Oligonucleotide compositions and methods thereof

Abstract

Among other things, the present disclosure provides various technologies including chirally controlled oligonucleotide compositions and technologies for manufacturing and using such oligonucleotide compositions. In some embodiments, the present disclosure provides technologies useful for editing of adenosine in transcripts, e.g., SERPINA1 transcripts. In some embodiments, the present disclosure provides methods for treating various conditions, disorders or diseases that can benefit from adenosine editing. In some embodiments, the present disclosure provides technologies useful for preventing or treating various conditions, disorders or diseases, e.g., alpha-1 antitrypsin deficiency.

Description

OLIGONUCLEOTIDE COMPOSITIONS AND METHODS THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application Nos. 63 / 766,951, filed March 4, 2025, 63 / 708,008, filed October 16, 2024, 63 / 690,288, filed September 3, 2024, and 63 / 690,280, filed September 3, 2024, the entirety of each of which is incorporated herein by reference. BACKGROUND

[0002] Alpha-1 antitrypsin (AAT) deficiency (AATD) is reported to be a genetic disorder in many cases caused by defects in the SERPINA1 gene (also known as PI, A1A, AAT, PI1, A1AT, nNIF, PRO2275, alpha1AT, etc.). AATD is reported to be associated with various phenotypes including lung and liver phenotypes. Various SERPINA1 mutations associated with AATD have been reported including E342K, (may also be referred to as E366K (see, e.g., UNIPROT entry P01009); the corresponding nucleic acid mutation may be referred to as 1024 G>A or 1096 G>A). SUMMARY

[0003] Alpha-1 antitrypsin (AAT) is reported to be an acute phase protein predominantly produced by hepatocytes. It is reported serum wild-type (WT) AAT can protect lungs against proteolytic enzymes such as neutrophil elastase. In some embodiments, alpha-1 antitrypsin deficiency is caused by mutations in the Serpin Family A Member 1 (SERPINA1) gene which according to some reports can follow an autosomal recessive inheritance pattern with a codominant genetic trait for AAT production. It is reported that 95% of severe AATD is due to homozygous substitution of a single amino acid, Glu342Lys in AAT, which can produce a misfolded, poorly secreted, and partially functional AAT protein (Z-AAT). It is reported that retention of Z-AAT protein in liver can cause proteotoxic stress leading to progressive gain of function liver disease from fibrosis to cirrhosis to hepatocellular carcinoma. Deficiency of WT AAT in serum is reported to result in loss of function leading to impaired neutrophil elastase inhibition and increased inflammation in extrahepatic tissues. This mostly leads to pulmonary disease which is manifested as chronic obstructive pulmonary disease (COPD),emphysema, and / or bronchiectasis.

[0004] There are currently very limited treatment options for AATD, most of which are based on symptom management. Among other things, the present disclosure recognizes a need for improved treatment of AATD. In some embodiments, the present disclosure provides technologies (e.g., WV-49090 compositions, doses, dosing regimen, etc.) for preventing or treating AATD and conditions, disorders or diseases associated therewith.

[0005] In some embodiments, WV-49090 specifically edits a 1024 G>A SERPINA1 mutant messenger ribonucleic acid (mRNA; Z) that encodes a Glu342Lys mutant AAT polypeptide to a SERPINA1 mRNA that can encode a Glu342 AAT polypeptide. 1024 G>A is an adenosine deaminase acting on RNA (ADAR)amenable mutation that has demonstrated correction with WV-49090 in animal models. Editing of 1024 G>A SERPINA1-Z mRNA may increase M-AAT protein level in serum and / or decrease accumulation of Z-AAT including polymeric Z-AAT in liver.

[0006] Prior to the present disclosure, safety profile of WV-49090 and its effects, e.g., safety, tolerability, pharmacokinetics, pharmacodynamics, etc., in human are not known. There is a potential for subjects with E342K mutation, e.g., Pi*ZZ subjects, to benefit from it, and there may be risks associated with it such as inflammatory and coagulation effects, effects in liver and kidney, risks or toxicities to subjects with Pi*ZZ, etc. Among other things, the present disclosure provides technologies for administering or delivering WV-49090 to subjects with E342K mutation, e.g., Pi*ZZ subjects. In some embodiments, the present disclosure confirms safety of certain provided technologies.

[0007] In some embodiments, the present disclosure provides technologies that can convert a 1024 G>A mutation to I which can be read as G during protein translation and thus correcting the G to A mutation for protein translation. Among other things, alteration of SERPINA1 in one or more of hepatocytes can prevent the progression of liver disease in subjects with AATD by reducing or eliminating production of the toxic Z protein (Z-AAT). In certain embodiments, Z protein production is eliminated or reduced by utilizing provided technologies. In certain embodiments, the disease is cured, does not progress, or has delayed progression compared to a subject who has not received the therapy or who has received an alternative therapy (e.g., augmentation therapy with AAT protein).

[0008] WV-49090 is a 30 mer oligonucleotide compound that has demonstrated sequence-specific A-to-I RNA editing of SERPINA1 mRNA comprising a 1024 G>A mutation using endogenous ADAR enzymes. WV- 49090 ADAR A-to-I editing of SERPINA1 mRNA 1024A and restoration of AAT function has been demonstrated in vitro and in mouse models. Structurally, WV-49090 is a 2’-F, 2’-MOE, and 2’-OMe modified oligonucleotide in which the internucleotidic linkages are independently phosphorothioate (PS), n001, and natural phosphate (PO) linkages). Chiral linkage phosphorous in WV-49090 is each independently stereodefined: linkage phosphorous of each PS linkage is in Sp configuration, and linkage phosphorous of each n001 linkage is in Rp configuration. As demonstrated herein, WV-49090 compositions are chirally controlled compositions in which WV-49090 or salts thereof (e.g., sodium salts) are highly enriched over other diastereomers or salts thereof.

[0009] Among other things, the present disclosure provides technologies (e.g., WV-49090 compositions, doses, dosing regimens, etc.) for treating AATD. In some embodiments, the present disclosure provides a method for treating AATD, comprising administering or delivering to a subject suffering therefrom WV-49090 as described herein. In some embodiments, the present disclosure provides technologies for treating conditions, diseases or disorders associated with AATD, comprising administering or delivering to a subject suffering therefrom WV-49090 as described herein. In some embodiments, the present disclosure provides a method for treating a condition, disease or disorder associated with AATD. In some embodiments, the present disclosure provides technologies for administering or delivering WV-49090 to human subjects.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1. (A) An example a flow diagram comprising various elements for WV-49090 drug substance manufacturing process. PO = phosphodiester linkage, PS = phosphorothioate linkage, PN = phosphoramidate diester linkage, DPSE = 2-(methyldiphenylsilyl)-1-(pyrrolidine-2-yl)ethan-1-ol, PSM = 2- (phenylsulfonyl)-1-((S)-pyrrolidin-2-yl)ethan-1-ol, CNE = cyanoethyl, IPC = In process control, IPT = In process test. (B) Additional steps in drug substance manufacturing process.

[0011] Figure 2. Example schematics of a study design. Abbreviations: C=cohort; MAD=multiple ascending dose; P1=Period 1 (SAD); P2=Period 2 (MAD); SAD=single ascending dose.

[0012] Figure 3. Example schematics of a study design. Abbreviations: AATD=alpha-1 antitrypsin deficiency; C=cohort; MAD=multiple ascending dose; P1=Period 1 (SAD); P2=Period 2 (MAD); SAD=single ascending dose. Dose level and frequency for Period 2 will be determined by the Data Monitoring Committee (DMC) as described in its charter and decided by the Sponsor. Dosing every other week (Q2W) may be reduced to dosing every 4 weeks (Q4W).

[0013] Figure 4. Example schematics of a study design. Abbreviations: AATD=alpha-1 antitrypsin deficiency; MAD=multiple ascending dose; SAD=single ascending dose.

[0014] Figure 5. Example schematics of a study design. Abbreviations: AATD=alpha-1 antitrypsin deficiency; MAD=multiple ascending dose; Q2W=dosing every other week; SAD=single ascending dose.

[0015] Figure 6. WV-49090 treatment led to an increase in circulating serum AAT protein from below the level of quantification. For each treatment group: arrows point to horizontal lines representing mean and median; mean numerical value is inset; each plotted circle is data for a single subject. Abbreviations: MAD=multiple ascending dose; SAD=single ascending dose.

[0016] Figure 7. WV-49090 treatment led to an increase in levels of M-AAT protein and increase in proportion of total AAT protein that was M-AAT protein. Arrows indicate doses of WV-49090. Abbreviations: MAD=multiple ascending dose; SAD=single ascending dose.

[0017] Figure 8. WV-49090 treatment led to an increase in levels of M-AAT protein and decrease in levels of Z-AAT protein. For MAD 200 mg, dosing period is up through week 12 and follow-up is thereafter. Each plotted line represents data collected from a single subject. Abbreviations: MAD=multiple ascending dose; SAD=single ascending dose.

[0018] Figure 9. WV-49090 treatment led to an increase in levels of M-AAT protein and decrease in levels of Z-AAT protein. For each treatment group: arrows point to horizontal lines representing mean and median; mean numerical value is inset; each plotted circle is data for a single subject. Abbreviations: MAD=multiple ascending dose; SAD=single ascending dose.

[0019] Figure 10. WV-49090 provided dynamic AAT protein response in a subject with a non-drug- related acute phase response. Abbreviations: CRP=C-reactive protein (CRP); MAD=multiple ascending dose; SAD=single ascending dose.DEFINITIONS

[0020] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0021] As used herein in the present disclosure, unless otherwise clear from context, (i) the term “a” or “an” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprising”, “comprise”, “including” (whether used with “not limited to” or not), and “include” (whether used with “not limited to” or not) may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; (iv) the term “another” may be understood to mean at least an additional / second one or more; and (v) where ranges are provided, endpoints are included.

[0022] Unless otherwise specified, description of oligonucleotides and elements thereof (e.g., base sequence, sugar modifications, internucleotidic linkages, linkage phosphorus stereochemistry, etc.) is from 5’ to 3’. Unless otherwise specified, oligonucleotides described herein may be provided and / or utilized in various forms including salt forms, particularly pharmaceutically acceptable salt forms. As those skilled in the art will appreciate after reading the present disclosure, in some embodiments, oligonucleotides may be provided as salts such as sodium or potassium salts. As those skilled in the art will appreciate, in some embodiments, individual oligonucleotides within a composition may be considered to be of the same constitution and / or structure even though, within such composition (e.g., a liquid composition), particular such oligonucleotides might be in different form(s) including salt form(s) (and may be dissolved and the oligonucleotide chain may exist as an anion form when, e.g., in a liquid composition) at a particular moment in time. For example, those skilled in the art will appreciate that, at a given pH, individual internucleotidic linkages along an oligonucleotide chain may be in an acid (H) form, or in one of a plurality of possible salt forms (e.g., a sodium salt, or a salt of a different cation, depending on which ions might be present in the preparation or composition)), and will understand that, so long as their acid forms (e.g., replacing all cations, if any, with H) are of the same constitution and / or structure, such individual oligonucleotides may properly be considered to be of the same constitution and / or structure.

[0023] Approximately: As used herein, the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art. In some embodiments, the terms “approximately” or “about” in reference to a number are generally taken to include numbers that fall within a range of 5%, 10%, 15%, 20%, 25%, or 30%, in either direction (greater than or less than) of the number unless otherwise stated or otherwise evident from the context. In some embodiments, a range is ±5%. In someembodiments, a range is ±10%.

[0024] Dosing regimen: As used herein, a “dosing regimen” or “therapeutic regimen” refers to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount.

[0025] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, active agent is present in a unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a controlled therapeutic effect when administered to a relevant population.

[0026] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0027] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.

[0028] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, a provided compound comprises more than one acid groups, for example, a provided oligonucleotide may comprise two or more acidic groups (e.g., in natural phosphate linkages and / or modifiedinternucleotidic linkages). In some embodiments, a pharmaceutically acceptable salt, or generally a salt, of such a compound comprises two or more cations, which can be the same or different. In some embodiments, in a pharmaceutically acceptable salt (or generally, a salt), each acidic group having sufficient acidity independently exists as its salt form (e.g., in an oligonucleotide comprising natural phosphate linkages and phosphorothioate internucleotidic linkages, each of the natural phosphate linkages and phosphorothioate internucleotidic linkages independently exists as its salt form). In some embodiments, a pharmaceutically acceptable salt of an oligonucleotide is a sodium salt of a provided oligonucleotide. In some embodiments, a pharmaceutically acceptable salt of an oligonucleotide is a sodium salt of a provided oligonucleotide, wherein each acidic linkage, e.g., each natural phosphate linkage and phosphorothioate internucleotidic linkage, exists as a sodium salt form (all sodium salt).

[0029] Subject: As used herein, the term “subject” or “test subject” refers to any organism to which a provided compound or composition is administered or delivered in accordance with the present disclosure, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. In some embodiments, a subject may be suffering from, and / or susceptible to a disease, disorder, and / or condition. Unless otherwise noted, a subject is a human subject.

[0030] Substantially: As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and / or chemical phenomena.

[0031] Suffering from: An individual who is “suffering from” a disease, disorder, and / or condition has been diagnosed with and / or displays one or more symptoms of a disease, disorder, and / or condition.

[0032] Susceptible to: An individual who is “susceptible to” a disease, disorder, and / or condition is one who has a higher risk of developing the disease, disorder, and / or condition than does a member of the general public. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition may not have been diagnosed with the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may not exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will not develop the disease, disorder, and / or condition.

[0033] Systemic: The phrases “systemic administration,” “administered systemically,” “peripheral administration,” and “administered peripherally” as used herein have their art-understood meaning referring to administration of a compound or composition such that it enters the recipient’s system.

[0034] Therapeutic agent: As used herein, the phrase “therapeutic agent” refers to any agent that, when administered to a subject, has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect. In some embodiments, a therapeutic agent is any substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition.

[0035] Therapeutically effective amount: In some embodiments, the term “therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of compound in a formulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and / or reduces incidence of one or more symptoms or features of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount. In some embodiments, a single dose is an infusion, which may take up to one or more hours.

[0036] Treat: As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.

[0037] Chirally controlled oligonucleotide composition: The terms “chirally controlled (stereocontrolled or stereodefined) oligonucleotide composition”, “chirally controlled (stereocontrolled or stereodefined) nucleic acid composition”, and the like, as used herein, refers to a composition that comprises a plurality of oligonucleotides (or nucleic acids, chirally controlled oligonucleotides or chirally controlled nucleic acids) which share 1) a common base sequence, 2) a common pattern of backbone linkages; 3) a common pattern of backbone chiral centers, and 4) a common pattern of backbone phosphorus modifications (oligonucleotides of a particular type), wherein the plurality of oligonucleotides (or nucleic acids) share the same stereochemistry at one or more chiral internucleotidic linkages (chirally controlled internucleotidic linkages, whose chiral linkage phosphorus is Rp or Sp, not a random Rp and Sp mixture as non-chirally controlled internucleotidic linkages). Level of the plurality of oligonucleotides (or nucleic acids) in a chirally controlled oligonucleotide composition is non-random (pre-determined, controlled). Chirally controlled oligonucleotide compositions are typicallyprepared through chirally controlled oligonucleotide preparation to stereoselectively form one or more chiral internucleotidic linkages (e.g., using chiral auxiliaries as exemplified in the present disclosure, compared to non-chirally controlled (stereorandom, non-stereoselective, racemic) oligonucleotide synthesis such as traditional phosphoramidite-based oligonucleotide synthesis using no chiral auxiliaries or chiral catalysts to purposefully control stereoselectivity). A chirally controlled oligonucleotide composition is enriched, relative to a substantially racemic preparation of oligonucleotides having the common base sequence, the common pattern of backbone linkages, and the common pattern of backbone phosphorus modifications, for oligonucleotides of the plurality. In some embodiments, a chirally controlled oligonucleotide composition comprises a plurality of oligonucleotides of a particular oligonucleotide type defined by: 1) base sequence; 2) pattern of backbone linkages; 3) pattern of backbone chiral centers; and 4) pattern of backbone phosphorus modifications, wherein it is enriched, relative to a substantially racemic preparation of oligonucleotides having the same base sequence, pattern of backbone linkages, and pattern of backbone phosphorus modifications, for oligonucleotides of the particular oligonucleotide type. As one having ordinary skill in the art readily appreciates, such enrichment can be characterized in that compared to a substantially racemic preparation, at each chirally controlled internucleotidic linkage, a higher level of the linkage phosphorus has the desired configuration. In some embodiments, each chirally controlled internucleotidic linkage independently has a diastereopurity of at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% with respect to its chiral linkage phosphorus. In some embodiments, each independently has a diastereopurity of at least 90%. In some embodiments, each independently has a diastereopurity of at least 95%. In some embodiments, each independently has a diastereopurity of at least 97%. In some embodiments, each independently has a diastereopurity of at least 98%. In some embodiments, oligonucleotides of a plurality have the same constitution. In some embodiments, oligonucleotides of a plurality have the same constitution and stereochemistry, and are structurally identical.

[0038] In some embodiments, the plurality of oligonucleotides in a chirally controlled oligonucleotide composition share the same base sequence, the same, if any, nucleobase, sugar, and internucleotidic linkage modifications, and the same stereochemistry (Rp or Sp) independently at linkage phosphorus chiral centers of one or more chirally controlled internucleotidic linkages, though stereochemistry of certain linkage phosphorus chiral centers may differ. In some embodiments, about 0.1%-100%, (e.g., about 1%-100%, 5%-100%, 10%- 100%, 20%-100%, 30%-100%, 40%-100%, 50%-100%, 60%-100%, 70%-100%, 80-100%, 90-100%, 95- 100%, 50%-90%, or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) of all oligonucleotides in a chirally controlled oligonucleotide composition are oligonucleotides of the plurality. In some embodiments, about 0.1%-100%, (e.g., about 1%-100%, 5%-100%, 10%-100%, 20%-100%, 30%-100%, 40%-100%, 50%-100%, 60%-100%, 70%-100%, 80-100%, 90-100%, 95-100%, 50%-90%, or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or at least 5%, 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) of all oligonucleotides in a chirally controlled oligonucleotide composition that share the common base sequence are oligonucleotides of the plurality. In some embodiments, about 0.1%-100%, (e.g., about 1%-100%, 5%-100%, 10%-100%, 20%- 100%, 30%-100%, 40%-100%, 50%-100%, 60%-100%, 70%-100%, 80-100%, 90-100%, 95-100%, 50%-90%, or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) of all oligonucleotides in a chirally controlled oligonucleotide composition that share the common base sequence, the common pattern of backbone linkages, and the common pattern of backbone phosphorus modifications are oligonucleotides of the plurality. In some embodiments, about 0.1%- 100%, (e.g., about 1%-100%, 5%-100%, 10%-100%, 20%-100%, 30%-100%, 40%-100%, 50%-100%, 60%- 100%, 70%-100%, 80-100%, 90-100%, 95-100%, 50%-90%, or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) of all oligonucleotides in a chirally controlled oligonucleotide composition, or of all oligonucleotides in a composition that share a common base sequence (e.g., of a plurality of oligonucleotide or an oligonucleotide type), or of all oligonucleotides in a composition that share a common base sequence, a common pattern of backbone linkages, and a common pattern of backbone phosphorus modifications (e.g., of a plurality of oligonucleotide or an oligonucleotide type), or of all oligonucleotides in a composition that share a common base sequence, a common patter of base modifications, a common pattern of sugar modifications, a common pattern of internucleotidic linkage types, and / or a common pattern of internucleotidic linkage modifications (e.g., of a plurality of oligonucleotide or an oligonucleotide type), or of all oligonucleotides in a composition that share the same constitution, are oligonucleotides of the plurality. In some embodiments, a percentage is at least (DP)NCI, wherein DP is a percentage selected from 85%-100%, and NCI is the number of chirally controlled internucleotidic linkage. In some embodiments, DP is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, DP is at least 85%. In some embodiments, DP is at least 90%. In some embodiments, DP is at least 95%. In some embodiments, DP is at least 96%. In some embodiments, DP is at least 97%. In some embodiments, DP is at least 98%. In some embodiments, DP is at least 99%. In some embodiments, DP reflects diastereopurity of linkage phosphorus chiral centers chirally controlled internucleotidic linkages. In some embodiments, diastereopurity of a linkage phosphorus chiral center of an internucleotidic linkage may be typically assessed using an appropriate dimer comprising such an internucleotidic linkage and the two nucleoside units being linked by the internucleotidic linkage. In some embodiments, the plurality of oligonucleotides share the same stereochemistry at about 1-50 (e.g., about 1-10, 1-20, 5-10, 5-20, 10-15, 10-20, 10-25, 10-30, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) chiral internucleotidic linkages. In some embodiments, the plurality of oligonucleotides share the same stereochemistry at about 0.1%- 100% (e.g., about 1%-100%, 5%-100%, 10%-100%, 20%-100%, 30%-100%, 40%-100%, 50%-100%, 60%-100%, 70%-100%, 80-100%, 90-100%, 95-100%, 50%-90%, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%) of chiral internucleotidic linkages. In some embodiments, each chiral internucleotidic linkage is a chiral controlled internucleotidic linkage, and the composition is a completely chirally controlled oligonucleotide composition. In some embodiments, not all chiral internucleotidic linkages are chiral controlled internucleotidic linkages, and the composition is a partially chirally controlled oligonucleotide composition. In some embodiments, a chirally controlled oligonucleotide composition comprises predetermined levels of individual oligonucleotide or nucleic acids types. For instance, in some embodiments a chirally controlled oligonucleotide composition comprises one oligonucleotide type at a predetermined level (e.g., as described above). In some embodiments, a chirally controlled oligonucleotide composition comprises more than one oligonucleotide type, each independently at a predetermined level. In some embodiments, a chirally controlled oligonucleotide composition comprises multiple oligonucleotide types, each independently at a predetermined level. In some embodiments, a chirally controlled oligonucleotide composition is a composition of oligonucleotides of an oligonucleotide type, which composition comprises a predetermined level of a plurality of oligonucleotides of the oligonucleotide type. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0039] Among other things, the present disclosure provides technologies for treating AATD, e.g., in a subject having a SERPINA1 Z allele, by administering or delivering WV-49090 to the subject as described in the present disclosure. In some embodiments, the present disclosure provides technologies, e.g., doses, dosing regimens, etc., for administering or delivering WV-49090 to human subjects. WV-49090

[0040] WV-49090 comprises an oligonucleotide moiety that may be described as (as those skilled in the art appreciate, 5’ to 3’ unless specified otherwise): 5’-mC[n001R]mC[Ssp]mC[Ssp][fl2r]A[Ssp][fl2r]G[Ssp][moe][m5C]p[moe]Ap[fl2r]G[Ssp][fl2r] C[Ssp]mUpmU[n001R]mCp[fl2r]A[Ssp][fl2r]G[n001R][fl2r]Up[moe][m5C][Ssp][fl2r]C[Ssp]mCpmU[n001 R]mUp[moe]Tp[fl2r]C[Ssp]dT[Ssp]d[3nU][Ssp]d[Hyp][n001S]mUp[fl2r]C[Ssp]mG[Ssp]mA[n001R]mU-3’: m: 2’-O-methyl modified nucleoside (may also be referred to as 2’-OMe modified nucleoside); [fl2r]: 2’-fluoro-2’-deoxy modified nucleoside (may also be referred to as 2’-F modified nucleoside); [moe]: 2’-O-(2-methoxyethyl) modified nucleoside; d: 2’-deoxy nucleoside; [m5C]: 5-methylcytidine;d[3nU]: 2’-deoxyisouridine (nucleobase isd[Hyp]: 2’-deoxyinosine; [Ssp]: Sp phosphorothioate linkage; p: phosphodiester linkage;[n001S]: Sp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate linkage (herein thelinkage phosphorus is in Sp configuration);[n001R]: Rp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate linkage (erein thelinkage phosphorus is in Rp configuration); and the 5’-carbon of the 5’-end mC is linked to the structure below via a phosphodiester group:.

[0041] WV-49090 may be described using Hierarchical Editing Language for Macromolecules (HELM) (see, e.g., Zhang, T. et al. J Chem Inf Model.2012 Oct 22;52(10):2796-806; Milton, J. et al. J Chem Inf Model. 2017 Jun 26;57(6):1233-1239; etc.) as below: RNA1{p.m(C)[n001R].m(C)[Ssp].m(C)[Ssp].[fl2r](A)[Ssp].[fl2r](G)[Ssp].[moe]([m5C])p.[moe](A)p.[fl2r]( G)[Ssp].[fl2r](C)[Ssp].m(U)p.m(U)[n001R].m(C)p.[fl2r](A)[Ssp].[fl2r](G)[n001R].[fl2r](U)p.[moe]([m5C])[ Ssp].[fl2r](C)[Ssp].m(C)p.m(U)[n001R].m(U)p.[moe](T)p.[fl2r](C)[Ssp].d(T)[Ssp].d([3nU])[Ssp].d([Hyp])[n 001S].m(U)p.[fl2r](C)[Ssp].m(G)[Ssp].m(A)[n001R].m(U)}|CHEM1{[GalNAc3C12oyl]}|CHEM2{[nC6o]}$ CHEM2,RNA1,1:R1-1:R1|CHEM2,CHEM1,1:R2-1:R1$$$V2.0, wherein: m: 2’-O-methyl modified nucleoside (may also be referred to as 2’-OMe modified nucleoside); [fl2r]: 2’-fluoro-2’-deoxy modified nucleoside (may also be referred to as 2’-F modified nucleoside); [moe]: 2’-O-(2-methoxyethyl) modified nucleoside; d: 2’-deoxy nucleoside;[m5C]: 5-methylcytidine; d[3nU]: 2’-deoxyisouridine (nucleobase isd[Hyp]: 2’-deoxyinosine; [Ssp]: Sp phosphorothioate linkage; p: phosphodiester linkage;[n001S]: Sp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate linkage (herein thelinkage phosphorus is in Sp configuration);[n001R]: Rp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate linkage (erein thelinkage phosphorus is in Rp configuration); [GalNAc3C12oyl]:[nC6o]: −NH−(CH2)6−, connected to [GalNAc3C12oyl] through −NH− and a phosphodiester linkage through −CH2−.

[0042] WV-49090 may be named by accepted oligonucleotide nomenclature: 5′-O-(6-(12-(tris(((3-((3-((5-((2-(acetylamino)-2-deoxy-β-D-galactopyranosyl)oxy)-1- oxopentyl)amino)propyl)amino)-3-oxopropoxy)methyl))methyl)amino-12-oxododecanamido)hexyl phospho)- [P(R)]-2′-O-methyl-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]cytidylyl-(3′→5′)-[P(S)]-2′-O- methyl-P-thiocytidyl-(3′→5′)-[P(S)]-2′-O-methyl-P-thiocytidyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P- thioadenylyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thioguanylyl-(3′→5′)-2′-O-(2-methoxyethyl)-5- methylcytidylyl-(3′→5′)-2′-O-(2-methoxyethyl)adenylyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thioguanylyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thiocytidyl-(3′→5′)-2′-O-methyluridylyl-(3′→5′)-[P(R)]-2′-O-methyl-P- deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]uridylyl-(3′→5′)-2′-O-methylcytidylyl-(3′→5′)-[P(S)]- 2′-fluoro-2′-deoxy-P-thioadenylyl-(3′→5′)-[P(R)]-2′-fluoro-2′-deoxy-P-deoxy-P-[(1,3-dimethylimidazolidin- 2-ylidene)amino]guanylyl-(3′→5′)-2′-fluoro-2′-deoxyuridylyl-(3′→5′)-[P(S)]-2′-O-(2-methoxyethyl)-P-thio- 5-methylcytidylyl-(3′→5′)-[P(S)]- 2′-fluoro-2′-deoxy-P-thiocytidyl-(3′→5′)-2′-O-methylcytidyl-(3′→5′)- [P(R)]-2′-O-methyl-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]uridylyl-(3′→5′)-2′-O- methyluridylyl-(3′→5′)-2′-O-(2-methoxyethyl)-5-methyluridylyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P- thiocytidyl-(3′→5′)-[P(S)]-P-thiothymidylyl-(3′→5′)-[P(S)]-2′-deoxy-P-thioisouridylyl-(3′→5′)-[P(S)]-2′- deoxy-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]inosinylyl-(3′→5′)-2′-O-methyluridylyl- (3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thiocytidyl-(3′→5′)-[P(S)]-2′-O-methyl-P-thioguanylyl-(3′→5′)-[P(R)]- 2′-O-methyl-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]adenylyl-(3′→5′)-2′-O-methyluridine.

[0043] In some embodiments, WV-49090 is provided in a composition, e.g., a pharmaceutical composition, and / or administered as one or more pharmaceutically acceptable salts. In some embodiments, the present disclosure provides pharmaceutically acceptable salts of WV-49090. In some embodiments, a pharmaceutically acceptable salt is a sodium salt. In some embodiments, the present disclosure provides WV- 49090 tetracosasodium salt. In some embodiments, a WV-49090 drug substance is WV-49090 tetracosasodium salt.

[0044] Structures of various forms of WV-49090 are illustrated herein. Structures of various structural components of WV-49090 (e.g., m, [fl2r], [moe], d, [m5C], d[3nU], d[Hyp], [Ssp], p, [n001S], [n001R], 5’-end GalNAc-containing moiety, [GalNAc3C12oyl], [nC6o], nucleobases, sugars, nucleosides, nucleotides, linkages, etc.) are also illustrated herein (e.g., in various forms of WV-49090, phosphoramidites, certain Starting Materials (in some cases, in useful protected forms), etc.).

[0045] Molecular formulae and molecular weights of WV-49090 and its tetracosasodium salt is described below: Molecular Formula (free acid form): C417H594F10N126O217P30S14 Molecular Weight (free acid form): 12412.04 g / mol Molecular Formula (tetracosasodium salt form): C417H570F10N126Na24O217P30S14 Molecular Weight (tetracosasodium salt form): 12939.60 g / mol

[0046] WV-49090 has 30 internucleotide linkages of which 10 are phosphodiester linkages and 20 are stereodefined internucleotide linkages. Out of 20 stereodefined internucleotide linkages, 14 are Sp phosphorothioate diester, 1 is Sp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate diester and 5 are Rp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate diester. 6-Amino-1-hexanol is linked at the 5’ terminus of the nucleic acid sequence via a phosphodiester linkage. A triantennary N-Acetyl galactosamine (GalNAc) is conjugated to the 6-amino-1-hexanol linker by the amide bond linkage between 5’-primary amine from the oligonucleotide and carboxylic acid moiety from the GalNAc ligand.

[0047] The structure of WV-49090 in its free acid form may be depicted as Formula I below:Formula I

[0048] WV-49090 tetracosasodium salt form may be described as Formula I-a below:Formula I-a

[0049] In Formula I and Formula I-a, due to the sizes of the structures, the structures are presented in multiple rows (The zig-zag lines represent the bond linkage between oxygen at 3′ to the phosphorus in the internucleotide linkage). As shown in these Formulae, each linkage in WV-49090 is independently a Sp phosphorothioate linkage, a Rp n001 linkage, a Sp n001 linkage, or a natural phosphate linkage, and in a WV- 49090 salt, acidic hydrogen atoms of the phosphorothioate and phosphate linkages may be independently replaced with cations, e.g., in the tetracosasodium salt, each replaced with sodium.

