO4, 1-100 mM NaHCO3, 0-50 mM Na2HPO4, 1-100 mM D-glucose, 0.1-50 mM CaCl2, and 0.1-50 mM MgCl2.

[0354] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 127 mM NaCl, 1.0 mM KCl, 1.2 mM KH2PO4, 26 mM NaHCO3, 10 mM D-glucose, 2.4 mM CaCl2, and 1.3 mM MgCl2.WSGR Docket No.47991-744.601

[0355] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 119 mM NaCl, 26.2 mM NaHCO3, 2.5 mM KCl, 1 mM NaH2PO4, 1.3 mM MgCl2, 10 mM glucose, and 2.5 mM CaCl2.

[0356] In some embodiments, the pharmaceutical composition does not comprise a preservative. In some embodiments, the pharmaceutical composition comprises a preservative.

[0357] In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of from 5-250 mg / mL.

[0358] In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of from 5-250, 5-247.5, 5-245, 5-242.5, 5-240, 5-237.5, 5-235, 5-232.5, 5-230, 5- 227.5, 5-225, 5-225.5, 5-220, 5-217.5, 5-215, 5-212.5, 5-210, 5-205.5, 5-205, 5-202.5, 5-200, 5-197.5, 5- 195, 5-192.5, 5-190, 5-187.5, 5-185, 5-182.5, 5-180, 5-177.5, 5-175, 5-172.5, 5-170, 5-167.5, 5-165, 5- 162.5, 5-160, 5-157.5, 5-155, 5-152.5, 5-150, 5-147.5, 5-145, 5-142.5, 5-140, 5-137.5, 5-135, 5-132.5, 5- 130, 5-127.5, 5-125, 5-122.5, 5-120, 5-117.5, 5-115, 5-112.5, 5-110, 5-107.5, 5-105, 5-102.5, 5-100, 5- 97.5, 5-95, 5-92.5, 5-90, 5-87.5, 5-85, 5-82.5, 5-80, 5-77.5, 5-75, 5-72.5, 5-70, 5-67.5, 5-65, 5-62.5, 5-60, 5-57.5, 5-55, 5-52.5, 5-50, 5-47.5, 5-45, 5-42.5, 5-40, 5-37.5, 5-35, 5-32.5, 5-30, 5-27.5, 5-25, 5-22.5, 5- 20, 5-17.5, 5-15, 5-12.5, or 5-10 mg / mL. In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of from 10-250, 15-250, 20-250, 25-250, 30-250, 35-250, 40-250, 45-250, 50-250, 55-250, 60-250, 65-250, 70-250, 75-250, 80-250, 85-250, 90-250, 95- 250, 100-250, 105-250, 110-250, 115-250, 120-250, 125-250, 130-250, 135-250, 140-250, 145-250, 150- 250, 155-250, 160-250, 165-250, 170-250, 175-250, 180-250, 185-250, 190-250, or 195-250, 200-250, 205-250, 210-250, 215-250, 220-250, 225-250, 230-250, 235-250, 240-250, or 245-250 mg / mL. In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of from at least 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, 110, 111, 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, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL. In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of from at most 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, 110, 111, 112, 113, 114, 115,WSGR Docket No.47991-744.601 116, 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, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL. In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of from 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, 110, 111, 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, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL.

[0359] In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of from 0.1 mg / mL to 250 mg / mL. In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, or 20 mg / mL. In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of about 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, or 200 mg / mL. In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of about 11 mg / mL, 22 mg / mL, 33 mg / mL, 44 mg / mL, 55 mg / mL, 66 mg / mL, 77 mg / mL, 88 mg / mL, 99 mg / mL, or 100 mg / mL in the diluent.

[0360] In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of from 0.1 mg / mL to 250 mg / mL, from 0.2 mg / mL to 250 mg / mL, from 0.3 mg / mL to 250 mg / mL, from 0.4 mg / mL to 250 mg / mL, from 0.5 mg / mL to 250 mg / mL, from 0.6 mg / mL to 250 mg / mL, from 0.7 mg / mL to 250 mg / mL, from 0.8 mg / mL to 250 mg / mL, from 0.9 mg / mL to 250 mg / mL, from 1.0 mg / mL to 250 mg / mL, from 1.1 mg / mL to 250 mg / mL, from 1.2 mg / mL to 250 mg / mL, from 1.3 mg / mL to 250 mg / mL, from 1.4 mg / mL to 250 mg / mL, from 1.5 mg / mL to 250 mg / mL, from 1.6 mg / mL to 250 mg / mL, from 1.7 mg / mL to 250 mg / mL, from 1.8 mg / mL to 250 mg / mL, from 1.9 mg / mL to 250 mg / mL, from 2.0 mg / mL to 250 mg / mL, from 2.1 mg / mL to 250WSGR Docket No.47991-744.601 mg / mL, from 2.2 mg / mL to 250 mg / mL, from 2.3 mg / mL to 250 mg / mL, from 2.4 mg / mL to 250 mg / mL, from 2.5 mg / mL to 250 mg / mL, from 2.6 mg / mL to 250 mg / mL, from 2.7 mg / mL to 250 mg / mL, from 2.8 mg / mL to 250 mg / mL, from 2.9 mg / mL to 250 mg / mL, from 3.0 mg / mL to 250 mg / mL, from 3.1 mg / mL to 250 mg / mL, from 3.2 mg / mL to 250 mg / mL, from 3.3 mg / mL to 250 mg / mL, from 3.4 mg / mL to 250 mg / mL, from 3.5 mg / mL to 250 mg / mL, from 3.6 mg / mL to 250 mg / mL, from 3.7 mg / mL to 250 mg / mL, from 3.8 mg / mL to 250 mg / mL, from 3.9 mg / mL to 250 mg / mL, from 4.0 mg / mL to 250 mg / mL, from 5.0 mg / mL to 250 mg / mL, from 6.0 mg / mL to 250 mg / mL, from 7.0 mg / mL to 250 mg / mL, from 8.0 mg / mL to 250 mg / mL, from 9.0 mg / mL to 250 mg / mL, from 10 mg / mL to 250 mg / mL, from 15 mg / mL to 250 mg / mL, from 20 mg / mL to 250 mg / mL, from 25 mg / mL to 250 mg / mL, from 30 mg / mL to 250 mg / mL, from 35 mg / mL to 250 mg / mL, from 40 mg / mL to 250 mg / mL, from 45 mg / mL to 250 mg / mL, from 50 mg / mL to 250 mg / mL, from 55 mg / mL to 250 mg / mL, from 60 mg / mL to 250 mg / mL, from 65 mg / mL to 250 mg / mL, from 70 mg / mL to 250 mg / mL, from 75 mg / mL to 250 mg / mL, from 80 mg / mL to 250 mg / mL, from 85 mg / mL to 250 mg / mL, from 90 mg / mL to 250 mg / mL, from 95 mg / mL to 250 mg / mL, from 100 mg / mL to 250 mg / mL, from 105 mg / mL to 250 mg / mL, from 110 mg / mL to 250 mg / mL, from 115 mg / mL to 250 mg / mL, from 120 mg / mL to 250 mg / mL, from 125 mg / mL to 250 mg / mL, from 130 mg / mL to 250 mg / mL, from 135 mg / mL to 250 mg / mL, from 140 mg / mL to 250 mg / mL, from 145 mg / mL to 250 mg / mL, from 150 mg / mL to 250 mg / mL, from 155 mg / mL to 250 mg / mL, from 160 mg / mL to 250 mg / mL, from 165 mg / mL to 250 mg / mL, from 170 mg / mL to 250 mg / mL, from 175 mg / mL to 250 mg / mL, from 180 mg / mL to 250 mg / mL, from 185 mg / mL to 250 mg / mL, from 190 mg / mL to 250 mg / mL, from 195 mg / mL to 250 mg / mL, from 200 mg / mL to 250 mg / mL, from 205 mg / mL to 250 mg / mL, from 210 mg / mL to 250 mg / mL, from 215 mg / mL to 250 mg / mL, from 220 mg / mL to 250 mg / mL, from 225 mg / mL to 250 mg / mL, from 230 mg / mL to 250 mg / mL, from 235 mg / mL to 250 mg / mL, from 240 mg / mL to 250 mg / mL, or from 245 mg / mL to 250 mg / mL.

[0361] In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of from 0.1 mg / mL to 250 mg / mL, from 0.1 mg / mL to 245 mg / mL, from 0.1 mg / mL to 240 mg / mL, from 0.1 mg / mL to 235 mg / mL, from 0.1 mg / mL to 230 mg / mL, from 0.1 mg / mL to 225 mg / mL, from 0.1 mg / mL to 220 mg / mL, from 0.1 mg / mL to 215 mg / mL, from 0.1 mg / mL to 210 mg / mL, from 0.1 mg / mL to 205 mg / mL, from 0.1 mg / mL to 200 mg / mL, from 0.1 mg / mL to 195 mg / mL, from 0.1 mg / mL to 190 mg / mL, from 0.1 mg / mL to 185 mg / mL, from 0.1 mg / mL to 180 mg / mL, from 0.1 mg / mL to 175 mg / mL, from 0.1 mg / mL to 170 mg / mL, from 0.1 mg / mL to 165 mg / mL, from 0.1 mg / mL to 160 mg / mL, from 0.1 mg / mL to 155 mg / mL, from 0.1 mg / mL to 150 mg / mL, from 0.1 mg / mL to 145 mg / mL, from 0.1 mg / mL to 140 mg / mL, from 0.1 mg / mL to 135 mg / mL, from 0.1 mg / mL to 130 mg / mL, from 0.1 mg / mL to 125 mg / mL, from 0.1 mg / mL to 120 mg / mL, from 0.1 mg / mL to 115 mg / mL, from 0.1 mg / mL to 110 mg / mL, from 0.1 mg / mL to 100 mg / mL, from 0.1 mg / mL to 95 mg / mL, from 0.1 mg / mL to 90 mg / mL, from 0.1 mg / mL to 85 mg / mL, from 0.1 mg / mL to 80 mg / mL, from 0.1 mg / mL to 75 mg / mL, from 0.1 mg / mL to 70 mg / mL, from 0.1 mg / mL to 65 mg / mL, from 0.1 mg / mL to 60 mg / mL, from 0.1 mg / mL to 55 mg / mL, from 0.1 mg / mL toWSGR Docket No.47991-744.601 50 mg / mL, from 0.1 mg / mL to 45 mg / mL, from 0.1 mg / mL to 40 mg / mL, from 0.1 mg / mL to 35 mg / mL, from 0.1 mg / mL to 30 mg / mL, from 0.1 mg / mL to 25 mg / mL, from 0.1 mg / mL to 20 mg / mL, from 0.1 mg / mL to 15 mg / mL, from 0.1 mg / mL to 10 mg / mL, from 0.1 mg / mL to 9 mg / mL, from 0.1 mg / mL to 8 mg / mL, from 0.1 mg / mL to 7 mg / mL, from 0.1 mg / mL to 6 mg / mL, from 0.1 mg / mL to 5 mg / mL, from 0.1 mg / mL to 4 mg / mL, from 0.1 mg / mL to 3.9 mg / mL, from 0.1 mg / mL to 3.8 mg / mL, from 0.1 mg / mL to 3.7 mg / mL, from 0.1 mg / mL to 3.6 mg / mL, from 0.1 mg / mL to 3.5 mg / mL, from 0.1 mg / mL to 3.4 mg / mL, from 0.1 mg / mL to 3.3 mg / mL, from 0.1 mg / mL to 3.2 mg / mL, from 0.1 mg / mL to 3.1 mg / mL, from 0.1 mg / mL to 3.0 mg / mL, from 0.1 mg / mL to 2.9 mg / mL, from 0.1 mg / mL to 2.8 mg / mL, from 0.1 mg / mL to 2.7 mg / mL, from 0.1 mg / mL to 2.6 mg / mL, from 0.1 mg / mL to 2.5 mg / mL, from 0.1 mg / mL to 2.4 mg / mL, from 0.1 mg / mL to 2.3 mg / mL, from 0.1 mg / mL to 2.2 mg / mL, from 0.1 mg / mL to 2.1 mg / mL, from 0.1 mg / mL to 2.0 mg / mL, from 0.1 mg / mL to 1.9 mg / mL, from 0.1 mg / mL to 1.8 mg / mL, from 0.1 mg / mL to 1.7 mg / mL, from 0.1 mg / mL to 1.6 mg / mL, from 0.1 mg / mL to 1.5 mg / mL, from 0.1 mg / mL to 1.4 mg / mL, from 0.1 mg / mL to 1.3 mg / mL, from 0.1 mg / mL to 1.2 mg / mL, from 0.1 mg / mL to 1.1 mg / mL, from 0.1 mg / mL to 1.0 mg / mL, from 0.1 mg / mL to 0.9 mg / mL, from 0.1 mg / mL to 0.8 mg / mL, from 0.1 mg / mL to 0.7 mg / mL, from 0.1 mg / mL to 0.6 mg / mL, from 0.1 mg / mL to 0.5 mg / mL, from 0.1 mg / mL to 0.4 mg / mL, from 0.1 mg / mL to 0.3 mg / mL, or from 0.1 mg / mL to 0.2 mg / mL.

[0362] In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of at least 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, 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, 110, 111, 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, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL in the diluent. In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of at most 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, 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, 110, 111, 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,WSGR Docket No.47991-744.601 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL in the diluent. In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of 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, 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, 110, 111, 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, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL in the diluent.

[0363] Pharmaceutical compositions comprising the agent, e.g., antisense oligonucleotide or antisense oligomer, of the described compositions and for use in any of the described methods can be prepared according to conventional techniques well-known in the pharmaceutical industry and described in the published literature. In some embodiments, a pharmaceutical composition for treating a subject comprises an effective amount of any antisense oligomer as described herein, or a pharmaceutically acceptable salt, solvate, hydrate or ester thereof. In some embodiments, the pharmaceutical composition described herein further comprises a pharmaceutically acceptable excipient, carrier, or diluent.

[0364] Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. A proper formulation is dependent upon the route of administration chosen and a summary of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference. In some embodiments, the pharmaceutical composition facilitates administration of the compound to an organism.

[0365] Such compositions may comprise buffers such as neutral buffered saline, phosphate buffered saline and the like; carbohydrates such as glucose, mannose, sucrose or dextrans, mannitol; proteins;WSGR Docket No.47991-744.601 polypeptides or amino acids such as glycine; antioxidants; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and preservatives.

[0366] The terms “pharmaceutical composition” and “pharmaceutical formulation” (or “formulation”) are used interchangeably and denote a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with one or more pharmaceutically acceptable excipients to be administered to a subject, e.g., a human in need thereof.

[0367] The term “pharmaceutically acceptable” denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use. “Pharmaceutically acceptable” can refer a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0368] The terms “pharmaceutically acceptable excipient,” “pharmaceutically acceptable carrier,” and “therapeutically inert excipient” can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents, excipients, preservatives, or lubricants used in formulating pharmaceutical products.

[0369] In some embodiments, the compositions are prepared with carriers that will protect the components of the composition against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral anti-gens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811, of which entire content is incorporated herein by reference.

[0370] Pharmaceutical compositions or formulations comprising the agent, e.g., antisense oligonucleotide, of the described compositions and for use in any of the described methods can be prepared according to conventional techniques well-known in the pharmaceutical industry and described in the published literature. In embodiments, a pharmaceutical composition or formulation for treating a subject comprises an effective amount of any antisense oligomer as described herein, or a pharmaceutically acceptable salt, solvate, hydrate or ester thereof. The pharmaceutical formulation comprising an antisense oligomer may further comprise a pharmaceutically acceptable excipient, diluent or carrier.WSGR Docket No.47991-744.601

[0371] Pharmaceutically acceptable salts are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio. (See, e.g., S. M. Berge, et al., J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference for this purpose. The salts can be prepared in situ during the final isolation and purification of the compounds, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other documented methodologies such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0372] In some embodiments, provided herein is a method of producing the pharmaceutical composition as described herein. Pharmaceutical Formulation

[0373] In some aspects, provided herein is a pharmaceutical formulation comprising: an antisense oligomer (ASO as described herein), wherein the ASO as described herein comprises a sequence with at least 80% sequence identity to any one of SEQ ID NOs: 21-67, 210-256 or 304-1099; and a pharmaceutically acceptable diluent; wherein about 0.1, 0.5, 1, 2.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60, 62.5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102.5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127.5, 130, 132.5, 135, 137.5, 140, 142.5, 145, 147.5, 150, 152.5, 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190, 192.5, 195, 197.5, 200, 202.5, 205, 207.5, 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5, 245, 247.5, or 250 mg of the ASO as described herein is dissolved or suspended in a solution at a concentration of from 0.1-250 mg / mL. In some embodiments, the ASO as described herein comprises a sequence with at least 80% sequence identity to any one of the sequences listed in listed in Tables 4A, 4B, 5A, 5B, 6A, 6B, 7, 8A, and 8B.WSGR Docket No.47991-744.601

[0374] In some embodiments, the ASO as described herein comprises a sequence with at least 60%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 884%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100% sequence identity to any one of SEQ ID NOs: 21-67, 210-256 or 304- 1099. In some embodiments, the ASO as described herein consists of a sequence with at least 60%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 884%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100% sequence identity to any one of SEQ ID NOs: 21-67, 210-256 or 304-1099. In some embodiments, the ASO as described herein consists of a sequence with at least 60%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 884%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100% sequence identity to any one of the sequences listed in listed in Tables 4A, 4B, 5A, 5B, 6A, 6B, 7, 8A, and 8B.