[0050] In some embodiments, a preparation of WV-49090 tetracosasodium salt is a solid, white to off- white powder. In some embodiments, water solution of WV-49090 tetracosasodium salt is a clear, colorless to pale yellow solution, and can have a concentration of about 25 mg / mL or more as determined by UV. In some embodiments, pH of 5% solution of WV-49090 tetracosasodium salt in purified water ranges from 6.0 – 8.0.

[0051] Extinction coefficient of WV-49090 at ambient temperature is 273,826 M-1cm-1(experimentally determined in deionized LC-MS grade water) at 260 nm. Unless noted otherwise, when UV is utilized to measure concentration / amount of WV-49090, 260 nm is utilized and this number is utilized in calculation, which equates to an absorptivity factor of about 22.1 OD / mg.

[0052] In some embodiments, WV-49090 is supplied as a lyophilized powder for reconstitution with sterile water to produce a pharmaceutical composition prior to subcutaneous administration. In some embodiments, the volume of water for reconstitution is about 5 mL. In some embodiments, WV-49090 reconstituted pharmaceutical composition contains no preservatives and is administered without delay.

[0053] In some embodiments, WV-49090 is provided and administered as a chirally controlled composition in which WV-49090 is enriched over other diastereomers.

[0054] Among other things, the present disclosure provides WV-49090 of high purity. In some embodiments, WV-49090 has a level of purity of about 65%-85%, e.g., about 65%-80%, about 65%-75%, or about 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, or 85%. In some embodiments, a level of purity is determined by IP-RP-UPLC described herein. In some embodiments, it is about 65% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 66% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 67% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 68% as determined by IP-RP- UPLC described herein. In some embodiments, it is about 69% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 70% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 71% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 72% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 73% as determined by IP-RP- UPLC described herein. In some embodiments, it is about 74% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 75% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 76% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 77% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 78% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 79% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 80% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 81% or more as determined by IP-RP-UPLC described herein. In some embodiments, it is about 82% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 83% as determined by IP-RP-UPLC described herein. In some embodiments, it is about 84% as determined by IP-RP-UPLC described herein. In some embodiments, purity is % area at a given wavelength, e.g., around 260 nm.

[0055] In some embodiments, level of impurities is about 10%-30% or lower. In some embodiments, it is about 10%-30%. In some embodiments, it is about 15%-30%. In some embodiments, it is about 20%-30%. In some embodiments, it is about 30% or lower. In some embodiments, it is about 29% or lower. In some embodiments, it is about 28% or lower. In some embodiments, it is about 27% or lower. In some embodiments, it is about 26% or lower. In some embodiments, it is about 25% or lower. In some embodiments, it is about 24% or lower. In some embodiments, it is about 23% or lower. In some embodiments, it is about 22% or lower. In some embodiments, it is about 21% or lower. In some embodiments, it is about 20% or lower. In some embodiments, it is about 19% or lower. In some embodiments, it is about 18% or lower. In some embodiments, it is about 17% or lower. In some embodiments, it is about 16% or lower. In some embodiments, it is about 15% or lower. In some embodiments, it is about 14% or lower. In some embodiments, it is about 13% or lower. In some embodiments, it is about 12% or lower. In some embodiments, it is about 11% or lower. In some embodiments, it is about 10% or lower. In some embodiments, level of impurity is assessed using IP-RP- UPLC. In some embodiments, purity is % area at a given wavelength, e.g., around 260 nm.

[0056] In some embodiments, WV-49090 has a stereochemical purity of about 80%-90%. In some embodiments, WV-49090 has a stereochemical purity of about 60% or more. WV-49090 has a stereochemical purity of about 65% or more. WV-49090 has a stereochemical purity of about 70% or more. WV-49090 has a stereochemical purity of about 75% or more. In some embodiments, WV-49090 has a stereochemical purity of about 80% or more. In some embodiments, WV-49090 has a stereochemical purity of about 85% or more. In some embodiments, WV-49090 has a stereochemical purity of about 90% or more. In some embodiments, WV- 49090 has a stereochemical purity of about 95% or more.

[0057] In some embodiments, the present disclosure provides various technologies for characterizing WV- 49090 preparations. In some embodiments, the present disclosure provides technologies for assessing purity of WV-49090 or compositions thereof.

[0058] In some embodiments, the present disclosure provides technologies for manufacturing WV-49090 or compositions thereof. In some embodiments, the present disclosure provides technologies for releasing WV- 49090 preparations (e.g., drug substance, drug product, etc.). Alpha-1 antitrypsin deficiency

[0059] Alpha-1 antitrypsin (AAT) deficiency (AATD) is a genetic disorder reportedly caused, in many cases, by defects in the SERPINA1 gene. Severe AATD is reported to be associated with various phenotypesincluding lung and liver phenotypes.

[0060] AATD is reportedly one of the most common genetic diseases in subjects of Northern European descent. Prevalence of severe AATD in the U.S. alone is reported to be 80,000-100,000. Similar numbers are estimated to be found in the EU by certain reports. According to some reports, the worldwide estimate for severe AATD has been pegged at 3 million people. It is reported that AATD can cause emphysema, sometimes with subjects developing emphysema in their third or fourth decade. It has also been reported that AATD can cause liver failure and hepatocellular carcinoma, with according to some reports up to 30% of subjects with severe AATD developing significant liver disease, including cirrhosis, fulminant liver failure, and hepatocellular carcinoma.

[0061] A mutation, c.1096G>A (may also be referred to as c.1024G>A), in SERPINA1 (Z-allele) is reported and can lead to a glutamate to lysine substitution at amino acid position 366 (E366K, may also be referred to as E342K, “Z mutation”) of the AAT protein (such E342K mutant AAT protein may be referred to as Z-AAT). AAT has several isoforms, one of which according to UniProt (P01009-1) is:In some embodiments, numbering, e.g., E366, E366K, etc., is based on SEQ ID NO: 1. In some embodiments, an E342 AAT polypeptide is or comprises SEQ ID NO: 1 or a portion thereof, wherein the portion comprises E366 (numbering based on SEQ ID NO: 1).

[0062] An AAT polypeptide containing residues 25-418 of SEQ ID NO: 1 has been reported, in which E at position 342 corresponds to E366 in SEQ ID NO: 1: EDPQGDAAQKTDTSHHDQDHPTFNKITPNLAEFAFSLYRQLAHQSNSTNIFFSPVSIATAFAMLSLGTIn some embodiments, such a polypeptide has a mutation of E to K at its position 342 which corresponds to E366K if using numbering according to SEQ ID NO: 1. In some embodiments, numbering, e.g., E342, E342K, etc., is based on SEQ ID NO: 2. In some embodiments, an E342 AAT polypeptide is or comprises SEQ ID NO: 2 or a portion thereof, wherein the portion comprises E342 (numbering based on SEQ ID NO: 2).

[0063] In some embodiments, an E342K (may also be referred to as E366K) mutant AAT has the sequence of (based on SEQ ID NO: 1):In some embodiments, numbering, e.g., K366, is based on SEQ ID NO: 3. In some embodiments, an E342K mutant AAT polypeptide is or comprises SEQ ID NO: 3 or a portion thereof, wherein the portion comprises K366 (numbering based on SEQ ID NO: 3).

[0064] In some embodiments, an E342K (may also be referred to as E366K) mutant AAT has the sequence of (based on SEQ ID NO: 2):In some embodiments, numbering, e.g., K342, is based on SEQ ID NO: 4. In some embodiments, an E342K mutant AAT polypeptide is or comprises SEQ ID NO: 4 or a portion thereof, wherein the portion comprises K342 (numbering based on SEQ ID NO: 4).

[0065] In some embodiments, M-AAT has the sequence of SEQ ID NO: 1. In some embodiments, Z-AAT has the sequence of SEQ ID NO: 3.

[0066] It is reported that E342K can affect protein conformation and secretion leading to reduced circulating levels of AAT. Alleles carrying the Z mutation may be referred to as PiZ alleles. Subjects homozygous for the PiZ allele may be referred to as Pi*ZZ carriers. It is reported that approximately 95% of subjects who are symptomatic for AATD have the Pi*ZZ genotype, and of those diagnosed, about 90% of patients with severe AATD have the ZZ mutation. According to some reports, about between 30,000 and 50,000 individuals in the United States have the Pi*ZZ genotype.

[0067] The pathophysiology of AATD can vary by the organ affected. Liver disease is reported to be due to a gain-of-function mechanism. It is reported that abnormally folded AAT, especially Z-type AAT (Z-AAT), aggregates and polymerizes within hepatocytes. According to some reports, AAT inclusions are found in Pi*ZZ subjects and are thought to cause cirrhosis and, in some cases, hepatocellular carcinoma. Evidence for the gain-of-function mechanism in liver disease is reported to be supported by null homozygotes. It is reported that these subjects produce no AAT and do not develop hepatocyte inclusions or liver disease.

[0068] It is reported that AATD leads to liver disease in up to about 50% of AAT subjects and leads to severe liver disease in up to about 30% of subjects. According to various reports, liver disease may manifest as the following: (a) cirrhosis during childhood that is self-limiting, (b) severe cirrhosis during childhood or adulthood that requires liver transplantation or leads to death, and (c) hepatocellular carcinoma that is often deadly. The onset of liver disease is reported to be bi-modal, predominantly affecting children or adults. According to some reports, childhood disease is self-limiting in many cases but may be led to end-stage, deadly cirrhosis. It is reported that up to about 18% of subjects with the Pi*ZZ genotype may develop clinically significant liver abnormalities during childhood. Approximately 2% of Pi*ZZ subjects are reported to develop severe liver cirrhosis leading to death during childhood (see, e.g., Sveger 1988; Volpert 2000). It is reported that adult-onset liver disease may affect subjects with all genotypes, but presents earlier in subjects with the Pi*ZZ genotype. Approximately 2-10% of AAT deficient subjects are reported to develop adult-onset liver disease.

[0069] Among other things, the present disclosure provides technologies (e.g., WV-49090 compositions, doses, dosing regimens, etc.) for treating AATD. In some embodiments, the present disclosure provides a method for treating AATD, comprising administering or delivering to a subject suffering therefrom WV-49090 as described herein. In some embodiments, the present disclosure provides technologies for treating conditions, diseases or disorders associated with AATD, comprising administering or delivering to a subject suffering therefrom WV-49090 as described herein. In some embodiments, the present disclosure provides a method for treating a condition, disease or disorder associated with AATD. In some embodiments, the present disclosure provides technologies for administering or delivering WV-49090 to human subjects.

[0070] In some embodiments, the present disclosure provides a method for treating AATD, comprising administering or delivering to a subject suffering therefrom WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein the subject has a G to A mutation in a Serpin Family A Member 1 (SERPINA1) gene that encodes a Glu342Lys mutation in an alpha-1 antitrypsin (AAT) polypeptide. In some embodiments, the present disclosure provides WV-49090 preparations, compositions, doses, etc. for use in a method for treating AATD in a subject suffering therefrom, wherein WV-49090 is administered or delivered at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a device containing WV-49090 for use in a method for treating AATD in a subject suffering therefrom, wherein WV-49090 is administered or delivered at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides uses of WV-49090 preparations, compositions, doses, etc. in the manufacture of a medicament for treating AATD, wherein the medicament is to be administered at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. As described herein, WV-49090 may be described as: (1): 5’-mC[n001R]mC[Ssp]mC[Ssp][fl2r]A[Ssp][fl2r]G[Ssp][moe][m5C]p[moe]Ap[fl2r]G[Ssp][fl2r] C[Ssp]mUpmU[n001R]mCp[fl2r]A[Ssp][fl2r]G[n001R][fl2r]Up[moe][m5C][Ssp][fl2r]C[Ssp]mCpmU[n001 R]mUp[moe]Tp[fl2r]C[Ssp]dT[Ssp]d[3nU][Ssp]d[Hyp][n001S]mUp[fl2r]C[Ssp]mG[Ssp]mA[n001R]mU-3’: m: 2’-O-methyl modified nucleoside (may also be referred to as 2’-OMe modified nucleoside); [fl2r]: 2’-fluoro-2’-deoxy modified nucleoside (may also be referred to as 2’-F modified nucleoside); [moe]: 2’-O-(2-methoxyethyl) modified nucleoside; d: 2’-deoxy nucleoside; [m5C]: 5-methylcytidine; d[3nU]: 2’-deoxyisouridine (nucleobase isd[Hyp]: 2’-deoxyinosine; [Ssp]: Sp phosphorothioate linkage; p: phosphodiester linkage; [n001S]: Sp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate linkage (wherein the linkage phosphorus is in Sp configuration); [n001R]: Rp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate linkage (wherein the linkage phosphorus is in Rp configuration); and the 5’-carbon of the 5’-end mC is linked to the structure below via a phosphodiester group:(2): RNA1{p.m(C)[n001R].m(C)[Ssp].m(C)[Ssp].[fl2r](A)[Ssp].[fl2r](G)[Ssp].[moe]([m5C])p.[moe](A)p.[fl2r]( G)[Ssp].[fl2r](C)[Ssp].m(U)p.m(U)[n001R].m(C)p.[fl2r](A)[Ssp].[fl2r](G)[n001R].[fl2r](U)p.[moe]([m5C])[Ssp].[fl2r](C)[Ssp].m(C)p.m(U)[n001R].m(U)p.[moe](T)p.[fl2r](C)[Ssp].d(T)[Ssp].d([3nU])[Ssp].d([Hyp])[n 001S].m(U)p.[fl2r](C)[Ssp].m(G)[Ssp].m(A)[n001R].m(U)}|CHEM1{[GalNAc3C12oyl]}|CHEM2{[nC6o]}$ CHEM2,RNA1,1:R1-1:R1|CHEM2,CHEM1,1:R2-1:R1$$$V2.0, wherein m: 2’-O-methyl modified nucleoside (may also be referred to as 2’-OMe modified nucleoside); [fl2r]: 2’-fluoro-2’-deoxy modified nucleoside (may also be referred to as 2’-F modified nucleoside); [moe]: 2’-O-(2-methoxyethyl) modified nucleoside; d: 2’-deoxy nucleoside; [m5C]: 5-methylcytidine; d[3nU]: 2’-deoxyisouridine (nucleobase isd[Hyp]: 2’-deoxyinosine; [Ssp]: Sp phosphorothioate linkage; p: phosphodiester linkage;[n001S]: Sp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate linkage (herein thelinkage phosphorus is in Sp configuration);[n001R]: Rp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate linkage (erein thelinkage phosphorus is in Rp configuration); [GalNAc3C12oyl]:[nC6o]: −NH−(CH2)6−, connected to [GalNAc3C12oyl] through −NH− and a phosphodiester linkage through −CH2−;(3): 5′-O-(6-(12-(tris(((3-((3-((5-((2-(acetylamino)-2-deoxy-β-D-galactopyranosyl)oxy)-1- oxopentyl)amino)propyl)amino)-3-oxopropoxy)methyl))methyl)amino-12-oxododecanamido)hexyl phospho)- [P(R)]-2′-O-methyl-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]cytidylyl-(3′→5′)-[P(S)]-2′-O- methyl-P-thiocytidyl-(3′→5′)-[P(S)]-2′-O-methyl-P-thiocytidyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P- thioadenylyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thioguanylyl-(3′→5′)-2′-O-(2-methoxyethyl)-5- methylcytidylyl-(3′→5′)-2′-O-(2-methoxyethyl)adenylyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thioguanylyl- (3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thiocytidyl-(3′→5′)-2′-O-methyluridylyl-(3′→5′)-[P(R)]-2′-O-methyl-P- deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]uridylyl-(3′→5′)-2′-O-methylcytidylyl-(3′→5′)-[P(S)]- 2′-fluoro-2′-deoxy-P-thioadenylyl-(3′→5′)-[P(R)]-2′-fluoro-2′-deoxy-P-deoxy-P-[(1,3-dimethylimidazolidin- 2-ylidene)amino]guanylyl-(3′→5′)-2′-fluoro-2′-deoxyuridylyl-(3′→5′)-[P(S)]-2′-O-(2-methoxyethyl)-P-thio- 5-methylcytidylyl-(3′→5′)-[P(S)]- 2′-fluoro-2′-deoxy-P-thiocytidyl-(3′→5′)-2′-O-methylcytidyl-(3′→5′)- [P(R)]-2′-O-methyl-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]uridylyl-(3′→5′)-2′-O- methyluridylyl-(3′→5′)-2′-O-(2-methoxyethyl)-5-methyluridylyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P- thiocytidyl-(3′→5′)-[P(S)]-P-thiothymidylyl-(3′→5′)-[P(S)]-2′-deoxy-P-thioisouridylyl-(3′→5′)-[P(S)]-2′- deoxy-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]inosinylyl-(3′→5′)-2′-O-methyluridylyl- (3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thiocytidyl-(3′→5′)-[P(S)]-2′-O-methyl-P-thioguanylyl-(3′→5′)-[P(R)]- 2′-O-methyl-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]adenylyl-(3′→5′)-2′-O-methyluridine; or (4):(free acid form).

[0071] In some embodiments, the present disclosure provides a method for treating AATD, comprising administering or delivering to a subject suffering therefrom WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein the subject expresses a Glu342Lys mutant AAT polypeptide, or a mutant SERPINA1 mRNA comprising 1024 G>A. In some embodiments, the present disclosure provides a method comprising administering or delivering to a subject suffering therefrom WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein the subject expresses a Glu342Lys mutant AAT polypeptide, or a mutant SERPINA1 mRNA comprising 1024 G>A. In some embodiments, the present disclosure provides a method comprising administering or delivering to a subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 mRNA in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for producing of a SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342 AAT polypeptide, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV- 49090 free acid form. In some embodiments, the present disclosure provides a method for reducing level of a 1024 G>A mutant SERPINA1 mRNA in a subject, comprising administering or delivering to the subject WV- 49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for increasing level of a SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342 AAT polypeptide, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, level of a SERPINA mRNA is or comprises a relative amount to a reference mRNA. In some embodiments, level of a SERPINA1 mRNA is or comprises percentage of total SERPINA1 mRNA. In some embodiments, a change is relative to baseline.

[0072] In some embodiments, the present disclosure provides a method for increasing plasma level of AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for producing a Glu342 AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for producing M-AAT in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600(e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for reducing level of a Glu342Lys mutant AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for reducing level of Z-AAT in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides method for increasing level of a Glu342 AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides method for increasing level of M-AAT in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, a level is or comprises a relative amount to a reference polypeptide. In some embodiments, a level is or comprises percentage of total AAT polypeptide. In some embodiments, the present disclosure provides a method for providing increased level of a wild-type AAT function in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, a change is relative to baseline. In some embodiments, a subject suffers from AATD. In some embodiments, a subject has a SERPINA1 Z-allele. In some embodiments, a subject has a Pi*ZZ genotype. In some embodiments, a subject suffers from Pi*ZZ AATD.

[0073] In some embodiments, the present disclosure provides technologies for modulating acute phase response. In some embodiments, the present disclosure provides technologies for modulating level of an acute phase response component. In some embodiments, an acute phase response component is or comprises an acute phase response protein. In some embodiments, an acute phase response protein is alpha-1 antitrypsin. In some embodiments, as described herein, a provided technology can increase level of AAT during acute phase response. In some embodiments, as described herein, a provided technology can increase level of M-AAT during acute phase response. In some embodiments, as described herein, a provided technology can increase level of Z-AAT during acute phase response. Acute phase response has been reported to be a key component of the innate immune system. It has been reported that acute phase response can be or comprise a rapid, systemic reaction of a body to injury, infection, inflammation, etc. In acute phase response, it has been reported that production of certain proinflammatory cytokines by various cells, e.g., activated immune cells in response to an inflammatory event (e.g., injury, stress, infection) can lead to modulation of protein synthesis by hepatocytes, among other effects. Modulation of protein synthesis in hepatocytes in acute phase response reportedly leads to increased synthesis of certain blood proteins termed acute phase proteins. AAT and C-reactive protein (CRP) have been reported as acute phase proteins. See, e.g., Cray C, et al. Acute phase response in animals: a review.Comp Med.2009 Dec;59(6):517-26 and Sanders CL, et al. COPD.2018 Feb;15(1):10-16.

[0074] In some embodiments, the present disclosure provides a method for providing acute phase response production of a polypeptide in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript, e.g., a mRNA. In some embodiments, the present disclosure provides a method for providing increased production of a polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript, e.g., a mRNA. In some embodiments, a target transcript is a SERPINA1 mRNA. In some embodiments, the present disclosure provides a method for providing acute phase response production of AAT polypeptide in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in an SERPINA1 transcript, e.g., a SERPINA1 mRNA. In some embodiments, the present disclosure provides a method for providing acute phase response production of M- AAT polypeptide in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in an SERPINA1 transcript, e.g., a SERPINA1 mRNA. In some embodiments, the present disclosure provides a method for providing increased production of AAT polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in an SERPINA1 transcript, e.g., a SERPINA1 mRNA. In some embodiments, the present disclosure provides a method for providing increased production of M-AAT polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in an SERPINA1 transcript, e.g., a SERPINA1 mRNA. In some embodiments, a SERPINA1 mRNA comprises 1024 G>A mutation. In some embodiments, a target adenosine is the 1024 G>A mutation in SERPINA1. In some embodiments, the present disclosure provides a method for providing acute phase response production of AAT polypeptide in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 transcript, e.g., a mutant SERPINA1 mRNA. In some embodiments, the present disclosure provides a method for providing an increased acute phase response AAT polypeptide level (e.g., serum level) in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 transcript, e.g., a mutant SERPINA1 mRNA. In some embodiments, the present disclosure provides a method for providing acute phase response production of M-AAT polypeptide in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 transcript, e.g., a mutant SERPINA1 mRNA. In some embodiments, the present disclosure provides a method for providing an increased acute phase response M- AAT polypeptide level (e.g., serum level) in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine from 1024 G>A mutation in amutant SERPINA1 transcript, e.g., a mutant SERPINA1 mRNA. In some embodiments, the present disclosure provides a method for providing acute phase response production of Z-AAT polypeptide in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 transcript, e.g., a mutant SERPINA1 mRNA. In some embodiments, the present disclosure provides a method for providing an increased acute phase response Z-AAT polypeptide level (e.g., serum level) in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 transcript, e.g., a mutant SERPINA1 mRNA. In some embodiments, the present disclosure provides a method for providing increased production of M-AAT polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 transcript, e.g., a mutant SERPINA1 mRNA. In some embodiments, the present disclosure provides a method for providing increased production of M-AAT polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 transcript, e.g., a mutant SERPINA1 mRNA. In some embodiments, the present disclosure provides a method for providing an increased M-AAT polypeptide level (e.g., serum level) in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 transcript, e.g., a mutant SERPINA1 mRNA. In some embodiments, the present disclosure provides a method for providing increased production of Z-AAT polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 transcript, e.g., a mutant SERPINA1 mRNA. In some embodiments, the present disclosure provides a method for providing an increased Z-AAT polypeptide level (e.g., serum level) in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 transcript, e.g., a mutant SERPINA1 mRNA. In some embodiments, providing increased production of AAT polypeptide in response to an inflammatory event in a subject comprises restoring increased production of AAT polypeptide in response to an inflammatory event in the subject. In some embodiments, providing increased production of M-AAT polypeptide in response to an inflammatory event in a subject comprises restoring increased production of M-AAT polypeptide in response to an inflammatory event in the subject. In some embodiments, an inflammatory event comprises or is an injury, stress, and / or infection. In some embodiments, an inflammatory event comprises or is a non-drug-related inflammatory event. In some embodiments, increased production comprises a higher level of production as compared to a baseline, e.g., a level of production prior to an inflammatory event. In some embodiments, an increased AAT polypeptide level is about 15, 16, 17, 18, 19 or 20 uM or higher in serum in a Pi*ZZ subject.In some embodiments, an increased AAT polypeptide level is about 20 uM or higher in serum in a Pi*ZZ subject. In some embodiments, an increased M-AAT polypeptide level is about 8, 9, or 10 uM or higher in serum in a Pi*ZZ subject. In some embodiments, an increased M-AAT polypeptide level is about 10 uM or higher in serum in a Pi*ZZ subject. In some embodiments, an increased Z-AAT polypeptide level is about 8, 9, or 10 uM or higher in serum in a Pi*ZZ subject. In some embodiments, an increased Z-AAT polypeptide level is about 10 uM or higher in serum in a Pi*ZZ subject. Various oligonucleotides and oligonucleotide compositions can be utilized in accordance with the present disclosure. In some embodiments, an oligonucleotide or oligonucleotide composition comprises or is an oligonucleotide or oligonucleotide composition described in WO 2016 / 097212 A1, US 10676737 B2, US 11781134 B2, US 2019040383 A1, US 2020199586 A1, US 2024141336 A1, WO 2017 / 220751 A1, US 10988763 B2, US 11649454 B2, US 12018257 B2, US 2019330622 A1, US 2021340529 A1, US 2023279392 A1, US 2024417721 A1, WO 2018 / 041973 A1, US 10941402 B2, US 11851656 B2, US 12203072 B2, US 2019218552 A1, US 2021238597 A1, US 2024271131 A1, US 2025223593 A1, WO 2021 / 071858 A1, US 2023220384 A1, WO 2021 / 243023 A1, US 2021380980 A1, WO 2022 / 026928 A1, US 2023272391 A1, WO 2022 / 099159 A1, WO 2022 / 246023 A1, US 2024263177 A1, WO 2023 / 278410 A1 or US 2025034564 A1; many oligonucleotides or oligonucleotide compositions generically or specifically described in these patent application publications are capable of editing the adenosine from1024 G>A in SERPINA1, and are incorporated herein by reference. In some embodiments, an oligonucleotide is WV-49090. In some embodiments, an oligonucleotide, e.g., WV-49090, is administered or delivered at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg its free acid form. In some embodiments, a dose is equivalent to about 200 to about 400 mg free acid form. In some embodiments, a dose is equivalent to about 200 mg free acid form. In some embodiments, a dose is equivalent to about 400 mg free acid form. In some embodiments, a dose is equivalent to about 600 mg free acid form. In some embodiments, each dose is independently equivalent to about 200 to about 400 mg free acid form. In some embodiments, each dose is independently equivalent to about 200 mg free acid form. In some embodiments, each dose is independently equivalent to about 400 mg free acid form. In some embodiments, an oligonucleotide, e.g., WV-49090, is administered about every two weeks. In some embodiments, an oligonucleotide, is administered or delivered about every four weeks. In some embodiments, an oligonucleotide is administered or delivered about monthly. In some embodiments, an oligonucleotide is administered or delivered less frequently than about monthly. In some embodiments, an oligonucleotide is administered or delivered subcutaneously.

[0075] In some embodiments, the present disclosure provides a method for providing acute phase response production of AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for providing acute phase response production of M-AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450,500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, providing acute phase response production of AAT polypeptide in a subject comprises restoring acute phase response production of AAT polypeptide in the subject. In some embodiments, providing acute phase response production of M-AAT polypeptide in a subject comprises restoring acute phase response production of M-AAT polypeptide in the subject. In some embodiments, the present disclosure provides a method for providing an increased acute phase response AAT polypeptide level (e.g., serum level) in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for providing an increased acute phase response M-AAT polypeptide level (e.g., serum level) in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for providing an increased acute phase response Z-AAT polypeptide level (e.g., serum level) in a subject, comprising administering or delivering to the subject WV- 49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for providing increased production of AAT polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for providing increased production of M-AAT polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for providing an increased AAT polypeptide level (e.g., serum level) in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for providing an increased M-AAT polypeptide level (e.g., serum level) in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for providing an increased Z-AAT polypeptide level (e.g., serum level) in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV- 49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, an increased AAT polypeptide level is about 15, 16, 17, 18, 19 or 20 uM or higher in serum in a Pi*ZZ subject. In some embodiments, an increased AAT polypeptide level is about 20 uM or higher in serum in a Pi*ZZ subject. In some embodiments, an increased M-AAT polypeptide level is about 8, 9, or 10 uM or higher in serum in a Pi*ZZ subject. In some embodiments,an increased M-AAT polypeptide level is about 10 uM or higher in serum in a Pi*ZZ subject. In some embodiments, an increased Z-AAT polypeptide level is about 8, 9, or 10 uM or higher in serum in a Pi*ZZ subject. In some embodiments, an increased Z-AAT polypeptide level is about 10 uM or higher in serum in a Pi*ZZ subject. In some embodiments, providing increased production of AAT polypeptide in response to an inflammatory event in a subject comprises restoring increased production of AAT polypeptide in response to an inflammatory event in the subject. In some embodiments, providing increased production of M-AAT polypeptide in response to an inflammatory event in a subject comprises restoring increased production of M- AAT polypeptide in response to an inflammatory event in the subject. In some embodiments, an inflammatory event comprises or is an injury, stress, and / or infection. In some embodiments, an inflammatory event comprises or is a non-drug-related inflammatory event. In some embodiments, increased production comprises a higher level of production as compared to a baseline, e.g., a level of production prior to an inflammatory event. In some embodiments, WV-49090 is administered or delivered at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg its free acid form. In some embodiments, a dose is equivalent to about 200 to about 400 mg WV-49090 free acid form. In some embodiments, a dose is equivalent to about 200 mg WV-49090 free acid form. In some embodiments, a dose is equivalent to about 400 mg WV-49090 free acid form. In some embodiments, a dose is equivalent to about 600 mg WV-49090 free acid form. In some embodiments, each dose is independently equivalent to about 200 to about 400 mg WV-49090 free acid form. In some embodiments, each dose is independently equivalent to about 200 mg WV-49090 free acid form. In some embodiments, each dose is independently equivalent to about 400 mg WV-49090 free acid form. In some embodiments, WV-49090 is administered about every two weeks. In some embodiments, WV-49090 is administered or delivered about every four weeks. In some embodiments, WV-49090 is administered or delivered about monthly. In some embodiments, WV-49090 is administered or delivered less frequently than about monthly. In some embodiments, WV-49090 is administered or delivered subcutaneously.

[0076] In some embodiments, following a dose of WV-49090, a subject exhibits an acute phase response increase in total AAT in response to an inflammatory event, e.g., a non-drug-related inflammatory event. In some embodiments, following a dose of WV-49090, a subject exhibits an acute phase response increase in M- AAT in response to an inflammatory event, e.g., a non-drug-related inflammatory event. In some embodiments, following two or more doses of WV-49090, a subject exhibits an acute phase response increase in total AAT in response to an inflammatory event, e.g., a non-drug-related inflammatory event. In some embodiments, following two or more doses of WV-49090, a subject exhibits an acute phase response increase in M-AAT in response to an inflammatory event, e.g., a non-drug-related inflammatory event.

[0077] In some embodiments, an acute phase response is associated with an inflammation. In some embodiments, an acute phase response is associated with an injury. In some embodiments, an acute phase response is associated with an infection. In some embodiments, an acute phase response is or comprises a reaction to an inflammation. In some embodiments, an acute phase response is or comprises a reaction to aninjury. In some embodiments, an acute phase response is or comprises a reaction to an infection. In some embodiments, an acute phase response is associated with a kidney stone. In some embodiments, assessment of increased production of a polypeptide, e.g., an AAT polypeptide, a M-AAT polypeptide, etc., is or comprises assessing level of such a polypeptide in blood. In some embodiments, assessment of increased production of a polypeptide, e.g., an AAT polypeptide, a M-AAT polypeptide, etc., is or comprises assessing level of such a polypeptide in serum. In some embodiments, an increased AAT polypeptide level is about 15, 16, 17, 18, 19 or 20 uM or higher in serum in a Pi*ZZ subject. In some embodiments, an increased AAT polypeptide level is about 20 uM or higher in serum in a Pi*ZZ subject. In some embodiments, an increased M-AAT polypeptide level is about 8, 9, or 10 uM or higher in serum in a Pi*ZZ subject. In some embodiments, an increased M- AAT polypeptide level is about 10 uM or higher in serum in a Pi*ZZ subject. In some embodiments, an increased Z-AAT polypeptide level is about 8, 9, or 10 uM or higher in serum in a Pi*ZZ subject. In some embodiments, an increased Z-AAT polypeptide level is about 10 uM or higher in serum in a Pi*ZZ subject. In some embodiments, as demonstrated herein, serum AAT level can reach about 20 uM in a Pi*ZZ subject during an acute phase response. In some embodiments, as demonstrated herein, serum AAT polypeptide level can reach about 20 uM in a Pi*ZZ subject during an acute phase response, wherein about 50% of AAT polypeptide is M-AAT polypeptide. In some embodiments, as demonstrated herein, serum M-AAT polypeptide level can reach about 10 uM in a Pi*ZZ subject during an acute phase response. In some embodiments, as demonstrated herein, serum Z-AAT polypeptide level can reach about 10 uM in a Pi*ZZ subject during an acute phase response. Those skilled in the art various technologies can be utilized to assess levels of AAT, M-AAT, or Z- AAT in accordance with the present disclosure. For example, in some embodiments, mass spectrometry technologies (e.g., LC-MS / MS) are utilized. In some embodiments, M-AAT at a level as described herein, e.g., about 8, 9, or 10 uM or higher in serum, and DNA comprising 1024 G>A mutation in SERPINA1 (e.g., Z allele SERPINA1 DNA). In some embodiments, a sample comprises AAT at a level as described herein, e.g., about 15, 16, 17, 18, 19 or 20 uM or higher in serum, M-AAT at a level as described herein, e.g., about 8, 9, or 10 uM or higher in serum, and DNA comprising 1024 G>A mutation in SERPINA1 (e.g., Z allele SERPINA1 DNA). In some embodiments, a sample comprises AAT polypeptide at a level as described herein, e.g., about 15, 16, 17, 18, 19 or 20 uM or higher in serum, M-AAT polypeptide at a level as described herein, e.g., about 8, 9, or 10 uM or higher in serum, and Z-AAT polypeptide at a level as described herein, e.g., about 8, 9, or 10 uM or higher in serum. In some embodiments, a sample comprises AAT polypeptide at a level as described herein, e.g., about 15, 16, 17, 18, 19 or 20 uM or higher in serum, M-AAT polypeptide at a level as described herein, e.g., about 8, 9, or 10 uM or higher in serum, Z-AAT polypeptide at a level as described herein, e.g., about 8, 9, or 10 uM or higher in serum, and DNA comprising 1024 G>A mutation in SERPINA1 (e.g., Z allele SERPINA1 DNA). In some embodiments, a sample does not contain M allele SERPINA1 DNA. In some embodiments, a sample comprises DNA (e.g., genomic DNA) encoding Z-AAT polypeptide. In some embodiments, a sample does not contain DNA encoding M-AAT polypeptide. In some embodiments, a sample does not contain genomic DNA encoding M-AAT polypeptide. In some embodiments, the ratio of DNAencoding Z-AAT polypeptide to DNA encoding M-AAT polypeptide is at least about 10, 50, 100 or more. In some embodiments, a sample is or comprises a blood sample. In some embodiments, a sample is or comprises a serum sample. In some embodiments, AAT polypeptide level is about or at least about 20 uM. In some embodiments, M-AAT level is about or at least about 10 uM. In some embodiments, a provided method comprises collecting a sample as described herein. In some embodiments, a provided method comprises assessing a sample as described herein. In some embodiments, a provided method comprises requesting collection of a sample. In some embodiments, a provided method comprises requesting assessment of a sample. In some embodiments, a provided method comprises assessing a sample, and determining level(s) of AAT, M- AAT and / or Z-AAT in serum. In some embodiments, a provided method comprises requesting assessment of a sample to determine level(s) of AAT, M-AAT and / or Z-AAT in serum. In some embodiments, a sample is a sample as described herein. In some embodiments, a level is determined to be a level as described herein. In some embodiments, a sample is from a Pi*ZZ subject.

[0078] In some embodiments, a subject suffers from an AATD-induced lung disease. In some embodiments, a subject has a confirmed diagnosis of stable, mild to moderate AATD-induced lung disease. In some embodiments, a subject suffers from an AATD-induced liver disease. In some embodiments, a subject has a confirmed diagnosis of stable, mild AATD-induced liver disease.

[0079] In some embodiments, two or more doses of WV-49090 are administered or delivered, each of which is independently equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, WV-49090 is administered in multiple forms one of which is a salt form. In some embodiments, WV-49090 is administered in one or more pharmaceutically acceptable salt forms. In some embodiments, one form is WV-49090 sodium salt. In some embodiments, each dose of WV-49090 is independently administered in a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier.

[0080] In some embodiments, WV-49090 is administered or delivered in a composition, e.g., a pharmaceutical composition, that comprises a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, a composition, e.g., a pharmaceutical composition, comprising a compound of Formula I or a pharmaceutically acceptable salt thereof is administered or delivered at a dose as described herein, e.g., equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg of WV-49090 free acid form. In some embodiments, the present disclosure provides a method for treating alpha-1 antitrypsin deficiency (AATD), comprising administering or delivering to a subject suffering therefrom a composition comprising a compound or a pharmaceutically acceptable salt thereof at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg of the compound, wherein the subject has a G to A mutation in a Serpin Family A Member 1 (SERPINA1) gene that encodes a Glu342Lys mutation in an alpha-1 antitrypsin (AAT) polypeptide, and wherein the compound has the structure of Formula I. In some embodiments, the present disclosure provides a method for treating alpha-1 antitrypsin deficiency (AATD), comprising administering or delivering to a subject suffering therefrom a compositioncomprising a compound or a pharmaceutically acceptable salt thereof at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg of the compound, wherein the subject expresses a Glu342Lys mutant AAT polypeptide, or a mutant SERPINA1 mRNA comprising 1024 G>A, and wherein the compound has the structure of Formula I. In some embodiments, the present disclosure provides a method, comprising administering or delivering to a subject a composition comprising a compound or a pharmaceutically acceptable salt thereof at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg of the compound, wherein the compound has the structure of Formula I. In some embodiments, the present disclosure provides a method for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 mRNA in a subject, comprising administering or delivering to the subject a composition comprising a compound or a pharmaceutically acceptable salt thereof at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg of the compound, wherein the compound has the structure of Formula I. In some embodiments, the present disclosure provides a method for producing of a SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342 AAT polypeptide, comprising administering or delivering to the subject a composition comprising a compound or a pharmaceutically acceptable salt thereof at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg of the compound, wherein the compound has the structure of Formula I. In some embodiments, the present disclosure provides a method for reducing level of a 1024 G>A mutant SERPINA1 mRNA in a subject, comprising administering or delivering to the subject a composition comprising a compound or a pharmaceutically acceptable salt thereof at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg of the compound, wherein the compound has the structure of Formula I. In some embodiments, the present disclosure provides a method for increasing level of a SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342 AAT polypeptide, comprising administering or delivering to the subject a composition comprising a compound or a pharmaceutically acceptable salt thereof at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg of the compound, and wherein the compound has the structure of Formula I. In some embodiments, the present disclosure provides a method for increasing plasma level of AAT polypeptide in a subject, comprising administering or delivering to the subject a composition comprising a compound or a pharmaceutically acceptable salt thereof at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg of the compound, wherein the compound has the structure of Formula I. In some embodiments, the present disclosure provides a method for producing a Glu342 AAT polypeptide in a subject, comprising administering or delivering to the subject a composition comprising a compound or a pharmaceutically acceptable salt thereof at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg of the compound, wherein the compound has the structure of Formula I. In some embodiments, the present disclosure provides a method for producing M-AAT in a subject, comprising administering or delivering to the subject a composition comprising a compound or a pharmaceutically acceptable salt thereof at a dose equivalent to about 200 to about 600 (e.g., about 200, 250,300, 350, 400, 450, 500, 550, 600, etc.) mg of the compound, wherein the compound has the structure of Formula I. In some embodiments, the present disclosure provides a method for reducing level of a Glu342Lys mutant AAT polypeptide in a subject, comprising administering or delivering to the subject a composition comprising a compound or a pharmaceutically acceptable salt thereof at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg of the compound, wherein the compound has the structure of Formula I. In some embodiments, the present disclosure provides a method for reducing level of Z-AAT in a subject, comprising administering or delivering to the subject a composition comprising a compound or a pharmaceutically acceptable salt thereof at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg of the compound, wherein the compound has the structure of Formula I. In some embodiments, the present disclosure provides a method for increasing level of a Glu342 AAT polypeptide in a subject, comprising administering or delivering to the subject a composition comprising a compound or a pharmaceutically acceptable salt thereof at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg of the compound, wherein the compound has the structure of Formula I. In some embodiments, the present disclosure provides a method for increasing level of M-AAT in a subject, comprising administering or delivering to the subject a composition comprising a compound or a pharmaceutically acceptable salt thereof at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg of the compound, wherein the compound has the structure of Formula I. In some embodiments, the present disclosure provides a method for providing increased level of a wild-type AAT function in a subject, comprising administering or delivering to the subject a composition comprising a compound or a pharmaceutically acceptable salt thereof at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg of the compound, wherein the compound has the structure of Formula I. In some embodiments, a composition comprises a pharmaceutically acceptable salt, e.g., a sodium salt of the compound. In some embodiments, a composition is a compound of Formula I or one or more pharmaceutically acceptable salts dissolved in a solution (e.g., a buffer) as described herein. In some embodiments, a composition is or comprises a solution of a compound of Formula I or one or more pharmaceutically acceptable salts thereof. In some embodiments, a composition is a pharmaceutical composition. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable carrier as described herein.

[0081] As demonstrated herein, in some embodiments, provided technologies can provide AAT level of about 11 micromolar or more in plasma in a Pi*ZZ subject. In some embodiments, provided technologies can provide M-AAT level of about 6 micromolar or more in a Pi*ZZ subject. In some embodiments, provided technologies can provide M-AAT level of about 7 micromolar or more in a Pi*ZZ subject. In some embodiments, provided technologies can provide M-AAT of about 60% or more of total AAT in plasma in a Pi*ZZ subject.

[0082] In some embodiments, a Glu342 AAT polypeptide comprises E366 in SEQ ID NO: 1. In some embodiments, a Glu342 AAT polypeptide is or comprises a portion of SEQ ID NO: 1, which portion comprisesE366 in SEQ ID NO: 1. In some embodiments, length of the portion is about or at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues. In some embodiments, a portion is or comprises AVLTIDEK. In some embodiments, such a portion has a unique sequence only found in polypeptide(s) encoded by SERPINA1. In some embodiments, a Glu342 AAT polypeptide is M-AAT. In some embodiments, level of a Glu342 AAT polypeptide is assessed by assessing level of a M-AAT peptide fragment, e.g., using mass spectrometry. In some embodiments, level of a Glu342 AAT polypeptide is assessed by assessing level of a M-AAT peptide fragment that is or comprises an amino acid sequence of AVLTIDEK, e.g., using mass spectrometry. In some embodiments, a M-AAT peptide fragment is AVLTIDEK.

[0083] In some embodiments, a Glu342Lys mutant AAT polypeptide comprises K366 in SEQ ID NO: 3. In some embodiments, a Glu342Lys mutant AAT polypeptide is or comprises a portion of SEQ ID NO: 3, which portion comprises K366 in SEQ ID NO: 3. In some embodiments, length of the portion is about or at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues. In some embodiments, a portion is or comprises AVLTIDK. In some embodiments, a portion is or comprises AVLTIDKK. In some embodiments, such a portion has a unique sequence only found in polypeptide(s) encoded by c.1024 G>A SERPINA1. In some embodiments, a Glu342Lys mutant AAT polypeptide is Z-AAT. In some embodiments, level of a Glu342Lys mutant AAT polypeptide is assessed by assessing level of a Z-AAT peptide fragment, e.g., using mass spectrometry. In some embodiments, level of a Glu342Lys mutant AAT polypeptide is assessed by assessing level of a Z-AAT peptide fragment that is or comprises an amino acid sequence of AVLTIDKK or AVLTIDK, e.g., using mass spectrometry. In some embodiments, level of a Glu342Lys mutant AAT polypeptide is assessed by assessing level of AVLTIDKK. In some embodiments, level of a Glu342Lys mutant AAT polypeptide is assessed by assessing level of AVLTIDK. In some embodiments, level of a Glu342Lys mutant AAT polypeptide is assessed by assessing levels of AVLTIDKK and AVLTIDK.

[0084] As those skilled in the art appreciate, an alpha-1 antitrypsin (AAT) polypeptide comprising AVLTIDK may be properly considered to have a Glu342Lys (or Glu366Lys) mutation even though the position of K may not be 342 (or 366), and a nucleic acid that encodes an alpha-1 antitrypsin (AAT) polypeptide comprising AVLTIDK may be properly considered to encodes a Glu342Lys (or Glu366Lys) mutation in an alpha-1 antitrypsin (AAT) polypeptide.

[0085] In some embodiments, total AAT level is assessed by assessing level of a M-AAT and / or a Z-AAT peptide fragment, e.g., using mass spectrometry or ELISA. In some embodiments, total AAT level is assessed by mass spectrometry, e.g., LC-MS / MS. In some embodiments, total AAT level is assessed by an immunoassay. In some embodiments, total AAT level is assessed by ELISA. In some embodiments, total AAT level is assessed using an antibody that can bind both M-AAT and Z-AAT.

[0086] In some embodiments, M-AAT level is assessed by assessing level of a M-AAT peptide fragment, e.g., using mass spectrometry or an immunoassay. In some embodiments, M-AAT level is assessed by mass spectrometry, e.g., LC-MS / MS. In some embodiments, M-AAT level is assessed by an immunoassay. In some embodiments, Z-AAT level is assessed by assessing level of a Z-AAT peptide fragment, e.g., using massspectrometry or an immunoassay. In some embodiments, Z-AAT level is assessed by mass spectrometry, e.g., LC-MS / MS. In some embodiments, Z-AAT level is assessed by an immunoassay. Pharmaceutical compositions

[0087] WV-49090 is typically administered or delivered through a pharmaceutical composition. In some embodiments, a pharmaceutical composition comprises WV-49090 and a pharmaceutically acceptable carrier.

[0088] In some embodiments, the present disclosure provides a method for treating AATD, comprising administering to a subject suffering therefrom a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein the subject has a G to A mutation in a Serpin Family A Member 1 (SERPINA1) gene that encodes a Glu342Lys mutant alpha-1 antitrypsin (AAT) polypeptide. In some embodiments, the present disclosure provides a method for treating AATD, comprising administering to a subject suffering therefrom a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein the subject has a G to A mutation in a Serpin Family A Member 1 (SERPINA1) gene that encodes a Glu342Lys mutation in an alpha-1 antitrypsin (AAT) polypeptide. In some embodiments, the present disclosure provides a method comprising administering to a subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides method for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342Lys mutant AAT polypeptide, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides method for producing of a SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342 AAT polypeptide, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV- 49090 free acid form. In some embodiments, the present disclosure provides a method for reducing level of a 1024 G>A mutant SERPINA1 mRNA in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for increasing level of a SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342 AAT polypeptide, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, a level is or comprises a relative amount to a reference mRNA. In some embodiments, a level is or comprises percentage of total SERPINA1 mRNA. In some embodiments, a change is relative to baseline.

[0089] In some embodiments, the present disclosure provides a method for producing a Glu342 AAT polypeptide in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for producing M-AAT in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for reducing level of a Glu342Lys mutant AAT polypeptide in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for reducing level of Z-AAT in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for increasing level of a Glu342 AAT polypeptide in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, the present disclosure provides a method for increasing level of M-AAT in a subject, comprising administering to the subject a pharmaceutical composition comprising WV- 49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. In some embodiments, a level is or comprises a relative amount to a reference polypeptide. In some embodiments, a level is or comprises percentage of total AAT polypeptide. In some embodiments, the present disclosure provides a method for providing increased level of a wild-type AAT function in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV- 49090 free acid form. In some embodiments, a change is relative to baseline. In some embodiments, a subject suffers from AATD. In some embodiments, a subject has a SERPINA1 Z-allele. In some embodiments, a subject has a Pi*ZZ genotype. In some embodiments, a subject suffers from Pi*ZZ AATD. In some embodiments, two or more doses of pharmaceutical compositions are administered, each of which is independently a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier and each at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550,600, etc.) mg WV-49090 free acid form. In some embodiments, each pharmaceutical composition has the same types of components. In some embodiments, a pharmaceutically acceptable carrier in each pharmaceutical composition is the same. In some embodiments, each pharmaceutical composition is the same.

[0090] In some embodiments, a Glu342 AAT polypeptide comprises E366 in SEQ ID NO: 1. In some embodiments, a Glu342 AAT polypeptide is or comprises a portion of SEQ ID NO: 1, which portion comprises E366 in SEQ ID NO: 1. In some embodiments, length of the portion is about or at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues. In some embodiments, a portion is or comprises AVLTIDEK. In some embodiments, such a portion has a unique sequence only found in polypeptide(s) encoded by SERPINA1. In some embodiments, a Glu342 AAT polypeptide is M-AAT. In some embodiments, level of a Glu342 AAT polypeptide is assessed by assessing level of a M-AAT peptide fragment that is or comprises AVLTIDEK, e.g., using mass spectrometry. In some embodiments, level of a Glu342 AAT polypeptide is assessed by assessing level of a M-AAT peptide fragment that is AVLTIDEK, e.g., using mass spectrometry.

[0091] In some embodiments, a Glu342Lys mutant AAT polypeptide comprises K366 in SEQ ID NO: 3. In some embodiments, a Glu342Lys mutant AAT polypeptide is or comprises a portion of SEQ ID NO: 3, which portion comprises K366 in SEQ ID NO: 3. In some embodiments, length of the portion is about or at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues. In some embodiments, a portion is or comprises AVLTIDK. In some embodiments, such a portion has a unique sequence only found in polypeptide(s) encoded by c.1024 G>A SERPINA1. In some embodiments, a Glu342Lys mutant AAT polypeptide is Z-AAT. In some embodiments, level of a Glu342Lys mutant AAT polypeptide is assessed by assessing level of a Z-AAT peptide fragment, e.g., using mass spectrometry. In some embodiments, level of a Glu342Lys mutant AAT polypeptide is assessed by assessing level of a Z-AAT peptide fragment that is or comprises AVLTIDKK or AVLTIDK, e.g., using mass spectrometry. In some embodiments, level of a Glu342Lys mutant AAT polypeptide is assessed by assessing level of a Z-AAT peptide fragment that is AVLTIDKK and / or a Z-AAT peptide fragment that is AVLTIDK, e.g., using mass spectrometry.

[0092] In some embodiments, the present disclosure provides methods wherein a pharmaceutical composition comprises a salt form of WV-49090. In some embodiments, a pharmaceutical composition comprises two or more forms of WV-49090. In some embodiments, a pharmaceutical composition comprises two or more pharmaceutically acceptable salt forms of WV-49090. In some embodiments, WV-49090 exists in the pharmaceutical composition as one or more pharmaceutically acceptable salt forms. In some embodiments, a pharmaceutically acceptable salt form is a sodium salt. In some embodiments, a pharmaceutical composition is a liquid composition comprising dissolved WV-49090. In some embodiments, a pharmaceutically acceptable carrier is or comprises a buffer. In some embodiments, a pharmaceutically acceptable carrier is or comprises a phosphate buffered solution. In some embodiments, a pharmaceutical composition has a pH of about 7. In some embodiments, a pharmaceutical composition has a pH of about 6-8. In some embodiments, a pharmaceutical composition has a pH of about 6.7 ± 1.0. In some embodiments, a composition has a WV-49090 purity of about65%-85%. In some embodiments, a composition has a WV-49090 purity of about 65%-75% or more. In some embodiments, purity is measured by IP-RP-UPLC using area % at 260 nm. In some embodiments, purity is measured by an IP-RP-UPLC method for purity as described herein. Doses and dosing regimens

[0093] In some embodiments, a dose is about 200-600 mg. In some embodiments, a dose is about 200- 250 mg. In some embodiments, a dose is about 250-300 mg. In some embodiments, a dose is about 300-350 mg. In some embodiments, a dose is about 350-400 mg. In some embodiments, a dose is about 400-450 mg. In some embodiments, a dose is about 450-500 mg. In some embodiments, a dose is about 550-600 mg. In some embodiments, a dose is about 200 mg. In some embodiments, a dose is about 250 mg. In some embodiments, a dose is about 300 mg. In some embodiments, a dose is about 350 mg. In some embodiments, a dose is about 400 mg. In some embodiments, a dose is about 450 mg. In some embodiments, a dose is about 500 mg. In some embodiments, a dose is about 550 mg. In some embodiments, a dose is about 600 mg.

[0094] In some embodiments, two or more doses are administered, and each dose is equivalent to about the same amount of WV-49090 free acid form. In some embodiments, WV-49090 in a dose is equivalent to about 200 mg WV-49090 free acid form. In some embodiments, WV-49090 in a dose is equivalent to about 250 mg WV-49090 free acid form. In some embodiments, WV-49090 in a dose is equivalent to about 300 mg WV-49090 free acid form. In some embodiments, WV-49090 in a dose is equivalent to about 350 mg WV- 49090 free acid form. In some embodiments, WV-49090 in a dose is equivalent to about 400 mg WV-49090 free acid form. In some embodiments, WV-49090 in a dose is equivalent to about 450 mg WV-49090 free acid form. In some embodiments, WV-49090 in a dose is equivalent to about 500 mg WV-49090 free acid form. In some embodiments, WV-49090 in a dose is equivalent to about 550 mg WV-49090 free acid form. In some embodiments, WV-49090 in a dose is equivalent to about 600 mg WV-49090 free acid form.

[0095] In some embodiments, WV-49090 in each dose is equivalent to about 200 mg WV-49090 free acid form. In some embodiments, WV-49090 in each dose is equivalent to about 250 mg WV-49090 free acid form. In some embodiments, WV-49090 in each dose is equivalent to about 300 mg WV-49090 free acid form. In some embodiments, WV-49090 in each dose is equivalent to about 350 mg WV-49090 free acid form. In some embodiments, WV-49090 in each dose is equivalent to about 400 mg WV-49090 free acid form. In some embodiments, WV-49090 in each dose is equivalent to about 450 mg WV-49090 free acid form. In some embodiments, WV-49090 in each dose is equivalent to about 500 mg WV-49090 free acid form. In some embodiments, WV-49090 in each dose is equivalent to about 550 mg WV-49090 free acid form. In some embodiments, WV-49090 in each dose is equivalent to about 600 mg WV-49090 free acid form.

[0096] In some embodiments, a dosing interval is about every two weeks. In some embodiments, a dosing interval is about every four weeks. In some embodiments, a dosing interval is about every eight weeks. In some embodiments, a dosing interval is about every twelve weeks. In some embodiments, a dosing interval is about monthly. In some embodiments, a dosing interval is about every two months. In some embodiments, adosing interval is about every three months. In some embodiments, a dosing interval is about quarterly.

[0097] In some embodiments, WV-49090 is administered about every two weeks. In some embodiments, two or more consecutive doses of WV-49090 are administered about every two weeks. In some embodiments, three or more consecutive doses of WV-49090 are administered about every two weeks. In some embodiments, two doses of WV-49090 are administered about every two weeks. In some embodiments, three doses of WV- 49090 are administered about every two weeks.

[0098] In some embodiments, WV-49090 is administered about every four weeks. In some embodiments, WV-49090 is administered about every eight weeks. In some embodiments, WV-49090 is administered about every twelve weeks. In some embodiments, WV-49090 is administered about monthly. In some embodiments, WV-49090 is administered about every two months. In some embodiments, WV-49090 is administered about every three months. In some embodiments, WV-49090 is administered about quarterly.

[0099] In some embodiments, two or more consecutive doses of WV-49090 are administered about every four weeks. In some embodiments, two or more consecutive doses of WV-49090 are administered about every eight weeks. In some embodiments, two or more consecutive doses of WV-49090 are administered about every twelve weeks. In some embodiments, two or more consecutive doses of WV-49090 are administered about monthly. In some embodiments, two or more consecutive doses of WV-49090 are administered about every two months. In some embodiments, two or more consecutive doses of WV-49090 are administered about every three months. In some embodiments, two or more consecutive doses of WV-49090 are administered about quarterly.

[0100] In some embodiments, three doses of WV-49090 are administered about every four weeks. In some embodiments, three doses of WV-49090 are administered about monthly.

[0101] In some embodiments, two or more doses of WV-49090 are administered, and each dose is equivalent to about the same amount of WV-49090 free acid form.

[0102] In some embodiments, a dosing regimen is or comprises administering WV-49090 about every two weeks, about every four weeks, about every eight weeks, about every twelve weeks, about monthly, about every two months, about every three months, or about quarterly, wherein WV-49090 in each dose is equivalent to about 200 to about 600 mg WV-49090 in free acid form. In some embodiments, a dosing regimen is or comprises administering WV-49090 at a dose equivalent to about 200 to about 600 mg WV-49090 in free acid form at a dosing interval of about every two weeks, about every four weeks, about every eight weeks, about every twelve weeks, about monthly, about every two months, about every three months, or about quarterly.

[0103] In some embodiments, a dosing regimen is or comprises administering WV-49090 about every two weeks, about every four weeks, about every eight weeks, about every twelve weeks, about monthly, about every two months, about every three months, or about quarterly, wherein WV-49090 in each dose is equivalent to about 200 to about 400 mg WV-49090 in free acid form. In some embodiments, a dosing regimen is or comprises administering WV-49090 at a dose equivalent to about 200 to about 400 mg WV-49090 in free acid form at a dosing interval of about every two weeks, about every four weeks, about every eight weeks, aboutevery twelve weeks, about monthly, about every two months, about every three months, or about quarterly.

[0104] In some embodiments, doses of WV-49090 are administered about every two weeks, wherein WV- 49090 in a dose is equivalent to about 200 mg WV-49090 in free acid form. In some embodiments, two or more consecutive doses of WV-49090 are administered about every two weeks, wherein WV-49090 in each dose is equivalent to about 200 mg WV-49090 in free acid form. In some embodiments, three or more consecutive doses of WV-49090 are administered about every two weeks, wherein WV-49090 in each dose is equivalent to about 200 mg WV-49090 in free acid form. In some embodiments, WV-49090 is administered about every two weeks, wherein WV-49090 in each dose is equivalent to about 200 mg WV-49090 in free acid form.

[0105] In some embodiments, doses of WV-49090 are administered about every two weeks, wherein WV- 49090 in a dose is equivalent to about 400 mg WV-49090 in free acid form. In some embodiments, two or more consecutive doses of WV-49090 are administered about every two weeks, wherein WV-49090 in each dose is equivalent to about 400 mg WV-49090 in free acid form. In some embodiments, three or more consecutive doses of WV-49090 are administered about every two weeks, wherein WV-49090 in each dose is equivalent to about 400 mg WV-49090 in free acid form. In some embodiments, WV-49090 is administered about every two weeks, wherein WV-49090 in each dose is equivalent to about 400 mg WV-49090 in free acid form.

[0106] In some embodiments, a dosing regimen is or comprises administering WV-49090 about every two weeks, wherein WV-49090 in each dose is equivalent to about 200 to about 400 mg WV-49090 in free acid form. In some embodiments, a dosing regimen is or comprises administering WV-49090 about every two weeks, wherein WV-49090 in each dose is equivalent to about 200 mg WV-49090 in free acid form. In some embodiments, a dosing regimen is or comprises administering WV-49090 about every two weeks, wherein WV-49090 in each dose is equivalent to about 400 mg WV-49090 in free acid form.

[0107] In some embodiments, doses of WV-49090 are administered about every four weeks, wherein WV- 49090 in a dose is equivalent to about 400 mg WV-49090 in free acid form. In some embodiments, two or more consecutive doses of WV-49090 are administered about every four weeks, wherein WV-49090 in each dose is equivalent to about 400 mg WV-49090 in free acid form. In some embodiments, three or more consecutive doses of WV-49090 are administered about every four weeks, wherein WV-49090 in each dose is equivalent to about 400 mg WV-49090 in free acid form. In some embodiments, WV-49090 is administered about every four weeks, wherein WV-49090 in each dose is equivalent to about 400 mg WV-49090 in free acid form.

[0108] In some embodiments, a dosing regimen is or comprises administering WV-49090 about every four weeks, wherein WV-49090 in each dose is equivalent to about 200 to about 400 mg WV-49090 in free acid form. In some embodiments, a dosing regimen is or comprises administering WV-49090 about every four weeks, wherein WV-49090 in each dose is equivalent to about 200 mg WV-49090 in free acid form. In some embodiments, a dosing regimen is or comprises administering WV-49090 about every four weeks, wherein WV-49090 in each dose is equivalent to about 400 mg WV-49090 in free acid form.

[0109] In some embodiments, doses of WV-49090 are administered about monthly, wherein WV-49090 in a dose is equivalent to about 400 mg WV-49090 in free acid form. In some embodiments, two or moreconsecutive doses of WV-49090 are administered about monthly, wherein WV-49090 in each dose is equivalent to about 400 mg WV-49090 in free acid form. In some embodiments, three or more consecutive doses of WV- 49090 are administered about monthly, wherein WV-49090 in each dose is equivalent to about 400 mg WV- 49090 in free acid form. In some embodiments, WV-49090 is administered about monthly, wherein WV-49090 in each dose is equivalent to about 400 mg WV-49090 in free acid form.

[0110] In some embodiments, a dosing regimen is or comprises administering WV-49090 about monthly, wherein WV-49090 in each dose is equivalent to about 200 to about 400 mg WV-49090 in free acid form. In some embodiments, a dosing regimen is or comprises administering WV-49090 about monthly, wherein WV- 49090 in each dose is equivalent to about 200 mg WV-49090 in free acid form. In some embodiments, a dosing regimen is or comprises administering WV-49090 about monthly, wherein WV-49090 in each dose is equivalent to about 400 mg WV-49090 in free acid form.