[0375] In some embodiments, the ASO as described herein is a compound having the structure depicted in formula (I) (free acid):(I), or a salt thereof.

[0376] In some embodiments, the ASO as described herein is a compound having the structure depicted in formula (II) (sodium salt):WSGR Docket No.47991-744.601(II).

[0377] In any of the structural formulae (graphic representation of a chemical compound) presented herein, where two curved lines and a straight line in between them are used to connect a phosphorus atom (“P”) and an oxygen atom (“O”), the two curved line and the straight line therebetween should be seen as a single integral segment, representing the covalent bond between the phosphorus atom and the oxygen atom, which is part of a backbone linkage (e.g., phosphodiester linkage or phosphorothioate linkage) between two neighboring nucleotides. Any of the vertices (corners) in any of those structural formulae where a curved line and a straight line join does not represent carbon atom or presence of -CH2- at the relevant location in the compound the structural formula represents.

[0378] In some cases, an ASO described herein is all-P-ambo-2'-O-(2-methoxyethyl)-P-thioadenylyl- (3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl- (3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl- (3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')- 2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')- 2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2- methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2- methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')- 2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')- 2'-O-(2-methoxyethyl)-5-methylcytidine, or a salt thereof.

[0379] In some cases, an ASO described herein is a sodium salt of all-P-ambo-2'-O-(2-methoxyethyl)- P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl- P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)- P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-WSGR Docket No.47991-744.601 thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P- thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P- thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-P- thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5- methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5- methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methylcytidine.

[0380] In some embodiments, about 1-500, 2-500, 3-500, 4-500, 5-500, 6-500, 7-500, 8-500, 9-500, 10- 500, 15-500, 20-500, 25-500, 30-500, 35-500, 40-500, 45-500, 50-500, 55-500, 60-500, 65-500, 70-500, 75-500, 80-500, 85-500, 90-500, 95-500, 100-500, 105-500, 110-500, 115-500, 120-500, 125-500, 130- 500, 135-500, 140-500, 145-500, 150-500, 155-500, 160-500, 165-500, 170-500, 175-500, 180-500, 185- 500, 190-500, 195-500, 205-500, 210-500, 215-500, 220-500, 225-500, 230-500, 235-500, 240-500, 245- 500, 250-500, 255-500, 260-500, 265-500, 270-500, 275-500, 280-500, 285-500, 290-500, 295-500, 300- 500, 305-500, 310-500, 315-500, 320-500, 325-500, 330-500, 335-500, 340-500, 345-500, 350-500, 355- 500, 360-500, 365-500, 370-500, 375-500, 380-500, 385-500, 390-500, 395-500, 400-500, 405-500, 410- 500, 415-500, 420-500, 425-500, 430-500, 435-500, 440-500, 445-500, 450-500, 455-500, 460-500, 465- 500, 470-500, 475-500, 480-500, 485-500, 490-500, or 495-500 mg of the ASO as described herein is dissolved or suspended in a solution at a concentration of from 5-200 mg / mL. In some embodiments, about 1-495, 1-490, 1-485, 1-480, 1-475, 1-470, 1-465, 1-460, 1-455, 1-450, 1-445, 1-440, 1-435, 1-430, 1-425, 1-420, 1-415, 1-410, 1-405, 1-400, 1-395, 1-390, 1-385, 1-380, 1-375, 1-370, 1-365, 1-360, 1-355, 1-350, 1-345, 1-340, 1-335, 1-330, 1-325, 1-320, 1-315, 1-310, 1-305, 1-300, 1-295, 1-290, 1-285, 1-280, 1-275, 1-270, 1-265, 1-260, 1-255, 1-250, 1-245, 1-240, 1-235, 1-230, 1-225, 1-220, 1-215, 1-210, 1-205, 1-200, 1-195, 1-190, 1-185, 1-180, 1-175, 1-170, 1-165, 1-160, 1-155, 1-150, 1-145, 1-140, 1-135, 1-130, 1-125, 1-120, 1-115, 1-110, 1-105, 1-100, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-0, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mg of the ASO as described herein is dissolved or suspended in a solution at a concentration of from 5-200 mg / mL.

[0381] In some embodiments, at least about 0.1, 0.5, 1, 2.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60, 62.5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102.5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127.5, 130, 132.5, 135, 137.5, 140, 142.5, 145, 147.5, 150, 152.5, 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190, 192.5, 195, 197.5, 200, 202.5, 205, 207.5, 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5, 245, 247.5, or 250 mg of the ASO as described herein is dissolved or suspended in a solution at a concentration of from 0.1-250 mg / mL. In some embodiments, at most about 0.1, 0.5, 1, 2.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60, 62.5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102.5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127.5, 130, 132.5, 135, 137.5, 140, 142.5, 145, 147.5, 150, 152.5, 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190, 192.5, 195, 197.5, 200, 202.5, 205, 207.5, 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5,WSGR Docket No.47991-744.601 245, 247.5, or 250 mg of the ASO as described herein is dissolved or suspended in a solution at a concentration of from 0.1-250 mg / mL. In some embodiments, about 0.1, 0.5, 1, 2.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60, 62.5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102.5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127.5, 130, 132.5, 135, 137.5, 140, 142.5, 145, 147.5, 150, 152.5, 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190, 192.5, 195, 197.5, 200, 202.5, 205, 207.5, 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5, 245, 247.5, or 250 mg of the ASO as described herein is dissolved or suspended in a solution at a concentration of from 0.1-250 mg / mL.

[0382] In some embodiments, the ASO as described herein is dissolved or suspended in a solution at a concentration of from 5-250, 5-247.5, 5-245, 5-242.5, 5-240, 5-237.5, 5-235, 5-232.5, 5-230, 5-227.5, 5- 225, 5-225.5, 5-220, 5-217.5, 5-215, 5-212.5, 5-210, 5-205.5, 5-205, 5-202.5, 5-200, 5-197.5, 5-195, 5- 192.5, 5-190, 5-187.5, 5-185, 5-182.5, 5-180, 5-177.5, 5-175, 5-172.5, 5-170, 5-167.5, 5-165, 5-162.5, 5- 160, 5-157.5, 5-155, 5-152.5, 5-150, 5-147.5, 5-145, 5-142.5, 5-140, 5-137.5, 5-135, 5-132.5, 5-130, 5- 127.5, 5-125, 5-122.5, 5-120, 5-117.5, 5-115, 5-112.5, 5-110, 5-107.5, 5-105, 5-102.5, 5-100, 5-97.5, 5- 95, 5-92.5, 5-90, 5-87.5, 5-85, 5-82.5, 5-80, 5-77.5, 5-75, 5-72.5, 5-70, 5-67.5, 5-65, 5-62.5, 5-60, 5-57.5, 5-55, 5-52.5, 5-50, 5-47.5, 5-45, 5-42.5, 5-40, 5-37.5, 5-35, 5-32.5, 5-30, 5-27.5, 5-25, 5-22.5, 5-20, 5- 17.5, 5-15, 5-12.5, or 5-10 mg / mL. In some embodiments, the ASO as described herein is dissolved or suspended in a solution at a concentration of from 10-250, 15-250, 20-250, 25-250, 30-250, 35-250, 40- 250, 45-250, 50-250, 55-250, 60-250, 65-250, 70-250, 75-250, 80-250, 85-250, 90-250, 95-250, 100-250, 105-250, 110-250, 115-250, 120-250, 125-250, 130-250, 135-250, 140-250, 145-250, 150-250, 155-250, 160-250, 165-250, 170-250, 175-250, 180-250, 185-250, 190-250, or 195-250, 200-250, 205-250, 210- 250, 215-250, 220-250, 225-250, 230-250, 235-250, 240-250, or 245-250 mg / mL. In some embodiments, the ASO as described herein is dissolved or suspended in a solution at a concentration of from at least 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, 110, 111, 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, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL. In some embodiments, the ASO as described herein is dissolved or suspended in a solution at a concentration of from at most 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,WSGR Docket No.47991-744.601 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, 110, 111, 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, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL. In some embodiments, the ASO as described herein is dissolved or suspended in a solution at a concentration of from 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, 110, 111, 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, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL.

[0383] In some embodiments, the pharmaceutically acceptable diluent comprises an artificial cerebral spinal fluid (aCSF) solution. In some embodiments, the solution comprises a cerebral spinal fluid (CSF) sample from the subject. In some embodiments, the ASO as described herein is solubilized or diluted in an iso-tonic solution.

[0384] In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate- buffered (pH 6.6-7.6) solution. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered (pH 6.0-8.0) solution. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered (pH 5.0-8.0) solution. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 4.5-8.5, pH 4.6-8.5, pH 4.7-8.5, pH 4.8-8.5, pH 4.9-8.5, pH5.0-8.5, pH 5.1-8.5, pH5.2-8.5, pH 5.3-8.5, pH5.4-8.5, pH 5.5-8.5, pH5.6-8.5, pH 5.7-8.5, pH 5.8-8.5, H 5.9-8.5, pH 6.0-8.5, pH 6.1-8.5, pH 6.2-8.5, pH 6.3-8.5, pH 6.4-8.5, pH 6.5-8.5, pH 6.6-8.5, pH 6.7-8.5, pH 6.8-8.5, pH 6.9-8.5, pH 7.0-8.5, pH 7.1-8.5, pH 7.2-8.5, pH 7.3-8.5, pH 7.4-8.5, pH 7.5-8.5, pH 7.6-8.5, pH 7.7-8.5, pH 7.8-8.5, pH 7.9-8.5, pH 8.0-8.5, pH 8.1- 8.5, pH 8.2-8.5, pH 8.3-8.5, or pH 8.4-8.5. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 4.5-8.3, pH 4.5-8.2, pH 4.5-8.1, pH 4.5- 8.0, pH 4.5-7.9, pH 4.5-7.8, pH 4.5-7.7, pH 4.5-7.6, pH 4.5-7.5, pH 4.5-7.4, pH 4.5-7.3, pH 4.5-7.2, pH 4.5-7.1, pH 4.5-7.0, pH 4.5-6.9, pH 4.5-6.8, pH 4.5-6.7, pH 4.5-6.6, pH 4.5-6.5, pH 4.5-6.4, pH 4.5-6.3, pH 4.5-6.2, pH 4.5-6.1, pH 4.5-6.0, pH 4.5-5.9, pH 4.5-5.8, pH 4.5-5.7, pH 4.5-5.6, pH 4.5-5.5, pH 4.5-WSGR Docket No.47991-744.601 5.4, pH 4.5-5.3, pH 4.5-5.2, pH 4.5-5.1, pH 4.5-5.0, pH 4.5-4.9, pH 4.5-4.8, pH 4.5-4.7, or pH 4.5-4.6. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 6.0-7.6, pH 6.1-7.6, pH 6.2-7.6, pH 6.3-7.6, pH 6.4-7.6, pH 6.5-7.6, pH 6.6-7.6, pH 6.7- 7.6, pH 6.8-7.6, pH 6.9-7.6, pH 7.0-7.6, pH 7.1-7.6, pH 7.2-7.6, pH 7.3-7.6, pH 7.4-7.6, or pH 7.5-7.6. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 6.6-8.0, pH 6.6-7.9, pH 6.6-7.8, pH 6.6-7.7, pH 6.6-7.6, pH 6.6-7.5, pH 6.6-7.4, pH 6.6- 7.3, pH 6.6-7.2, pH 6.6-7.1, pH 6.6-7.0, pH 6.6-6.9, pH 6.6-6.8, or pH 6.6-6.7. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 6.0-8.0, pH 6.1-8.0, pH 6.2-8.0, pH 6.3-8.0, pH 6.4-8.0, pH 6.5-8.0, pH 6.6-8.0, pH 6.7-8.0, pH 6.8-8.0, pH 6.9-8.0, pH 7.0-8.0, pH 7.1-8.0, pH 7.2-8.0, pH 7.3-8.0, pH 7.4-8.0, pH 7.5-8.0, pH 7.6-8.0, pH 7.7-8.0, pH 7.8- 8.0, or pH 7.9-8.0. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 6.0-7.9, pH 6.0-7.8, pH 6.0-7.7, pH 6.0-7.6, pH 6.0-7.5, pH 6.0-7.4, pH 6.0-7.3, pH 6.0-7.2, pH 6.0-7.1, pH 6.0-7.0, pH 6.0-6.9, pH 6.0-6.8, pH 6.0-6.7, pH 6.0-6.6, pH 6.0- 6.5, pH 6.0-6.4, pH 6.0-6.3, pH 6.0-6.2, or pH 6.0-6.1. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 5.7-8.5, 5.8-8.4, 5.9-8.3, 6.0-8.2, 6.1-8.1, 6.2-8.0, 6.3-7.9, 6.4-7.8, 6.5-7.7, or 6.6-7.6. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH about 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, or 8.0. In some embodiments, the ASO as described herein is solubilized or diluted in a phosphate-buffered solution with pH 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, or 8.0.

[0385] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 25-250 mM NaCl.

[0386] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 25-250, 30-250, 35-250, 40-250, 45-250, 50-250, 55-250, 60-250, 65-250, 70-250, 75-250, 80-250, 85-250, 90-250, 95-250, 100-250, 105-250, 110-250, 115-250, 120-250, 125-250, 130-250, 135- 250, 140-250, 145-250, 150-250, 155-250, 160-250, 165-250, 170-250, 175-250, 180-250, 185-250, 190- 250, 195-250, 200-250, 205-250, 210-250, 215-250, 220-250, 225-250, 230-250, 235-250, 240-250, or 245-250 mM NaCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 25-245, 25-240, 25-235, 25-230, 25-225, 25-220, 25-215, 25-210, 25-205, 25-200, 25- 195, 25-190, 25-185, 25-180, 25-175, 25-170, 25-165, 25-160, 25-155, 25-150, 25-145, 25-140, 25-135, 25-130, 25-125, 25-120, 25-115, 25-110, 25-105, 25-110, 25-105, 25-100, 25-95, 25-90, 25-85, 25-80, 25-75, 25-70, 25-65, 25-60, 25-55, 25-50, 25-45, 25-40, 25-35, or 25-30 mM NaCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 30-245, 35- 240, 40-235, 45-230, 50-225, 55-220, 60-215, 65-210, 70-205, 75-200, 80-195, 85-190, 90-185, 95-180, 100-175, 105-170, 110-165, 115-160, 120-155, 125-150, 130-145 or 135-140 mM NaCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 100-140, 101- 140, 102-140, 103-140, 104-140, 105-140, 106-140, 107-140, 108-140, 109-140, 110-140, 111-140, 112-WSGR Docket No.47991-744.601 140, 113-140, 114-140, 115-140, 116-140, 117-140, 118-140, 119-140, 120-140, 121-140, 122-140, 123- 140, 124-140, 125-140, 126-140, 127-140, 128-140, 129-140, 130-140, 131-140, 132-140, 133-140, 134- 140, 135-140, 136-140, 137-140, 138-140, or 139-140 mM NaCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 100-139, 100-138, 100-137, 100-136, 100-135, 100-134, 100-133, 100-132, 100-131, 100-130, 100-129, 100-128, 100-127, 100-126, 100-125, 100-124, 100-123, 100-122, 100-121, 100-120, 100-119, 100-118, 100-117, 100-116, 100-115, 100-114, 100-113, 100-112, 100-111, 100-110, 100-109, 100-108, 100-107, 100-106, 100-105, 100-104, 100-103, 100-102, or 100-101 mM NaCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 mM NaCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 mM NaCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 mM NaCl.