[0111] In some embodiments, doses of WV-49090 are administered about every two weeks, wherein WV- 49090 in a dose is equivalent to about 600 mg WV-49090 in free acid form. In some embodiments, two or more consecutive doses of WV-49090 are administered about every two weeks, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form. In some embodiments, three or more consecutive doses of WV-49090 are administered about every two weeks, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form.

[0112] In some embodiments, two or more consecutive doses of WV-49090 are administered about every two weeks, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form. In some embodiments, two or more consecutive doses of WV-49090 are administered about every four weeks, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form. In some embodiments, two or more consecutive doses of WV-49090 are administered about every eight weeks, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form. In some embodiments, two or more consecutive doses of WV-49090 are administered about every twelve weeks, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form. In some embodiments, two or more consecutive doses of WV-49090 are administered about monthly, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form. In some embodiments, two or more consecutive doses of WV- 49090 are administered about every two months, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form. In some embodiments, two or more consecutive doses of WV-49090 are administered about every three months, wherein WV-49090 in each dose is equivalent to about 600 mg WV- 49090 in free acid form. In some embodiments, two or more consecutive doses of WV-49090 are administered about quarterly, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form.

[0113] In some embodiments, WV-49090 is administered about every two weeks, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form. In some embodiments, WV-49090 is administered about every four weeks, wherein WV-49090 in each dose is equivalent to about 600 mg WV- 49090 in free acid form. In some embodiments, WV-49090 is administered about every eight weeks, whereinWV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form. In some embodiments, WV-49090 is administered about every twelve weeks, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form. In some embodiments, WV-49090 is administered about monthly, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form. In some embodiments, WV-49090 is administered about every two months, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form. In some embodiments, WV-49090 is administered about every three months, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form. In some embodiments, WV-49090 is administered about quarterly, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 in free acid form.

[0114] In some embodiments, each dose is independently administered as a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier as described herein. In some embodiments, two or more doses are about the same mg. In some embodiments, each dose is about the same mg. In some embodiments, pharmaceutical compositions administered for two or more doses are about the same in terms of components and their relative amounts. In some embodiments, pharmaceutical compositions administered for all doses are about the same in terms of components and their relative amounts. In some embodiments, one or more earlier doses are independently lower than one or more later doses. In some embodiments, one or more earlier doses independently are higher than one or more later doses.

[0115] In some embodiments, a composition has a WV-49090 purity of about 65%-85%. In some embodiments, a composition has a WV-49090 purity of about 65%-80%. In some embodiments, a composition has a WV-49090 purity of about 65%-75% or more. In some embodiments, purity is measured by IP-RP-UPLC using area % at 260 nm. In some embodiments, purity is measured by an IP-RP-UPLC method for purity as described herein. In some embodiments, stereochemical purity of WV-49090 is about 80% or more. In some embodiments, stereochemical purity of WV-49090 is about 85% or more. In some embodiments, stereochemical purity of WV-49090 is about 80%-90%. In some embodiments, stereochemical purity is assessed by dimer modeling. In some embodiments, amount of WV-49090 is measured by UV at 260 nm. In some embodiments, amount of WV-49090 is measured by UV at 260 nm and 22.1 OD / mg.

[0116] In some embodiments, “about” is + / − 1% (99% to 101% of a value). In some embodiments, it is + / − 2%. In some embodiments, it is + / − 3%. In some embodiments, it is + / − 4%. In some embodiments, it is + / − 5%. In some embodiments, it is + / − 6%. In some embodiments, it is + / − 7%. In some embodiments, it is + / − 8%. In some embodiments, it is + / − 9%. In some embodiments, it is + / − 10%.

[0117] Unless specified otherwise, amounts, concentrations, doses, etc., of WV-49090 are of the free acid form.

[0118] Amounts, concentrations, doses, etc. are typically purity corrected and include stereoisomers (not adjusted by stereochemical purity) (see, e.g., certain examples described for making drug products). In some embodiments, purity is measured by IP-RP-UPLC as described herein based on % area at 260 nm.Manufacturing

[0119] In some embodiments, the present disclosure provides technologies for manufacturing WV-49090 or a sat thereof, e.g., WV-49090 tetracosasodium salt. In some embodiments, the present disclosure provides technologies for manufacturing a WV-49090 drug substance. In some embodiments, the present disclosure provides technologies for manufacturing a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical composition is a WV-49090 drug product. In some embodiments, the present disclosure provides WV-49090 drug products. In some embodiments, there are multiple WV-49090 forms in a composition, one or more of which are each independently a salt form. In some embodiments, each salt form is independently a pharmaceutically acceptable salt form. In some embodiments, WV-49090 exists in a pharmaceutically acceptable salt form in a composition. In some embodiments, WV-49090 exists in WV-49090 tetracosasodium salt in a composition. In some embodiments, a pharmaceutical composition is WV-49090 tetracosasodium salt in a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical composition is WV-49090 tetracosasodium salt in a buffer matrix. In some embodiments, a pharmaceutical composition is WV-49090 tetracosasodium salt in a buffer matrix in a powder form. In some embodiments, WV-49090 tetracosasodium salt is dissolved in a buffer. In some embodiments, a pharmaceutical composition is WV-49090 tetracosasodium salt in a buffer matrix as a powder which can be utilized to provide a composition for subcutaneous administration upon addition of water.

[0120] In some embodiments, WV-49090 or a salt thereof, e.g., WV-49090 tetracosasodium salt, is chemically manufactured in compliance with Good Manufacturing Practice (cGMP) regulations.

[0121] In some embodiments, a provided technology comprises a multi-step process that includes solid- phase oligonucleotide synthesis, cleavage of the crude protected oligonucleotide from the solid support, removal of protecting groups (deprotection), concentration and desalting of the deprotected amino oligonucleotide and conjugation of the N-acetylgalactosamine (GalNAc) ligand to the primary amine at the 5’- end of the full length oligonucleotide (in 6-amino-1-hexanol coupled to the 5’-end nucleoside), preparative anion exchange (AEX) chromatographic purification, concentration and / or desalting, filtration, lyophilization, and packaging. A flow diagram depicting a manufacturing process is shown in Figure 1 (A: upstream; B: downstream) as an example.

[0122] In some embodiments, stereochemistry of WV-49090 or salts thereof is established through control of starting materials for synthesis as well as manufacturing process. For example, in some embodiments, provided technologies comprise use of phosphoramidites prepared from the chiral auxiliaries (L)-DPSE ((S)- (2-(methyldiphenylsilyl)-1-((S)-pyrrolidin-2-yl)ethan-1-ol)), (L)-PSM ((S)-2-(phenylsulfonyl)-1-((S)- pyrrolidin-2-yl)ethan-1-ol), and (D)-PSM ((R)-2-(phenylsulfonyl)-1-((R)-pyrrolidin-2-yl)ethan-1-ol) during coupling steps to ensure that the intended stereodefined Sp phosphorothioate diester, and Rp N-(1,3- dimethylimidazolidin-2-ylidene) phosphoramidate diester, and Sp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate diester, respectively, are obtained.

[0123] A useful manufacturing process for WV-49090 tetracosasodium salt as a drug substance and certain results are described below as an example. A Useful Manufacturing Process

[0124] In some embodiments, a manufacturing process comprises or consists of synthesizing the oligonucleotide, containing a combination of three kinds of internucleotidic linkages (phosphodiester, stereodefined phosphorothioate diester, and stereodefined phosphoramidate diester), on solid support using phosphoramidite chemistry. In some embodiments, cycles for constructing linkages are, as shown in the synthesis cycles below. In various cycles illustrated herein, each cycle to introduce a stereodefined phosphorothioate or stereodefined phosphoramidate linkage consists of 5′-detritylation, coupling, capping of exposed chiral auxiliary secondary amine (Capping-1), thiolation or imidation respectively, and capping of unreacted 5′-hydroxyl groups (Capping-2), and each cycle to introduce a phosphodiester consists of detritylation, coupling, oxidation, and Capping-2. Each coupling reaction is carried out by activation of the appropriate phosphoramidite and reaction with the free 5′-hydroxyl group of a support-immobilized protected nucleoside or oligonucleotide. After the appropriate number of cycles, the alkylamine linker is attached via the phosphodiester chemistry cycle.

[0125] The (L) and (D)-PSM chiral auxiliary and cyanoethyl phosphate protecting groups are removed from the crude oligonucleotide by on-column treatment with diethylamine (DEA) in acetonitrile (ACN). The (L)- DPSE chiral auxiliaries are removed by treatment with TEA.HF (triethylamine hydrofluoride) solution. The crude oligonucleotide is then cleaved from the solid support by treatment with ammonium hydroxide. This reaction also effects the global deprotection of exocyclic amino groups (acetyl, benzoyl, and isobutyryl) and the trifluoroacetyl (TFA) protection from the alkylamine at the 5’ end. The resulting deprotected crude oligonucleotide is separated from the solid support by filtration for further processing.

[0126] The triantennary GalNAc acetyl derivative is conjugated to the deprotected crude oligonucleotide by first concentrating and desalting the crude oligonucleotide via Tangential Flow Filtration (TFF). The crude oligonucleotide is then further concentrated by lyophilization before conjugating the GalNAc acid to the crude oligonucleotide. The GalNAc conjugate is deprotected by treatment with ammonium hydroxide to form the final crude WV-49090 oligonucleotide. The resulting WV-49090 crude oligonucleotide is purified using preparative anion exchange (AEX) chromatography. The purified oligonucleotide is concentrated and desalted by TFF, followed by filtration, lyophilization and packaging to yield WV-49090 or a salt thereof, e.g., WV- 49090 tetracosasodium salt, in some embodiments, as a drug substance. A useful cycle for phosphorothioate assemblyA useful cycle for phosphate assembly

[0127] Various steps to manufacture WV-49090 drug substance are described in further detail below. Stage 1: Synthesis

[0128] Synthesis of the oligonucleotide is carried out on Controlled Pore Glass (CPG) solid support functionalized with the first base 5’-ODMTr-2’-O-Me-U, on an automated oligonucleotide synthesizer. All reactions take place on the solid support packed in a column.

[0129] Detritylation

[0130] To initiate the synthesis, the CPG-5’-ODMTr-2’-O-Me-U solid support is subjected to acid- catalyzed removal of the DMTr protecting group from the 5′-hydroxyl by treatment with dichloroacetic acid (DCA) in toluene. Complete DMTr removal is ensured by inline UV monitoring based on a watch command inthe synthesis program. The DMTr removal is performed in the same way at the beginning of each synthesis cycle. In every case, following detritylation, the support-bound material is washed with acetonitrile in preparation for the next step of the synthesis.

[0131] Coupling Coupling with ETT ActivatorStereoselective coupling with CMIMT Activator

[0132] Elongation of the growing oligonucleotide chain is achieved by reaction of the 5’-hydroxyl group of the support-bound oligonucleotide with an excess of a solution of the protected phosphoramidite, in the presence of an activator, either 5-(ethylthio)-1H-tetrazole (ETT) or 1-cyanomethyl imidazole triflate salt (CMIMT) dissolved in acetonitrile. The phosphoramidites are dissolved in acetonitrile or an acetonitrile co- solvent system. The phosphoramidite required in each coupling step is determined by the oligonucleotide sequence of WV-49090. For introduction of phosphodiester linkage, cyanoethyl phosphoramidites and ETT activator are used. For introduction of a stereodefined phosphorothioate or phosphoramidate linkage, (L)- DPSE or (L)- or (D)-PSM derived phosphoramidite respectively, and the CMIMT activator are used. In either case, the phosphoramidite / activator solutions are mixed inline, pushed onto the synthesis column, then recirculated through the column for appropriate amount of time. Subsequently the column is washed with acetonitrile.

[0133] Capping-1

[0134] Capping 1 can protect the secondary amine which results from an oxazaphospholidine ring opening on an auxiliary group during a coupling step, rendering it unreactive for the remainder of the synthesis. The secondary amine is capped by flowing capping reagent B ([Cap B]: acetic anhydride / 2,6-lutidine / acetonitrile (2:3:5, v:v:v) through the synthesis column.

[0135] Oxidation, Thiolation or Imidation

[0136] A newly created P(III) phosphite triester linkage is treated in one of three ways: 1. Oxidation by treatment with iodine in pyridine : water (90:10,v:v), resulting in generation of a P(V) phosphotriester linkage.2. Thiolation by treatment with xanthane hydride (XH) in pyridine:acetonitrile (1:1,v:v) resulting in the generation of a stereodefined P(V) phosphorothioate triester linkage.3. Imidation by treatment with 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADIH) in acetonitrile resulting in the generation of a stereodefined P(V) phosphoramidate triester linkage.

[0137] In each case, after the step, the synthesis column is washed with acetonitrile.

[0138] Capping-2

[0139] Typically, a coupling reaction proceeds in very high yield but it is not quantitative. A small proportion of the 5'-hydroxy groups, available in any given cycle, fails to couple with the activated phosphoramidite. To prevent side reaction during subsequent cycles, these sites are blocked by performing the capping-2 step, using capping reagents (1:1, v:v) (capping reagent A [Cap A]: N-methylimidazole / acetonitrile (20:80,v:v) and Cap B). As a result, 5'-O-acetylated (‘capped’) support-bound oligonucleotide sequences are formed. The column is washed with acetonitrile.

[0140] Oligonucleotide Assembly and Final Step

[0141] Independent iteration of the three cycles shown above, using appropriate protected phosphoramidites allows assembly of an entire protected sequence with a TFA protecting group present at the 5'-alkylamine terminal position. Stage 2: Cleavage and Deprotection

[0142] Removal of phosphate protecting groups, (L) and (D)-PSM and (L)-DPSE chiral auxiliaries from stereodefined phosphoramidate triester and phosphorothioate triester, cleavage of the crude oligonucleotide from the solid support, removal of exocyclic nucleobase protecting groups and the isolation of the deprotected crude from the solid support is performed in a four-step process.

[0143] Step 1: PSM Chiral Auxiliary and Cyanoethyl Removal with Diethylamine Treatment

[0144] The crude oligonucleotide on the solid support is treated on column with a solution of diethylamine in ACN which simultaneously removes cyanoethyl protecting groups from the phosphate triester linkages, and (L)-and (D)-PSM chiral auxiliary from the stereodefined phosphorothioate triester and stereodefined phosphoramidate triester to generate phosphodiester, stereodefined phosphorothioate, and stereodefined phosphoramidate diester linkages, respectively, as shown above.

[0145] Step 2: DPSE Chiral Auxiliary Removal with Fluoride Treatment

[0146] The crude oligonucleotide on the solid support is treated with a temperature-controlled solution of TEA·HF in a mixture of dimethyl sulfoxide (DMSO) and H2O to effect removal of the DPSE chiral auxiliary. This process converts the stereodefined phosphorothioate triester to a stereodefined phosphorothioate diester as shown above.

[0147] Step 3: Cleavage and Deprotection

[0148] The crude oligonucleotide is then cleaved from the solid support by treatment with ammonium hydroxide in an appropriately sized pressure-rated vessel. This reaction also effects the global deprotection of exocyclic amino groups (acetyl, benzoyl, and isobutyryl) and the trifluoroacetyl (TFA) protection from the alkylamine at the 5′ end.

[0149] Step 4: Crude Amine Filtration

[0150] The resulting deprotected crude oligonucleotide is isolated from the solid support by filtration. Stage 3: GalNAc Conjugation

[0151] Step 1: Crude Desalting

[0152] In some embodiments, WV-49090 amine solution comprises or consists of a mixture of WV- 49090-amine, truncated failure sequences, deprotection reagents and residue of protecting groups. The deprotected oligonucleotide is desalted using TFF to yield crude WV-49090-amine in aqueous solution. After the crude desalting, the ammonium counter-ions are replaced with sodium counter-ions on the phosphodiester and phosphorothioate backbones of the sequence and the solution is diafiltered against WFI to achieve the crude WV-49090-amine in water.

[0153] Step 2: Crude concentration (Lyophilization)

[0154] The diafiltered crude WV-49090-amine is further concentrated by lyophilization step.

[0155] Step 3: Conjugation

[0156] The lyophilized material is dissolved in WFI to achieve desired concentration. In a liquid phase coupling reaction, the WV-49090-amine is conjugated with acetyl protected GalNAc acid in presence of HATU (hexafluorophosphate azabenzotriazole tetramethyl uronium) and DIPEA (N,N-diisopropyl ethylamine). The conjugation reaction is monitored with an in-process UPLC test.

[0157] Step 4: Conjugation Deprotection

[0158] Upon completion of conjugation step, the conjugation reaction mixture is incubated with an equal volume of ammonium hydroxide at controlled temperature to deprotect the acetyl ester groups on the GalNAc. The deprotection reaction is monitored with an in-process UPLC test. Stage 4: Purification by Anion Exchange Chromatography

[0159] Purification of the crude oligonucleotide solution is accomplished by AEX chromatography. A solution of crude conjugated oligonucleotide is loaded onto the purification column packed with TSK-GEL Super Q-5PW media. The purification run is performed using acetonitrile / sodium hydroxide eluents at controlled temperature. A sodium chloride gradient is used to elute the oligonucleotide from the column. The elution profile is monitored by ultraviolet (UV) spectrophotometry. The fractions are collected and neutralized with a sodium phosphate buffer. The fractions and mock pools are evaluated by IP-RP-UPLC. Stage 5: Concentration and Desalting (Final UF / DF)

[0160] The selected fraction pool is then concentrated and diafiltered against purified water to remove the purification buffer by TFF using 5 kDa regenerated cellulose membrane cassettes. The UF / DF process proceeds as follows, the selected pool of fractions is neutralized with sodium phosphate monobasic solution and then concentrated to a target concentration. The concentrated oligonucleotide is diafiltered against purified water before final concentration to the target concentration and collected. Stage 6: Filtration, Lyophilization, and Packaging

[0161] The oligonucleotide solution is filtered through a 0.2-micron filter and then placed in freeze dryingtrays for lyophilization. After lyophilization, the purified drug substance is isolated as a solid powder. Starting Materials

[0162] Certain useful starting materials are listed below:Tosoh TSK-Gel Super Q-5PWPurification media

[0163] Stereochemistry can be established through control of the starting materials for synthesis as well as the synthetic process. Stereodefined phosphoramidites can be prepared from appropriately protected nucleosides and a chiral auxiliary, e.g., (L)-DPSE, (L)-PSM, or (D)-PSM. The chemical purity of the stereodefined phosphoramidite can be determined by31P NMR. Configuration can be determined by various technologies including NMR technologies. In some embodiments, configuration is determined using31P NMR,1H NMR, and / or19F NMR. As the stereochemical configuration of the protected nucleoside and chiral auxiliaries are fixed, in some instances there are 2 possible diastereomers (trans and cis) that can result from the coupling reaction, of which the trans form is predominant, with the cis form being present as a minor impurity.

[0164] During the manufacture process, various in-process controls can be applied. Upon completion of the synthesis and the cleavage and deprotection stages, the presence of WV-49090 in the resulting crude oligonucleotide can be identified by MS-MS (e.g., ESI-MS / MS) and LC-MS and its purity quantified by IP- RP-UPLC. During purification, individual fractions as well as selected mock pools can be evaluated for purity and impurities by IP-RP-UPLC. In some embodiments, a drug substance or a drug product is manufactured meeting one or more or all of the following criteria. In some embodiments, WV-49090 has a certain level of purity as described herein. In some embodiments, WV-49090 tetracosasodium salt has a certain level of purity as described herein. In some embodiments, WV-49090 or a salt thereof has a certain level of purity in a composition, e.g., a pharmaceutical composition. In some embodiments, WV-49090 or a salt thereof has a certain level of purity in a drug substance. In some embodiments, WV-49090 or a salt thereof has a certain level of purity in a drug product. In some embodiments, WV-49090 or a salt thereof is WV-49090 tetracosasodium salt. In some embodiments, WV-49090 has a level of purity of about 65%-85%, e.g., about 65%-80%, about 65%-75%, or about 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, or 85% or more as determined by IP-RP-UPLC described herein. Characterization

[0165] Among other things, the present disclosure provides technologies for assessing WV-49090 or compositions thereof.

[0166] Products can be characterized by various technologies. For example, WV-49090 preparations may be characterized by mass spectrometry. For one preparation, electrospray ionization mass spectrometry (ESI- MS) analysis was performed and the experimentally determined value of 12411 Da is consistent with the theoretical average mass (free acid form) of WV-49090 drug substance (12412 Da). In some embodiments, the sequence of WV-49090 or a salt thereof was confirmed by ESI-MS / MS sequencing. For example, in one assessment, at least one sequence-relevant fragment ion was observed for 30 nucleotides in the sequence within 5 ppm error of each calculated (expected) mass as compared to the observed mass. Since the monoisotopic mass of the full-length oligonucleotide was also verified in the ESI-MS / MS analysis, then the identities and locations of all 30 nucleotides have been demonstrated and the sequence was confirmed.

[0167] Stereochemical identity comprises the combination of the absolute stereochemical configuration of each chiral linkage phosphorus in an oligonucleotide (Rp or Sp) (for WV-49090 or a salt thereof, each linkage phosphorus in a phosphorothioate or phosphoramidate group). This combination can give rise to a single diastereomer which is unique among 2ndiastereomers (n = number of chiral linkage phosphorus). In the case of WV-49090 or a salt thereof, this combination can be illustrated with 5’- OnRSSSSOOSSOnROSnROSSOnROOSSSnSOSSnR -3’, wherein “S”, “nS”, “nR”, and “O” represent Sp phosphorothioate diester, Sp-N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate diester, Rp N-(1,3- dimethylimidazolidin-2-ylidene) phosphoramidate diester, and phosphodiester linkages, respectively. WV- 49090 or a salt thereof also comprises 2’-fluoro (F), 2’-O-(2-methoxyethyl), and 2’- O-methyl (OMe) modifications.

[0168] Establishment of stereochemical identity comprises control of starting materials for synthesis as well as the manufacturing process. Use of phosphoramidites prepared from the chiral auxiliaries (L)-DPSE and / or (L)-PSM, (L)-PSM, and (D)-PSM during the coupling step ensures that the intended stereodefined Sp phosphorothioate diester, Rp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate diester and Sp N-(1,3- dimethylimidazolidin-2-ylidene) phosphoramidate diester linkages respectively, are obtained. Consistent use of stereodefined phosphoramidites for each coupling reaction allows for control of stereochemical identity of each phosphorothioate or phosphoramidate linkage.

[0169] Stereochemical identity can be confirmed using various technologies in accordance with the present disclosure. For example, it can be confirmed by measurement using several different techniques, which in combination, and by comparison with appropriate standards, provide accurate information about, and confirmation of, this attribute. Useful analytical techniques include NMR (1H,19F,31P, multidimensional, etc.) and enzymatic digestion. In some embodiments, a lot characterized by NMR and enzymatic digestion is utilized as a reference standard lot. In some embodiments, a reference standard lot is utilized to determine stereochemical identify by UPLC as part of batch release.

[0170] In some instances, NMR are performed in phosphate buffer (e.g., about pH 7.0). In some embodiments, NMR is referenced to water based on DSS standard. Observed data from certain experiments are described below.

[0171] Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR)

[0172] 1H NMR spectrum of a WV-49090 preparation comprises or consists of many sharp resonances in the region 1.0 - 8.5 ppm, e.g., sharp singlets in the region 1.7 - 1.9 ppm considered to be from 5-CH3group of 5-methyl cytosine and thymine.1H NMR spectra were calibrated through trimethylsilylpropanesulfonate (DSS). Sharp singlets in 2.0 ppm were considered to be from CH3group in the N-acetyl of triantennary GalNAc. Sharp singlets in the region 2.8 - 3.0 ppm were considered to be from N-CH3group of 1,3-dimethyl-2-imidazolin-2- ylidene. Sharp signals in 3.1 – 3.5 ppm were considered to belong to N-CH2- of 1,3-dimethyl-2-imidazolin-2- ylidene and O-CH3groups. Peaks of protons from ribose and linkers are found in the region 1.0 - 6.6 ppm whereas peaks of 5-H of cytosine(C) and uracil(U) are overlapping in the region 5.7 - 6.1 ppm. Peaks in 7.3 – 8.5 ppm were from aromatic protons from the base. The1H NMR spectrum contains signals that are consistent with WV-49090 oligonucleotide structure and the chemical shifts of the individual regions of peaks are summarized below:

[0173] Phosphorous NMR Spectroscopy

[0174] 31P NMR spectrum of a WV-49090 preparation was acquired and recorded at 161.98 MHz for phosphorus at about 348K.31P NMR spectra were indirectly calibrated through trimethylsilylpropanesulfonate (DSS). Sixteen peaks that correspond to ten PO and six PN backbone linkages were observed in the region between -3.0 and 0.1 ppm, and six PN peaks appeared in the up field (-3.0 ppm to -2.2 ppm) compared to ten PO peaks (-1.5 to 0.1 ppm) due to nitrogen’s weaker electronegativity compared to oxygen. There were eleven peaks integrating for a total of fourteen phosphorus atoms observed in the phosphorothioate diester region between 54.7 and 55.7 ppm. Overall, the PS / PN / PO signals are consistent with the stereodefined PS / PN / PO backbone of the WV-49090 drug substance. A summary of31P NMR data for a preparation of WV-49090 is presented below:

[0175] Fluorine NMR Spectroscopy

[0176] 1D19F NMR spectrum of a WV-49090 preparation was acquired and recorded at 376.52 MHz.19F NMR spectra were indirectly calibrated through trimethylsilylpropanesulfonate (DSS). Twelve peaks were observed in the region between -202.9 and -199.7 ppm and were integrated for a total of 10 fluorine atoms. The 2’-F peaks at -202.28 ppm and -202.29 ppm were integrated for a total of one fluorine atom and the 2’-F peaks at -202.87 and -202.87 ppm were integrated for a total of one fluorine atom. Without the intention to be limited by theory, the splitting could be due to long range19F -31P couplings. The total of 102’-F peaks is consistent with the WV-49090 drug substance oligonucleotide structure. A summary of19F NMR Data for a WV-49090 preparation is presented below:

[0177] In some embodiments, the present disclosure provides reference standards. In some embodiments, a standard has characterization data as described herein (e.g., MS-MS, LC-MS, enzymatic digestion, NMR, etc.). In some embodiments, a standard has characterization data as described herein (e.g., MS-MS, LC-MS, enzymatic digestion, NMR, etc.). In some embodiments,1H NMR of a standard has peaks with chemical shifts as described in the table above. In some embodiments,31P NMR of a standard has peaks with chemical shifts and integral as described in the table above. In some embodiments,31F NMR of a standard has peaks with chemical shifts and integral as described in the table above. In some embodiments, a reference standard is used in one or more analytical procedures for testing identification (e.g., by MS-MS and / or LC-MS), purity, impurities, stereochemical identification, etc. of WV-49090 (e.g., in WV-49090 preparations such as drug substances, drug products, etc.). In some embodiments, one or more analytical procedures are by IP-RP-UPLC. In some embodiments, one or more analytical procedures are utilized as part of batch release. For example, in some embodiments, a reference standard, e.g., one characterized by NMR, enzymatic digestion, etc. is used to determine stereochemical identity by UPLC as part of batch release.

[0178] In some embodiments, stereochemical identity of WV-49090 was confirmed by enzymatic digestion. In some embodiments, stereochemical configurations of various chiral linkage phosphorus of WV- 49090 are confirmed by enzymatic digestion.

[0179] Stereoselectivity of each phosphoramidite coupling step to produce stereodefined phosphorothioate or phosphoramidate linkage in WV-49090 is very high. The overall stereochemical purity of the oligonucleotide is a product of the combination of the stereoselectivities of the 14 phosphorothioate and 6 phosphoramidate linkages found in WV-49090.

[0180] In some embodiments, stereopurity is assessed using dimer modeling. In an assessment, to assess stereochemical purity of a WV-49090 preparation, dimers, and their respective reference dimers were analyzed by UPLC-MS for mass confirmation and by UPLC for purity of the Sp and Rp diastereomers. Analysis of these samples was completed on crude dimers to show representative stereoselectivity of each linkage in the synthesis process. The sequence specific dimers were synthesized in duplicate with the same process conditions used to synthesize full-length WV-49090, which accurately represents the phosphorothioate and phosphoramidate linkages. The average purity of the Sp and Rp diastereomers is reported below:

[0181] WV-49090 stereochemical purity can be attributed to the product of the stereochemical purities of each of the 14 phosphorothioate and the 6 phosphoramidate linkages. Using the data in above, the diastereomeric purity of a WV-49090 preparation was determined to be 84.73% by RP-UPLC analysis using dimer modeling. In some embodiments, diastereomeric purity of a WV-49090 is about or at least about 80%. In some embodiments, it is about or at least about 85%. In some embodiments, stereochemical purity of each chiral linkage phosphorus in WV-49090 is about or at least about 96%. In some embodiments, stereochemical purity of one and no more than one chiral linkage phosphorus in WV-49090 is about 96%. In some embodiments, the chiral linkage phosphorus is between d[3nU] and d[Hyp]. In some embodiments, stereochemical purity of a chiral linkage phosphorus in WV-49090 is about or at least about 98%. In some embodiments, stereochemical purity of each chiral linkage phosphorus in WV-49090 is about or at least about 98% except the phosphorothioate linkage between d[3nU] and d[Hyp].

[0182] FTIR spectrum can be used to characterize and assess WV-49090 preparations. FTIR of a solid WV-49090 tetracosasodium salt as a drug substance was recorded. The major absorbance band at 1641 cm-1is consistent with amide C=O, C=N and C=C stretch vibrations. An absorption peak at 2938 cm-1is consistent with C-H stretch of alkyl groups. Broad peaks in the 3200 –3336 cm-1region are also consistent with N-H / O- H stretch of amine / hydroxy groups.

[0183] Various technologies can be utilized to characterize and assess counter ions in accordance with the present disclosure. In some embodiments, sodium content is determined by inductively coupled plasma optical emission spectroscopy (ICP-OES) at a wavelength of 589.592 nm. For example, a sodium content value of 3.9% has been determined by ICP-OES for a preparation of a WV-49090 drug substance lot, in agreement with the theoretical sodium content value of 4.3% (w / w) (tetracosasodium salt).

[0184] In some embodiments, a lyophilized preparation of a WV-49090 drug substance preparation is solid, white to off-white powder. In some embodiments, pH of a WV-49090 drug substance in purified waterwas found to be about 6.0 – 8.0 (5% solution).

[0185] The molar extinction coefficient of a WV-49090 drug substance preparation was experimentally determined in water to be 273,826 M-1cm-1using a lot at ambient temperature. Using a molecular weight of 12404.74 g / mol (free acid form), this equates to an absorptivity factor of 22.1 OD / mg.

[0186] In various embodiments, impurities are controlled at low levels as described herein. For example, in some embodiments, impurity level is lower than about 32% as described herein.

[0187] A WV-49090 drug substance preparation (including associated impurities) were assessed in GLP in vitro genotoxicity studies and in an in vivo combined micronucleus and alkaline comet study. No genotoxicity was observed.

[0188] Various preparations of WV-49090 drug substance have met specified limits for residual solvents and elemental impurities.

[0189] Release specifications of WV-49090 drug substance may include one or more specifications described herein, e.g., appearance (e.g., white to off white powder by visual inspection), sequence identity (consistent with molecular sequence, e.g., by MS / MS), molecular weight (e.g., 12412 ± 3 Da by LC-MS), stereochemical identity (e.g., % RT difference no more than about 2% of the RT of a reference standard by IP- RP-UPLC), purity (e.g., ≥ 68% (area%) by IP-RP-UPLC at 260 nm), impurities (e.g., : ≤ 32% (area%) by IP- RP-UPLC), sodium content (e.g., about 3.6-4.9% by ICP-OES, etc.), water content (e.g., ≤ 15% by USP <921> or Ph. Eur. 2.5.12), assay (free acid, anhydrous) (e.g., about 100 ± 20% by UV spectrophotometry at 260 nm optionally with correction for water and sodium content), pH of solution in purified water (e.g., 6.0-8.0 by USP <791> or Ph. Eur. 2.2.3), residual solvents (e.g., by gas chromatography), elemental impurities (e.g., by ICP- MS), bacterial endotoxins (e.g., ≤0.5 EU / mg, by USP <85> or Ph. Eur 2.6.14), bioburden (total microbial aerobic count, total yeast and molds count, etc. (e.g., both ≤100 CFU / g, by USP <61 or Ph. Eur 2.6.12).

[0190] In some embodiments, the present disclosure provides technologies for assessing WV-49090 purity and / or impurities.

[0191] In some embodiments, water content of WV-49090 substance, e.g., a WV-49090 drug substance, was determined by Karl Fischer titration as per USP <921>.

[0192] Among other things, the present disclosure provides WV-49090 of high purity as described herein. In some embodiments, the present disclosure provides WV-49090 of high stereochemical purity, e.g., as determined utilizing IP-RP-UPLC. In some embodiments, presence, absence and / or levels are assessed using provided technologies, e.g., IP-RP-UPLC as described herein. In some embodiments, purity and impurities of WV-49090 can be assessed by IP-RP-UPLC. In some embodiments, purity and impurities of WV-49090 can be assessed by IP-RP-UPLC using a C18 column. In some embodiments, separation is accomplished using a gradient of mobile phase A (0.3% hexafluoroisopropanol (HFIP) / 0.2% TEA in water) and mobile phase B (50% acetonitrile in water). A useful set of parameters are provided in Table 1 below (Set A Parameters) and have been utilized to determine levels of purity / impurity for various preparations described herein. Various impurities including diastereomer impurities can be separated using this method. In some embodiments, thepresent disclosure provides a method for characterizing WV-49090 or a salt thereof, or a composition comprising WV-49090 or a salt thereof, comprising HPLC or UPLC analysis comprising one or more or all of the parameters (e.g., column, one or more solvents in mobile phase A, one or more solvents in mobile phase B, a mobile phase comprising one or more or all solvents in mobile phase A, a mobile phase comprising one or more or all solvents in mobile phase B, mobile phase A, mobile phase B, flow rate, run time, gradient, etc.).

[0193] Table 1. Set A Parameters.

[0194] In some embodiments, the present disclosure provides technologies for confirming stereochemical identity of WV-49090 or a diastereomer thereof with respect to one or more linkage phosphorus. In some embodiments, stereochemical identity of WV-49090 is determined or confirmed by IP-RP-UPLC. In some embodiments, separation is accomplished using a gradient of mobile phase A (0.35% hexafluoroisopropanol (HFIP) / 0.25% TEA in water) and mobile phase B (50% acetonitrile in water). A useful set of parameters are provided in Table 2 below (Set B Parameters). In some embodiments, the present disclosure provides a method for characterizing WV-49090 or a salt thereof, or a composition comprising WV-49090 or a salt thereof, comprising HPLC or UPLC analysis comprising one or more or all of the parameters (e.g., column, one or more solvents in mobile phase A, one or more solvents in mobile phase B, a mobile phase comprising one or more or all solvents in mobile phase A, a mobile phase comprising one or more or all solvents in mobile phase B, mobile phase A, mobile phase B, flow rate, run time, gradient, etc.). In some embodiments, the present disclosure provides a method for confirming WV-49090 stereochemical identity, comprising HPLC or UPLC analysis comprising one or more or all of the parameters.

[0195] Table 2. Set B Parameters.

[0196] In some embodiments, a storage condition for a WV-49090 drug substance is or comprises about −20ºC. In some embodiments, a storage condition for a WV-49090 drug substance is or comprises −20 ± 5ºC. In some embodiments, a storage condition for a WV-49090 drug substance is or comprises about 5°C. In some embodiments, a storage condition for a WV-49090 drug substance is or comprises 5°C ± 3°C. Additional Manufacturing Technologies

[0197] Additional technologies for manufacturing WV-49090 are described below as examples.

[0198] In some embodiments, [GalNAc3C12oyl] and [nC6o] was introduced in one cycle. In some embodiments, a manufacturing is or comprises a 3’ to 5’ synthesis on solid support (e.g., see cycles above), and after the 5’-end mC was installed, the following phosphoramidite (“GalNAc Amidite”) was utilized to couple to the 5’-OH of the mC:

[0199] In some embodiments, coupling is performed in the presence of ETT in MeCN. In some embodiments, following coupling is oxidation (e.g., in the presence of I2 / pyridine-H2O). In some embodiments, after oxidation an oligonucleotide comprising the structure below was produced:In some embodiments, an oligonucleotide is a precursor to WV-49090, and in the oligonucleotide, compared to WV-49090, each hydroxy group in GalNAc in WV-49090 is independently protected (e.g., as −OAc) in the oligonucleotide, each nucleobase in WV-49090 is independently and optionally protected (e.g., as described in various phosphoramidites) in the oligonucleotide, each phosphate linkage in WV-49090 is independently a P(V) phosphotriester linkage (e.g., as in a cycle described above) in the oligonucleotide, each phosphorothioate linkage in WV-49090 is independently a P(V) phosphorothioate triester linkage (e.g., as in a cycle described above) in the oligonucleotide, and each phosphoramidate linkage in WV-49090 is independently a P(V) phosphoramidate triester linkage (e.g., as in a cycle described above) in the oligonucleotide. In some embodiments, after cleavage and deprotection (e.g., see above for PSM chiral auxiliary and cyanoethyl removal with diethylamine treatment, DPSE chiral auxiliary removal with fluoride treatment, cleavage and deprotection, etc.), WV-49090 was provided. In some embodiments, after filtration a crude WV-49090 solution composition was provided. Crude WV-49090 compositions can be further processed, e.g., purification, concentration, desalting, filtration, lyophilization, packaging, characterization, etc. to provide WV-49090 compositions and preparations, e.g., drug substance preparations.

[0200] Incorporating GalNAc into WV-49090 using GalNAc Amidite can provide various advantages, including saving manufacturing time, simplifying manufacturing operations (in some embodiments, reducing or avoiding manufacturing interruptions (e.g., associated with a cycle for incorporating [n6Co])), and reducing manufacturing cost. Among other things, incorporating GalNAc into WV-49090 using GalNAc Amidite can be performed at various scales including of about 0.75 mmol or above, and can be readily scaled up (e.g., from about 0.75 mmol to up to about 900 mmol or more). In some embodiments, a useful GalNAc Amide coupling cycle comprises deblocking, coupling and oxidation. In some embodiments, deblocking comprises contacting an oligonucleotide on a solid support with 3% DCA in toluene. In some embodiments, manufacturing uses a column and a suitable flow rate is utilized, and DMTr removal is monitored using in-line UV monitoring. In some embodiments, coupling comprises contacting a de-blocked oligonucleotide with a composition comprising GalNAc Amidite and an activator. In some embodiments, an activator is ETT. In some embodiments, manufacturing uses a column and a suitable flow rate and a suitable circulation time are utilized for coupling. In some embodiments, oxidation comprises contacting an oligonucleotide with I2 / pyridine-H2O. In some embodiments, manufacturing uses a column and a suitable flow rate and a suitable circulation time areutilized for oxidation. Drug Product

[0201] In some embodiments, the present disclosure provides a pharmaceutical composition comprising or delivering WV-49090 and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising or delivering WV-49090 in a pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising WV-49090 tetracosasodium salt and a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical composition is a WV-49090 drug product. In some embodiments, the present disclosure provides a WV-49090 drug product. In some embodiments, a WV-49090 drug product comprises a WV-49090 drug substance, e.g., WV-49090 tetracosasodium salt manufactured using a process described above. In some embodiments, there are two or more WV-49090 forms in a pharmaceutical composition. In some embodiments, a form is a salt form. In some embodiments, a form is a pharmaceutically acceptable salt form. In some embodiments, a form is a sodium salt form. In some embodiments, a form is a WV-49090 tetracosasodium salt. In some embodiments, there are two or more pharmaceutically acceptable salt forms in a pharmaceutical composition. In some embodiments, each form in a pharmaceutical composition is independently a salt form. In some embodiments, each form in a pharmaceutical composition is independently a pharmaceutically acceptable salt form. In some embodiments, a WV-49090 preparation or composition is a lyophilized powder for reconstitution into a pharmaceutical composition. In some embodiments, a pharmaceutical composition is WV-49090 in a buffer matrix. In some embodiments, a pharmaceutical composition is WV-49090 tetracosasodium salt in a buffer matrix. In some embodiments, a pharmaceutical composition is WV-49090 in a buffer solution. In some embodiments, a pharmaceutical composition is WV-49090 tetracosasodium salt in a buffer solution.

[0202] In some embodiments, a pharmaceutically acceptable carrier is or comprises a buffered solution. In some embodiments, a pharmaceutically acceptable carrier is or comprises a phosphate buffered solution.

[0203] In some embodiments, a pharmaceutical composition is for subcutaneous (SC) administration.

[0204] Certain WV-49090 drug products and useful manufacturing technologies are described below as examples.

[0205] In some embodiments, a WV-49090 pharmaceutical composition, e.g., a drug product is packaged in a 10R USP / EP Type 1 clear glass vial sealed with a bromobutyl rubber stopper and an aluminium overseal with a red flip-off button. In some embodiments, a drug product vial contains WV-49090 drug substance equivalent to about 80 mg WV-49090 free acid form. In some embodiments, the components of a WV-49090 drug product comprise or are WV-49090 in a buffer matrix.

[0206] In some embodiments, a WV-49090 drug product is a white to off-white solid which upon reconstitution with water yields clear, colorless to pale yellow solution, essentially free from visible particulates. In some embodiments, pH of a solution containing 80 mg WV-49090 in 5 mL water for injection (WFI) is 6.7± 1.0 with osmolality in the range of 35 - 75 mOsm / kg.

[0207] A WV-49090 drug product is typically a sterile solution. In some embodiments, a drug product lot may be made by pooling multiple drug substance lots.

[0208] In some embodiments, a drug product has a purity as described herein, e.g., those described for WV-49090 or a salt thereof (e.g., tetracosasodium salt salt), a WV-49090 drug substance, etc. In some embodiments, purity is assessed using an IP-RP-UPLC method described herein for purity.

[0209] In some embodiments, WV-49090 drug substance containers can be thawed or kept at 2-8°C for approximately 24 hours (e.g., less than 48 hours), followed by equilibrating at room temperature for at least 30 minutes. Employing the % purity, % sodium content and % water content of drug substance preparations pure full-length product (FLP) is calculated. In some embodiments, Buffer matrix in the amount of approximately 60% of the calculated target batch volume can be employed to dissolve drug substance in the formulation vessel. In some embodiments, the drug substance from each container can be transferred to the formulation vessel and an adequate amount of buffer matrix is used to rinse any remaining drug substance in the containers.

[0210] In some embodiments, a drug substance is mixed adequately and upon complete dissolution, an in- process sample can be taken to measure pH, density and concentration by ultraviolet (UV) spectrophotometry at 260 nm. In some embodiments, remaining solution mass in the formulation can be weighed. In some embodiments, based on purity corrected WV-49090 drug substance concentration, density and solution mass, the required amount of buffer to achieve a final concentration of about 25 mg / mL can be calculated. In some embodiments, additional buffer can then be slowly added to the formulation vessel to achieve calculated total drug solution.

[0211] In some embodiments, contents of a vessel is mixed to ensure homogenous solution and in-process samples are collected for pH, osmolality, concentration by UV spectrophotometry at 260 nm, density, etc. In some embodiments, a final compounded formulation can undergo bioburden reduction filtration following which it can be stored overnight at 2-8 °C, if required. In some embodiments, a pre-filtration bioburden sample cam be taken prior to sterile filtration of the compounded bulk solution. In some embodiments, the final compounded formulation can be sterile filtered through two 0.22 µm filters in series prior to filling. In some embodiments, sterile filter units can be checked for filter integrity by bubble point method prior to and post filtration.

[0212] In some embodiments, target fill weight per vial is determined based on target fill volume of 3.2 mL (in some instances, ± 4%) and measured density. In some embodiments, filled vials can undergo 100% weight checks, followed by partial stoppering and loading on trays. In some embodiments, loading carts can be used for aseptic transfer of these trays into the sterilized lyophilizer. In some embodiments, trays are loaded into lyophilizer and lyophilization cycle is executed.

[0213] In some embodiments, freeze-dried or lyophilized vials can be unloaded onto a loading cart for transport back for crimping. In some embodiments, crimping can be performed in Grade A within the restrictedaccess barrier system (RABS). In some embodiments, filled units can be inspected and stored at cold storage (2 - 8 °C) until further processing. In some embodiments, vials can then be visually inspected before sampling for release, stability testing, and packaging or storage.

[0214] In some embodiments, vials, stoppers, and overseals are sterilized. In some embodiments, vials are supplied ready-to-use (RTU) by a manufacturer. In some embodiments, vial trays are aseptically introduced into Grade B and stored until ready for use. In some embodiments, on the day of the fill, vial trays are introduced into filling machine (Grade A within RABS enclosure). In some embodiments, stoppers are supplied as ready- to-sterilize by a manufacturer, bags containing closure parts are opened in Grade C and re-packed into sterilization bags, and each bag is sealed, placed into sterilization container and autoclaved for ≥ 60 min at 123 ± 2ºC. In some embodiments, aluminum over seals (flip caps) are supplied as ready-to-sterilize by a manufacturer, bags containing closure parts are opened in Grade C and re-packed into sterilization bags, and each bag is sealed, placed into sterilization container and autoclaved for ≥ 60 min at 123 ± 2ºC.

[0215] In some embodiments, process controls and in-process control tests and acceptance limits applied during the manufacture of WV-49090 drug product include WV-49090 concentration, pH, osmolality, bioburden, filter integrity, fill weight, appearance, etc.

[0216] In some embodiments, manufacture of WV-49090 drug product comprises in-process concentration measurements via ultraviolet (UV) spectrophotometry. In some embodiments, an in-process concentration measurement is made upon the initial dilution (reconstitution) of WV-49090 drug substance.

[0217] Release specifications of a WV-49090 drug product may include one or more specifications described herein, e.g., appearance (e.g., white to off white powder by visual inspection; clear, colorless to pale yellow solution, essentially free from visible particulates after reconstitution (e.g., about 80 mg WV-49090 in 5 mL water) by visual inspection; etc.), identity (e.g., consistent with structure, e.g., by MS / MS, or confirmed if %RT difference is no more than 3% of the RT of a reference standard by IP-RP-UPLC), molecular weight (e.g., 12412 ± 3 Da; by LC-MS), purity (e.g., ≥ 68% (area%) by IP-RP-UPLC at 260 nm), impurities (e.g., ≤ 32% (area %) by IP-RP-UPLC at 260 nm), assay (100% label claim) (e.g., about 100 ± 10% of excepted amount, by UV spectrophotometry at 260 nm, corrected by purity), pH (e.g., about 80 mg reconstituted in about 5 mL of water, 5.7-7.7 by USP <791> or Ph. Eur.2.2.3), osmolality (e.g., about 80 mg reconstituted in about 5 mL of water, 35-75 mOsm / kg, USP <785> or Ph. Eur.2.2.35), water content (e.g., USP <921> Karl Fischer, ≤ 15% (% w / w)), reconstitution time (e.g., about 80 mg reconstituted in about 5 mL of water, ≤ 8 minutes by visual inspection), bacterial endotoxins (e.g., ≤ 0.58 EU / mg, by USP <85> or Ph. Eur 2.6.14), sterility (e.g., USP <71> or Ph. Eur.2.6.1), uniformity of dose units (e.g., USP <905> or Ph. Eur.2.9.40), particulate matter (e.g., USP <788> or Ph. Eur.2.9.19), container closure integrity testing (e.g., USP <1207>), etc.

[0218] In some embodiments, IP-RP-UPLC technologies utilizing one or more or all Set A Parameters are utilized for assessing identity (retention time), purity and / or impurities. In some embodiments, purity level is 65%-85% as described herein. In some embodiments, it is about 70% or more. In some embodiments, it is about 71% or more. In some embodiments, it is about 72% or more. In some embodiments, it is about 73% ormore. In some embodiments, it is about 74% or more. In some embodiments, it is about 75% or more. In some embodiments, it is about 76% or more. In some embodiments, it is about 77% or more. In some embodiments, it is about 78% or more. In some embodiments, it is about 79% or more. In some embodiments, it is about 80% or more. In some embodiments, it is about 81% or more. In some embodiments, it is about 82% or more. In some embodiments, it is about 83% or more. In some embodiments, it is about 84% or more. In some embodiments, it is about 85% or more. In some embodiments, it is measured by IP-RP-UPLC area % at 260 nm. In some embodiments, IP-RP-UPLC technologies utilizing one or more or all Set B Parameters are utilized for confirming WV-49090 stereochemical identity. In some embodiments, the present disclosure provides a device, e.g., a container, containing WV-49090. In some embodiments, the present disclosure provides a device, e.g., a container, containing a WV-49090 drug product. In some embodiments, a container closure system for WV-49090 drug product comprises or consists of a 10R USP / EP Type 1 clear glass vial sealed with a bromobutyl rubber stopper and an aluminium overseal with a red flip-off button.

[0219] In some embodiments, pharmaceutical compositions of WV-49090 are administered subcutaneously. In some embodiments, the present disclosure provides a product comprising a pharmaceutical composition of WV-49090. In some embodiments, the present disclosure provides a vial comprising a pharmaceutical composition of WV-49090. In some embodiments, the present disclosure provides a device (e.g., a device for subcutaneous administration) comprising a pharmaceutical composition of WV-49090. In some embodiments, a device is or comprises a container. In some embodiments, a device is a syringe. In some embodiments, the present disclosure provides a syringe comprising a pharmaceutical composition of WV- 49090. In some embodiments, a device is an autoinjector. In some embodiments, the present disclosure provides an autoinjector comprising a pharmaceutical composition of WV-49090. In some embodiments, the present disclosure provides a composition comprising or delivering a dose of WV-49090 as described herein (e.g., equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form). In some embodiments, a device contains or delivers a dose of WV-49090 as described herein, wherein WV-49090 is in a pharmaceutical composition (e.g., equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form). In some embodiments, a device contains or delivers a dose of WV-49090 equivalent to about 200 mg WV-49090 in free acid form, wherein WV-49090 is in a pharmaceutical composition. In some embodiments, a device contains or delivers a dose of WV-49090 equivalent to about 400 mg WV-49090 in free acid form, wherein WV-49090 is in a pharmaceutical composition. In some embodiments, a device is for subcutaneous administration.

[0220] In some embodiments, a storage condition for a WV-49090 drug product is or comprises about - 20ºC. In some embodiments, a storage condition for a WV-49090 drug product is or comprises -20 ± 5ºC. In some embodiments, a storage condition for a WV-49090 drug product is or comprises about 5°C. In some embodiments, a storage condition for a WV-49090 drug product is or comprises 5°C ± 3°C. In some embodiments, a storage condition for a WV-49090 drug product is or comprises about 25°C. In some embodiments, a storage condition for a WV-49090 drug product is 25°C ± 2°C.