[0387] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-20 mM KCl.

[0388] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-40, 0.1-39, 0.1-38, 0.1-37, 0.1-36, 0.1-35, 0.1-34, 0.1-33, 0.1-32, 0.1-31, 0.1-30, 0.1-29, 0.1-28, 0.1-27, 0.1-26, 0.1-25, 0.1-24, 0.1-23, 0.1-22, 0.1-21, 0.1-20, 0.1-19, 0.1-18, 0.1-17, 0.1-16, 0.1- 15, 0.1-14, 0.1-13, 0.1-12, 0.1-10, 0.1-9, 0.1-8, 0.1-7, 0.1-6, 0.1-5, 0.1-4, 0.1-3, 0.1-2, or 0.1-1 mM KCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.2- 40, 0.3-40, 0.4-40, 0.5-40, 0.6-40, 0.7-40, 0.8-40, 0.9-40, 1-40, 2-40, 3-40, 4-40, 5-40, 6-40, 7-40, 8-40, 9-40, 10-40, 11-40, 12-40, 13-40, 14-40, 15-40, 16-40, 17-40, 18-40, 19-40, 20-40, 21-40, 22-40, 23-40, 24-40, 25-40, 26-40, 27-40, 28-40, 29-40, 30-40, 31-40, 32-40, 33-40, 34-40, 35-40, 36-40, 37-40, 38-40, or 39-40 mM KCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-3.5, 0.2-3.5, 0.3-3.5, 0.4-3.5, 0.5-3.5, 0.6-3.5, 0.7-3.5, 0.8-3.5, 0.9-3.5, 1.0-3.5, 1.1-3.5, 1.2-3.5, 1.3-3.5, 1.4-3.5, 1.5-3.5, 1.6-3.5, 1.7-3.5, 1.8-3.5, 1.9-3.5, 2.0-3.5, 2.1-3.5, 2.2-3.5, 2.3- 3.5, 2.4-3.5, 2.5-3.5, 2.6-3.5, 2.7-3.5, 2.8-3.5, 2.9-3.5, 3.0-3.5, 3.1-3.5, 3.2-3.5, 3.3-3.5, or 3.4-3.5 mM KCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-3.4, 0.1-3.3, 0.1-3.2, 0.1-3.1, 0.1-3.0, 0.1-2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1- 2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8, 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM KCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 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,WSGR Docket No.47991-744.601 3.1, 3.2, 3.3, 3.4, or 3.5 mM KCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 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, or 3.5 mM KCl. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 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, or 3.5 mM KCl.

[0389] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-50 mM Na2HPO4.

[0390] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.01-100, 0.02-100, 0.03-100, 0.04-100, 0.05-100, 0.06-100, 0.07-100, 0.08-100, 0.09-100, 0.1-100, 0.2-100, 0.3-100, 0.4-100, 0.5-100, 0.6-100, 0.7-100, 0.8-100, 0.9-100, 1-100, 2-100, 3-100, 4- 100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45- 100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM Na2HPO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.01- 95, 0.01-90, 0.01-85, 0.01-80, 0.01-75, 0.01-70, 0.01-65, 0.01-60, 0.01-55, 0.01-50, 0.01-45, 0.01-40, 0.01-35, 0.01-30, 0.01-25, 0.01-20, 0.01-15, 0.01-10, 0.01-9, 0.01-8, 0.01-7, 0.01-6, 0.01-5, 0.01-4, 0.01- 3, 0.01-2, 0.01-1, 0.01-0.9, 0.01-0.8, 0.01-0.7, 0.01-0.6, 0.01-0.5, 0.01-0.4, 0.01-0.3, 0.01-0.2, 0.01-0.1, 0.01-0.09, 0.01-0.08, 0.01-0.07, 0.01-0.06, 0.01-0.05, 0.01-0.04, 0.01-0.03, or 0.01-0.02 mM Na2HPO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1- 3.0, 0.1-2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1-2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8, 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1- 0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM Na2HPO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-3.0, 0.2-3.0, 0.3-3.0, 0.4-3.0, 0.5-3.0, 0.6-3.0, 0.7-3.0, 0.8-3.0, 0.9-3.0, 1.0-3.0, 1.2-3.0, 1.3-3.0, 1.4-3.0, 1.5-3.0, 1.6-3.0, 1.7-3.0, 1.8-3.0, 1.9-3.0, 2.0-3.0, 2.1- 3.0, 2.2-3.0, 2.3-3.0, 2.4-3.0, 2.5-3.0, 2.6-3.0, 2.7-3.0, 2.8-3.0, or 2.9-3.0 mM Na2HPO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 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, or 3.0 mM Na2HPO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 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, or 3.0 mM Na2HPO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 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, or 3.0 mM Na2HPO4.

[0391] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-50 mM NaH2PO4.

[0392] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.01-100, 0.02-100, 0.03-100, 0.04-100, 0.05-100, 0.06-100, 0.07-100, 0.08-100, 0.09-100, 0.1-100, 0.2-100, 0.3-100, 0.4-100, 0.5-100, 0.6-100, 0.7-100, 0.8-100, 0.9-100, 1-100, 2-100, 3-100, 4-WSGR Docket No.47991-744.601 100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45- 100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.01- 95, 0.01-90, 0.01-85, 0.01-80, 0.01-75, 0.01-70, 0.01-65, 0.01-60, 0.01-55, 0.01-50, 0.01-45, 0.01-40, 0.01-35, 0.01-30, 0.01-25, 0.01-20, 0.01-15, 0.01-10, 0.01-9, 0.01-8, 0.01-7, 0.01-6, 0.01-5, 0.01-4, 0.01- 3, 0.01-2, 0.01-1, 0.01-0.9, 0.01-0.8, 0.01-0.7, 0.01-0.6, 0.01-0.5, 0.01-0.4, 0.01-0.3, 0.01-0.2, 0.01-0.1, 0.01-0.09, 0.01-0.08, 0.01-0.07, 0.01-0.06, 0.01-0.05, 0.01-0.04, 0.01-0.03, or 0.01-0.02 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1- 3.0, 0.1-2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1-2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8, 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1- 0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-3.0, 0.2-3.0, 0.3-3.0, 0.4-3.0, 0.5-3.0, 0.6-3.0, 0.7-3.0, 0.8-3.0, 0.9-3.0, 1.0-3.0, 1.2-3.0, 1.3-3.0, 1.4-3.0, 1.5-3.0, 1.6-3.0, 1.7-3.0, 1.8-3.0, 1.9-3.0, 2.0-3.0, 2.1- 3.0, 2.2-3.0, 2.3-3.0, 2.4-3.0, 2.5-3.0, 2.6-3.0, 2.7-3.0, 2.8-3.0, or 2.9-3.0 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 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, or 3.0 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 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, or 3.0 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 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, or 3.0 mM NaH2PO4.

[0393] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-50 mM CaCl2.

[0394] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-50, 0.2-50, 0.3-50, 0.4-50, 0.5-50, 0.6-50, 0.7-50, 0.8-50, 0.9-50, 1.0-50, -50, 1.1-50, 1.2- 50, 1.3-50, 1.4-50, 1.5-50, 1.6-50, 1.7-50, 1.8-50, 1.9-50, 2.0-50, 2.1-50, 2.2-50, 2.3-50, 2.4-50, 2.5-50, 2.6-50, 2.7-50, 2.8-50, 2.9-50, 3.0-50, 3.1-50, 3.2-50, 3.3-50, 3.4-50, 3.5-50, 3.6-50, 3.7-50, 3.8-50, 3.9- 50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 15-50, 20-50, 25-50, 130-50, 35-50, 40-50, or 45-50 mM CaCl2. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-45, 0.1-40, 0.1-35, 0.1-30, 0.1-25, 0.1-20, 0.1-15, 0.1-10, 0.1-5, 0.1-4, 0.1-4.9, 0.1-4.8, 0.1-4.7, 0.1-4.6, 0.1-4.5, 0.1-4.4, 0.1-4.3, 0.1-4.2, 0.1-4.1, 0.1-4.0, 0.1-3.9, 0.1-3.8, 0.1-3.7, 0.1-3.6, 0.1- 3.5, 0.1-3.4, 0.1-3.3, 0.1-3.2, 0.1-3.1, 0.1-3.0, 0.1-2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1-2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8, 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1- 1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM CaCl2. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 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, or 4.0 mM CaCl2. In some embodiments, the ASO as described herein isWSGR Docket No.47991-744.601 solubilized or diluted in a buffer comprising at most 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, or 4.0 mM CaCl2. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 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, or 4.0 mM CaCl2.

[0395] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-50 mM MgCl2.

[0396] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-50, 0.2-50, 0.3-50, 0.4-50, 0.5-50, 0.6-50, 0.7-50, 0.8-50, 0.9-50, 1.0-50, -50, 1.1-50, 1.2- 50, 1.3-50, 1.4-50, 1.5-50, 1.6-50, 1.7-50, 1.8-50, 1.9-50, 2.0-50, 2.1-50, 2.2-50, 2.3-50, 2.4-50, 2.5-50, 2.6-50, 2.7-50, 2.8-50, 2.9-50, 3.0-50, 3.1-50, 3.2-50, 3.3-50, 3.4-50, 3.5-50, 3.6-50, 3.7-50, 3.8-50, 3.9- 50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 10-50, 15-50, 20-50, 25-50, 130-50, 35-50, 40-50, or 45-50 mM MgCl2. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-45, 0.1-40, 0.1-35, 0.1-30, 0.1-25, 0.1-20, 0.1-15, 0.1-10, 0.1-5, 0.1-4, 0.1-4.9, 0.1-4.8, 0.1-4.7, 0.1-4.6, 0.1-4.5, 0.1-4.4, 0.1-4.3, 0.1-4.2, 0.1-4.1, 0.1-4.0, 0.1-3.9, 0.1-3.8, 0.1-3.7, 0.1-3.6, 0.1- 3.5, 0.1-3.4, 0.1-3.3, 0.1-3.2, 0.1-3.1, 0.1-3.0, 0.1-2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1-2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8, 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1- 1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM MgCl2. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 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, or 4.0 mM MgCl2. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 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, or 4.0 mM MgCl2. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 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, or 4.0 mM MgCl2.

[0397] In some embodiments, the ASO is solubilized or diluted in a buffer further comprising 1-100 mM NaHCO3, 1-100 mM KHCO3, or a combination thereof.

[0398] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 1-100 mM NaHCO3.

[0399] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 1-99, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mM NaHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 2-100, 3-100, 4-100, 5-100, 6-100, 7- 100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60- 100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM NaHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 24.0-28.0, 24.0-27.9, 24.0-WSGR Docket No.47991-744.601 27.8, 24.0-27.7, 24.0-27.6, 24.0-27.5, 24.0-27.4, 24.0-27.3, 24.0-27.2, 24.0-27.1, 24.0-27.0, 24.0-26.9, 24.0-26.8, 24.0-26.7, 24.0-26.6, 24.0-26.5, 24.0-26.4, 24.0-26.3, 24.0-26.2, 24.0-26.1, 24.0-26.0, 24.0- 25.9, 4.0-25.8, 24.0-25.7, 24.0-25.6, 24.0-25.5, 24.0-25.4, 24.0-25.3, 24.0-25.2, 24.0-25.1, 24.0-25.0, 24.0-24.9, 24.0-24.8, 24.0-24.7, 24.0-24.6, 24.0-24.5, 24.0-24.4, 24.0-24.3, 24.0-24.2, or 24.0-24.1 mM NaHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 24.1-28.0, 24.2-28.0, 24.3-28.0, 24.4-28.0, 24.5-28.0, 24.6-28.0, 24.7-28.0, 24.8-28.0, 24.9- 28.0, 25.0-28.0, 25.1-28.0, 25.2-28.0, 25.3-28.0, 25.4-28.0, 25.5-28.0, 25.6-28.0, 25.7-28.0, 25.8-28.0, 25.9-28.0, 26.0-28.0, 26.1-28.0, 26.2-28.0, 26.3-28.0, 26.4-28.0, 26.5-28.0, 26.6-28.0, 26.7-28.0, 26.8- 28.0, 26.9-28.0, 27.0-28.0, 27.1-28.0, 27.2-28.0, 27.3-28.0, 27.4-28.0, 27.5-28.0, 27.6-28.0, 27.7-28.0, 27.8-28.0, or 27.9-28.0 mM NaHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM NaHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM NaHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM NaHCO3.

[0400] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 1-100 mM KHCO3.

[0401] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 1-99, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mM KHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 2-100, 3-100, 4-100, 5-100, 6-100, 7- 100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60- 100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM KHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 24.0-28.0, 24.0-27.9, 24.0-27.8, 24.0-27.7, 24.0-27.6, 24.0-27.5, 24.0-27.4, 24.0-27.3, 24.0-27.2, 24.0-27.1, 24.0-27.0, 24.0-26.9, 24.0- 26.8, 24.0-26.7, 24.0-26.6, 24.0-26.5, 24.0-26.4, 24.0-26.3, 24.0-26.2, 24.0-26.1, 24.0-26.0, 24.0-25.9, 4.0-25.8, 24.0-25.7, 24.0-25.6, 24.0-25.5, 24.0-25.4, 24.0-25.3, 24.0-25.2, 24.0-25.1, 24.0-25.0, 24.0- 24.9, 24.0-24.8, 24.0-24.7, 24.0-24.6, 24.0-24.5, 24.0-24.4, 24.0-24.3, 24.0-24.2, or 24.0-24.1 mM KHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 24.1-28.0, 24.2-28.0, 24.3-28.0, 24.4-28.0, 24.5-28.0, 24.6-28.0, 24.7-28.0, 24.8-28.0, 24.9- 28.0, 25.0-28.0, 25.1-28.0, 25.2-28.0, 25.3-28.0, 25.4-28.0, 25.5-28.0, 25.6-28.0, 25.7-28.0, 25.8-28.0, 25.9-28.0, 26.0-28.0, 26.1-28.0, 26.2-28.0, 26.3-28.0, 26.4-28.0, 26.5-28.0, 26.6-28.0, 26.7-28.0, 26.8- 28.0, 26.9-28.0, 27.0-28.0, 27.1-28.0, 27.2-28.0, 27.3-28.0, 27.4-28.0, 27.5-28.0, 27.6-28.0, 27.7-28.0,WSGR Docket No.47991-744.601 27.8-28.0, or 27.9-28.0 mM KHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM KHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM KHCO3. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, or 28.0 mM KHCO3.

[0402] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-50 mM KH2PO4.

[0403] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-100, 0.01-100, 0.02-100, 0.03-100, 0.04-100, 0.05-100, 0.06-100, 0.07-100, 0.08-100, 0.09- 100, 0.1-100, 0.2-100, 0.3-100, 0.4-100, 0.5-100, 0.6-100, 0.7-100, 0.8-100, 0.9-100, 1-100, 2-100, 3- 100, 4-100, 5-100, 6-100, 7-100, 8-100, 9-100, 10-100, 15-100, 20-100, 25-100, 30-100, 35-100, 40-100, 45-100, 50-100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-95, 0-90, 0-85, 0-80, 0-75, 0-70, 0-65, 0-60, 0-55, 0-50, 0-45, 0-40, 0-35, 0-30, 0-25, 0-20, 0-15, 0-10, 0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0-1, 0-0.9, 0-0.8, 0-0.7, 0-0.6, 0-0.5, 0-0.4, 0-0.3, 0-0.2, 0-0.1, 0-0.09, 0-0.08, 0-0.07, 0-0.06, 0-0.05, 0-0.04, 0-0.03, or 0-0.02 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.01-95, 0.01- 90, 0.01-85, 0.01-80, 0.01-75, 0.01-70, 0.01-65, 0.01-60, 0.01-55, 0.01-50, 0.01-45, 0.01-40, 0.01-35, 0.01-30, 0.01-25, 0.01-20, 0.01-15, 0.01-10, 0.01-9, 0.01-8, 0.01-7, 0.01-6, 0.01-5, 0.01-4, 0.01-3, 0.01-2, 0.01-1, 0.01-0.9, 0.01-0.8, 0.01-0.7, 0.01-0.6, 0.01-0.5, 0.01-0.4, 0.01-0.3, 0.01-0.2, 0.01-0.1, 0.01-0.09, 0.01-0.08, 0.01-0.07, 0.01-0.06, 0.01-0.05, 0.01-0.04, 0.01-0.03, or 0.01-0.02 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-3.0, 0-2.9, 0-2.8, 0-2.7, 0-2.6, 0-2.5, 0-2.4, 0-2.3, 0-2.2, 0-2.1, 0-2.0, 0-1.9, 0-1.8, 0-1.7, 0-1.6, 0-1.5, 0-1.4, 0-1.3, 0- 1.2, 0-1.1, 0-1.0, 0-0.9, 0-0.8, 0-0.7, 0-0.6, 0-0.5, 0-0.4, 0-0.3, or 0-0.2 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-3.0, 0.1- 2.9, 0.1-2.8, 0.1-2.7, 0.1-2.6, 0.1-2.5, 0.1-2.4, 0.1-2.3, 0.1-2.2, 0.1-2.1, 0.1-2.0, 0.1-1.9, 0.1-1.8, 0.1-1.7, 0.1-1.6, 0.1-1.5, 0.1-1.4, 0.1-1.3, 0.1-1.2, 0.1-1.1, 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1- 0.4, 0.1-0.3, or 0.1-0.2 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-3.0, 0.1-3.0, 0.2-3.0, 0.3-3.0, 0.4-3.0, 0.5-3.0, 0.6-3.0, 0.7-3.0, 0.8-3.0, 0.9-3.0, 1.0-3.0, 1.2-3.0, 1.3-3.0, 1.4-3.0, 1.5-3.0, 1.6-3.0, 1.7-3.0, 1.8-3.0, 1.9-3.0, 2.0-3.0, 2.1-3.0, 2.2- 3.0, 2.3-3.0, 2.4-3.0, 2.5-3.0, 2.6-3.0, 2.7-3.0, 2.8-3.0, or 2.9-3.0 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 0, 0.1, 0.2, 0.3, 0.4, 0.5,WSGR Docket No.47991-744.601 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, or 3.0 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 0, 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, or 3.0 mM KH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 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, or 3.0 mM KH2PO4.

[0404] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-50 mM NaH2PO4.

[0405] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-50, 0-45, 0-40, 0-35, 0-30, 0-25, 0-20, 0-19, 0-18, 0-17, 0-16, 0-15, 0-14, 0-13, 0-12, 0-11, 0-10, 0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0-1, 0-0.9, 0-0.8, 0-0.7, 0-0.6, 0-0.5, 0-0.4, 0-0.3, or 0-0.2 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0.1-50, 0.1-45, 0.1-40, 0.1-35, 0.1-30, 0.1-25, 0.1-20, 0.1-19, 0.1-18, 0.1-17, 0.1-16, 0.1-15, 0.1-14, 0.1-13, 0.1-12, 0.1-11, 0.1-10, 0.1-9, 0.1-8, 0.1-7, 0.1-6, 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-50, 0.1-50, 0.2-50, 0.3-50, 0.4- 50, 0.5-50, 0.6-50, 0.7-50, 0.8-50, 0.9-50, 1-50, 2-50, 3-50, 4-50, 5-50, 6-50, 7-50, 8-50, 9-50, 1-50, 11- 50, 12-50, 13-50, 14-50, 15-50, 16-50, 17-50, 18-50, 19-50, 20-50, 25-50, 30-50, 35-50, 40-50, or 45-50 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0-20, 0.1-20, 0.2-20, 0.3-20, 0.4-20, 0.5-20, 0.6-20, 0.7-20, 0.8-20, 0.9-20, 1-20, 2-20, 3-20, 4-20, 5-20, 6-20, 7-20, 8-20, 9-20, 10-20, 11-20, 12-20, 13-20, 14-20, 15-20, 16-20, 17-20, 18-20, or 19- 20 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 0, 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, or 20 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 0, 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, or 20 mM NaH2PO4. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 0, 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, or 20 mM NaH2PO4.

[0406] In some embodiments, the ASO is solubilized or diluted in a buffer further comprising carbohydrates. In some embodiments, the carbohydrates comprise D-glucose. In some embodiments, the ASO is solubilized or diluted in a buffer further comprising 1-100 mM D-glucose.

[0407] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 1-100 mM D-glucose.

[0408] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 1-100, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 mM D-glucose. In some embodiments, the ASO as describedWSGR Docket No.47991-744.601 herein is solubilized or diluted in a buffer comprising 2-100, 3-100, 4-100, 5-100, 6-100, 7-100, 8-100, 9- 100, 10-100, 11-100, 12-100, 13-100, 14-100, 15-100, 16-100, 17-100, 18-100, 19-100, 20-100, 21-100, 22-100, 23-100, 24-100, 25-100, 26-100, 29-100, 28-100, 29-100, 30-100, 35-100, 40-100, 45-100, 50- 100, 55-100, 60-100, 65-100, 70-100, 75-100, 80-100, 85-100, 90-100, or 95-100 mM D-glucose. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 2-30, 3- 30, 4-30, 5-30, 6-30, 7-30, 8-30, 9-30, 10-30, 11-30, 12-30, 13-30, 14-30, 15-30, 16-30, 17-30, 18-30, 19- 30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, or 29-30 mM D-glucose. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at least 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, or 30 mM D- glucose. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising at most 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, or 30 mM D-glucose. In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 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, or 30 mM D-glucose.

[0409] In some embodiments, the ASO is solubilized or diluted in a buffer comprising 25-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM Na2HPO4, 0.1-50 mM NaH2PO4, 0.1-50 mM CaCl2, and 0.1-50 mM MgCl2.

[0410] In some embodiments, the ASO is solubilized or diluted in a buffer comprising 150 mM NaCl, 3.0 mM KCl, 0.7 mM Na2HPO4, 0.3 mM NaH2PO4, 0.79 mM MgCl2, and 1.4 mM CaCl2.

[0411] In some embodiments, the ASO is solubilized or diluted in a buffer further comprising an antioxidant. In some embodiments, the antioxidant is t-butylhydroxyquinoline (TBHQ), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or any combination thereof. In some embodiments, the ASO is solubilized or diluted in a buffer further comprising an antioxidant, wherein the antioxidant is ascorbic acid (vitamin C), glutathione, lipoic acid, uric acid, carotenes, α-tocopherol (vitamin E), ubiquinol (coenzyme Q), or any combination thereof.

[0412] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 25-250 mM NaCl, 0.1-20 mM KCl, 0-50 mM KH2PO4, 1-100 mM NaHCO3, 0-50 mM NaH2PO4, 1-100 mM D-glucose, 0.1-50 mM CaCl2, 0.1-50 mM MgCl2, or any combination thereof.

[0413] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 25-250 mM NaCl, 0.1-20 mM KCl, 0-50 mM KH2PO4, 1-100 mM NaHCO3, 0-50 mM NaH2PO4, 1-100 mM D-glucose, 0.1-50 mM CaCl2, and 0.1-50 mM MgCl2.

[0414] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 127 mM NaCl, 1.0 mM KCl, 1.2 mM KH2PO4, 26 mM NaHCO3, 10 mM D-glucose, 2.4 mM CaCl2, and 1.3 mM MgCl2.

[0415] In some embodiments, the ASO as described herein is solubilized or diluted in a buffer comprising 119 mM NaCl, 26.2 mM NaHCO3, 2.5 mM KCl, 1 mM NaH2PO4, 1.3 mM MgCl2, 10 mM glucose, and 2.5 mM CaCl2.WSGR Docket No.47991-744.601

[0416] In some embodiments, the pharmaceutical formulation does not comprise a preservative. In some embodiments, the pharmaceutical formulation comprises a preservative.

[0417] In some embodiments, the ASO as described herein is solubilized or diluted to a concentration of from 5-250 mg / mL in the diluent.

[0418] In some embodiments, the ASO as described herein is solubilized or diluted to a concentration of from 5-250, 5-247.5, 5-245, 5-242.5, 5-240, 5-237.5, 5-235, 5-232.5, 5-230, 5-227.5, 5-225, 5-225.5, 5- 220, 5-217.5, 5-215, 5-212.5, 5-210, 5-205.5, 5-205, 5-202.5, 5-200, 5-197.5, 5-195, 5-192.5, 5-190, 5- 187.5, 5-185, 5-182.5, 5-180, 5-177.5, 5-175, 5-172.5, 5-170, 5-167.5, 5-165, 5-162.5, 5-160, 5-157.5, 5- 155, 5-152.5, 5-150, 5-147.5, 5-145, 5-142.5, 5-140, 5-137.5, 5-135, 5-132.5, 5-130, 5-127.5, 5-125, 5- 122.5, 5-120, 5-117.5, 5-115, 5-112.5, 5-110, 5-107.5, 5-105, 5-102.5, 5-100, 5-97.5, 5-95, 5-92.5, 5-90, 5-87.5, 5-85, 5-82.5, 5-80, 5-77.5, 5-75, 5-72.5, 5-70, 5-67.5, 5-65, 5-62.5, 5-60, 5-57.5, 5-55, 5-52.5, 5- 50, 5-47.5, 5-45, 5-42.5, 5-40, 5-37.5, 5-35, 5-32.5, 5-30, 5-27.5, 5-25, 5-22.5, 5-20, 5-17.5, 5-15, 5-12.5, or 5-10 mg / mL in the diluent. In some embodiments, the ASO as described herein is solubilized or diluted to a concentration of from 10-250, 15-250, 20-250, 25-250, 30-250, 35-250, 40-250, 45-250, 50- 250, 55-250, 60-250, 65-250, 70-250, 75-250, 80-250, 85-250, 90-250, 95-250, 100-250, 105-250, 110- 250, 115-250, 120-250, 125-250, 130-250, 135-250, 140-250, 145-250, 150-250, 155-250, 160-250, 165- 250, 170-250, 175-250, 180-250, 185-250, 190-250, or 195-250, 200-250, 205-250, 210-250, 215-250, 220-250, 225-250, 230-250, 235-250, 240-250, or 245-250 mg / mL in the diluent. In some embodiments, the ASO as described herein is solubilized or diluted to a concentration of from at least 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, 110, 111, 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, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL in the diluent. In some embodiments, the ASO as described herein is solubilized or diluted to a concentration of from at most 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, 110, 111, 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, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188,WSGR Docket No.47991-744.601 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL in the diluent. In some embodiments, the ASO as described herein is solubilized or diluted to a concentration of from 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, 110, 111, 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, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL in the diluent.

[0419] In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of the ASO is present in the pharmaceutical composition at a concentration of from 0.1 mg / mL to 250 mg / mL. In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, or 20 mg / mL. In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of about 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, or 200 mg / mL. In some embodiments, the ASO is present in the pharmaceutical composition at a concentration of about 22.5 mg / mL, 25 mg / mL, 27.5 mg / mL, 30 mg / mL, 32.5 mg / mL, 35 mg / mL, 37.5 mg / mL, 40 mg / mL, 42.5 mg / mL, 45 mg / mL, 47.5 mg / mL, 50 mg / mL, 52.5 mg / mL, 55 mg / mL, 57.5 mg / mL, 60 mg / mL, 62.5 mg / mL, 65 mg / mL, 67.5 mg / mL, 70 mg / mL, 72.5 mg / mL, 75 mg / mL, 77.5 mg / mL, 80 mg / mL, 82.5 mg / mL, 85 mg / mL, 87.5 mg / mL, 90 mg / mL, 92.5 mg / mL, 95 mg / mL, 97.5 mg / mL, 100 mg / mL, 102.5 mg / mL, 105 mg / mL, 107.5 mg / mL, 110 mg / mL, 112.5 mg / mL, 115 mg / mL, 117.5 mg / mL, 120 mg / mL, 122.5 mg / mL, 125 mg / mL, 127.5 mg / mL, 130 mg / mL, 132.5 mg / mL, 135 mg / mL, 137.5 mg / mL, 140 mg / mL, 142.5 mg / mL, 145 mg / mL, 147.5 mg / mL, 150 mg / mL, 152.5 mg / mL, 155 mg / mL, 157.5 mg / mL, 160 mg / mL, 162.5 mg / mL, 165 mg / mL, 167.5 mg / mL, 170 mg / mL, 172.5 mg / mL, 175 mg / mL, 177.5 mg / mL, 180 mg / mL, 182.5 mg / mL, 185 mg / mL, 187.5 mg / mL, 190 mg / mL, 192.5 mg / mL, 195 mg / mL, 197.5 mg / mL, 200 mg / mL, 202.5 mg / mL, 205 mg / mL, 207.5 mg / mL, 210 mg / mL, 212.5 mg / mL, 215 mg / mL, 217.5 mg / mL, 220 mg / mL, 222.5 mg / mL, 225 mg / mL, 227.5 mg / mL, 230 mg / mL, 232.5 mg / mL, 235 mg / mL, 237.5 mg / mL, 240 mg / mL, 242.5 mg / mL, 245 mg / mL, 247.5 mg / mL, or 250 mg / mL. In some embodiments,WSGR Docket No.47991-744.601 the ASO as described herein is solubilized or diluted to a concentration of 11 mg / mL, 22 mg / mL, 33 mg / mL, 44 mg / mL, 55 mg / mL, 66 mg / mL, 77 mg / mL, 88 mg / mL, 99 mg / mL, or 100 mg / mL in the diluent.

[0420] In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of from 0.1 mg / mL to 250 mg / mL, from 0.2 mg / mL to 250 mg / mL, from 0.3 mg / mL to 250 mg / mL, from 0.4 mg / mL to 250 mg / mL, from 0.5 mg / mL to 250 mg / mL, from 0.6 mg / mL to 250 mg / mL, from 0.7 mg / mL to 250 mg / mL, from 0.8 mg / mL to 250 mg / mL, from 0.9 mg / mL to 250 mg / mL, from 1.0 mg / mL to 250 mg / mL, from 1.1 mg / mL to 250 mg / mL, from 1.2 mg / mL to 250 mg / mL, from 1.3 mg / mL to 250 mg / mL, from 1.4 mg / mL to 250 mg / mL, from 1.5 mg / mL to 250 mg / mL, from 1.6 mg / mL to 250 mg / mL, from 1.7 mg / mL to 250 mg / mL, from 1.8 mg / mL to 250 mg / mL, from 1.9 mg / mL to 250 mg / mL, from 2.0 mg / mL to 250 mg / mL, from 2.1 mg / mL to 250 mg / mL, from 2.2 mg / mL to 250 mg / mL, from 2.3 mg / mL to 250 mg / mL, from 2.4 mg / mL to 250 mg / mL, from 2.5 mg / mL to 250 mg / mL, from 2.6 mg / mL to 250 mg / mL, from 2.7 mg / mL to 250 mg / mL, from 2.8 mg / mL to 250 mg / mL, from 2.9 mg / mL to 250 mg / mL, from 3.0 mg / mL to 250 mg / mL, from 3.1 mg / mL to 250 mg / mL, from 3.2 mg / mL to 250 mg / mL, from 3.3 mg / mL to 250 mg / mL, from 3.4 mg / mL to 250 mg / mL, from 3.5 mg / mL to 250 mg / mL, from 3.6 mg / mL to 250 mg / mL, from 3.7 mg / mL to 250 mg / mL, from 3.8 mg / mL to 250 mg / mL, from 3.9 mg / mL to 250 mg / mL, from 4.0 mg / mL to 250 mg / mL, from 5.0 mg / mL to 250 mg / mL, from 6.0 mg / mL to 250 mg / mL, from 7.0 mg / mL to 250 mg / mL, from 8.0 mg / mL to 250 mg / mL, from 9.0 mg / mL to 250 mg / mL, from 10 mg / mL to 250 mg / mL, from 15 mg / mL to 250 mg / mL, from 20 mg / mL to 250 mg / mL, from 25 mg / mL to 250 mg / mL, from 30 mg / mL to 250 mg / mL, from 35 mg / mL to 250 mg / mL, from 40 mg / mL to 250 mg / mL, from 45 mg / mL to 250 mg / mL, from 50 mg / mL to 250 mg / mL, from 55 mg / mL to 250 mg / mL, from 60 mg / mL to 250 mg / mL, from 65 mg / mL to 250 mg / mL, from 70 mg / mL to 250 mg / mL, from 75 mg / mL to 250 mg / mL, from 80 mg / mL to 250 mg / mL, from 85 mg / mL to 250 mg / mL, from 90 mg / mL to 250 mg / mL, from 95 mg / mL to 250 mg / mL, from 100 mg / mL to 250 mg / mL, from 105 mg / mL to 250 mg / mL, from 110 mg / mL to 250 mg / mL, from 115 mg / mL to 250 mg / mL, from 120 mg / mL to 250 mg / mL, from 125 mg / mL to 250 mg / mL, from 130 mg / mL to 250 mg / mL, from 135 mg / mL to 250 mg / mL, from 140 mg / mL to 250 mg / mL, from 145 mg / mL to 250 mg / mL, from 150 mg / mL to 250 mg / mL, from 155 mg / mL to 250 mg / mL, from 160 mg / mL to 250 mg / mL, from 165 mg / mL to 250 mg / mL, from 170 mg / mL to 250 mg / mL, from 175 mg / mL to 250 mg / mL, from 180 mg / mL to 250 mg / mL, from 185 mg / mL to 250 mg / mL, from 190 mg / mL to 250 mg / mL, from 195 mg / mL to 250 mg / mL, 200 mg / mL to 250 mg / mL, from 205 mg / mL to 250 mg / mL, from 210 mg / mL to 250 mg / mL, from 215 mg / mL to 250 mg / mL, from 220 mg / mL to 250 mg / mL, from 225 mg / mL to 250 mg / mL, from 230 mg / mL to 250 mg / mL, from 235 mg / mL to 250 mg / mL, from 240 mg / mL to 250 mg / mL, or from 245 mg / mL to 250 mg / mL.