[0221] Among other things, the present disclosure provides the following example Embodiments: 1. A method for treating alpha-1 antitrypsin deficiency (AATD), comprising administering or delivering to a subject suffering therefrom WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein the subject has a G to A mutation in a Serpin Family A Member 1 (SERPINA1) gene that encodes a Glu342Lys mutation in an alpha-1 antitrypsin (AAT) polypeptide, and wherein WV-49090 may be described as: (1): 5’-mC[n001R]mC[Ssp]mC[Ssp][fl2r]A[Ssp][fl2r]G[Ssp][moe][m5C]p[moe]Ap[fl2r]G[Ssp][fl2r] C[Ssp]mUpmU[n001R]mCp[fl2r]A[Ssp][fl2r]G[n001R][fl2r]Up[moe][m5C][Ssp][fl2r]C[Ssp]mCpmU[n001 R]mUp[moe]Tp[fl2r]C[Ssp]dT[Ssp]d[3nU][Ssp]d[Hyp][n001S]mUp[fl2r]C[Ssp]mG[Ssp]mA[n001R]mU-3’: m: 2’-O-methyl modified nucleoside; [fl2r]: 2’-fluoro-2’-deoxy modified nucleoside; [moe]: 2’-O-(2-methoxyethyl) modified nucleoside; d: 2’-deoxy nucleoside; [m5C]: 5-methylcytidine; d[3nU]: 2’-deoxyisouridine (nucleobase isd[Hyp]: 2’-deoxyinosine; [Ssp]: Sp phosphorothioate linkage; p: phosphodiester linkage; [n001S]: Sp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate linkage (wherein the linkage phosphorus is in Sp configuration); [n001R]: Rp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate linkage (wherein the linkage phosphorus is in Rp configuration); and wherein the 5’-carbon of the 5’-end mC is linked to the structure below via a phosphodiester group:(2): RNA1{p.m(C)[n001R].m(C)[Ssp].m(C)[Ssp].[fl2r](A)[Ssp].[fl2r](G)[Ssp].[moe]([m5C])p.[moe](A)p.[fl2r]( G)[Ssp].[fl2r](C)[Ssp].m(U)p.m(U)[n001R].m(C)p.[fl2r](A)[Ssp].[fl2r](G)[n001R].[fl2r](U)p.[moe]([m5C])[ Ssp].[fl2r](C)[Ssp].m(C)p.m(U)[n001R].m(U)p.[moe](T)p.[fl2r](C)[Ssp].d(T)[Ssp].d([3nU])[Ssp].d([Hyp])[n 001S].m(U)p.[fl2r](C)[Ssp].m(G)[Ssp].m(A)[n001R].m(U)}|CHEM1{[GalNAc3C12oyl]}|CHEM2{[nC6o]}$ CHEM2,RNA1,1:R1-1:R1|CHEM2,CHEM1,1:R2-1:R1$$$V2.0; m: 2’-OMe modified nucleoside; [fl2r]: 2’-F modified nucleoside; [moe]: 2’-O-(2-methoxyethyl) modified nucleoside; d: 2’-deoxy nucleoside; [m5C]: 5-methylcytidine; [3nU]: N-3-uridine; d[Hyp]: 2’-deoxyinosine; [Ssp]: Sp phosphorothioate linkage; p: phosphodiester linkage;[n001S]: Sp N-(1,3-dimethylimidazolidin-2-ylidenyl) phosphoramidate linkage (herein thelinkage phosphorus is in Sp configuration);[n001R]: N-(1,3-dimethylimidazolidin-2-ylidenyl) phosphoramidate linkage (erein thelinkage phosphorus is in Rp configuration); [GalNAc3C12oyl]:[nC6o]: −NH−(CH2)6−, connected to [GalNAc3C12oyl] through −NH− and a phosphodiester linkage through −CH2−; (3):5′-O-(6-(12-(tris(((3-((3-((5-((2-(acetylamino)-2-deoxy-b-D-galactopyranosyl)oxy)-1- oxopentyl)amino)propyl)amino)-3-oxopropoxy)methyl))methyl)amino-12-oxododecanamido)hexyl phospho)- [P(R)]-2′-O-methyl-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]cytidylyl-(3′→5′)-[P(S)]-2′-O- methyl-P-thiocytidyl-(3′→5′)-[P(S)]-2′-O-methyl-P-thiocytidyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P- thioadenylyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thioguanylyl-(3′→5′)-2′-O-(2-methoxyethyl)-5- methylcytidylyl-(3′→5′)-2′-O-(2-methoxyethyl)adenylyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thioguanylyl- (3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thiocytidyl-(3′→5′)-2′-O-methyluridylyl-(3′→5′)-[P(R)]-2′-O-methyl-P- deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]uridylyl-(3′→5′)-2′-O-methylcytidylyl-(3′→5′)-[P(S)]- 2′-fluoro-2′-deoxy-P-thioadenylyl-(3′→5′)-[P(R)]-2′-fluoro-2′-deoxy-P-deoxy-P-[(1,3-dimethylimidazolidin- 2-ylidene)amino]guanylyl-(3′→5′)-2′-fluoro-2′-deoxyuridylyl-(3′→5′)-[P(S)]-2′-O-(2-methoxyethyl)-P-thio- 5-methylcytidylyl-(3′→5′)-[P(S)]- 2′-fluoro-2′-deoxy-P-thiocytidyl-(3′→5′)-2′-O-methylcytidyl-(3′→5′)- [P(R)]-2′-O-methyl-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]uridylyl-(3′→5′)-2′-O- methyluridylyl-(3′→5′)-2′-O-(2-methoxyethyl)-5-methyluridylyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P- thiocytidyl-(3′→5′)-[P(S)]-P-thiothymidylyl-(3′→5′)-[P(S)]-2′-deoxy-P-thioisouridylyl-(3′→5′)-[P(S)]-2′- deoxy-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]inosinylyl-(3′→5′)-2′-O-methyluridylyl- (3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thiocytidyl-(3′→5′)-[P(S)]-2′-O-methyl-P-thioguanylyl-(3′→5′)-[P(R)]- 2′-O-methyl-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]adenylyl-(3′→5′)-2′-O-methyluridine; or(free acid form). 2. A method for treating alpha-1 antitrypsin deficiency (AATD), comprising administering or delivering to a subject suffering therefrom WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein the subject expresses a Glu342Lys mutant AAT polypeptide, or a mutant SERPINA1 mRNA comprising 1024 G>A, and wherein WV- 49090 is as described in Embodiment 1. 3. A method, comprising administering or delivering to a subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 4. A method for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 mRNA in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 5. A method for producing of a SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342 AAT polypeptide, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 6. A method for reducing level of a 1024 G>A mutant SERPINA1 mRNA in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 7. A method for increasing level of a SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342 AAT polypeptide, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, and wherein WV-49090 is as described in Embodiment 1. 8. The method of any one of Embodiments 6-7, wherein the level is or comprises a relative amount to a reference mRNA. 9. The method of any one of Embodiments 6-8, wherein the level is or comprises percentage of total SERPINA1 mRNA. 10. The method of any one of Embodiments 6-9, wherein the change is relative to baseline. 11. A method for producing a Glu342 AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 12. A method for producing M-AAT in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550,600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 13. A method for reducing level of a Glu342Lys mutant AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 14. A method for reducing level of Z-AAT in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 15. A method for increasing level of a Glu342 AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 16. A method for increasing level of M-AAT in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 17. The method of any one of Embodiments 13-16, wherein the level is or comprises a relative amount to a reference polypeptide. 18. The method of any one of Embodiments 13-17, wherein the level is or comprises percentage of total AAT polypeptide. 19. A method for providing increased level of a wild-type AAT function in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 20. The method of any one of Embodiments 13-19, wherein the change is relative to baseline. 21. A method for providing acute phase response production of AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 22. A method for providing acute phase response production of M-AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV- 49090 is as described in Embodiment 1. 23. A method for providing acute phase response production of Z-AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV- 49090 is as described in Embodiment 1.24. A method for providing an increased acute phase response AAT polypeptide level in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV- 49090 is as described in Embodiment 1. 25. A method for providing an increased acute phase response AAT polypeptide serum level in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV- 49090 is as described in Embodiment 1. 26. A method for providing acute phase response AAT polypeptide serum level about 15, 16, 17, 18, 19, 20 uM or higher in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV- 49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 27. A method for providing an increased acute phase response M-AAT polypeptide level in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV- 49090 is as described in Embodiment 1. 28. A method for providing an increased acute phase response M-AAT polypeptide serum level in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV- 49090 is as described in Embodiment 1. 29. A method for providing acute phase response M-AAT polypeptide serum level about 8, 9, or 10 uM or higher in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 30. A method for providing an increased acute phase response Z-AAT polypeptide level in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV- 49090 is as described in Embodiment 1. 31. A method for providing an increased acute phase response Z-AAT polypeptide serum level in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV- 49090 is as described in Embodiment 1. 32. A method for providing acute phase response Z-AAT polypeptide serum level about 8, 9, or 10 uM or higher in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1.33. The method of any one of Embodiments 21-32, wherein providing acute phase response production of AAT polypeptide in a subject comprises restoring acute phase response production of AAT polypeptide in the subject. 34. A method for providing increased production of AAT polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 35. A method for providing an increased AAT polypeptide level in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 36. A method for providing an increased AAT polypeptide serum level in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 37. A method for providing an AAT polypeptide level about 15, 16, 17, 18, 19, 20 uM or higher in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 38. The method of any one of Embodiments 34-37, wherein providing increased production of AAT polypeptide in response to an inflammatory event in the subject comprises restoring increased production of AAT polypeptide in response to an inflammatory event in the subject. 39. A method for providing acute phase response production of M-AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV- 49090 is as described in Embodiment 1. 40. The method of Embodiment 39, wherein providing acute phase response production of AAT polypeptide in a subject comprises restoring acute phase response production of AAT polypeptide in the subject. 41. A method for providing increased production of M-AAT polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 42. A method for providing an increased M-AAT polypeptide level in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1.43. A method for providing an increased M-AAT polypeptide serum level in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 44. A method for providing an increased M-AAT polypeptide serum level about 8, 9 or 10 uM in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 45. A method for providing increased production of Z-AAT polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 46. A method for providing an increased Z-AAT polypeptide level in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 47. A method for providing an increased Z-AAT polypeptide serum level in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 48. A method for providing an increased Z-AAT polypeptide serum level about 8, 9 or 10 uM in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in Embodiment 1. 49. The method of any one of Embodiments 41-48, wherein providing increased production of M-AAT polypeptide in response to an inflammatory event in the subject comprises restoring increased production of M- AAT polypeptide in response to an inflammatory event in the subject. 50. The method of any one of Embodiments 34-38 and 41-43, wherein an inflammatory event comprises or is a non-drug-related inflammatory event. 51. The method of any one of Embodiments 34-38 and 41-50, wherein increased production comprises a higher level of production as compared to a baseline, optionally wherein the baseline is a level of production prior to the inflammatory event. 52. The method of any one of Embodiments 21-51, wherein the acute phase response serum level of AAT in a subject is about 20 uM or higher. 53. The method of any one of Embodiments 21-52, wherein the acute phase response serum level of M- AAT in a subject is about 10 uM or higher.54. The method of any one of Embodiments 21-53, wherein the acute phase response serum level of Z- AAT in a subject is about 10 uM or higher. 55. The method of any one of Embodiments 21-54, wherein the acute phase response is associated with a kidney stone. 56. The method of any one of Embodiments 2-55, wherein the subject suffers from AATD. 57. The method of any one of Embodiments 2-56, wherein the subject has a SERPINA1 Z-allele. 58. A method for treating alpha-1 antitrypsin deficiency (AATD) in a human subject expressing a Glu342Lys mutant AAT polypeptide, or a mutant SERPINA1 mRNA comprising 1024 G>A, comprising administering to the human subject WV-49090 at a dose equivalent to about 200 to about 600 mg WV-49090 free acid form at a dosing interval of about every 2 weeks, about every 4 weeks, about every 8 weeks, about every 12 weeks, about monthly, about every two months, about every three months, or about quarterly. 59. The method of Embodiment 58, wherein WV-49090 is administered at a dose equivalent to about 200 mg to about 400 mg WV-49090 free acid form. 60. The method of any one of the preceding Embodiments, wherein the subject is homozygous for a Glu342Lys mutation. 61. The method of any one of Embodiments 1-60, wherein the subject suffers from an AATD-induced lung disease. 62. The method of any one of Embodiments 1-61, wherein the subject suffers from an AATD-induced liver disease. 63. The method of any one of the preceding Embodiments, wherein the subject has a Pi*ZZ genotype. 64. The method of any one of the preceding Embodiments, wherein two or more doses of WV-49090 are administered or delivered, each of which is independently equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. 65. The method of any one of the preceding Embodiments, wherein WV-49090 is administered in multiple forms one of which is a salt form. 66. The method of any one of the preceding Embodiments, wherein WV-49090 is administered in one or more pharmaceutically acceptable salt forms. 67. The method of any one of Embodiments 65-66, wherein one form is WV-49090 sodium salt. 68. The method of any one of Embodiments 65-67, wherein each dose of WV-49090 is independently administered in a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier. 69. A method for treating AATD, comprising administering to a subject suffering therefrom a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV- 49090 free acid form, wherein the subject has a G to A mutation in a Serpin Family A Member 1 (SERPINA1) gene that encodes a Glu342Lys mutant alpha-1 antitrypsin (AAT) polypeptide.70. A method for treating AATD, comprising administering to a subject suffering therefrom a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV- 49090 free acid form, wherein the subject has a G to A mutation in a Serpin Family A Member 1 (SERPINA1) gene that encodes a Glu342Lys mutation in an alpha-1 antitrypsin (AAT) polypeptide. 71. A method, comprising administering to a subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. 72. A method for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342Lys mutant AAT polypeptide, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. 73. A method for producing of a SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342 AAT polypeptide, comprising administering to the subject a pharmaceutical composition comprising WV- 49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. 74. A method for reducing level of a 1024 G>A mutant SERPINA1 mRNA in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. 75. A method for increasing level of a SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342 AAT polypeptide, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. 76. The method of any one of Embodiments 74-75, wherein the level is or comprises a relative amount to a reference mRNA. 77. The method of any one of Embodiments 74-76, wherein the level is or comprises percentage of total SERPINA1 mRNA. 78. The method of any one of Embodiments 74-77, wherein the change is relative to baseline. 79. A method for producing a Glu342 AAT polypeptide in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. 80. A method for producing M-AAT in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. 81. A method for reducing level of a Glu342Lys mutant AAT polypeptide in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. 82. A method for reducing level of Z-AAT in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV- 49090 free acid form. 83. A method for increasing level of a Glu342 AAT polypeptide in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. 84. A method for increasing level of M-AAT in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV- 49090 free acid form. 85. The method of any one of Embodiments 81-84, wherein the level is or comprises a relative amount to a reference polypeptide. 86. The method of any one of Embodiments 81-85, wherein the level is or comprises percentage of total AAT polypeptide. 87. A method for providing increased level of a wild-type AAT function in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. 88. The method of any one of Embodiments 81-87, wherein the change is relative to baseline. 89. The method of any one of Embodiments 70-88, wherein the subject suffers from AATD. 90. The method of any one of Embodiments 70-89, wherein the subject has a SERPINA1 Z-allele. 91. The method of any one of Embodiments 69-90, wherein the subject has a Pi*ZZ genotype. 92. The method of any one of Embodiments 69-90, wherein the subject suffers from Pi*ZZ AATD. 93. The method of any one of Embodiments 69-92, wherein two or more doses of pharmaceutical compositions are administered, each of which is independently a pharmaceutical composition comprising WV- 49090 and a pharmaceutically acceptable carrier and each at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form. 94. The method of Embodiment 93, wherein each pharmaceutical composition has the same types of components.95. The method of Embodiment 93, wherein the pharmaceutically acceptable carrier in each pharmaceutical composition is the same. 96. The method of Embodiment 93, wherein each pharmaceutical composition is the same. 97. The method of any one of the preceding Embodiments, wherein two or more consecutive doses are administered about every two weeks. 98. The method of any one of the preceding Embodiments, wherein seven or more consecutive doses are administered about every two weeks. 99. The method of any one of the preceding Embodiments, wherein two or more consecutive doses are administered about every four weeks. 100. The method of any one of the preceding Embodiments, wherein two or more consecutive doses are administered about every eight weeks. 101. The method of any one of the preceding Embodiments, wherein two or more consecutive doses are administered about every twelve weeks. 102. The method of any one of the preceding Embodiments, wherein two or more consecutive doses are administered about monthly. 103. The method of any one of the preceding Embodiments, wherein two or more consecutive doses are administered about every two months. 104. The method of any one of the preceding Embodiments, wherein two or more consecutive doses are administered about every three months. 105. The method of any one of the preceding Embodiments, wherein two or more consecutive doses are administered about quarterly. 106. The method of any one of the preceding Embodiments, wherein two or more doses are administered, and each dose is equivalent to about the same amount of WV-49090 free acid form. 107. The method of any one of the preceding Embodiments, wherein WV-49090 in a dose is equivalent to about 200 mg WV-49090 free acid form. 108. The method of any one of the preceding Embodiments, wherein WV-49090 in a dose is equivalent to about 250 mg WV-49090 free acid form. 109. The method of any one of the preceding Embodiments, wherein WV-49090 in a dose is equivalent to about 300 mg WV-49090 free acid form. 110. The method of any one of the preceding Embodiments, wherein WV-49090 in a dose is equivalent to about 350 mg WV-49090 free acid form. 111. The method of any one of the preceding Embodiments, wherein WV-49090 in a dose is equivalent to about 400 mg WV-49090 free acid form. 112. The method of any one of the preceding Embodiments, wherein WV-49090 in a dose is equivalent to about 450 mg WV-49090 free acid form. 113. The method of any one of the preceding Embodiments, wherein WV-49090 in a dose is equivalent toabout 500 mg WV-49090 free acid form. 114. The method of any one of the preceding Embodiments, wherein WV-49090 in a dose is equivalent to about 550 mg WV-49090 free acid form. 115. The method of any one of the preceding Embodiments, wherein WV-49090 in a dose is equivalent to about 600 mg WV-49090 free acid form. 116. The method of any one of Embodiments 1-106, wherein WV-49090 in each dose is equivalent to about 200 mg WV-49090 free acid form. 117. The method of any one of Embodiments 1-106, wherein WV-49090 in each dose is equivalent to about 250 mg WV-49090 free acid form. 118. The method of any one of Embodiments 1-106, wherein WV-49090 in each dose is equivalent to about 300 mg WV-49090 free acid form. 119. The method of any one of Embodiments 1-106, wherein WV-49090 in each dose is equivalent to about 350 mg WV-49090 free acid form. 120. The method of any one of Embodiments 1-106, wherein WV-49090 in each dose is equivalent to about 400 mg WV-49090 free acid form. 121. The method of any one of Embodiments 1-106, wherein WV-49090 in each dose is equivalent to about 450 mg WV-49090 free acid form. 122. The method of any one of Embodiments 1-106, wherein WV-49090 in each dose is equivalent to about 500 mg WV-49090 free acid form. 123. The method of any one of Embodiments 1-106, wherein WV-49090 in each dose is equivalent to about 550 mg WV-49090 free acid form. 124. The method of any one of Embodiments 1-106, wherein WV-49090 in each dose is equivalent to about 600 mg WV-49090 free acid form. 125. The method of Embodiment 116, wherein two or more consecutive doses of WV-49090 are administered about every two weeks and WV-49090 in each dose is equivalent to about 200 mg WV-49090 free acid form. 126. The method of Embodiment 116, wherein seven or more consecutive doses of WV-49090 are administered about every two weeks and WV-49090 in each dose is equivalent to about 200 mg WV-49090 free acid form. 127. The method of Embodiment 120, wherein two or more consecutive doses of WV-49090 are administered about every four weeks and WV-49090 in each dose is equivalent to about 400 mg WV-49090 free acid form. 128. The method of Embodiment 120, wherein two or more consecutive doses of WV-49090 are administered about monthly and WV-49090 in each dose is equivalent to about 400 mg WV-49090 free acid form. 129. The method of any one of Embodiments 125-128, wherein WV-49090 is administered subcutaneously.130. A method, comprising administering WV-49090 to a population of subjects, wherein: none of the subjects have a mutation in a Serpin Family A Member 1 (SERPINA1) gene that encodes a Glu342Lys mutant alpha-1 antitrypsin (AAT) polypeptide; and each subject is independently administered WV-49090 in a dose that is equivalent to about 30 mg WV- 49090 free acid form. 131. The method of Embodiment 130, wherein no or no more than about 3 treatment emergent adverse effects were observed within about 8 days after WV-49090 administration; 132. The method of any one of Embodiments 130-131, wherein each observed treatment emergent adverse effect is assessed as mild to moderate in intensity; and 133. The method of any one of Embodiments 130-132, wherein each observed treatment emergent adverse effect is not casually related to WV-49090. 134. The method of any one of Embodiments 130-133, wherein no safety issue is identified from laboratory parameters, vitals and / or ECG. 135. The method of any one of Embodiments 130-134, wherein WV-49090 is administered subcutaneously. 136. The method of any one of Embodiments 130-135, wherein each subject is determined to be healthy. 137. The method of any one of Embodiments 130-136, wherein the population consists of 8 subjects. 138. The method of any one of Embodiments 130-136, wherein the population consists of 8 healthy subjects. 139. The method of any one of Embodiments 130-138, wherein plasma AUC0-24h observed in the 48 hours after the administration is about 520 hr*ng / mL. 140. The method of any one of Embodiments 130-139, wherein plasma Cmax observed in the 48 hours after the administration is about 40 ng / mL. 141. The method of any one of Embodiments 130-140, wherein none of the subjects is administered a dose of WV-49090 prior to the administration of WV-49090 in a dose that is equivalent to about 30 mg WV-49090 free acid form. 142. The method of any one of Embodiments 130-141, wherein none of the subjects is administered a dose of WV-49090 subsequent to the administration of WV-49090 in a dose that is equivalent to about 30 mg WV- 49090 free acid form. 143. The method of any one of Embodiments 130-142, wherein none of the subjects is administered a dose of WV-49090 subsequent to the administration of WV-49090 in a dose that is equivalent to about 30 mg WV- 49090 free acid form. 144. The method of any one of Embodiments 130-143, wherein WV-49090 is administered in multiple forms one of which is a salt form. 145. The method of any one of Embodiments 130-144, wherein WV-49090 is administered in one or more pharmaceutically acceptable salt forms. 146. The method of any one of Embodiments 130-145, wherein one form is WV-49090 sodium salt. 147. The method of any one of Embodiments 130-146, wherein WV-49090 is administered in apharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier. 148. The method of any one of the preceding Embodiments, wherein about is ±1%. 149. The method of any one of the preceding Embodiments, wherein about is ±2%. 150. The method of any one of the preceding Embodiments, wherein about is ±3%. 151. The method of any one of the preceding Embodiments, wherein about is ±4%. 152. The method of any one of the preceding Embodiments, wherein about is ±5%. 153. The method of any one of the preceding Embodiments, wherein about is ±6%. 154. The method of any one of the preceding Embodiments, wherein about is ±7%. 155. The method of any one of the preceding Embodiments, wherein about is ±8%. 156. The method of any one of the preceding Embodiments, wherein about is ±9%. 157. The method of any one of the preceding Embodiments, wherein about is ±10%. 158. The method of any one of the preceding Embodiments, wherein the pharmaceutical composition comprises a salt form of WV-49090. 159. The method of any one of the preceding Embodiments, wherein the pharmaceutical composition comprises two or more forms of WV-49090. 160. The method of any one of the preceding Embodiments, wherein the pharmaceutical composition comprises two or more pharmaceutically acceptable salt forms of WV-49090. 161. The method of any one of the preceding Embodiments, wherein WV-49090 exists in the pharmaceutical composition as one or more pharmaceutically acceptable salt forms. 162. The method of any one of Embodiments 159-161, wherein a pharmaceutically acceptable salt form is a sodium salt. 163. The method of any one of the preceding Embodiments, wherein a pharmaceutical composition is a liquid composition comprising dissolved WV-49090. 164. The method of any one of the preceding Embodiments, wherein a pharmaceutically acceptable carrier is or comprises a buffer. 165. The method of any one of the preceding Embodiments, wherein a pharmaceutically acceptable carrier is or comprises a phosphate buffered solution. 166. The method of any one of the preceding Embodiments, wherein a pharmaceutical composition has a pH of about 7. 167. The method of any one of the preceding Embodiments, wherein a pharmaceutical composition has a pH of about 6-8. 168. The method of Embodiment 166, wherein a pharmaceutical composition has a pH of about 6.7 ± 1.0. 169. The method of any one of the preceding Embodiments, wherein the composition has a WV-49090 purity of about 65%-85%. 170. The method of any one of the preceding Embodiments, wherein the composition has a WV-49090 purity of about 65%-80%.171. The method of any one of the preceding Embodiments, wherein the composition has a WV-49090 purity of about 65%-75% or more. 172. The method of any one of Embodiments 169-171, wherein the purity is measured by IP-RP-UPLC using area % at 260 nm. 173. The method of any one of Embodiments 169-171, wherein the purity is measured by an IP-RP-UPLC method for purity as described herein. 174. The method of Embodiment 173, wherein the purity is measured by an IP-RP-UPLC method comprising one or more parameters from Table 1. 175. The method of any one of the preceding Embodiments, wherein stereochemical purity of WV-49090 is about 80% or more. 176. The method of any one of the preceding Embodiments, wherein stereochemical purity of WV-49090 is about 85% or more. 177. The method of any one of the preceding Embodiments, wherein stereochemical purity of WV-49090 is about 80%-90%. 178. The method of any one of the preceding Embodiments, wherein stereochemical purity is assessed by dimer modeling. 179. The method of any one of the preceding Embodiments, wherein the amount of WV-49090 is measured by UV at 260 nm and 22.1 OD / mg. 180. The method of any one of the preceding Embodiments, wherein a WV-49090 drug substance is manufactured by a process described herein. 181. The method of any one of the preceding Embodiments, wherein a WV-49090 drug substance is characterized by one or more methods described herein. 182. The method of any one of the preceding Embodiments, wherein stereochemical identity of WV-49090 is confirmed by IP-RP-UPLC. 183. The method of any one of the preceding Embodiments, wherein stereochemical identity of WV-49090 is confirmed by an IP-RP-UPLC method for stereochemical identity as described herein. 184. The method of any one of the preceding Embodiments, wherein a WV-49090 drug substance is released by one or more methods described herein. 185. The method of any one of the preceding Embodiments, wherein a WV-49090 drug substance is stored using one or more methods described herein. 186. The method of any one of Embodiments 180-185, wherein the WV-49090 drug substance is a sodium salt. 187. The method of any one of the preceding Embodiments, wherein a WV-49090 drug product is manufactured by a process described herein. 188. The method of any one of the preceding Embodiments, wherein a WV-49090 drug product is characterized by one or more methods described herein.189. The method of any one of the preceding Embodiments, wherein a WV-49090 drug product is released by one or more methods described herein. 190. The method of any one of the preceding Embodiments, wherein a WV-49090 drug product is stored by one or more methods described herein. 191. The method of any one of the preceding Embodiments, wherein a pharmaceutical composition is manufactured by a process described herein. 192. The method of any one of the preceding Embodiments, wherein a pharmaceutical composition is characterized by one or more methods described herein. 193. The method of any one of the preceding Embodiments, wherein a pharmaceutical composition is released by one or more methods described herein. 194. The method of any one of the preceding Embodiments, wherein a pharmaceutical composition is stored by one or more methods described herein. 195. The method of any one of the preceding Embodiments, wherein WV-49090 is administered subcutaneously. 196. The method of any one of the preceding Embodiments, wherein a mutant SERPINA1 mRNA encoding Glu342Lys in AAT in the subject is edited, and the edited AAT mRNA encodes a Glu342Lys mutant AAT polypeptide. 197. The method of any one of the preceding Embodiments, wherein a mutant SERPINA1 mRNA encoding Glu342Lys in AAT in the subject is edited, and the edited AAT mRNA encodes a Glu342 AAT polypeptide. 198. The method of any one of the preceding Embodiments, wherein a single dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject and no WV-49090 is administered to the subject in the following about or at least about 8 weeks. 199. The method of any one of the preceding Embodiments, wherein a single dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject and no WV-49090 is administered to the subject in the following about or at least about 12 weeks. 200. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, total AAT level of about 11 micromolar or more in plasma is observed. 201. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, total AAT level of about 11.8 micromolar or more in plasma is observed. 202. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, total AAT level of about 12.9 micromolar or more in plasma is observed. 203. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, total AATlevel of about 11 or more micromolar in plasma is observed about two weeks after administration. 204. The method of any one of Embodiments 200-203, wherein the baseline total AAT level is below a level of quantification. 205. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD subjects, mean total AAT level of about 11 micromolar in plasma is observed. 206. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD subjects, mean total AAT level of about 11.8 micromolar in plasma is observed. 207. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD subjects, mean total AAT level of about 12.9 micromolar in plasma is observed. 208. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD subjects, mean total AAT level of about 11 micromolar in plasma is observed about two weeks after administration. 209. The method of any one of Embodiments 205-207, wherein mean total AAT protein increases from below a level of quantification at baseline to about 10.8 micromolar about two weeks after administration. 210. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient, M-AAT representing about or more than about 60% of total AAT in plasma is observed. 211. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient, M-AAT representing about or more than about 60% of total AAT in plasma is observed about two weeks after administration. 212. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean M-AAT representing about or more than about 60% of total AAT in plasma is observed. 213. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean M-AAT representing about or more than about 60% of total AAT in plasma is observed about two weeks after administration. 214. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, M-AAT level of about 4.0 micromolar or more in plasma is observed. 215. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, M-AAT levelof about 4.8 micromolar or more in plasma is observed. 216. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, M-AAT level of about 6.9 micromolar or more in plasma is observed. 217. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, M-AAT level of about 6.9 micromolar or more in plasma is observed about two weeks after administration. 218. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean M-AAT level of about 6.9 micromolar in plasma is observed. 219. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean M-AAT level of about 6.9 micromolar in plasma is observed about two weeks after administration. 220. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, decrease of Z-AAT level of about or at least about 47.3% in plasma is observed. 221. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, decrease of Z-AAT level of about or at least about 48.8% in plasma is observed. 222. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean decrease of Z-AAT level of about or at least about 47.3% in plasma is observed. 223. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean decrease of Z-AAT level of about or at least about 48.8% in plasma is observed. 224. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient, increase of total AAT from baseline is observed about two days after administration. 225. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient, increase of total AAT from baseline is observed about 8 weeks after administration. 226. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient, increase of total AAT from baseline is observed about 12 weeks after administration. 227. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient, M-AAT isobserved about two days after administration. 228. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient, M-AAT is observed about 8 weeks after administration. 229. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient, M-AAT is observed about 12 weeks after administration. 230. The method of any one of the preceding Embodiments, wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to a Pi*ZZ AATD subject, total AAT level of about 11.9 micromolar or more in plasma is observed. 231. The method of Embodiment 230, wherein the baseline total AAT level is below a level of quantification. 232. The method of any one of the preceding Embodiments, wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to Pi*ZZ AATD subjects, mean total AAT level of about 11.9 micromolar in plasma is observed. 233. The method of Embodiment 232, wherein mean total AAT protein increases from below a level of quantification at baseline to about 11.9 micromolar. 234. The method of any one of the preceding Embodiments, wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to a Pi*ZZ AATD patient, M-AAT representing about or more than about 64.4% of total AAT in plasma is observed. 235. The method of any one of the preceding Embodiments, wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to Pi*ZZ AATD patients, mean M-AAT representing about or more than about 64.4% of total AAT in plasma is observed. 236. The method of any one of the preceding Embodiments, wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to a Pi*ZZ AATD patient, M-AAT representing about or more than about 50% of total AAT in plasma is observed for at least about two months following last dose. 237. The method of any one of the preceding Embodiments, wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to Pi*ZZ AATD patients, mean M-AAT representing about or more than about 50% of total AAT in plasma is observed for at least about two months following last dose. 238. The method of any one of the preceding Embodiments, wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to a Pi*ZZ AATD subject, M-AAT level of about 7.2 micromolar or more in plasma is observed. 239. The method of any one of the preceding Embodiments, wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to Pi*ZZ AATD patients,mean M-AAT level of about 7.2 micromolar in plasma is observed. 240. The method of any one of the preceding Embodiments, wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to a Pi*ZZ AATD subject, decrease of Z-AAT level of about or at least about 60.3% in plasma is observed. 241. The method of any one of the preceding Embodiments, wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to Pi*ZZ AATD patients, mean decrease of Z-AAT level of about or at least about 60.3% in plasma is observed. 242. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, total AAT level of about 12.8 micromolar or more in plasma is observed. 243. The method of Embodiment 242, wherein the baseline total AAT level is below a level of quantification. 244. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to Pi*ZZ AATD subjects, mean total AAT level of about 12.8 micromolar in plasma is observed. 245. The method of Embodiment 244, wherein mean total AAT protein increases from below a level of quantification at baseline to about 12.8 micromolar. 246. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient, M-AAT representing about or more than about 47.2% of total AAT in plasma is observed. 247. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean M-AAT representing about or more than about 47.2% of total AAT in plasma is observed. 248. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, M-AAT level of about 5.3 micromolar or more in plasma is observed. 249. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean M-AAT level of about 5.3 micromolar in plasma is observed. 250. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, decrease of Z-AAT level of about or at least about 49.0% in plasma is observed. 251. The method of any one of the preceding Embodiments, wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean decrease of Z-AAT level of about or at least about 49.0% in plasma is observed. 252. The method of any one of the preceding Embodiments, comprising assessing level of neutrophilelastase inhibition. 253. The method of any one of the preceding Embodiments, wherein a subject exhibits acute phase response production of AAT polypeptide. 254. The method of any one of the preceding Embodiments, wherein a subject exhibits acute phase response production of M-AAT polypeptide. 255. The method of any one of the preceding Embodiments, wherein a subject exhibits increased production of AAT polypeptide in response to an inflammatory event. 256. The method of any one of the preceding Embodiments, wherein a subject exhibits increased production of M-AAT polypeptide in response to an inflammatory event. 257. The method of Embodiment 255 or 256, wherein the inflammatory event is a non-drug-related inflammatory event. 258. The method of any one of the preceding Embodiments, wherein an increase in neutrophil elastase inhibition from baseline is observed. 259. The method of any one of the preceding Embodiments, wherein WV-49090 administration is well- tolerated. 260. The method of any one of the preceding Embodiments, wherein no serious adverse events is observed in at least 57 days after a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient. 261. The method of any one of the preceding Embodiments, wherein no serious adverse events is observed in at least 57 days after a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to two or more Pi*ZZ AATD patients. 262. The method of any one of the preceding Embodiments, wherein no serious adverse events are observed. 263. A composition comprising WV-49090. 264. The composition of Embodiment 263, wherein a form of WV-49090 in the composition is a pharmaceutically acceptable salt form. 265. The composition of any one of Embodiments 263-264, wherein each form of WV-49090 in the composition is independently a salt form. 266. The composition of any one of Embodiments 263-265, wherein each form of WV-49090 in the composition is independently a pharmaceutically acceptable salt form. 267. The composition of any one of Embodiments 263-266, wherein a form of WV-49090 in the composition is a sodium salt. 268. The composition of any one of Embodiments 263-267, wherein the composition has a WV-49090 purity of about 65%-90%. 269. The composition of any one of Embodiments 263-267, wherein the composition has a WV-49090 purity of about 65%-85%. 270. The composition of any one of Embodiments 263-267, wherein the composition has a WV-49090 purityof about 65%-80%. 271. The composition of any one of Embodiments 263-267, wherein the composition has a WV-49090 purity of about 65%-75%. 272. The composition of any one of Embodiments 268-271, wherein the purity is measured by IP-RP-UPLC using area % at 260 nm. 273. The composition of any one of Embodiments 268-271, wherein the purity is measured by an IP-RP- UPLC method for purity as described herein. 274. The composition of Embodiment 273, wherein the purity is assessed by an IP-RP-UPLC method comprising one or more parameters from Table 1. 275. The composition of Embodiment 273, wherein the purity is assessed by an IP-RP-UPLC method using parameters from Table 1. 276. The composition of any one of Embodiments 263-273, wherein stereochemical purity of WV-49090 is about 80% or more. 277. The composition of any one of Embodiments 263-273, wherein stereochemical purity of WV-49090 is about 85% or more. 278. The composition of any one of Embodiments 263-273, wherein stereochemical purity of WV-49090 is about 80%-90%. 279. The composition of any one of Embodiments 263-278, wherein stereochemical purity is assessed by dimer modeling. 280. The composition of any one of Embodiments 263-279, wherein the composition is a liquid composition wherein WV-49090 is dissolved. 281. The composition of any one of Embodiments 263-280, wherein the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. 282. The composition of Embodiment 281, wherein the pharmaceutically acceptable carrier is or comprises a phosphate buffered solution. 283. The composition of any one of Embodiments 263-282, wherein the composition has a pH of about 7. 284. The composition of any one of Embodiments 263-282, wherein the composition has a pH of about 6- 8. 285. The composition of any one of Embodiments 263-282, wherein the composition has a pH of about 6.7 ± 1.0. 286. The composition of any one of Embodiments 263-285, wherein the concentration of WV-49090 is equivalent to about 25 mg / mL WV-49090 free acid form. 287. The composition of Embodiment 286, wherein the composition is packaged into a vial, wherein the volume of the composition in the vial is about 3.2 mL. 288. The composition of any one of Embodiments 263-287, wherein the composition is packaged into a vial, wherein the amount of WV-49090 in the vial is equivalent to about 80 mg WV-49090 free acid form.289. The composition of any one of Embodiments 263-288, wherein the amount of WV-49090 is measured by UV at 260 nm. 290. The composition of any one of Embodiments 263-289, wherein the amount of WV-49090 is measured by UV at 260 nm and 22.1 OD / mg. 291. The composition of any one of Embodiments 263-279, wherein the composition is a WV-49090 drug substance. 292. The composition of any one of Embodiments 263-291, wherein the WV-49090 drug substance in the composition is manufactured by a process described herein. 293. The composition of any one of Embodiments 263-292, wherein the WV-49090 drug substance in the composition is characterized by one or more methods described herein. 294. The composition of any one of Embodiments 263-293, wherein the WV-49090 drug substance in the composition is released by one or more methods described herein. 295. The composition of any one of Embodiments 263-294, wherein the WV-49090 drug substance is stored using one or more methods described herein. 296. The composition of any one of Embodiments 263-295, wherein the WV-49090 drug substance is sodium salt. 297. The composition of any one of Embodiments 263-290 and 292-296, wherein the composition is a WV- 49090 drug product. 298. The composition of Embodiment 297, wherein the WV-49090 drug product is manufactured by a process described herein. 299. The composition of any one of Embodiments 297-298, wherein the WV-49090 drug product is characterized by one or more methods described herein. 300. The composition of any one of Embodiments 297-299, wherein the WV-49090 drug product is released by one or more methods described herein. 301. The composition of any one of Embodiments 297-300, wherein the WV-49090 drug product is stored using one or more methods described herein. 302. The composition of any one of Embodiments 263-290, wherein the composition is manufactured by a process described herein. 303. The composition of any one of Embodiments 263-290 and 302, wherein a pharmaceutical composition is characterized by one or more methods described herein. 304. The composition of any one of Embodiments 263-290 and 302-303, wherein a pharmaceutical composition is released by one or more methods described herein. 305. The composition of any one of Embodiments 263-290 and 302-304, wherein a pharmaceutical composition is stored by one or more methods described herein. 306. The composition of any one of Embodiments 263-305, wherein the composition is or delivers a dose of WV-49090 of any one of Embodiments 1-262.307. The composition of any one of Embodiments 268-306, wherein about is ±1%. 308. The composition of any one of Embodiments 268-306, wherein about is ±2%. 309. The composition of any one of Embodiments 268-306, wherein about is ±3%. 310. The composition of any one of Embodiments 268-306, wherein about is ±4%. 311. The composition of any one of Embodiments 268-306, wherein about is ±5%. 312. The composition of any one of Embodiments 268-306, wherein about is ±6%. 313. The composition of any one of Embodiments 268-306, wherein about is ±7%. 314. The composition of any one of Embodiments 268-306, wherein about is ±8%. 315. The composition of any one of Embodiments 268-306, wherein about is ±9%. 316. The composition of any one of Embodiments 268-306, wherein about is ±10%. 317. The composition of any one of Embodiments 263-316, for use in a method of any one of Embodiments 1-262. 318. A method for manufacturing a WV-49090 composition according to a method described in the specification. 319. The method of Embodiment 318, comprising utilizing IP-RP-UPLC to assess purity and / or impurities in the manufactured WV-49090 composition and release the preparation if the purity and / or impurities meet certain criteria. 320. The method of any one of Embodiments 318-319, wherein the composition is a drug substance. 321. The method of any one of Embodiments 318-319, wherein the composition is a drug product. 322. A method for releasing a WV-49090 preparation, comprising utilizing IP-RP-UPLC to assess purity and / or impurities in the WV-49090 preparation and release the preparation if the purity and / or impurities meet certain criteria. 323. A method for assessing purity of WV-49090 utilizing IP-RP-UPLC. 324. The method of any one of Embodiment 319-323, wherein the IP-RP-UPLC utilized one or more parameters described in the specification. 325. The method of Embodiment 324, wherein the IP-RP-UPLC method comprises one or more parameters in Table 1. 326. The method of any one of Embodiments 318-321, comprising a method of any one of Embodiments 322-325. 327. A method for confirming stereochemical identity of WV-49090 utilizing IP-RP-UPLC. 328. The method of any one of Embodiments 318-327, wherein stereochemical identity of WV-49090 is confirmed by an IP-RP-UPLC method for stereochemical identity as described herein. 329. The method of Embodiment 327, wherein the IP-RP-UPLC method comprises one or more parameters in Table 2. 330. The method of Embodiment 327, wherein the IP-RP-UPLC method uses parameters in Table 2. 331. The method of any one of Embodiments 318-326, comprising a method of any one of Embodiments327-330. 332. The method of any one of Embodiments 318-331, wherein the composition is a composition in any one of Embodiments 263-317. 333. A vial comprising a composition of any one of Embodiments 263-317. 334. A device comprising a composition of any one of Embodiments 263-317. 335. The device of Embodiment 334, wherein the device is for subcutaneous administration. 336. The device of Embodiment 334 or 335, wherein the device is or comprises a syringe. 337. The device of Embodiment 334 or 335, wherein the device is or comprises an autoinjector. 338. The device of any one of Embodiments 334-337, wherein the device contains or delivers a dose of WV- 49090 of any one of Embodiments 1-262. 339. The device of any one of Embodiments 334-337, wherein the device contains or delivers WV-49090 equivalent to about 200 mg free acid form. 340. The device of any one of Embodiments 334-337, wherein the device contains or delivers WV-49090 equivalent to about 400 mg free acid form. 341. The device of any one of Embodiments 334-337, wherein the device contains or delivers WV-49090 equivalent to about 600 mg free acid form. 342. The device of any one of Embodiments 334-341, wherein the device is or comprises a vial. 343. Use of a composition of any one of Embodiments 263-317 in the manufacture of a medicament for a method of any one of Embodiments 1-262. 344. WV-49090, for use in a method of any one of Embodiments 1-262. 345. Use of WV-49090 in the manufacture of a medicament for a method of any one of Embodiments 1- 262. 346. A method for providing acute phase response production of a polypeptide in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript. 347. A method for modulating level of an acute phase protein in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript. 348. A method for providing increased production of a polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript. 349. The method of any one of Embodiments 346-348, wherein the polypeptide is an AAT polypeptide. 350. The method of any one of Embodiments 346-348, wherein the polypeptide is a M-AAT polypeptide. 351. The method of any one of Embodiments 346-348, wherein the polypeptide is a Z-AAT polypeptide. 352. A method for providing an increased acute phase response AAT level in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a targetadenosine in a target transcript. 353. A method for providing an increased acute phase response AAT serum level in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript. 354. A method for providing increased AAT level in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript. 355. A method for providing increased AAT serum level in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript. 356. The method of any one of Embodiments 352-355, wherein the increased level is about 15, 16, 17, 18, 19, or 20 uM or higher. 357. The method of Embodiment 356, wherein the increased level is about 20 uM or higher. 358. A method for providing an increased acute phase response M-AAT level in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript. 359. A method for providing an increased acute phase response M-AAT serum level in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript. 360. A method for providing increased M-AAT level in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript. 361. A method for providing increased M-AAT serum level in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript. 362. The method of any one of Embodiments 358-362, wherein the increased level is about 8, 9, 10 uM or higher. 363. The method of Embodiment 362, wherein the increased level is about 10 uM or higher. 364. A method for providing an increased acute phase response Z-AAT level in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript. 365. A method for providing an increased acute phase response Z-AAT serum level in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript. 366. A method for providing increased Z-AAT level in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition forediting a target adenosine in a target transcript. 367. A method for providing increased Z-AAT serum level in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript. 368. The method of any one of Embodiments 364-367, wherein the increased level is about 8, 9, 10 uM or higher. 369. The method of Embodiment 368, wherein the increased level is about 10 uM or higher. 370. The method of any one of Embodiments 348-369, wherein the inflammatory event is a non-drug-related inflammatory event. 371. The method of any one of Embodiments 348- 370, wherein the increased production is higher than a baseline production, optionally wherein the baseline production is prior to the inflammatory event. 372. The method of any one of Embodiments 346-371, wherein the target transcript is a mRNA. 373. The method of any one of Embodiments 346-372, wherein the target transcript is a SERPINA1 transcript. 374. The method of any one of Embodiments 346-373, wherein the target transcript is a SERPINA1 mRNA. 375. The method of any one of Embodiments 346-374, wherein the target adenosine is 1024 G>A in SERPINA1 mRNA. 376. The method of any one of Embodiments 346-375, wherein the subject has a Pi*ZZ genotype. 377. A sample, comprising M-AAT at a level of about 8, 9, 10 uM or higher in serum. 378. The sample of Embodiment 377, wherein the level of M-AAT is about 10 uM or higher in serum. 379. A sample, comprising AAT at a level of about 15, 16, 17, 18, 19 or 20 uM or higher in serum. 380. The sample of any one of Embodiments 377-379, wherein the level of AAT is about 20 uM or higher in serum. 381. A sample, comprising Z-AAT at a level of about 8, 9, 10 uM or higher in serum. 382. The sample of any one of Embodiments 377-381, wherein the level of Z-AAT is about 10 uM or higher in serum. 383. The sample of any one of Embodiments 377-382, wherein the sample comprises genomic DNA encoding Z-AAT. 384. The sample of any one of Embodiments 377-383, wherein the sample does not contain genomic DNA encoding Z-AAT. 385. The sample of any one of Embodiments 377-384, wherein the sample is obtained from a Pi*ZZ subject. 386. The sample of any one of Embodiments 377-385, wherein the sample is a blood sample. 387. The sample of any one of Embodiments 377-386, wherein the sample is a serum sample. 388. The method of any one of the preceding Embodiments, comprising assessing M-AAT level in serum in a sample of any one of the preceding Embodiments. 389. A method, comprising assessing M-AAT level in serum in a sample of any one of the precedingEmbodiments. 390. The method of any one of the preceding Embodiments, comprising assessing Z-AAT level in serum in a sample of any one of the preceding Embodiments. 391. A method, comprising assessing Z-AAT level in serum in a sample of any one of the preceding Embodiments. 392. The method of any one of the preceding Embodiments, comprising assessing AAT level in serum in a sample of any one of the preceding Embodiments. 393. A method, comprising assessing AAT level in serum in a sample of any one of the preceding Embodiments. 394. A compound, oligonucleotide, composition, method, process, use, device, sample, dose or dosing regimen described in the specification. EXEMPLIFICATION