[0421] In some embodiments, the ASO as described herein is present in the pharmaceutical composition at a concentration of from 0.1 mg / mL to 250 mg / mL, from 0.1 mg / mL to 245 mg / mL, from 0.1 mg / mL to 240 mg / mL, from 0.1 mg / mL to 235 mg / mL, from 0.1 mg / mL to 230 mg / mL, from 0.1 mg / mL to 225WSGR Docket No.47991-744.601 mg / mL, from 0.1 mg / mL to 220 mg / mL, from 0.1 mg / mL to 215 mg / mL, from 0.1 mg / mL to 210 mg / mL, from 0.1 mg / mL to 205 mg / mL, from 0.1 mg / mL to 200 mg / mL, from 0.1 mg / mL to 195 mg / mL, from 0.1 mg / mL to 190 mg / mL, from 0.1 mg / mL to 185 mg / mL, from 0.1 mg / mL to 180 mg / mL, from 0.1 mg / mL to 175 mg / mL, from 0.1 mg / mL to 170 mg / mL, from 0.1 mg / mL to 165 mg / mL, from 0.1 mg / mL to 160 mg / mL, from 0.1 mg / mL to 155 mg / mL, from 0.1 mg / mL to 150 mg / mL, from 0.1 mg / mL to 145 mg / mL, from 0.1 mg / mL to 140 mg / mL, from 0.1 mg / mL to 135 mg / mL, from 0.1 mg / mL to 130 mg / mL, from 0.1 mg / mL to 125 mg / mL, from 0.1 mg / mL to 120 mg / mL, from 0.1 mg / mL to 115 mg / mL, from 0.1 mg / mL to 110 mg / mL, from 0.1 mg / mL to 100 mg / mL, from 0.1 mg / mL to 95 mg / mL, from 0.1 mg / mL to 90 mg / mL, from 0.1 mg / mL to 85 mg / mL, from 0.1 mg / mL to 80 mg / mL, from 0.1 mg / mL to 75 mg / mL, from 0.1 mg / mL to 70 mg / mL, from 0.1 mg / mL to 65 mg / mL, from 0.1 mg / mL to 60 mg / mL, from 0.1 mg / mL to 55 mg / mL, from 0.1 mg / mL to 50 mg / mL, from 0.1 mg / mL to 45 mg / mL, from 0.1 mg / mL to 40 mg / mL, from 0.1 mg / mL to 35 mg / mL, from 0.1 mg / mL to 30 mg / mL, from 0.1 mg / mL to 25 mg / mL, from 0.1 mg / mL to 20 mg / mL, from 0.1 mg / mL to 15 mg / mL, from 0.1 mg / mL to 10 mg / mL, from 0.1 mg / mL to 9 mg / mL, from 0.1 mg / mL to 8 mg / mL, from 0.1 mg / mL to 7 mg / mL, from 0.1 mg / mL to 6 mg / mL, from 0.1 mg / mL to 5 mg / mL, from 0.1 mg / mL to 4 mg / mL, from 0.1 mg / mL to 3.9 mg / mL, from 0.1 mg / mL to 3.8 mg / mL, from 0.1 mg / mL to 3.7 mg / mL, from 0.1 mg / mL to 3.6 mg / mL, from 0.1 mg / mL to 3.5 mg / mL, from 0.1 mg / mL to 3.4 mg / mL, from 0.1 mg / mL to 3.3 mg / mL, from 0.1 mg / mL to 3.2 mg / mL, from 0.1 mg / mL to 3.1 mg / mL, from 0.1 mg / mL to 3.0 mg / mL, from 0.1 mg / mL to 2.9 mg / mL, from 0.1 mg / mL to 2.8 mg / mL, from 0.1 mg / mL to 2.7 mg / mL, from 0.1 mg / mL to 2.6 mg / mL, from 0.1 mg / mL to 2.5 mg / mL, from 0.1 mg / mL to 2.4 mg / mL, from 0.1 mg / mL to 2.3 mg / mL, from 0.1 mg / mL to 2.2 mg / mL, from 0.1 mg / mL to 2.1 mg / mL, from 0.1 mg / mL to 2.0 mg / mL, from 0.1 mg / mL to 1.9 mg / mL, from 0.1 mg / mL to 1.8 mg / mL, from 0.1 mg / mL to 1.7 mg / mL, from 0.1 mg / mL to 1.6 mg / mL, from 0.1 mg / mL to 1.5 mg / mL, from 0.1 mg / mL to 1.4 mg / mL, from 0.1 mg / mL to 1.3 mg / mL, from 0.1 mg / mL to 1.2 mg / mL, from 0.1 mg / mL to 1.1 mg / mL, from 0.1 mg / mL to 1.0 mg / mL, from 0.1 mg / mL to 0.9 mg / mL, from 0.1 mg / mL to 0.8 mg / mL, from 0.1 mg / mL to 0.7 mg / mL, from 0.1 mg / mL to 0.6 mg / mL, from 0.1 mg / mL to 0.5 mg / mL, from 0.1 mg / mL to 0.4 mg / mL, from 0.1 mg / mL to 0.3 mg / mL, or from 0.1 mg / mL to 0.2 mg / mL.

[0422] In some embodiments, the ASO as described herein is solubilized or diluted to a concentration of at least 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, 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, 110, 111, 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, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194,WSGR Docket No.47991-744.601 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL in the diluent. In some embodiments, the ASO as described herein is solubilized or diluted to a concentration of at most 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, 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, 110, 111, 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, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL in the diluent. In some embodiments, the ASO as described herein is solubilized or diluted to a concentration of 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, 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, 110, 111, 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, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL in the diluent.

[0423] In some embodiments, the ASO as described herein is formulated in a dose volume adjusted depending on the subject’s age, sex, and / or body mass index (BMI). In some embodiments, the ASO as described herein is formulated in a dose volume of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mL. In some embodiments, the ASO as described herein is formulated in a dose volume of 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2, 2.25, 2.5.2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, or 10 mL. In some embodiments, the ASO as described herein is formulated in a dose volume of less than 20 mL, less than 19 mL, less than 18 mL, less than 17 mL, less than 16 mL, less than 15 mL, less than 14 mL, less than 13 mL, less than 12WSGR Docket No.47991-744.601 mL, less than 11 mL, less than 10 mL, less than 9 mL, less than 8 mL, less than 7 mL, less than 6 mL, less than 5 mL, less than 4 mL, less than 3 mL, less than 2 mL, less than 1 mL. In some embodiments, the ASO as described herein is formulated in a dose volume of more than 1 mL, more than 2 mL, more than 3 mL, more than 4 mL, more than 5 mL, more than 6 mL, more than 7 mL, more than 8 mL, more than 9 mL, more than 10 mL, more than 11 mL, more than 12 mL, more than 13 mL, more than 14 mL, more than 15 mL, more than 16 mL, more than 17 mL, more than 18 mL, more than 19 mL, more than 20 mL. In some embodiments, the ASO as described herein is formulated in a dose volume of at least 0.5 mL, at least 1 mL, at least 2 mL, at least 3 mL, at least 4 mL, at least 5 mL, at least 6 mL, at least 7 mL, at least 8 mL, at least 9 mL, at least 10 mL, at least 11 mL, at least 12 mL, at least 13 mL, at least 14 mL, at least 15 mL, at least 16 mL, at least 17 mL, at least 18 mL, at least 19 mL, at least 20 mL.

[0424] In some embodiments, the ASO as described herein is formulated in a final dose volume adjusted depending on the subject’s age, sex, and / or body mass index (BMI). In some embodiments, the ASO as described herein is formulated in a final dose volume of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mL. In some embodiments, the ASO as described herein is formulated in a final dose volume of 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2, 2.25, 2.5.2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, or 10 mL. In some embodiments, the ASO as described herein is formulated in a final dose volume of less than 20 mL, less than 19 mL, less than 18 mL, less than 17 mL, less than 16 mL, less than 15 mL, less than 14 mL, less than 13 mL, less than 12 mL, less than 11 mL, less than 10 mL, less than 9 mL, less than 8 mL, less than 7 mL, less than 6 mL, less than 5 mL, less than 4 mL, less than 3 mL, less than 2 mL, less than 1 mL. In some embodiments, the ASO as described herein is formulated in a final dose volume of more than 1 mL, more than 2 mL, more than 3 mL, more than 4 mL, more than 5 mL, more than 6 mL, more than 7 mL, more than 8 mL, more than 9 mL, more than 10 mL, more than 11 mL, more than 12 mL, more than 13 mL, more than 14 mL, more than 15 mL, more than 16 mL, more than 17 mL, more than 18 mL, more than 19 mL, more than 20 mL. In some embodiments, the ASO as described herein is formulated in a final dose volume of at least 0.5 mL, at least 1 mL, at least 2 mL, at least 3 mL, at least 4 mL, at least 5 mL, at least 6 mL, at least 7 mL, at least 8 mL, at least 9 mL, at least 10 mL, at least 11 mL, at least 12 mL, at least 13 mL, at least 14 mL, at least 15 mL, at least 16 mL, at least 17 mL, at least 18 mL, at least 19 mL, at least 20 mL.

[0425] In some aspects, provided herein is a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: i) an active pharmaceutical ingredient, and ii) a pharmaceutically acceptable diluent; wherein the liquid composition is not buffered by a buffering agent; and wherein: (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, and / or (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject.

[0426] In some aspects, also provided herein is a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising:(i) an active pharmaceutical ingredient, and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition lacks Na2HPO4 and / orWSGR Docket No.47991-744.601 NaH2PO4; and wherein: (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, and / or (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject. In some embodiments, the liquid composition lacks phosphate ions. In some embodiments, the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion.

[0427] In some aspects, also provided herein is a pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an active pharmaceutical ingredient, and (ii) a pharmaceutically acceptable diluent consisting of: a) NaCl, b) KCl, c) MgCl2 or MgCl26H2O, and d) CaCl2 or CaCl22H2O. In some embodiments, the liquid composition lacks phosphate ions. In some embodiments, the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion.

[0428] In some embodiments, the pharmaceutically acceptable diluent provided herein is suitable for preparation of any pharmaceutical formulation intrathecal administration. For instance, any active pharmaceutical ingredient suitable for intrathecal administration may be formulated using the pharmaceutically acceptable diluent provided herein. The active pharmaceutical ingredient can be a small molecule or a biologic, such as an organic chemical compound, an antisense oligonucleotide, a DNA, an antibody or any other protein or polypeptide, a living organism such as bacterium or fungi, viral vector, or viral-like particle, or any combination thereof.

[0429] In some embodiments, the pharmaceutical formulation does not comprise a preservative. In some embodiments, the pharmaceutical formulation comprises a preservative.

[0430] A pharmaceutical composition used in the therapeutic methods of the invention is formulated to be compatible with its intended route of administration.

[0431] In some embodiments, the pharmaceutical formulation is suitable for an intracerebroventricular or intrathecal injection.

[0432] In some embodiments, the pharmaceutical formulation is suitable for oral, rectal, intranasal, intradermal, subcutaneous, intrathecal, intracerebroventricular, intraperitoneal, intramuscular, intravitreal, intravenous, intracranial, intrabuccal, or sublingual administration. In some embodiments, the pharmaceutical formulation is suitable for intradermal, subcutaneous, intrathecal, intranasal, intracranial, intracerebroventricular, intraperitoneal, intramuscular, intravitreal, or intravenous injection.

[0433] In some embodiments, the pharmaceutical formulation is packaged in a single-use vial. In some embodiments, the pharmaceutical formulation is packaged in a multiple use vial.

[0434] Pharmaceutical formulations comprising the agent, e.g., antisense oligonucleotide or antisense oligomer, of the described compositions and for use in any of the described methods can be prepared according to conventional techniques well-known in the pharmaceutical industry and described in the published literature. In some embodiments, a pharmaceutical formulation for treating a subject comprises an effective amount of any antisense oligomer as described herein, or a pharmaceutically acceptable salt, solvate, hydrate or ester thereof. In some embodiments, the pharmaceutical composition described herein further comprises a pharmaceutically acceptable excipient, carrier, or diluent.WSGR Docket No.47991-744.601

[0435] Such compositions may comprise buffers such as neutral buffered saline, phosphate buffered saline and the like; carbohydrates such as glucose, mannose, sucrose or dextrans, mannitol; proteins; polypeptides or amino acids such as glycine; antioxidants; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and preservatives.

[0436] A pharmaceutical composition used in the therapeutic methods of the invention is formulated to be compatible with its intended route of administration.

[0437] The terms “pharmaceutical composition” and “pharmaceutical formulation” (or “formulation”) are used interchangeably and denote a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with one or more pharmaceutically acceptable excipients to be administered to a subject, e.g., a human in need thereof.

[0438] In some embodiments, the compositions are formulated into any of many possible dosage forms such as, but not limited to, solutions, liquids, tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas. In some embodiments, the compositions are formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and / or dextran. The suspension may also contain stabilizers. In some embodiments, a pharmaceutical formulation or composition of the present invention includes, but is not limited to, a solution, emulsion, microemulsion, foam or liposome-containing formulation (e.g., cationic or noncationic liposomes).

[0439] The pharmaceutical composition or formulation described herein may comprise one or more penetration enhancers, carriers, excipients or other active or inactive ingredients as appropriate and well- known to those of skill in the art or described in the published literature. In embodiments, liposomes also include sterically stabilized liposomes, e.g., liposomes comprising one or more specialized lipids. These specialized lipids result in liposomes with enhanced circulation lifetimes. In embodiments, a sterically stabilized liposome comprises one or more glycolipids or is derivatized with one or more hydrophilic polymers, such as a polyethylene glycol (PEG) moiety. In embodiments, a surfactant is included in the pharmaceutical formulation or compositions. The use of surfactants in drug products, formulations and emulsions is well-known in the art. In embodiments, the present invention employs a penetration enhancer to effect the efficient delivery of the antisense oligonucleotide or antisense oligomer, e.g., to aid diffusion across cell membranes and / or enhance the permeability of a lipophilic drug. In embodiments, the penetration enhancers are a surfactant, fatty acid, bile salt, chelating agent, or non-chelating nonsurfactant.

[0440] In embodiments, the pharmaceutical formulation comprises multiple antisense oligonucleotides or antisense oligomers. In embodiments, the antisense oligonucleotide or antisense oligomer is administered in combination with another drug or therapeutic agent.

[0441] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. Solutions or suspensions used for parenteral, intranasal, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water forWSGR Docket No.47991-744.601 injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. For example, depending on the injection site, the vehicle may contain water, synthetic or vegetable oil, and / or organic co-solvents. In certain instances, such as with lyophilized product or a concentrate, the parenteral formulation would be reconstituted or diluted prior to administration. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Depot formulations, providing controlled or sustained release of an invention composition, may include injectable suspensions of nano / micro particles or nano / micro or non-micronized crystals.

[0442] For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, poly(ol) (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

[0443] Sterile injectable solutions can be prepared by incorporating the composition in the required amount in an appropriate solvent with one or a com-bination of ingredients enumerated above, as required, followed by filtered sterilization. Prevention of the action of micro-organisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.

[0444] Generally, dispersions are prepared by incorporating the active composition into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monost...

Claims

WSGR Docket No.47991-744.601 CLAIMS WHAT IS CLAIMED IS:

1. A pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition is not buffered by a buffering agent; and wherein: (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

2. A pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition lacks Na2HPO4and / or NaH2PO4; and wherein: (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

3. The pharmaceutical formulation of claim 1 or 2, wherein the liquid composition lacks phosphate ions.

4. The pharmaceutical formulation of any one of claims 1-3, wherein the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion.