[0222] The foregoing has been a description of certain embodiments of provided technologies. Embodiments and examples of the disclosure are illustrative and non-limiting.

[0223] Various properties, activities, functions, advantages, etc. of certain embodiments of the provided technologies may be more fully demonstrated and understood from the examples described below. Example 1. Studies in vitro and in Animals

[0224] Among other things, the present disclosure provides data including those in mice and monkeys indicating that WV-49090 can be assessed in human subjects.

[0225] Among other things, WV-49090 provided sequence-specific A-to-I editing and production of E342 AAT polypeptide in various models including patient-derived cell lines and animal models.

[0226] In vivo, SERPINA11024 A-to-I editing, AAT protein restoration, and improvements in survival were achieved in NSG-PiZ mouse models. Subcutaneous (SC) administration of WV-49090 was associated with findings in the liver, kidney, injection sites, and findings consistent with pro-inflammatory effects in both mice and monkeys. In monkeys, transient complement activation was noted following WV-49090 administration. In mice, WV-49090 was associated with findings in the spleen and thymus, as well as effects on coagulation. A 13-week repeat dose toxicology study in mice was completed, which included a 5-week interim phase necropsy. In the 5-week group from the 13-week study, following WV-49090 administration every other week via SC injection (30, 100, or 300 mg / kg / dose; 3 total doses), pertinent, non-adverse, findings included prolonged APTT, decreases in glucose and cholesterol, and decreases in albumin with increased globulin reflected in a decrease in A / G ratio. Non-adverse, microscopic changes were observed in the liver, kidney, injection sites, spleen, and lymph nodes. For the 13-week study following WV-49090 administration every other week via SC injection (a total of 7 doses), WV-49090 was well tolerated with no impact on the health and well-being of the animals. The NOAEL was considered to be the highest dose of 300 mg / kg / dosewhen administered every other week via SC administration for a total of 7 doses.

[0227] In a non-GLP toxicity study in cynomolgus monkeys, mild to marked renal tubular degeneration / regeneration with intratubular hemorrhage and casts observed microscopically, combined with clinical pathology evidence of decreased renal function, was considered adverse based on the severity and extent of the changes following seven weekly SC doses of 60 mg / kg / week WV-49090, a dose level resulting in a WV- 49090 concentration that can be many multiples of concentrations that can be effective.

[0228] A 13-week GLP repeat dose toxicology study in monkeys was completed which included a 5-week interim phase necropsy. In the 5-week interim group from the 13-week study, following 5 weeks of WV-49090 administration every other week via SC injection (a total of 3 doses), minimal renal tubular degeneration / regeneration was noted in a single male at 70 mg / kg / dose, the top dose tested, and was not considered adverse due to the mild nature of the finding and lack of accompanying necrotic changes or association with functional impact or change in the well-being of the animal. In the 13-week main study on Day 92, following 13-weeks of dosing every other week via SC injection (a total of 7 doses), moderate renal tubular degeneration / regeneration at 70 mg / kg / dose was considered adverse due to the expected impact on organ function at this level of severity. There was also minimal to mild multiorgan (gallbladder, cecum, colon, rectum. heart, and kidney) arterial inflammation (arteritis / periarteritis) at 70 mg / kg / dose which may not be considered clinically relevant as monkeys can be more sensitive than humans to oligonucleotide-mediated complement activation (Shen et al., 2014). After a 13-week recovery period (Day 183), there was a complete recovery of the renal tubular degeneration / regeneration in monkeys. The NOAEL was considered to be the dose of 20 mg / kg / dose when administered every other week via SC administration for a total of 7 doses over 13 weeks.

[0229] These findings among other things establishes that WV-49090 is sufficiently safe for assessment in human subjects. Example 2. Clinical Studies of WV-49090 in Healthy Human Subjects

[0230] Among other things, safety of WV-49090 are assessed in clinical trials in healthy human subjects to demonstrate safety of WV-49090 at various doses and dosage regimens in humans. A useful clinical study protocol is presented below as an example. In some embodiments, a clinical trial is or comprises one or more conditions, protocols, methods, criteria, out measures, designs, objectives, endpoints, etc. of the study described below. In some embodiments, a clinical trial is conducted according to a study described below. Those skilled in the art appreciate that a study may be adjusted. A Phase 1, Randomized, Double-blind, Placebo-controlled, Safety, Tolerability, and Pharmacokinetic Study of Single Ascending Doses and Multiple Doses of WV-49090 in Healthy Participants

[0231] Among other things, a study assesses one or more of safety and tolerability of WV-49090 in healthy participants with wild-type SERPINA1, including pharmacokinetics (PK), dose ranges, any treatment emergent adverse events (TEAEs), etc. In some embodiments, a study has 2 parts (Period 1 and Period 2): Study Arms and Duration:Study arms in both Period 1 and Period 2 are up to 6 WV-49090 and up to 2 placebo treated participants (3:1 active : placebo) in each of the planned cohorts. Period 1 SAD: duration for each participant is expected to be up to 16 weeks: Screening of up to 28 days, followed by a single dose administration on Day 1, followed by safety, tolerability, and PK assessment through Day 85. Period 2 Multidose: duration for each participant is expected to be up to 20 weeks: Screening of up to 28 days, followed by 3 dose administrations on Weeks 0, 2, and 4, followed by safety, tolerability, and PK assessment through Day 113 Visit (i.e., Day 85 following last dose administration).

[0232] In some embodiments, a WV-49090 composition, e.g., a WV-49090 drug product, is a lyophilized powder. In some embodiments, it is a lyophilized powder for injection, composed of WV-49090 drug substance in a buffer matrix. In some embodiments, a WV-49090 drug product is filled in a 10R USP / EP Type 1 clear glass vials sealed with a rubber stopper and an aluminum overseal with a red flip-off button. In some embodiments, prior to administration, a WV-49090 drug product is reconstituted with sterile water for injection, which results in a sterile, preservative-free injection solution for SC administration.

[0233] In some embodiments, an objective is or comprises to evaluate safety and tolerability of WV- 49090. In some embodiments, endpoints are or comprise incidence of treatment emergent adverse events (TEAEs), related TEAE, severe TEAE, serious TEAE, changes in safety assessment parameters (e.g., physical exam, vital signs, clinical laboratory results, electrocardiograms (ECGs) [including any changes to QTcF]), and / or tolerability based on incidence of discontinuation due to TEAEs. In some embodiments, an objective is or comprises evaluation of pharmacokinetics (PK) of WV-49090 after a single dose in healthy participants and / or PK of WV-49090 after multiple doses in healthy participants. In some embodiments, endpoints are or comprise PK parameters of WV-49090 in plasma, including AUCinf, AUC0-24h, AUC0-48h, AUClast, Cmax, tmax, etc., and / or PK parameters of WV-49090 in plasma following first and last doses, including AUCtau, AUC0-24h, AUC0-48h, AUClast, Cmax, tmax, etc. In some embodiments, an objective is or comprises evaluation of urine excretion of WV-49090. In some embodiments, endpoints are or comprise amount excreted (Ae), Ae%, cumulative Ae% (cum Ae%) for WV-49090, and / or potential metabolites in urine.

[0234] Period 1 evaluates single ascending doses of WV-49090 in up to five cohorts of up to 8 healthy participants each (3:1 active : placebo). An additional cohort (Cohort 6) may be included to evaluate concentration-QTc. Participants may be on-study for up to 12 weeks. A sentinel strategy is employed for the first 2 participants (1 active:1 placebo) of every new dose level during the SAD portion (Period 1) and in the multiple dose portion (Period 2) of the study, with a 48-hour observation period to assess for acute safety events. The Dose Escalation Committee (DEC) and the DMC review available data through Day 8 that include key PK parameters and safety for each dose cohort, as well as previously accumulated safety data and available PK data, to recommend subsequent dose escalation. Various doses including those for dose escalation are chosen in view of factors described herein including recommendations by DEC and / or DMC.

[0235] Dose Escalation Stopping Criteria (Period 1)

[0236] Dose escalation is paused until further evaluation by the DMC if any of the following criteria are met. If it is confirmed that a stopping criterion was met, no further dosing takes place until after submission and approval of a substantial amendment if the DMC recommends the trial can continue. · One or more at least possibly related Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 TEAE or CTCAE grade 3 laboratory abnormality in a single cohort. o All grade 3 toxicities for vital signs must be confirmed with a repeat measurement obtained within 1 hour. o All grade 3 toxicities for laboratory parameters must be confirmed with a repeat measurement obtained within 24 hours. · Two or more at least possibly related CTCAE gradeEAEs or CTCAE Grade 2 laboratory abnormalities in a single cohort. o All grade 2 toxicities for vital signs must be confirmed with a repeat measurement obtained within 1 hour. o All grade 2 toxicities for laboratory parameters must be confirmed with a repeat measurement obtained within 24 hours. · Any at least possibly related SAE in a single cohort.

[0237] In Period 2, a single cohort of up to 8 healthy participants including up to 6 WV-49090 and 2 placebo treated participants (3:1 active : placebo) receives multiple doses of WV-49090. Participants may be on-study for up to 16 weeks. The DEC and DMC review available safety and PK data from Period 1 to select the dose to be explored in Period 2 for multiple dosing within the dose range evaluated in Period 1 (provided that safety and PK data are supportive) at which no stopping criteria were met and at which the safety profile is considered to be acceptable.

[0238] Per an investigator’s judgement, dosing is discontinued for an individual participant at any time in the study is: · Participant experiences any severe event or SAE (including clinically significant hypersensitivity) considered at least possibly related to study drug. · Participant has any medical condition that is judged by an investigator to jeopardize the participant’s safety if he or she continues to receive the study drug.

[0239] Screening

[0240] Screening determines participant eligibility for the study. Screening can be initiated up to 4 weeks prior to dosing.

[0241] Screening assessments can occur on multiple days, provided they are within the Screening period (Day -28 up to Day -2).

[0242] Genetic Evaluation: Where the selected testing method permits, genetic testing confirming PI*MM. Some genetic testing cannot distinguish between PI*MM and PI*M / Null. If such tests are employed,AAT testing is required to confirm normal AAT levels >1.0 g / L.

[0243] Re-Screening: Genetic samples collected as part of an approved testing during screening for this study can be used to confirm eligibility should they be re-screened (e.g., for a later study cohort).

[0244] Treatment

[0245] Period 1 (Single Ascending Dose).

[0246] Period 1 evaluates single ascending doses of WV-49090 in up to five cohorts of up to 8 healthy participants each. Each cohort include up to 6 WV-49090 treated and 2 placebo treated participants (3:1 active : placebo). Participants receive a single SC dose of WV-49090 or placebo on Day 1.

[0247] Starting dose and dose escalation are designed based on the following considerations: · The initial dose level is 30 mg. · Subsequent doses are increased by 3.3-fold of the prior dose, and later cohorts have equal or lesser fold increases as compared to earlier cohorts. · The upper bound of the 90% prediction interval of the subsequent dose should not exceed AUC0-24h (132 hr*µg / mL) and Cmax (20.8 µg / mL). · The highest dose does not exceed 600 mg.

[0248] In some embodiments, a dose is about 100 mg. In some embodiments, a dose is about 150 mg. In some embodiments, a dose is about 200 mg. In some embodiments, a dose is about 250 mg. In some embodiments, a dose is about 300 mg. In some embodiments, a dose is about 350 mg. In some embodiments, a dose is about 400 mg. In some embodiments, a dose is about 450 mg. In some embodiments, a dose is about 500 mg. In some embodiments, a dose is about 550 mg. In some embodiments, a dose is about 600 mg.

[0249] The Dose Escalation Committee (DEC) and the Data Monitoring Committee (DMC) review available safety and PK data for each dose cohort in combination with all available, previously accumulated safety data, as well as available PK data from participants enrolled in the study to date, to recommend subsequent dose escalation. Various doses including those for dose escalation are chosen in view of factors described herein including recommendations by DEC and / or DMC. The minimum safety data to be reviewed in any cohort are safety data in at least 6 participants in the given cohort in which 8 participants are dosed in a 3:1 ratio (study drug : placebo). The minimum plasma PK data to be reviewed in any cohort are data in at least 4 (active) participants in the given cohort (i.e., 4 participants that received WV-49090, not placebo). In some embodiments, safety information is available from a minimum of Day 8 while PK data is available through Day 3 (48 hours post dose) for any cohort and cumulative data from previous cohorts.

[0250] A sentinel strategy is employed for the first 2 participants (1 active, 1 placebo) of every new dose level during the SAD portion of the study. The sentinel participants are dosed and monitored in the clinic for 48 hours to identify any potential acute safety events. If neither of these sentinel participants experiences stopping criteria and if there are no other safety concerns during this 48-hour period, the remaining 6 participants are randomized in a blinded fashion to active study drug (n=5) or placebo (n=1) and may be dosed on the same day. These participants are observed in clinic for 48 hours after administration of study drug.Participants attend weekly clinic visits on Weeks 0 through 12 to be followed for safety, tolerability, and PK assessments through Day 85 per the schedule of assessments (SoA).

[0251] If Period 1 Dose Escalation Stopping Criteria are met at any point, dosing is paused until further review and confirmation by the DMC. No further dosing takes place until after submission and approval of a substantial amendment if the DMC recommends the trial can continue.

[0252] Period 2: Multiple Doses

[0253] In Period 2, a single cohort of up to 8 healthy participants, including up to 6 WV-49090 and up to 2 placebo treated participants (3:1 active : placebo), participate in a multidose assessment of WV-49090. A sentinel strategy is employed for the first 2 participants (1 active:1 placebo), with a 48-hour observation period to assess for acute safety events. The DEC and DMC review available safety and PK data from Period 1 to select the most appropriate dose for evaluation in Period 2 based upon an acceptable PK profile and safety profile. The dose selected for evaluation in Period 2 is within the dose range evaluated in Period 1 (provided that safety and PK data are supportive) at which no stopping criteria were met and at which the safety profile is considered to be acceptable. At least 4 weeks of safety data for the proposed dose and all available data from the study must be available from Period 1 in order to inform the DEC and DMC Period 2 dose selection. WV- 49090 or placebo are administered every other week (Q2W) over 4 weeks (total of 3 doses; Weeks 0, 2, and 4). Following the first dose (Week 0) and last dose (Week 4), participants stay in the clinic for at least two nights for PK assessments. Following the second dose (Week 2) participants are observed for safety evaluation in the clinic for at least 4 hours post-study drug administration or per local SOP (whichever is longer). All participants attend weekly follow-up clinic visits for safety, tolerability, and PK assessments through Week 12 followed by visits every 4 weeks through week 16 or early termination visit.

[0254] In Period 2, dosing is paused or discontinued (per an investigator’s judgment) for an individual participant.

[0255] Follow-up

[0256] Following completion of study treatment, participants continue to have follow-up visits for up to 12 weeks. Safety assessments are completed and safety laboratory samples, and PK samples are drawn during these visits.

[0257] Early Termination

[0258] If a participant withdraws from the study early, the participant should complete an early termination (ET) visit.

[0259] Study Population

[0260] Participants must meet all inclusion criteria and none of the exclusion criteria during screening. For eligibility purposes, abnormal laboratory or vital signs or ECG results may be repeated once during the Screening period or Day -1 (as applicable) for confirmation if an abnormal result is observed at the initial assessment.

[0261] Participants who do not meet all inclusion / exclusion criteria are considered screen failures.Participants who fail screening may be rescreened.

[0262] Deviations to recruitment and enrollment criteria, also known as eligibility waivers or exemptions, are not permitted.

[0263] Inclusion Criteria

[0264] Participants are eligible to be included in the study only if all of the following criteria apply: 1. Participant is capable of understanding and is willing to provide written informed consent prior to any study-related procedures. 2. Participant is capable of understanding and adhering to all the requirements, procedures, instructions, and restrictions required by the protocol including scheduled visits, drug administration plan, laboratory tests, and likely to complete the study as planned. 3. Healthy. As determined by an investigator, based on a medical evaluation, including medical history, concomitant medications, full physical examination, vital signs, laboratory tests, and ECGs at Screening and Day -1. Per an investigator’s judgement, there should be no evidence of cardiovascular, pulmonary, endocrine, hepatic, biliary, gastrointestinal, neurological, hematological, immunological, metabolic, skeletal, renal, psychiatric disorders, or cancer within the past 5 years prior to screening visit (except localized or in situ cancer of the skin). Clinical abnormality or laboratory parameter(s) outside normal range must not be clinically significant or unlikely to introduce additional risk to the participant nor interfere with the study procedures nor the interpretation of any of the study assessments. 4. Male or female healthy participants 18-65 years of age at screening visit. 5. Participant has a body mass index (BMI) between 18 to 32 kg / m2inclusive at Screening and Day -1 Visits. 6. Genetic testing confirming PI*MM. 7. Participant has been a non-smoker for at least 1 year prior to screening and agrees to abstain from tobacco and nicotine containing products for the duration of the study. 8. Women of childbearing potential (WOCBP) must be: a. Non-pregnant as determined by a negative serum pregnancy test at Screening and negative highly sensitive urine pregnancy test on Day -1; b. Non lactating; c. Agree to use a highly-effective method of contraception from 28 days prior to Day 1 and for at least 16 weeks following last study drug administration. Exception: Women exclusively engaging in same-sex sexual activities are not required to meet this criterion; and d. Must be willing to forgo ova (egg) donation for at least 16 weeks following the last study drug administration. 9. Women of non-childbearing potential are defined as meeting at least 1 of the following criteria: a. At least 12 months post-menopausal and has an FSH >40 mIU / mL. b. Surgically sterile, defined as having a documented bilateral oophorectomy, or hysterectomy.10. Male participants must be willing to follow contraceptive requirements and should not impregnate anyone while they are in the study and for at least 24 weeks following the last dose of study drug. In addition, participant must be willing to forgo sperm donation for at least 24 weeks following the last dose of study drug. Men exclusively engaging in same-sex sexual activities are not required to meet this criterion.

[0265] Exclusion Criteria

[0266] Participants are excluded from the study if any of the following criteria apply: 1. Participant has a history of multiple drug allergies or of allergic reaction to an oligonucleotide or to N- acetylgalactosamine (GalNAc). 2. Participant has a history of intolerance or any medical condition that might interfere with SC injection(s). 3. History or signs or symptoms of severe (bacterial, viral, parasitic, or fungal) infection within 4 weeks prior to Screening or Day 1 Visits. 4. History or signs or symptoms of an acute illness (including COVID-19) within 10 days prior to dosing on Day 1 Visit. Exception: mild seasonal allergies. 5. Positive COVID-19 test at time of Screening (if required per site SOP) and at Day -1 Visit. 6. Participant received a COVID-19 or any other vaccine within 14 days before dosing on Day 1 Visit or is scheduled for vaccination anytime during the study. 7. Participant has total bilirubin > upper limit of normal (ULN) though participants with documented Gilbert’s syndrome with normal conjugated bilirubin are eligible; aspartate transaminase (AST) and / or alanine transaminase (ALT) >ULN at Screening and Day -1. 8. Participant has estimated glomerular filtration rate (eGFR) 60 ml / min / 1.73mm2(calculated by the Cockcroft-Gault formula) at Screening and Day -1. 9. Participant has a positive serology for hepatitis B or hepatitis C at Screening; participants with positive hepatitis B serology may be enrolled if there is evidence the participant received HBV immunization. 10. Participant is known to be positive for human immunodeficiency virus (HIV) and / or positive serology for HIV 1 / 2 where testing is permitted per local regulations. 11. Participant has a history of regular alcohol consumption exceeding 14 standard drinks / week.1 standard drink is equivalent to 14g ethanol or 5 US fluid ounces (fl oz) (150 mL) of wine (approximately 12% alcohol by volume), 12 fl oz (360 mL) of beer (approximately 5% alcohol by volume), or 1.5 fl oz (45mL) of hard liquor (approximately 40% alcohol by volume), within 1 year prior to the screening visit. 12. Participant has a history of caffeine consumption exceeding 8 cups of coffee / day (1 cup = 8 fl oz [240mL]) within 14 days prior to first study dose, or consumption of any caffeine or chocolate containing products for 3 days prior to clinical research unit (CRU) admission. Caffeine-containing food and / or beverages (e.g., tea, cola) should be considered equivalent to coffee.13. Unwilling to abstain from alcohol for 48 hours prior to dosing at each of the dosing visits. 14. Participant has a positive alcohol test at Screening and / or Day -1 Visits. 15. Any prescribed or recreational substance use (irrespective of legality) within 6 months prior to screening or unwilling to refrain from such use for the duration of the study. 16. Positive drug screen at Screening and / or Day -1 Visits. 17. Positive cotinine test at Screening and / or Day -1 Visits. 18. Use of prescription or non-prescription medications, including vitamin, dietary, and herbal supplements (including St John’s Wort) within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study treatment unless, e.g., in the opinion of an investigator and sponsor, the medication does not interfere with interpretation of study assessments. Contraception and hormone replacement therapy (HRT) are permitted. If needed, over-the-counter (OTC) medications such as paracetamol / acetaminophen may be used acutely. 19. History of major surgery in the 3 months prior to screening visit and / or planned surgery for the duration of the study. 20. Sustained hypertension defined as at least 2 repeated measurements at least 15 minutes apart of systolic pressure exceeding 130 mm Hg and / or diastolic pressure exceeding 80 mm Hg at Screening and / or Day -1 Visits. 21. Supine pulse rate <45 beats per minute (bpm) or >100 bpm at Screening and / or Day 1 Visits. 22. One or more of the following abnormal ECG findings at Screening and / or Day -1 Visits: a. Second- or third-degree atrioventricular block b. QRS >120 msec c. QTcF >450 msec for males or >470 msec for females d. PR interval >200 msec e. Any rhythm other than sinus rhythm that is considered clinically significant by an investigator. 23. History of risk factors for Torsade de Pointes including unexplained syncope, known long QT syndrome, heart failure, myocardial infarction, angina, or clinically significant abnormal laboratory assessments including hypokalemia, hypercalcemia, or hypomagnesemia. 24. Family history of long QT syndrome or Brugada syndrome. 25. Donation of blood or blood products in excess of 500 mL within 12 weeks prior to screening visit and / or unwilling to refrain from blood donation for the duration of the study. 26. Participant has any medical or social condition which in the opinion of an investigator, would make the participant unsuitable for participation in the study, for study treatment, or could interfere with the assessments of safety or PK, or completion of the study. 27. Participant has received an investigational agent within 3 months or 5 half-lives (if known), or twice the duration of biological effect (if known), whichever is longer, before Screening, or who is in follow- up of another clinical study of an investigational agent at the time of the screening visit.28. Exposure to more than 4 new chemical entities within 12 months prior to the Day 1 Visit. 29. Prior treatment with any oligonucleotide or small interfering RNA within 12 months prior to the Day 1 Visit. 30. Participant is directly or indirectly involved in the conduct and administration of this trial as an investigator, sub-investigator, trial coordinator, or other trial staff member, or the participant is a first- degree family member, significant other, or relative residing with one of the above persons involved directly or indirectly in the trial.

[0267] Study Drugs Administered

[0268] Study drugs include WV-49090 and placebo. Details on study drugs are provided below:Abbreviations: SC = subcutaneous; Q2W = every other week Study Periods

[0269] Anatomical SC injection sites can be determined by an investigator for each participant. If theabdomen is selected as an injection site, it is recommended that the participant be supine when the injection is administered. Rotation of injection sites for multiple dose period is allowed.

[0270] Safety Assessments

[0271] The safety assessments are or comprise the following: · AEs · Concomitant medications · Full and symptom-directed physical examinations · Vital signs · Weight / BMI · Digital continuous and triplicate 12-lead ECGs · Clinical laboratory evaluations · Pregnancy testing (if applicable)

[0272] In a study, AE is can be defined as any untoward medical occurrence in a participant enrolled into this study regardless of its causal relationship to study treatment, and a TEAE as any new AE that begins following study WV-49090 administration that was not present before exposure to study drug treatment or any condition already present that worsens in either intensity or frequency after exposure to WV-49090 administration.

[0273] AE severity (except for injection site reactions) is evaluated using the criteria outlined in National Cancer Institute (NCI)-CTCAE Version 5.0. In a study, an SAE is defined as any event that results in: · Death · Is immediately life-threatening. A life-threatening event does not include an AE that if it had occurred in a more severe form, might have caused death · Requires inpatient hospitalization or prolongation of existing hospitalization · Results in persistent or significant disability / incapacity · Is a congenital anomaly · Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered SAEs when they, based upon appropriate medical judgment, may jeopardize the participant or may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.

[0274] Individual signs or symptoms (e.g., erythema, swelling, etc.) at the injection site reported by a participant following study drug administration are recorded as an injection site reaction and as an AE if grade 1 or more: Grading of Injection Site Reactions (FDA, 2007)

[0275] In some embodiments, for an event with multiple occurrences during a study, the event is only counted once in occurrence summary, the maximum severity is used when reporting the severity, the highest level of association is used to characterize relatedness to study drug in reporting.

[0276] In some embodiments, the number and percentage of participants who have at least a TEAE, a grade 3 or 4 TEAE, a study drug-related TEAE as judged by an investigator are summarized by dose group; in addition, the number and percentage of participants who have a TEAE that leads to study drug discontinuation or who died due to occurrence of a TEAE are also summarized by dose group. The percentage for the aforementioned summaries can be calculated based on the number of participants in each dose group.