5. A pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent consisting of: (a) NaCl, (b) KCl, (c) MgCl2 or MgCl26H2O, and (d) CaCl2 or CaCl22H2O.

6. The pharmaceutical formulation of any one of claims 1-5, wherein the liquid composition comprises 0.1-50 mM CaCl2 or CaCl22H2O.

7. The pharmaceutical formulation of any one of claims 1-6, wherein the liquid composition comprises 1-2 mM CaCl2 or CaCl22H2O.WSGR Docket No.47991-744.601 8. The pharmaceutical formulation of any one of claims 1-7, wherein the liquid composition comprises about 1.4 mM CaCl2 or CaCl22H2O.

9. The pharmaceutical formulation of any one of claims 1-8, wherein the liquid composition comprises 0.1-50 mM MgCl2 or MgCl26H2O.

10. The pharmaceutical formulation of any one of claims 1-8, wherein the liquid composition comprises 0.5-1.5 mM MgCl2 or MgCl26H2O.

11. The pharmaceutical formulation of any one of claims 1-8, wherein the liquid composition comprises about 0.79 mM MgCl2 or MgCl26H2O.

12. The pharmaceutical formulation of any one of claims 1-11, wherein the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM CaCl2 or CaCl22H2O, and 0.1-50 mM MgCl2 or MgCl2 6H2O.

13. A pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent; wherein the liquid composition lacks calcium ions and / or magnesium ions; and wherein: (a) the liquid composition comprises potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

14. The pharmaceutical composition of any one of claims 1-13, wherein: (a) the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (b) the pharmaceutical formulation has a shelf life of a time period when stored at -20 °C or a temperature and relative humidity; (c) the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (d) the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (e) the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (f) the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period;WSGR Docket No.47991-744.601 (g) the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (h) the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; and / or (i) no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period.

15. The pharmaceutical composition of any one of claims 1-13, wherein no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period.

16. A pharmaceutical formulation, wherein the pharmaceutical formulation is a liquid composition comprising: (i) an antisense oligomer (ASO), and (ii) a pharmaceutically acceptable diluent, wherein: (a) the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (b) the pharmaceutical formulation has a shelf life of a time period when stored at -20 °C or a temperature and relative humidity; (c) the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (d) the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (e) the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (f) the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (g) the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (h) the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; and / orWSGR Docket No.47991-744.601 (i) no observable particulate formation or no formation of particulate that has a dimension larger than 50 µm is observed after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period.

17. The pharmaceutical formulation of any one of claims 14-16, wherein the temperature is 4 °C, 25 °C, 30 °C, 37 °C, or 40 °C.

18. The pharmaceutical formulation of any one of claims 14-17, wherein the relative humidity is about 55%, 60%, 65%, 70%, or 75%.

19. The pharmaceutical formulation of any one of claims 14-18, wherein the time period is at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

20. The pharmaceutical formulation of any one of claims 2-19, wherein the liquid composition comprises a buffering agent.

21. The pharmaceutical formulation of claim 20, wherein the buffering agent has a pKa at 25 °C of about 4.75; about 5.64; about 1.70, about 6.04, and about 9.09; about 3.1, about 4.7 and about 6.4; or about 6.

50.

22. The pharmaceutical formulation of claim 20, wherein the buffering agent is an effective buffer at a pH range of from about 3.6 to 5.6, from about 5.5 to 6.5, from about 5.5 to 7.4, from about 3.0 to 6.2, or from about 5.8 to 7.

2.

23. The pharmaceutical formulation of claim 20, wherein the buffering agent is selected from the group consisting of acetate, succinate, histidine, citrate, 2-[Bis(2-hydroxyethyl)amino]-2- (hydroxymethyl)propane-1,3-diol (Bis-Tris), and any combination thereof.

24. The pharmaceutical formulation of any one of claims 1-23, wherein the liquid composition is formulated for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject.

25. The pharmaceutical formulation of any one of claims 1-23, wherein the liquid composition is formulated for administration into cerebrospinal fluid in a brain of a human subject.

26. The pharmaceutical formulation of any one of claims 1-25, wherein the ASO comprises at least one modified sugar moiety.

27. The pharmaceutical formulation of any one of claims 1-26, wherein each nucleotide of the antisense oligomer comprises a modified sugar moiety.

28. A kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO, and wherein the liquid composition is not buffered by a buffering agent; andWSGR Docket No.47991-744.601 wherein: (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

29. A kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO, wherein the liquid composition lacks Na2HPO4and / or NaH2PO4; and wherein: (a) the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

30. The kit of claim 28 or 29, wherein the liquid composition lacks phosphate ions.

31. The kit of any one of claims 28-30, wherein the liquid composition comprises calcium ion, magnesium ion, and / or potassium ion.

32. A kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent consisting of: (a) NaCl, (b) KCl, (c) MgCl2or MgCl26H2O, and (d) CaCl2or CaCl22H2O, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; and wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO.

33. The kit of any one of claims 28-32, wherein the liquid composition comprises 0.1-50 mM CaCl2 or CaCl22H2O.

34. The kit of any one of claims 28-32, wherein the liquid composition comprises 1-2 mM CaCl2 or CaCl22H2O.

35. The kit of any one of claims 28-34, wherein the liquid composition comprises about 1.4 mM CaCl2 or CaCl22H2O.WSGR Docket No.47991-744.601 36. The kit of any one of claims 28-35, wherein the liquid composition comprises 0.1-50 mM MgCl2 or MgCl26H2O.

37. The kit of any one of claims 28-35, wherein the liquid composition comprises 0.5-1.5 mM MgCl2 or MgCl26H2O.

38. The kit of any one of claims 28-35, wherein the liquid composition comprises about 0.79 mM MgCl2 or MgCl26H2O.

39. The kit of any one of claims 28-38, wherein the liquid composition comprises 5-250 mM NaCl, 0.1- 20 mM KCl, 0.1-50 mM CaCl2 or CaCl22H2O, and 0.1-50 mM MgCl2 or MgCl26H2O.

40. A kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO, wherein the liquid composition lacks calcium ions and / or magnesium ions; and wherein: (a) the liquid composition comprises potassium ion, (b) the pharmaceutical formulation is formulated or suitable for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject, and / or (c) each nucleobase of the ASO comprises a modified sugar moiety.

41. The kit of any one of claims 28-40, wherein: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO, and wherein: (a) the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (b) the pharmaceutical formulation has a shelf life of a time period when stored at -20 °C or a temperature and relative humidity; (c) the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (d) the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period;WSGR Docket No.47991-744.601 (e) the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (f) the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (g) the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (h) the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; and / or (i) no observable particulate formation is observed after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period.

42. The kit of any one of claims 28-40, wherein no observable particulate formation is observed after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period.

43. A kit comprising: (i) a concentrate comprising an antisense oligomer (ASO); and (ii) a pharmaceutically acceptable diluent, wherein the concentrate is miscible with the pharmaceutically acceptable diluent; wherein mixing the ASO with the pharmaceutically acceptable diluent results in a liquid composition comprising the ASO, and wherein: (a) the ASO is stable in the pharmaceutical formulation after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (b) the pharmaceutical formulation has a shelf life of a time period when stored at -20 °C or a temperature and relative humidity; (c) the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.92 is not more than 2.5% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (d) the percent impurities in the pharmaceutical formulation according to an HPLC relative retention time of 0.98 is not more than 3.5% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (e) the percent of any unspecified impurities in the pharmaceutical formulation according to HPLC is not more than 1.8% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period;WSGR Docket No.47991-744.601 (f) the percent of total impurities in the pharmaceutical formulation according to HPLC is not more than 10% after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (g) the pH of the pharmaceutical composition is from 6.6 to 7.6 after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; (h) the osmolality of the pharmaceutical composition is from 310 to 360 mOsm / kg after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period; and / or (i) no observable particulate formation is observed after storage of the pharmaceutical formulation at -20 °C or a temperature and relative humidity for a time period.

44. The kit of any one of claims 41-43, wherein the temperature is 4 °C, 25 °C, 30 °C, 37 °C, or 40 °C.

45. The kit of any one of claims 41-44, wherein the relative humidity is about 55%, 60%, 65%, 70%, or 75%.

46. The kit of any one of claims 41-45, wherein the time period is at least 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, or 52 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years.

47. The kit of any one of claims 29-46, wherein the liquid composition comprises a buffering agent.

48. The kit of claim 47, wherein the buffering agent has a pKa at 25 °C of about 4.75, about 5.64, about 1.70, about 6.04, about 9.09, about 3.1, about 4.7, about 6.4, or about 6.

50.

49. The kit of claim 47, wherein the buffering agent is an effective buffer at a pH range of from about 3.6 to 5.6, from about 5.5 to 6.5, from about 5.5 to 7.4, from about 3.0 to 6.2, or from about 5.8 to 7.

2.

50. The kit of claim 47, wherein the buffering agent is selected from the group consisting of acetate, succinate, histidine, citrate, 2-[Bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol (Bis-Tris), and any combination thereof.

51. The kit of any one of claims 28-50, wherein the liquid composition is formulated for administration into an intrathecal space, cerebrospinal fluid, or a brain of a human subject.

52. The kit of any one of claims 28-50, wherein the liquid composition is formulated for administration into cerebrospinal fluid in a brain of a human subject.

53. The kit of any one of claims 28-52, wherein the ASO comprises at least one modified sugar moiety.

54. The kit of any one of claims 28-53, wherein each nucleotide of the antisense oligomer comprises a modified sugar moiety.

55. The kit of any one of claims 28-54, further comprising: (iii) instructions for diluting or solubilizing the ASO in the pharmaceutically acceptable diluent.

56. The pharmaceutical formulation of any one of claims 1-27, or the kit of any one of claims 28-55, wherein the liquid composition comprises 25-250 mM NaCl.WSGR Docket No.47991-744.601 57. The pharmaceutical formulation of any one of claims 1-27 or 56, or the kit of any one of claims 28- 56, wherein the liquid composition comprises 0.1-20 mM KCl.

58. The pharmaceutical formulation of any one of claims 1-27, 56, or 57, or the kit of any one of claims 28-57, wherein the liquid composition comprises 2-4 mM KCl.

59. The pharmaceutical formulation of any one of claims 1-27 or 56-58, or the kit of any one of claims 28-58, wherein the liquid composition about 3 mM KCl.

60. The pharmaceutical formulation of any one of claims 1-27 or 56-59, or the kit of any one of claims 28-59, wherein the liquid composition comprises 100-160 mM NaCl.

61. The pharmaceutical formulation of any one of claims 1-27 or 56-59, or the kit of any one of claims 28-59, wherein the liquid composition comprises about 150 mM NaCl.

62. The pharmaceutical formulation of any one of claims 1-27 or 56-60, or the kit of any one of claims 28-60, wherein the liquid composition comprises 125-145 mM NaCl.

63. The pharmaceutical formulation of any one of claims 1-27 or 56-62, or the kit of any one of claims 28-62, wherein the liquid composition comprises about 130 mM NaCl.

64. The pharmaceutical formulation of any one of claims 13-27 or 56-63, or the kit of any one of claims 40-63, wherein the liquid composition comprises a buffered (pH 6.6 – 7.6) solution.

65. The pharmaceutical formulation of any one of claims 13-27 or 56-63, or the kit of any one of claims 40-63, wherein the liquid composition comprises a buffered (pH 6.8 – 7.2) solution.

66. The pharmaceutical formulation of any one of claims 13-27 or 56-63, or the kit of any one of claims 40-63, wherein the liquid composition comprises a buffered (pH 6.9 – 7.1) solution.

67. The pharmaceutical formulation of any one of claims 13-27 or 56-66, or the kit of any one of claims 40-66, wherein the liquid composition comprises 0.1-50 mM Na2HPO4.

68. The pharmaceutical formulation of any one of claims 13-27 or 56-67, or the kit of any one of claims 40-67, wherein the liquid composition comprises 0.1-50 mM NaH2PO4.

69. The pharmaceutical formulation of any one of claims 13-27 or 56-68, or the kit of any one of claims 40-68, wherein the liquid composition comprises 5-250 mM NaCl, 0.1-20 mM KCl, 0.1-50 mM Na2HPO4, and 0.1-50 mM NaH2PO4.

70. The pharmaceutical formulation of any one of claims 1-27 or 56-69, wherein the ASO is solubilized in the pharmaceutically acceptable diluent.

71. The pharmaceutical formulation of any one of claims 1-27 or 56-70, or the kit of any one of claims 28-69, wherein the pharmaceutically acceptable diluent is an isotonic solution.

72. The pharmaceutical formulation of any one of claims 1-27 or 56-71, or the kit of any one of claims 28-69 or 71, wherein the ASO is not substantially polydisperse.

73. The pharmaceutical formulation of any one of claims 1-27 or 56-72, or the kit of any one of claims 28-69 or 71-72, wherein the liquid composition has an osmolality of less than 150 mM.

74. The pharmaceutical formulation of any one of claims 1-27 or 56-73, or the kit of any one of claims 28-69 or 71-73, wherein the liquid composition has an osmolality of about 130 mM.WSGR Docket No.47991-744.601 75. The pharmaceutical formulation of any one of claims 1-27 or 56-74, or the kit of any one of claims 28-69 or 71-74, wherein the liquid composition further comprises a carbohydrate.

76. The pharmaceutical formulation or the kit of claim 75, wherein the carbohydrate comprises D- glucose.

77. The pharmaceutical formulation of any one of claims 1-27 or 56-76, or the kit of any one of claims 28-69 or 71-76, wherein the liquid composition further comprises 1-100 mM D-glucose.

78. The pharmaceutical formulation of any one of claims 1-27 or 56-77, or the kit of any one of claims 28-69 or 71-77, wherein the liquid composition further comprises an antioxidant.

79. The pharmaceutical formulation or the kit of claim 78, wherein the antioxidant is t- butylhydroxyquinoline (TBHQ), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or any combination thereof.

80. The pharmaceutical formulation of any one of claims 1-27 or 56-79, or the kit of any one of claims 28-69 or 71-79, wherein the liquid composition does not comprise a preservative.

81. The pharmaceutical formulation of any one of claims 1-27 or 56-80, or the kit of any one of claims 28-69 or 71-80, wherein the liquid composition is packaged in a single-use vial.

82. The pharmaceutical formulation of any one of claims 1-27 or 56-81, or the kit of any one of claims 28-69 or 71-81, wherein the liquid composition is formulated or suitable for administration (i) as a bolus injection; (ii) by infusion with a delivery pump; (iii) by intracerebroventricular injection; and / or (iv) by intrathecal injection.

83. The pharmaceutical formulation of any one of claims 1-27 or 56-82, or the kit of any one of claims 28-69 or 71-82, wherein the ASO comprises a 2’-O-methoxyethyl moiety.

84. The pharmaceutical formulation of any one of claims 1-27 or 56-83, or the kit of any one of claims 28-69 or 71-83, wherein the ASO comprises a thymidine comprising a 2’-O-methoxyethyl moiety.

85. The pharmaceutical formulation of any one of claims 1-27 or 56-84, or the kit of any one of claims 28-69 or 71-84, wherein each nucleobase of the ASO comprises a 2’-O-methoxyethyl moiety.

86. The pharmaceutical formulation of any one of claims 1-27 or 56-85, or the kit of any one of claims 28-69 or 71-85, wherein the ASO consists of from 8 to 50 nucleobases.

87. The pharmaceutical formulation of any one of claims 1-27 or 56-85, or the kit of any one of claims 28-69 or 71-85, wherein the ASO consists of less than 35 nucleobases.

88. The pharmaceutical formulation of any one of claims 1-27 or 56-85, or the kit of any one of claims 28-69 or 71-85, wherein the ASO consists of from 16 to 20 nucleobases.

89. The pharmaceutical formulation of any one of claims 1-27 or 56-85, or the kit of any one of claims 28-69 or 71-85, wherein the ASO consists of from 12 to 20 nucleobases.

90. The pharmaceutical formulation of any one of claims 1-27 or 56-85, or the kit of any one of claims 28-69 or 71-85, wherein the ASO consists of from 8 to 20 nucleobases.WSGR Docket No.47991-744.601 91. The pharmaceutical formulation of any one of claims 1-27 or 56-90, or the kit of any one of claims 28-69 or 71-90, wherein the ASO comprises a 5’-methylcytosine (5’-MeC).

92. The pharmaceutical formulation of any one of claims 1-27 or 56-91, or the kit of any one of claims 28-69 or 71-91, wherein each cytosine of the ASO is a 5’-methylcytosine (5’-MeC).

93. The pharmaceutical formulation of any one of claims 1-27 or 56-92, or the kit of any one of claims 28-69 or 71-92, wherein the ASO comprises a phosphorothioate linkage.

94. The pharmaceutical formulation of any one of claims 1-27 or 56-93, or the kit of any one of claims 28-69 or 71-93, wherein each internucleoside linkage of the ASO is a phosphorothioate linkage.

95. The pharmaceutical formulation of any one of claims 1-27 or 56-94, or the kit of any one of claims 28-69 or 71-94, wherein the ASO comprises a locked nucleic acid (LNA).

96. The pharmaceutical formulation of any one of claims 1-27 or 56-95, or the kit of any one of claims 28-69 or 71-95, wherein the liquid composition comprises 1 mL to 20 mL of the pharmaceutically acceptable diluent, 2 mL to 10 mL of the pharmaceutically acceptable diluent, or 1 mL to 5 mL of the pharmaceutically acceptable diluent.

97. The pharmaceutical formulation of any one of claims 1-27 or 56-96, or the kit of any one of claims 28-69 or 71-96, wherein the liquid composition comprises from 0.1 mL to 50 mL of the pharmaceutically acceptable diluent.

98. The pharmaceutical formulation of any one of claims 1-27 or 56-96, or the kit of any one of claims 28-69 or 71-96, wherein the liquid composition comprises about 0.1, 0.5, 1, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45 or 50 mL of the pharmaceutically acceptable diluent.

99. The pharmaceutical formulation of any one of claims 1-27 or 56-98, or the kit of any one of claims 28-69 or 71-98, wherein the liquid composition comprises from about 0.5 milligrams to about 500 milligrams of the ASO.

100. The pharmaceutical formulation or the kit of claim 99, wherein the liquid composition comprises 0.1, 0.5, 1, 2.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60, 62.5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102.5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127.5, 130, 132.5, 135, 137.5, 140, 142.5, 145, 147.5, 150, 152.5, 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190, 192.5, 195, 197.5, 200, 202.5, 205, 207.5, 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5, 245, 247.5, or 250 mg of the ASO.

101. The pharmaceutical formulation of any one of claims 1-27 or 56-100, or the kit of any one of claims 28-69 or 71-100, wherein the ASO is present in the liquid composition at a concentration of from 0.1-500 mg / mL.

102. The pharmaceutical formulation of any one of claims 1-27 or 56-101, or the kit of any one of claims 28-69 or 71-101, wherein the ASO is present in the liquid composition at a concentration of from 0.1 mg / mL to 250 mg / mL.WSGR Docket No.47991-744.601 103. The pharmaceutical formulation of any one of claims 1-27 or 56-101, or the kit of any one of claims 28-69 or 71-101, wherein the ASO is present in the pharmaceutical formulation at a concentration of from 6.7 mg / mL to 188 mg / mL, from 6.8 mg / mL to 187 mg / mL, from 3 mg / mL to 100 mg / mL, or from 3 mg / mL to 33 mg / mL.

104. The pharmaceutical formulation of any one of claims 1-27 or 56-100, or the kit of any one of claims 28-69 or 71-100, wherein the ASO is present in the liquid composition at a concentration of about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, or 33 mg / mL.

105. The pharmaceutical formulation of any one of claims 1-27 or 56-100, or the kit of any one of claims 28-69 or 71-100, wherein the ASO is present in the liquid composition at a concentration of 11 mg / mL, 22 mg / mL, 33 mg / mL, 44 mg / mL, 55 mg / mL, 66 mg / mL, 77 mg / mL, 88 mg / mL, 99 mg / mL, or 100 mg / mL.

106. The pharmaceutical formulation of any one of claims 1-27 or 56-100, or the kit of any one of claims 28-69 or 71-100, wherein the ASO is present in the liquid composition at a concentration of about 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22.5 mg / mL, 25 mg / mL, 27.5 mg / mL, 30 mg / mL, 32.5 mg / mL, 35 mg / mL, 37.5 mg / mL, 40 mg / mL, 42.5 mg / mL, 45 mg / mL, 47.5 mg / mL, 50 mg / mL, 52.5 mg / mL, 55 mg / mL, 57.5 mg / mL, 60 mg / mL, 62.5 mg / mL, 65 mg / mL, 67.5 mg / mL, 70 mg / mL, 72.5 mg / mL, 75 mg / mL, 77.5 mg / mL, 80 mg / mL, 82.5 mg / mL, 85 mg / mL, 87.5 mg / mL, 90 mg / mL, 92.5 mg / mL, 95 mg / mL, 97.5 mg / mL, 100 mg / mL, 102.5 mg / mL, 105 mg / mL, 107.5 mg / mL, 110 mg / mL, 112.5 mg / mL, 115 mg / mL, 117.5 mg / mL, 120 mg / mL, 122.5 mg / mL, 125 mg / mL, 127.5 mg / mL, 130 mg / mL, 132.5 mg / mL, 135 mg / mL, 137.5 mg / mL, 140 mg / mL, 142.5 mg / mL, 145 mg / mL, 147.5 mg / mL, 150 mg / mL, 152.5 mg / mL, 155 mg / mL, 157.5 mg / mL, 160 mg / mL, 162.5 mg / mL, 165 mg / mL, 167.5 mg / mL, 170 mg / mL, 172.5 mg / mL, 175 mg / mL, 177.5 mg / mL, 180 mg / mL, 182.5 mg / mL, 185 mg / mL, 187.5 mg / mL, 190 mg / mL, 192.5 mg / mL, 195 mg / mL, 197.5 mg / mL, 200 mg / mL, 202.5 mg / mL, 205 mg / mL, 207.5 mg / mL, 210 mg / mL, 212.5 mg / mL, 215 mg / mL, 217.5 mg / mL, 220 mg / mL, 222.5 mg / mL, 225 mg / mL, 227.5 mg / mL, 230 mg / mL, 232.5 mg / mL, 235 mg / mL, 237.5 mg / mL, 240 mg / mL, 242.5 mg / mL, 245 mg / mL, 247.5 mg / mL, or 250 mg / mL.

107. The pharmaceutical formulation of any one of claims 1-27 or 56-106, or the kit of any one of claims 28-69 or 71-106, wherein the ASO comprises a sequence with at least 80% sequence identity to any one of SEQ ID NOs: 21-67, 210-256 or 304-1099.

108. The pharmaceutical formulation of any one of claims 1-27 or 56-106, or the kit of any one of claims 28-69 or 71-106, wherein the ASO comprises a sequence with at least 83%, 88%, 94% or 100% sequence identity to any one of SEQ ID NOs: 21-67, 210-256 or 304-1099.WSGR Docket No.47991-744.601 109. The pharmaceutical formulation of any one of claims 1-27 or 56-106, or the kit of any one of claims 28-69 or 71-106, wherein the ASO consists of a sequence with at least 83%, 88%, 94% or 100% sequence identity to any one of SEQ ID NOs: 21-67, 210-256 or 304-1099.

110. The pharmaceutical formulation of any one of claims 1-27 or 56-106, or the kit of any one of claims 28-69 or 71-106, wherein the ASO is a compound according to the following chemical structure:(I), or a salt thereof.

111. The pharmaceutical formulation of any one of claims 1-27 or 56-106, or the kit of any one of claims 28-69 or 71-106, wherein the ASO is a compound according to the following chemical structure:WSGR Docket No.47991-744.601 112. A liquid pharmaceutical formulation consisting essentially of: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound according to the following chemical structure:(I), or a salt thereof; (b) calcium chloride dihydrate (CaCl22H2O) at a concentration of about 0.1 mM to about 50 mM; (c) magnesium chloride hexahydrate (MgCl26H2O) at a concentration of about 0.1 mM to about 50 mM; (d) potassium chloride (KCl) at a concentration of about 0.1 mM to about 20 mM; (e) sodium chloride (NaCl) at a concentration of about 25 mM to about 250 mM; and (f) water.

113. The pharmaceutical composition of claim 112, wherein the pharmaceutical formulation further comprises sodium hydroxide (NaOH) and / or hydrochloric acid (HCl) in amounts that provide a pH of the pharmaceutical formulation at 6.6 to 7.

6.

114. The pharmaceutical composition of claim 112, wherein the pharmaceutical formulation further comprises sodium hydroxide (NaOH) at a concentration of about 0.1 mM to about 20 mM, and / or hydrochloric acid (HCl) at a concentration of about 0.1 mM to about 20 mM.

115. A liquid pharmaceutical formulation consisting essentially of: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound according to the following chemical structure:WSGR Docket No.47991-744.601(I), or a salt thereof; (b) calcium chloride dihydrate (CaCl22H2O) at a concentration of about 0.1 mM to about 50 mM; (c) magnesium chloride hexahydrate (MgCl26H2O) at a concentration of about 0.1 mM to about 50 mM; (d) potassium chloride (KCl) at a concentration of about 0.1 mM to about 20 mM; (e) sodium chloride (NaCl) at a concentration of about 25 mM to about 250 mM; (f) sodium hydroxide (NaOH) at a concentration of about 0.1 mM to about 20 mM, and / or hydrochloric acid (HCl) at a concentration of about 0.1 mM to about 20 mM; and (g) water.

116. The pharmaceutical composition of any one of claims 112-115, wherein the concentration of the ASO is about 0.1 mg / mL to about 250 mg / mL.

117. The pharmaceutical composition of any one of claims 112-115, wherein the concentration of the ASO is from 6.7 mg / mL to 188 mg / mL, from 6.8 mg / mL to 187 mg / mL, from 3 mg / mL to 100 mg / mL, or from 3 mg / mL to 33 mg / mL.

118. The pharmaceutical composition of any one of claims 112-115, wherein the concentration of the ASO is about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, or 33 mg / mL.WSGR Docket No.47991-744.601 119. The pharmaceutical composition of any one of claims 112-115, wherein the concentration of the ASO is 11 mg / mL, 22 mg / mL, 33 mg / mL, 44 mg / mL, 55 mg / mL, 66 mg / mL, 77 mg / mL, 88 mg / mL, 99 mg / mL, or 100 mg / mL.

120. The pharmaceutical composition of any one of claims 112-115, wherein the concentration of the ASO is about 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22.5 mg / mL, 25 mg / mL, 27.5 mg / mL, 30 mg / mL, 32.5 mg / mL, 35 mg / mL, 37.5 mg / mL, 40 mg / mL, 42.5 mg / mL, 45 mg / mL, 47.5 mg / mL, 50 mg / mL, 52.5 mg / mL, 55 mg / mL, 57.5 mg / mL, 60 mg / mL, 62.5 mg / mL, 65 mg / mL, 67.5 mg / mL, 70 mg / mL, 72.5 mg / mL, 75 mg / mL, 77.5 mg / mL, 80 mg / mL, 82.5 mg / mL, 85 mg / mL, 87.5 mg / mL, 90 mg / mL, 92.5 mg / mL, 95 mg / mL, 97.5 mg / mL, 100 mg / mL, 102.5 mg / mL, 105 mg / mL, 107.5 mg / mL, 110 mg / mL, 112.5 mg / mL, 115 mg / mL, 117.5 mg / mL, 120 mg / mL, 122.5 mg / mL, 125 mg / mL, 127.5 mg / mL, 130 mg / mL, 132.5 mg / mL, 135 mg / mL, 137.5 mg / mL, 140 mg / mL, 142.5 mg / mL, 145 mg / mL, 147.5 mg / mL, 150 mg / mL, 152.5 mg / mL, 155 mg / mL, 157.5 mg / mL, 160 mg / mL, 162.5 mg / mL, 165 mg / mL, 167.5 mg / mL, 170 mg / mL, 172.5 mg / mL, 175 mg / mL, 177.5 mg / mL, 180 mg / mL, 182.5 mg / mL, 185 mg / mL, 187.5 mg / mL, 190 mg / mL, 192.5 mg / mL, 195 mg / mL, 197.5 mg / mL, 200 mg / mL, 202.5 mg / mL, 205 mg / mL, 207.5 mg / mL, 210 mg / mL, 212.5 mg / mL, 215 mg / mL, 217.5 mg / mL, 220 mg / mL, 222.5 mg / mL, 225 mg / mL, 227.5 mg / mL, 230 mg / mL, 232.5 mg / mL, 235 mg / mL, 237.5 mg / mL, 240 mg / mL, 242.5 mg / mL, 245 mg / mL, 247.5 mg / mL, or 250 mg / mL.

121. The pharmaceutical composition of any one of claims 112-120, wherein the concentration of calcium chloride dihydrate is 0.2 mM to 25 mM, 0.5 mM to 10 mM, 0.75 mM to 5 mM, or 1 mM to 2 mM.

122. The pharmaceutical composition of any one of claims 112-120, wherein the concentration of calcium chloride dihydrate is from about 1 mM to about 2 mM.

123. The pharmaceutical composition of any one of claims 112-120, wherein the concentration of calcium chloride dihydrate is about 1.4 mM.

124. The pharmaceutical composition of any one of claims 112-123, wherein the concentration of magnesium chloride hexahydrate is 0.2 mM to 25 mM, 0.3 mM to 15 mM, 0.4 mM to 5 mM, 0.5 mM to 1.5 mM, or 0.6 mM to 1 mM.

125. The pharmaceutical composition of any one of claims 112-123, wherein the concentration of magnesium chloride hexahydrate is from about 0.6 mM to about 1 mM.

126. The pharmaceutical composition of any one of claims 112-123, wherein the concentration of magnesium chloride hexahydrate is about 0.79 mM.

127. The pharmaceutical composition of any one of claims 112-126, wherein the concentration of potassium chloride is 0.5 mM to 10 mM, 1 mM to 7.5 mM, or 2 mM to 5 mM.

128. The pharmaceutical composition of any one of claims 112-126, wherein the concentration of potassium chloride is from about 2 mM to about 5 mM.

129. The pharmaceutical composition of any one of claims 112-126, wherein the concentration of potassium chloride is about 3 mM.WSGR Docket No.47991-744.601 130. The pharmaceutical composition of any one of claims 112-129, wherein the concentration of sodium chloride is 25 mM to 250 mM, 100 mM to 160 mM, 110 mM to 140 mM, or 130 mM to 160 mM.

131. The pharmaceutical composition of any one of claims 112-129, wherein the concentration of sodium chloride is from about 125 mM to 145 mM.

132. The pharmaceutical composition of any one of claims 112-129, wherein the concentration of sodium chloride is about 130 mM.

133. The pharmaceutical composition of any one of claims 112-129, wherein the concentration of sodium chloride is from about 140 mM to 160 mM.

134. The pharmaceutical composition of any one of claims 112-129, wherein the concentration of sodium chloride is about 150 mM.

135. The pharmaceutical composition of any one of claims 112-134, wherein: (i) the concentration of calcium chloride dihydrate is from about 0.5 mM to about 5 mM; (ii) the concentration of magnesium chloride hexahydrate is from about 0.3 mM to about 1.25 mM; (iii) the concentration of potassium chloride is from about 1 mM to about 10 mM; and (iv) the concentration of sodium chloride is from about 100 mM to 180 mM.

136. The pharmaceutical composition of any one of claims 112-134, wherein: (i) the concentration of calcium chloride dihydrate is from about 1 mM to about 2 mM; (ii) the concentration of magnesium chloride hexahydrate is from about 0.6 mM to about 1 mM; (iii) the concentration of potassium chloride is from about 2 mM to about 5 mM; and (iv) the concentration of sodium chloride is from about 120 mM to 160 mM.

137. The pharmaceutical composition of any one of claims 112-134, wherein: (i) the concentration of the ASO is about 3 mg / mL, about 4.5 mg / mL, about 7 mg / mL, or about 33 mg / mL; (ii) the concentration of calcium chloride dihydrate is about 1.4 mM; (iii) the concentration of magnesium chloride hexahydrate is about 0.79 mM; (iv) the concentration of potassium chloride is about 3 mM; and (v) the concentration of sodium chloride is about 150 mM.

138. The pharmaceutical composition of any one of claims 112-137, wherein the pH of the pharmaceutical composition is about 6.6 to about 7.

6.

139. The pharmaceutical composition of any one of claims 112-137, wherein the pH of the pharmaceutical composition is about 6.8 to about 7.

2.

140. The pharmaceutical composition of any one of claims 112-137, wherein the pH of the pharmaceutical composition is about 6.9 to about 7.

1.

141. The pharmaceutical composition of any one of claims 112-140, wherein the volume of the pharmaceutical composition is about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 12 mL, about 15 mL, about 20 mL, about 25 mL.WSGR Docket No.47991-744.601 142. The pharmaceutical composition of any one of claims 112-140, wherein the volume of the pharmaceutical composition is about 10 mL.

143. A liquid pharmaceutical formulation consisting essentially of: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound according to the following chemical structure:(I), or a salt thereof; (b) calcium ion (Ca2+) at a concentration of about 0.1 mM to about 50 mM; (c) magnesium ion (Mg2+) at a concentration of about 0.1 mM to about 50 mM; (d) potassium ion (K+) at a concentration of about 0.1 mM to about 20 mM; (e) sodium ion (Na+) at a concentration of about 25 mM to about 250 mM; (f) chloride ion (Cl-) at a concentration of about 25 mM to about 250 mM; and (g) water.

144. A liquid pharmaceutical formulation consisting essentially of: (a) an antisense oligomer (ASO) at a concentration of about 0.1 mg / mL to about 500 mg / mL, wherein the ASO is a compound according to the following chemical structure:WSGR Docket No.47991-744.601(I), or a salt thereof; (b) calcium ion (Ca2+) at a concentration of about 1.4 mM; (c) magnesium ion (Mg2+) at a concentration of about 0.79 mM; (d) potassium ion (K+) at a concentration of about 3 mM; (e) sodium ion (Na+) at a concentration of about 160 mM; (f) chloride ion (Cl-) at a concentration of about 160 mM; and (g) water.

145. A method of treating or reducing the likelihood of developing a disease or condition in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of claims 1-27 or 56-144.

146. The method of claim 145, wherein the subject is a human subject.

147. The method of claim 145, wherein the human subject is at most 18 years old at a first dose of the pharmaceutical composition.

148. The method of claim 145, wherein the method comprises administering the ASO at a first dose of from about 0.5 milligrams to about 500 milligrams.

149. The method of claim 145, wherein the method comprises administering multiple doses of the ASO.

150. The method of any one of claims 145-149, wherein the disease or condition is characterized by a reduced expression or function of NaV1.1 protein in the subject.

151. The method of any one of claims 145-149, wherein the disease or condition is Dravet Syndrome.

152. The method of any one of claims 145-151, wherein the subject is characterized by having:WSGR Docket No.47991-744.601 (i) seizure onset prior to 12 months of age with recurrent focal motor or hemiconvulsive or generalized tonic-clonic seizures, which are often prolonged and triggered by hyperthermia; (ii) no past history of causal magnetic resonance imaging lesion; (iii) no other known etiology of any diseases or conditions except Dravet Syndrome; (iv) normal development at seizure onset; (v) a pathogenic variant, or variant of uncertain significance in an SCN1A gene; (vi) at least 2 prior treatments for epilepsy that either had lack of adequate seizure control; (vii) 4 or more convulsive seizures during the 28 days prior to administering, wherein the convulsive seizures are Hemiclonic, Focal With Motor Signs, Focal To Bilateral Tonic Clonic Convulsion, Generalized Tonic Clonic Convulsion, Tonic, Tonic or Atonic (Drop Attacks), or Clonic; (viii) a current intervention for epilepsy or medication with at least one antiepileptic drug at a dose which has been stable for at least 4 weeks, wherein the interventions for epilepsy is a ketogenic diet, a vagal nerve stimulator, or a cannabinoid or marijuana-derived product; or (ix) any combination of (i) – (viii).

153. The method of any one of claims 145-152, wherein the subject is characterized by not having one or more of the following: (a) one of the following mutations in the SCN1A gene: Thr226Met, Leu263Val, Val422Leu, Thr1174Ser, Trp1204Arg, Pro1345Ser, Gln1489Lys, Phe1499Leu, Arg1575Cys, Val1611Phe, Leu1624Pro, Arg1648Cys, Leu1649Gln, Leu1670Trp, Gly1674Arg, and Asp1866Tyr; (b) a known pathogenic mutation in another gene that causes epilepsy, wherein the pathogenic mutation is homozygous in cases of known recessive disease; (c) currently treated with a sodium channel blocker as maintenance treatment and an anticoagulant, wherein the sodium channel blocker is phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, or rufinamide, and wherein the anticoagulant is not an aspirin; (d) clinically, significantly unstable medical conditions other than epilepsy; (e) clinically, relevant symptoms or a clinically significant illness in the 4 weeks prior to administering, other than epilepsy; (f) a history of brain or spinal cord disease other than epilepsy, Dravet Syndrome or a history of bacterial meningitis or brain malformation; (g) a spinal deformity or other condition that alters the free flow of cerebrospinal fluid (CSF) or having an implanted CSF drainage shunt; (h) clinically significant abnormal laboratory values prior to administering; (i) aspartate aminotransferase or alanine aminotransferase >2.5-fold upper limit of normal, serum creatinine greater than an upper limit of normal or platelet count less than a lower limit of normal;WSGR Docket No.47991-744.601 (j) clinically relevant abnormalities in the 12-lead electrocardiogram (ECG) measured at prior to administering; (k) a psychiatric or behavioral disorder; (l) currently or in the past 4 weeks, medication of an anticoagulant, wherein the anticoagulant is not aspirin; or (m) any combination of (a) – (l).

154. The method of any one of claims 145-153, wherein the subject is from 1 to 18, from 2 to 18, from 3 to 18, from 4 to 18, from 5 to 18, from 6 to 18, from 7 to 18, from 8 to 18, from 9 to 18, from 10 to 18, from 11 to 18, from 12 to 18, from 13 to 18, from 14 to 18, from 15 to 18, from 16 to 18, or from 17 to 18 years old.

155. The method of any one of claims 145-153, wherein the subject is a human from 1 to 17, from 1 to 16, from 1 to 15, from 1 to 14, from 1 to 13, from 1 to 12, from 1 to 11, from 1 to 10, from 1 to 9, from 1 to 8, from 1 to 7, from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, or from 1 to 2 years old.

156. The method of any one of claims 145-153, wherein the subject is less than a year old or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years old.

157. The method of any one of claims 145-156, wherein the pharmaceutical composition is administered into the intrathecal space of the subject.

158. The method of any one of claims 145-156, wherein the pharmaceutical composition is administered into the cerebrospinal fluid of the subject.

159. The method of any one of claims 145-156, wherein the pharmaceutical composition is administered into the brain of the subject.

160. The method of any one of claims 145-156, wherein the pharmaceutical composition is administered into the cerebrospinal fluid in the brain of the subject.

161. The method of any one of claims 145-160, wherein the pharmaceutical composition is administered as a bolus injection.

162. The method of claim 161, wherein the method comprises administering the pharmaceutical composition as a bolus injection over 1 to 60 minutes, 1 to 50 minutes, 1 to 40 minutes, 1 to 30 minutes, 1 to 20 minutes, 1 to 10 minutes, 1 to 5 minutes, or 1 to 3 minutes.

163. The method of any one of claims 145-160, wherein the pharmaceutical composition is administered by infusion with a delivery pump.

164. The method of any one of claims 145-163, wherein the pharmaceutical composition is administered by intracerebroventricular injection.

165. The method of any one of claims 145-163, wherein the pharmaceutical composition is administered by intrathecal injection.

166. The method of any one of claims 145-165, wherein the method reduces or ameliorates at least one symptom of Dravet Syndrome in the human subject.

167. The method of claim 166, wherein the symptom of Dravet Syndrome is a seizure.WSGR Docket No.47991-744.601 168. The method of any one of claims 145-167, wherein the administration reduces or ameliorates seizure frequency, seizure intensity, or seizure duration.

169. The method of any one of claims 145-168, wherein the method further comprises assessing tolerability or effectiveness of the pharmaceutical composition.

170. The method of any one of claims 145-169, wherein the method further comprises administering to the subject a pharmaceutical composition comprising the ASO at subsequent doses of from about 0.5 milligrams to about 500 milligrams.

171. The method of claim 170, wherein the subsequent dose is 0.1, 0.5, 1, 2.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60, 62.5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, 100, 102.5, 105, 107.5, 110, 112.5, 115, 117.5, 120, 122.5, 125, 127.5, 130, 132.5, 135, 137.5, 140, 142.5, 145, 147.5, 150, 152.5, 155, 157.5, 160, 162.5, 165, 167.5, 170, 172.5, 175, 177.5, 180, 182.5, 185, 187.5, 190, 192.5, 195, 197.5, 200, 202.5, 205, 207.5, 210, 212.5, 215, 217.5, 220, 222.5, 225, 227.5, 230, 232.5, 235, 237.5, 240, 242.5, 245, 247.5, or 250 mg.

172. The method of claim 170 or 171, wherein the subsequent dose is lower than the previous dose following an indication that administration of the previous dose is not tolerated.

173. The method of claim 170 or 171, wherein the subsequent dose is the same as the previous dose following an indication that administration of the previous dose is tolerated.

174. The method of claim 170 or 171, wherein the subsequent dose is higher than the previous dose following an indication that administration of the previous dose is tolerated.

175. The method of claim 170 or 171, wherein the subsequent dose is the same as the previous dose following an indication that administration of the previous dose is effective.

176. The method of claim 170 or 171, wherein the subsequent dose is lower than the previous dose following an indication that administration of the previous dose is effective.

177. The method of claim 170 or 171, wherein the subsequent dose is higher than the previous dose following an indication that administration of the previous dose is not effective.

178. The method of any one of claims 170-177, wherein the subsequent doses are administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after administration of the previous dose.

179. The method of any one of claims 145-178, wherein dose frequency is maintained or reduced following an indication that the previous dose is effective.

180. The method of any one of claims 145-179, wherein dose frequency is increased following an indication that the previous dose is not effective.

181. The method of any one of claims 145-180, wherein the method further comprises administrating at least one additional therapeutic agent or therapy.

182. The method of claim 181, wherein the at least one additional therapeutic agent or therapy is administered at the same time as the dose.

183. The method of claim 181, wherein the at least one additional therapeutic agent or therapy is administered prior to administration of the dose.WSGR Docket No.47991-744.601 184. The method of claim 181, wherein the at least one additional therapeutic agent or therapy is administered after administration of the dose.

185. The method of any one of claims 150-184, wherein the reduced expression or function of NaV1.1 protein is associated with an altered splicing of a nonsense-mediated RNA decay-inducing exon from a pre-mRNA that contains the NMD exon and encodes NaV1.1 protein.

186. The method of any one of claims 150-185, wherein the ASO promotes exclusion of the NMD exon from the pre-mRNA that contains the NMD exon and that encodes the NaV1.1 protein.

187. The method of any one of claims 150-186, wherein the ASO binds to a targeted portion of a pre- mRNA that contains the NMD exon and that encodes the NaV1.1 protein.

188. The method of claim 187, wherein the ASO promotes exclusion of the NMD exon from the pre- mRNA that contains the NMD exon and that encodes the NaV1.1 protein.

189. The method of any one of claims 185-188, wherein the ASO increases a level of processed mRNA encoding the NaV1.1 protein when the ASO is introduced into the cell.

190. The method of any one of claims 185-189, wherein the ASO increases a level of the NaV1.1 protein when the ASO is introduced into the cell.

191. The method of any one of claims 185-190, wherein the targeted portion is within an intron sequence flanking the NMD exon.

192. The method of any one of claims 185-190, wherein the targeted portion comprises at least one nucleotide of the NMD exon.

193. The method of any one of claims 185-190, wherein the targeted portion is within the NMD exon.

194. A method of making the pharmaceutical composition of any one of claims 1-27 or 56-144, wherein the method comprises diluting the antisense oligomer (ASO) in the pharmaceutically acceptable diluent, thereby making the liquid composition.

195. The method of claim 194, wherein the ASO is present in the liquid composition at a concentration of 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, 30 mg / mL, 33 mg / mL, 44 mg / mL, 55 mg / mL, 66 mg / mL, 77 mg / mL, 88 mg / mL, 99 mg / mL, 100 mg / mL, 22.5 mg / mL, 25 mg / mL, 27.5 mg / mL, 30 mg / mL, 32.5 mg / mL, 35 mg / mL, 37.5 mg / mL, 40 mg / mL, 42.5 mg / mL, 45 mg / mL, 47.5 mg / mL, 50 mg / mL, 52.5 mg / mL, 55 mg / mL, 57.5 mg / mL, 60 mg / mL, 62.5 mg / mL, 65 mg / mL, 67.5 mg / mL, 70 mg / mL, 72.5 mg / mL, 75 mg / mL, 77.5 mg / mL, 80 mg / mL, 82.5 mg / mL, 85 mg / mL, 87.5 mg / mL, 90 mg / mL, 92.5 mg / mL, 95 mg / mL, 97.5 mg / mL, 100 mg / mL, 102.5 mg / mL, 105 mg / mL, 107.5 mg / mL, 110 mg / mL, 112.5 mg / mL, 115 mg / mL, 117.5 mg / mL, 120 mg / mL, 122.5 mg / mL, 125 mg / mL, 127.5 mg / mL, 130 mg / mL, 132.5 mg / mL, 135 mg / mL, 137.5 mg / mL, 140 mg / mL, 142.5 mg / mL, 145 mg / mL, 147.5 mg / mL, 150 mg / mL, 152.5 mg / mL, 155 mg / mL, 157.5 mg / mL, 160 mg / mL, 162.5 mg / mL, 165 mg / mL, 167.5 mg / mL, 170 mg / mL, 172.5 mg / mL, 175 mg / mL, 177.5 mg / mL, 180 mg / mL, 182.5 mg / mL, 185 mg / mL, 187.5 mg / mL, 190 mg / mL, 192.5 mg / mL, 195 mg / mL, 197.5 mg / mL, 200 mg / mL, 202.5 mg / mL, 205 mg / mL, 207.5 mg / mL, 210 mg / mL, 212.5 mg / mL, 215WSGR Docket No.47991-744.601 mg / mL, 217.5 mg / mL, 220 mg / mL, 222.5 mg / mL, 225 mg / mL, 227.5 mg / mL, 230 mg / mL, 232.5 mg / mL, 235 mg / mL, 237.5 mg / mL, 240 mg / mL, 242.5 mg / mL, 245 mg / mL, 247.5 mg / mL, or 250 mg / mL.

196. The method of claim 195, wherein the method further comprises diluting the liquid composition with an additional volume of the pharmaceutically acceptable diluent, thereby making the liquid composition.

197. The method of claim 196, wherein the ASO is present in the liquid composition at a concentration of wherein the ASO is present in the liquid composition at a concentration of from 0.1-500 mg / mL, from 0.1 mg / mL to 250 mg / mL, from 6.7 mg / mL to 188 mg / mL, from 6.8 mg / mL to 187 mg / mL, from 3 mg / mL to 100 mg / mL, or from 3 mg / mL to 33 mg / mL, or about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, 30 mg / mL, or 33 mg / mL.

198. The method of any one of claims 194-197, wherein the method further comprises filtering the liquid composition.

199. The method of claim 198, wherein filtering comprises filtering the liquid composition at least twice or through at least two membranes.

200. The method of claim 198 or 199, wherein filtering comprises filtering the liquid composition through a 0.45-μm membrane and a 0.2-μm membrane.

201. The method of claim 199 or 200, wherein the at least two membranes, the 0.45-μm membrane, and / or the 0.2-μm membrane comprises a polyethersulfone membrane.

202. The method of any one of claims 194-201, wherein the method further comprises filling a vial with the liquid composition.

203. The method of claim 202, wherein the vial is sterilized and / or depyrogenated.

204. The method of claim 202 or 203, wherein the method further comprises fitting the vial with a stopper.

205. The method of claim 204, wherein the stopper is sterilized and / or depyrogenated.

206. The method of any one of claims 202-205, wherein the method further comprises capping the vial with a seal.

207. The method of claim 206, wherein the seal is sterilized and / or depyrogenated.

208. The method of any one of claims 194-207, wherein the method is performed aseptically.

209. The method of any one of claims 194-208, wherein the method further comprises storing the vial for a time period at a temperature.

210. The method of claim 209, wherein the temperature is -20 ± 5 °C.

211. The method of claim 209 or 210, wherein the time period is no more than 36 months.

212. The method of claim 211, wherein the time period is no more than 24 months.

213. The method of any one of claims 209-212, wherein the method further comprises administering the liquid composition to a human subject after the storing.

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