[0277] Pharmacokinetic Assessments

[0278] Blood samples are collected for measurement of plasma concentrations of WV-49090 and for potential analysis of metabolites.

[0279] Plasma and urine samples for analysis of exposure to WV-49090 are collected at various time points. Samples can be collected, e.g., at the following time points: · Period 1 Plasma PK: Samples are collected predose within 30 min prior to dose, and postdose at 30 min (±5 min), 1 hr (±5 min), 2 hr (±5 min), 4 hr (±10 min), 6 hr (±10 min), 8 hr (±10 min), 12 hr (±10 min), 24 hr (±30 min), 36 hr (±4 hr), and 48 hr (±4 hr). A sample is collected at each of the following visits: Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78 (±3 days), and Day 85 (±5 days) / ET. · Period 1 Urine PK: Samples are collected over 0-4 hr, 4-8 hr, 8-12 hr, 1218 hr, 18-24 hr, 24-36 hr, and 36-48 hr. · Period 2 Plasma PK: Day 1 and Day 29 samples are collected predose within 30 min prior to dose, and postdose at 30 min (±5 min), 1 hr (±5 min), 2 hr (±5 min), 4 hr (±10 min), 6 hr (±10 min), 8 hr (±10 min), 12 hr (±10 min), 24 hr (±30 min), 36 hr (±4 hr), and 48 hr (±4 hr). A Day 15 predosesample is collected at 30 min prior to dose. A sample is collected at each of the following visits: Days 8, 21, 36, 43, 50, 57, 64, 71, 78, 85 (±3 days) and Day 113 (±5 days) / ET.

[0280] Urine samples are collected for measurement of concentration of WV-49090 and potential metabolites. The following parameters are assessed for WV-49090: · Ae: amount excreted in urine · Ae%: the percentage of the administered dose that is excreted in urine · Cum Ae%: cumulative Ae%

[0281] The timing of sampling may be altered, and PK samples may be obtained at additional time points during the course of a study based on newly available data (e.g., to obtain data nearer the time of peak plasma concentration) to ensure appropriate monitoring of the PK profile.

[0282] Blood samples can be used to evaluate PK profile of WV-49090 including assessed by the following PK parameters, if applicable: · AUCinf: area under the curve from time 0 to infinity · AUC0-24h: area under the curve from time 0 to 24 hours · AUC0-48h: area under the curve from time 0 to 48 hours · AUClast: area under the curve from time 0 to the last measurable concentration · AUCext: area under the curve extrapolated to infinity · AUCtau: area under the curve over a dosing interval · Cmax: maximum observed concentration · tmax: time to occurrence of Cmax· t½: terminal half-life · Vd: volume of distribution · CL: clearance

[0283] Samples collected for analyses of WV-49090 plasma concentration may also be used to evaluate safety aspects arising during or after the study.

[0284] In some embodiments, samples for antibodies to WV-49090 are collected.

[0285] Various technologies can be utilized to assess collected data. In some embodiments, baseline for a SAD participant is defined as the last non-missing measurement collected prior to the administration of the single dose. In some embodiments, baseline for a multiple-dose participant is defined as the last non-missing measurement collected prior to the administration of study drug at Week 0 of multiple-dose period. In some embodiments, descriptive statistics (n, mean, standard deviation [SD], median, minimum and maximum values for continuous variables, and number and percentage of participants in each category for categorical variables) is used for data summary by treatment group for each cohort.

[0286] In some embodiments, PK parameters for WV-49090 and potential metabolites are calculated using non-compartmental methods. In some embodiments, PK parameters are summarized for each WV-49090 dosegroup on the PK population using descriptive statistics: n, arithmetic mean, median, SD, minimum, maximum, and percent coefficient of variation (CV%). In some embodiments, geometric mean and geometric CV% are calculated for Cmaxand AUCs.

[0287] A useful protocol schema is provided in Figure 2 as an example.

[0288] Among other things, the present disclosure provides PK data through 48 hours and safety data through day 8 for 30 mg WV-49090 cohort. The safety data reviewed included: AEs, vital signs, repeat 12- lead ECGs, safety laboratory (including hematology and chemistry panels) collected over the 8 days. Sentinel participants were dosed (WV-49090 and placebo) prior to the inclusion of the remaining participants for a total of 8 participants (6-WV-49090 and 2-placebo) all conducted in a blinded fashion. The participants included 6 females and 2 males. The mean age was 36.8 years old (SD 10.70) all were of the white race. No discontinued participant. There were 3 Treatment Emergent Adverse Effects (TEAEs) reported. All of the TEAEs were assessed as mild to moderate in intensity and not casually related to study drug. Review of laboratory parameters, vitals and ECG did not identify any safety issue. Only WV-49090 treated participants were analyzed for WV-49090 concentration. After administering a single dose of 30 mg subcutaneously, the peak concentration was achieved with a median time of 8 hours. The AUC0-24h and the Cmax (mean ± SD) were 519 ± 90.7 hr*ng / mL and 40.4 ± 11.6 ng / mL, respectively. In some embodiments, a cohort receives a dose of 100 mg. In some embodiments, a cohort receives a dose of 200 mg. In some embodiments, a cohort receives a dose of 400 mg. In some embodiments, a cohort receives a dose of 600 mg. In some embodiments, a cohort receives a total of three doses of 600 mg every two weeks.

[0289] Certain exemplary results from a clinical study of WV-49090 in healthy volunteers are shown in the tables below. Among other things, such results confirm that WV-49090 was safe and well-tolerated in the study.EXAMPLE 3. Clinical Studies of WV-49090 in AATD Human Subjects

[0290] Safety and efficacy of WV-49090 are also assessed in clinical trials in AATD patients. A useful clinical study protocol is presented below as an example. In some embodiments, a clinical trial is or comprises one or more conditions, protocols, methods, criteria, out measures, designs, objectives, endpoints, etc. of the study described below. In some embodiments, a clinical trial is conducted according to a study described below. Those skilled in the art appreciate that a study may be adjusted. An Open-label Phase 1b / 2a Study of WV-49090 in Participants with AATD Pi*ZZ

[0291] In some embodiments, a clinical study with WV-49090 is a Phase 1b / 2a open-label study to evaluate the safety, tolerability, PK, PD, clinical effects, etc. of subcutaneous (SC) WV-49090 in patients with AATD Pi*ZZ genotype. In some embodiments, a study assesses safety and tolerability of WV-49090. In some embodiments, a study assesses safety, tolerability, PD, and PK of single ascending doses and multiple ascending doses of WV-49090 in participants with Pi*ZZ AATD. In some embodiments, a study assesses the safety and tolerability of WV-49090 in participants with Pi*ZZ AATD. In some embodiments, a study assesses PK of WV-49090 (e.g., plasma PK). In some embodiments, a study assesses PD of WV-49090, e.g., based on Z- AAT, M-AAT, and total AAT levels in serum. In some embodiments, an objective is or comprises evaluation of the safety and tolerability of WV-49090 in participants with Pi*ZZ AATD. In some embodiments, endpoints are or comprise incidence of treatment-emergent adverse events (TEAEs), related TEAEs, severe TEAEs, serious TEAEs; changes in safety assessment parameters (i.e., physical examination, vital signs, clinical laboratory results, and electrocardiograms [ECGs]); and / or tolerability based on incidence of discontinuation or withdrawal due to TEAEs. In some embodiments, an objective is or comprises of evaluation of pharmacodynamics (PD) effect of WV-49090, e.g., as measured by Z-AAT and M-AAT levels in serum, and / or total AAT (Z and M) serum levels. In some embodiments, endpoints are or comprises change over time from baseline in levels of serum Z AAT, M-AAT, and / or total AAT (Z and M). In some embodiments, an objectiveis or comprises evaluation of pharmacokinetics (PK) of WV-49090 after a single dose and following repeat doses in AATD participants. In some embodiments, endpoints are or comprises PK parameters of WV-49090 in plasma, e.g., area under the curve from time 0 to last measurable concentration (AUClast), maximum concentration of drug (Cmax), time to Cmax(Tmax), etc. In some embodiments, an objective is or comprises evaluation of PD effect of WV-49090 on serum AAT neutrophil elastase inhibition activity, and / or serum biomarkers, and / or PD and concentration of WV-49090 in liver. In some embodiments, endpoints are or comprise change from baseline in levels of serum AAT neutrophil elastase inhibition activity, change from baseline in the levels of biomarkers of AAT activity, in liver biopsies of a subset of participants assessment of edited WT SERPINA1 mRNA transcript, WV-49090 concentrations, etc., changes in pulmonary function tests (PFT), and / or changes in liver elastography (e.g. FibroScan®). [0...

Claims

CLAIMS 1. A method for treating alpha-1 antitrypsin deficiency (AATD), comprising administering or delivering to a subject suffering therefrom WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein the subject has a G to A mutation in a Serpin Family A Member 1 (SERPINA1) gene that encodes a Glu342Lys mutation in an alpha-1 antitrypsin (AAT) polypeptide, and wherein WV-49090 may be described as: (1): 5’-mC[n001R]mC[Ssp]mC[Ssp][fl2r]A[Ssp][fl2r]G[Ssp][moe][m5C]p[moe]Ap[fl2r]G[Ssp][fl2r] C[Ssp]mUpmU[n001R]mCp[fl2r]A[Ssp][fl2r]G[n001R][fl2r]Up[moe][m5C][Ssp][fl2r]C[Ssp]mCpmU[n001 R]mUp[moe]Tp[fl2r]C[Ssp]dT[Ssp]d[3nU][Ssp]d[Hyp][n001S]mUp[fl2r]C[Ssp]mG[Ssp]mA[n001R]mU-3’: m: 2’-O-methyl modified nucleoside; [fl2r]: 2’-fluoro-2’-deoxy modified nucleoside; [moe]: 2’-O-(2-methoxyethyl) modified nucleoside; d: 2’-deoxy nucleoside; [m5C]: 5-methylcytidine; d[3nU]: 2’-deoxyisouridine (nucleobase isd[Hyp]: 2’-deoxyinosine; [Ssp]: Sp phosphorothioate linkage; p: phosphodiester linkage; [n001S]: Sp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate linkage (wherein the linkage phosphorus is in Sp configuration); [n001R]: Rp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate linkage (wherein the linkage phosphorus is in Rp configuration); and wherein the 5’-carbon of the 5’-end mC is linked to the structure below via a phosphodiester group:RNA1{p.m(C)[n001R].m(C)[Ssp].m(C)[Ssp].[fl2r](A)[Ssp].[fl2r](G)[Ssp].[moe]([m5C])p.[moe](A)p.[fl2r]( G)[Ssp].[fl2r](C)[Ssp].m(U)p.m(U)[n001R].m(C)p.[fl2r](A)[Ssp].[fl2r](G)[n001R].[fl2r](U)p.[moe]([m5C])[ Ssp].[fl2r](C)[Ssp].m(C)p.m(U)[n001R].m(U)p.[moe](T)p.[fl2r](C)[Ssp].d(T)[Ssp].d([3nU])[Ssp].d([Hyp])[n 001S].m(U)p.[fl2r](C)[Ssp].m(G)[Ssp].m(A)[n001R].m(U)}|CHEM1{[GalNAc3C12oyl]}|CHEM2{[nC6o]}$ CHEM2,RNA1,1:R1-1:R1|CHEM2,CHEM1,1:R2-1:R1$$$V2.0; m: 2’-OMe modified nucleoside; [fl2r]: 2’-F modified nucleoside; [moe]: 2’-O-(2-methoxyethyl) modified nucleoside; d: 2’-deoxy nucleoside; [m5C]: 5-methylcytidine; [3nU]: N-3-uridine; d[Hyp]: 2’-deoxyinosine; [Ssp]: Sp phosphorothioate linkage; p: phosphodiester linkage;[n001S]: Sp N-(1,3-dimethylimidazolidin-2-ylidenyl) phosphoramidate linkage (erein thelinkage phosphorus is in Sp configuration);[n001R]: Rp N-(1,3-dimethylimidazolidin-2-ylidenyl) phosphoramidate linkage (herein thelinkage phosphorus is in Rp configuration); [GalNAc3C12oyl]:[nC6o]: −NH−(CH2)6−, connected to [GalNAc3C12oyl] through −NH− and a phosphodiester linkage through −CH2−; (3):5′-O-(6-(12-(tris(((3-((3-((5-((2-(acetylamino)-2-deoxy-b-D-galactopyranosyl)oxy)-1- oxopentyl)amino)propyl)amino)-3-oxopropoxy)methyl))methyl)amino-12-oxododecanamido)hexyl phospho)- [P(R)]-2′-O-methyl-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]cytidylyl-(3′→5′)-[P(S)]-2′-O- methyl-P-thiocytidyl-(3′→5′)-[P(S)]-2′-O-methyl-P-thiocytidyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P- thioadenylyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thioguanylyl-(3′→5′)-2′-O-(2-methoxyethyl)-5- methylcytidylyl-(3′→5′)-2′-O-(2-methoxyethyl)adenylyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thioguanylyl- (3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thiocytidyl-(3′→5′)-2′-O-methyluridylyl-(3′→5′)-[P(R)]-2′-O-methyl-P- deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]uridylyl-(3′→5′)-2′-O-methylcytidylyl-(3′→5′)-[P(S)]- 2′-fluoro-2′-deoxy-P-thioadenylyl-(3′→5′)-[P(R)]-2′-fluoro-2′-deoxy-P-deoxy-P-[(1,3-dimethylimidazolidin- 2-ylidene)amino]guanylyl-(3′→5′)-2′-fluoro-2′-deoxyuridylyl-(3′→5′)-[P(S)]-2′-O-(2-methoxyethyl)-P-thio- 5-methylcytidylyl-(3′→5′)-[P(S)]- 2′-fluoro-2′-deoxy-P-thiocytidyl-(3′→5′)-2′-O-methylcytidyl-(3′→5′)- [P(R)]-2′-O-methyl-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]uridylyl-(3′→5′)-2′-O- methyluridylyl-(3′→5′)-2′-O-(2-methoxyethyl)-5-methyluridylyl-(3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P- thiocytidyl-(3′→5′)-[P(S)]-P-thiothymidylyl-(3′→5′)-[P(S)]-2′-deoxy-P-thioisouridylyl-(3′→5′)-[P(S)]-2′- deoxy-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]inosinylyl-(3′→5′)-2′-O-methyluridylyl- (3′→5′)-[P(S)]-2′-fluoro-2′-deoxy-P-thiocytidyl-(3′→5′)-[P(S)]-2′-O-methyl-P-thioguanylyl-(3′→5′)-[P(R)]- 2′-O-methyl-P-deoxy-P-[(1,3-dimethylimidazolidin-2-ylidene)amino]adenylyl-(3′→5′)-2′-O-methyluridine; or(free acid form).

2. A method for treating alpha-1 antitrypsin deficiency (AATD), comprising administering or delivering to a subject suffering therefrom WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein the subject expresses a Glu342Lys mutant AAT polypeptide, or a mutant SERPINA1 mRNA comprising 1024 G>A, and wherein WV- 49090 is as described in claim 1.

3. A method, comprising administering or delivering to a subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1.

4. A method for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 mRNA in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1.

5. A method for producing of a SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342 AAT polypeptide, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1.

6. A method for reducing level of a 1024 G>A mutant SERPINA1 mRNA in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1.

7. A method for increasing level of a SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342 AAT polypeptide, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, and wherein WV-49090 is as described in claim 1.

8. The method of claim 6 or 7, wherein the level is or comprises a relative amount to a reference mRNA and / or wherein the level is or comprises percentage of total SERPINA1 mRNA.

9. A method for producing a Glu342 AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1.

10. A method for producing M-AAT in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1.

11. A method for reducing level of a Glu342Lys mutant AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1.

12. A method for reducing level of Z-AAT in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1.

13. A method for increasing level of a Glu342 AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1.

14. A method for increasing level of M-AAT in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1.

15. The method of any one of claims 11-14, wherein the level is or comprises a relative amount to a reference polypeptide and / or wherein the level is or comprises percentage of total AAT polypeptide.

16. A method for providing increased level of a wild-type AAT function in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1.

17. The method of any one of claims 6-8 and 11-16, wherein the change is relative to baseline.

18. A method for providing acute phase response production of AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1, optionally wherein providing acute phase response production of AAT polypeptide in a subject comprises restoring acute phase response production of AAT polypeptide in the subject; or a method for providing an increased acute phase response AAT polypeptide level in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV- 49090 is as described in claim 1, optionally wherein providing acute phase response production of AAT polypeptide in a subject comprises restoring acute phase response production of AAT polypeptide in the subject; or a method for providing an acute phase response AAT polypeptide level about 15, 16, 17, 18, 19, 20 uM or higher in serum in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV- 49090 free acid form, wherein WV-49090 is as described in claim 1, optionally wherein providing acute phase response production of AAT polypeptide in a subject comprises restoring acute phase response production of AAT polypeptide in the subject.

19. A method for providing increased production of AAT polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1, optionally wherein providing increased production of AAT polypeptide in response to an inflammatory event in the subject comprises restoring increased production of AAT polypeptide in response to an inflammatory event in the subject; or a method for providing an increased AAT polypeptide level in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1; or a method for providing an AAT polypeptide level about 15, 16, 17, 18, 19, 20 uM or higher in serum in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV- 49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1.

20. A method for providing acute phase response production of M-AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV- 49090 is as described in claim 1, optionally wherein providing acute phase response production of AAT polypeptide in a subject comprises restoring acute phase response production of AAT polypeptide in the subject; or a method for providing an increased acute phase response M-AAT polypeptide level in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV- 49090 is as described in claim 1; or a method for providing an acute phase response M-AAT polypeptide level about 8, 9, or 10 uM or higher in serum in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV- 49090 free acid form, wherein WV-49090 is as described in claim 1; or a method for providing acute phase response production of Z-AAT polypeptide in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1; or a method for providing an increased acute phase response Z-AAT polypeptide level in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV- 49090 is as described in claim 1; ora method for providing acute phase response M-AAT polypeptide level about 8, 9, or 10 uM or higher in serum in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1; or a method for providing an acute phase response Z-AAT polypeptide level about 8, 9, or 10 uM or higher in serum in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1.

21. A method for providing increased production of M-AAT polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1, optionally wherein providing increased production of M- AAT polypeptide in response to an inflammatory event in the subject comprises restoring increased production of M-AAT polypeptide in response to an inflammatory event in the subject; or a method for providing increased M-AAT polypeptide level in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1; or a method for providing M-AAT polypeptide level about 8, 9, or 10 uM or higher in serum in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1; or a method for providing increased production of Z-AAT polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1; or a method for providing increased Z-AAT polypeptide level in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1; or a method for providing Z-AAT polypeptide level about 8, 9, or 10 uM or higher in serum in response to an inflammatory event in a subject, comprising administering or delivering to the subject WV-49090 at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form, wherein WV-49090 is as described in claim 1.

22. The method of claims 19 or 21, wherein an inflammatory event comprises or is a non-drug-related inflammatory event and / or wherein increased production comprises a higher level of production as comparedto a baseline, optionally wherein the baseline is a level of production prior to the inflammatory event.

23. The method of any one of claims 3-22, wherein the subject suffers from AATD.

24. The method of any one of claims 2-23, wherein the subject has a SERPINA1 Z-allele.

25. A method for treating alpha-1 antitrypsin deficiency (AATD) in a human subject expressing a Glu342Lys mutant AAT polypeptide, or a mutant SERPINA1 mRNA comprising 1024 G>A, comprising administering to the human subject WV-49090 at a dose equivalent to about 200 to about 600 mg WV-49090 free acid form at a dosing interval of about every 2 weeks, about every 4 weeks, about every 8 weeks, about every 12 weeks, about monthly, about every two months, about every three months, or about quarterly.

26. The method of claim 25, wherein WV-49090 is administered at a dose equivalent to about 200 mg to about 400 mg WV-49090 free acid form.

27. The method of any one of the preceding claims, wherein the subject is homozygous for a Glu342Lys mutation.

28. The method of any one of claims 1-27, wherein the subject suffers from an AATD-induced lung disease and / or wherein the subject suffers from an AATD-induced liver disease.

29. The method of any one of the preceding claims, wherein the subject has a Pi*ZZ genotype.

30. The method of any one of the preceding claims, wherein two or more doses of WV-49090 are administered or delivered, each of which is independently equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form.

31. The method of any one of the preceding claims, wherein WV-49090 is administered in multiple forms one of which is a salt form and / or wherein WV-49090 is administered in one or more pharmaceutically acceptable salt forms; optionally wherein one form is WV-49090 sodium salt.

32. The method of claim 31, wherein each dose of WV-49090 is independently administered in a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier.

33. A method for treating AATD, comprising administering to a subject suffering therefrom a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV- 49090 free acid form, wherein the subject has a G to A mutation in a Serpin Family A Member 1 (SERPINA1) gene that encodes a Glu342Lys mutant alpha-1 antitrypsin (AAT) polypeptide.

34. A method for treating AATD, comprising administering to a subject suffering therefrom a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV- 49090 free acid form, wherein the subject has a G to A mutation in a Serpin Family A Member 1 (SERPINA1) gene that encodes a Glu342Lys mutation in an alpha-1 antitrypsin (AAT) polypeptide.

35. A method, comprising administering to a subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250,300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form.

36. A method for editing a target adenosine from 1024 G>A mutation in a mutant SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342Lys mutant AAT polypeptide, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form.

37. A method for producing of a SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342 AAT polypeptide, comprising administering to the subject a pharmaceutical composition comprising WV- 49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form.

38. A method for reducing level of a 1024 G>A mutant SERPINA1 mRNA in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form.

39. A method for increasing level of a SERPINA1 mRNA in a subject, wherein the mRNA encodes a Glu342 AAT polypeptide, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form.

40. The method of any one of claims 38-39, wherein the level is or comprises a relative amount to a reference mRNA and / or wherein the level is or comprises percentage of total SERPINA1 mRNA.

41. A method for producing a Glu342 AAT polypeptide in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form.

42. A method for producing M-AAT in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form.

43. A method for reducing level of a Glu342Lys mutant AAT polypeptide in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form.

44. A method for reducing level of Z-AAT in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV- 49090 free acid form.

45. A method for increasing level of a Glu342 AAT polypeptide in a subject, comprising administering tothe subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form.

46. A method for increasing level of M-AAT in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV- 49090 free acid form.

47. The method of any one of claims 43-46, wherein the level is or comprises a relative amount to a reference polypeptide and / or wherein the level is or comprises percentage of total AAT polypeptide.

48. A method for providing increased level of a wild-type AAT function in a subject, comprising administering to the subject a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form.

49. The method of any one of claims 38-40 and 43-48, wherein the change is relative to baseline.

50. The method of any one of claims 35-49, wherein the subject suffers from AATD.

51. The method of any one of claims 34-50, wherein the subject has a SERPINA1 Z-allele.

52. The method of any one of claims 33-51, wherein the subject has a Pi*ZZ genotype.

53. The method of any one of claims 33-51, wherein the subject suffers from Pi*ZZ AATD.

54. The method of any one of claims 33-53, wherein two or more doses of pharmaceutical compositions are administered, each of which is independently a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier and each at a dose equivalent to about 200 to about 600 (e.g., about 200, 250, 300, 350, 400, 450, 500, 550, 600, etc.) mg WV-49090 free acid form.

55. The method of claim 54, wherein: (i) each pharmaceutical composition has the same types of components; (ii) the pharmaceutically acceptable carrier in each pharmaceutical composition is the same; and / or (iii) each pharmaceutical composition is the same.

56. The method of any one of the preceding claims, wherein two or more consecutive doses are administered about every two weeks, about every four weeks, about every eight weeks, about every twelve weeks, about monthly, about every two months, about every three months, or about quarterly or seven or more consecutive doses are administered about every two weeks.

57. The method of any one of the preceding claims, wherein two or more doses are administered, and each dose is equivalent to about the same amount of WV-49090 free acid form.

58. The method of any one of the preceding claims, wherein WV-49090 in a dose is equivalent to about 200, 250, 300, 350, 400, 450, 500, 550, or 600 mg WV-49090 free acid form.

59. The method of any one of the preceding claims, wherein WV-49090 in each dose is equivalent to about 200, 250, 300, 350, 400, 450, 500, 550, or 600 mg WV-49090 free acid form.

60. The method of claim 59, wherein: (i) two or more consecutive doses of WV-49090 are administered about every two weeks and WV- 49090 in each dose is equivalent to about 200 mg WV-49090 free acid form, optionally wherein WV-49090 is administered subcutaneously; or (ii) seven or more consecutive doses of WV-49090 are administered about every two weeks and WV- 49090 in each dose is equivalent to about 200 mg WV-49090 free acid form, optionally wherein WV-49090 is administered subcutaneously.

61. The method of claim 59, wherein: (i) two or more consecutive doses of WV-49090 are administered about every four weeks and WV- 49090 in each dose is equivalent to about 400 mg WV-49090 free acid form, optionally wherein WV-49090 is administered subcutaneously; or (ii) two or more consecutive doses of WV-49090 are administered about monthly and WV-49090 in each dose is equivalent to about 400 mg WV-49090 free acid form, optionally wherein WV-49090 is administered subcutaneously.

62. A method, comprising administering WV-49090 to a population of subjects, wherein: none of the subjects have a mutation in a Serpin Family A Member 1 (SERPINA1) gene that encodes a Glu342Lys mutant alpha-1 antitrypsin (AAT) polypeptide; and each subject is independently administered WV-49090 in a dose that is equivalent to about 30 mg WV- 49090 free acid form.

63. The method of claim 62, wherein: (i) no or no more than about 3 treatment emergent adverse effects were observed within about 8 days after WV-49090 administration; (ii) each observed treatment emergent adverse effect is assessed as mild to moderate in intensity; (iii) each observed treatment emergent adverse effect is not casually related to WV-49090; and / or (iv) no safety issue is identified from laboratory parameters, vitals and / or ECG.

64. The method of claim 62 or 63, wherein: (i) each subject is determined to be healthy; (ii) the population consists of 8 subjects; and / or (iii) the population consists of 8 healthy subjects.

65. The method of any one of claims 62-64, wherein: (i) plasma AUC0-24hobserved in the 48 hours after the administration is about 520 hr*ng / mL; and / or (ii) plasma Cmaxobserved in the 48 hours after the administration is about 40 ng / mL.

66. The method of any one of claims 62-65, wherein: (i) none of the subjects is administered a dose of WV-49090 prior to the administration of WV-49090 in a dose that is equivalent to about 30 mg WV-49090 free acid form; and / or(ii) none of the subjects is administered a dose of WV-49090 subsequent to the administration of WV-49090 in a dose that is equivalent to about 30 mg WV-49090 free acid form.

67. The method of any one of claims 62-66, wherein WV-49090 is administered in multiple forms one of which is a salt form and / or wherein WV-49090 is administered in one or more pharmaceutically acceptable salt forms; optionally wherein one form is WV-49090 sodium salt.

68. The method of any one of claims 62-67, wherein WV-49090 is administered in a pharmaceutical composition comprising WV-49090 and a pharmaceutically acceptable carrier.

69. The method of any one of claims 32-68, wherein: (i) the pharmaceutical composition comprises a salt form of WV-49090; (ii) the pharmaceutical composition comprises two or more forms of WV-49090; (iii) the pharmaceutical composition comprises two or more pharmaceutically acceptable salt forms of WV-49090, optionally wherein a pharmaceutically acceptable salt form is a sodium salt; and / or (iv) WV-49090 exists in the pharmaceutical composition as one or more pharmaceutically acceptable salt forms, optionally wherein a pharmaceutically acceptable salt form is a sodium salt.

70. The method of any one of the preceding claims, wherein about is ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9%, or ±10%.

71. The method of any one of the preceding claims, wherein: (i) a pharmaceutical composition is a liquid composition comprising dissolved WV-49090; (ii) a pharmaceutical composition has a pH of about 7, a pH of about 6-8, or a pH of about 6.7 ± 1.0; and / or (ii) a pharmaceutically acceptable carrier is or comprises a buffer and / or a phosphate buffered solution.

72. The method of any one of the preceding claims, wherein the composition has a WV-49090 purity of about 65%-85%, 65%-80%, or 65%-75% or more, optionally wherein the purity is measured by IP-RP-UPLC using area % at 260 nm or an IP-RP- UPLC method for purity as described herein, optionally wherein the purity is measured by an IP-RP-UPLC method comprising one or more parameters from Table 1.

73. The method of any one of the preceding claims, wherein stereochemical purity of WV-49090 is about 80% or 85% or more or about 80%-90% and / or wherein stereochemical purity is assessed by dimer modeling.

74. The method of any one of the preceding claims, wherein the amount of WV-49090 is measured by UV at 260 nm and 22.1 OD / mg.

75. The method of any one of the preceding claims, wherein stereochemical identity of WV-49090 is confirmed by IP-RP-UPLC, optionally an IP-RP-UPLC method for stereochemical identity as described herein.

76. The method of any one of the preceding claims, wherein a WV-49090 drug substance is manufactured, characterized, released, or stored by a process or one or more methods described herein; optionally wherein the WV-49090 drug substance is a sodium salt.

77. The method of any one of the preceding claims, wherein a WV-49090 drug product is manufactured, characterized, released, or stored by a process or one or more methods described herein.

78. The method of any one of the preceding claims, wherein a pharmaceutical composition is manufactured, characterized, released, and / or stored by a process or one or more methods described herein.

79. The method of any one of the preceding claims, wherein WV-49090 is administered subcutaneously.

80. The method of any one of the preceding claims, wherein a mutant SERPINA1 mRNA encoding Glu342Lys in AAT in the subject is edited, and the edited AAT mRNA encodes a Glu342Lys mutant AAT polypeptide; and / or wherein a mutant SERPINA1 mRNA encoding Glu342Lys in AAT in the subject is edited, and the edited AAT mRNA encodes a Glu342 AAT polypeptide.

81. The method of any one of the preceding claims, wherein a single dose equivalent to about 200 mg WV- 49090 free acid form is administered to a Pi*ZZ AATD subject and no WV-49090 is administered to the subject in the following about or at least about 8 weeks or in the following about or at least about 12 weeks.

82. The method of any one of the preceding claims, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, total AAT level of about 11 micromolar or more in plasma is observed, optionally about two weeks after administration, or wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, total AAT level of about 11.8 or 12.9 micromolar or more in plasma is observed; optionally wherein the baseline total AAT level is below a level of quantification.

83. The method of any one of the preceding claims, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD subjects, mean total AAT level of about 11 micromolar in plasma is observed, optionally about two weeks after administration, or wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD subjects, mean total AAT level of about 11.8 or 12.9 micromolar in plasma is observed; optionally wherein mean total AAT protein increases from below a level of quantification at baseline to about 10.8 micromolar about two weeks after administration.

84. The method of any one of the preceding claims, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient, M-AAT representing about or more than about 60% of total AAT in plasma is observed, optionally about two weeks after administration; and / or wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean M-AAT representing about or more than about 60% of total AAT in plasma is observed, optionally about two weeks after administration.

85. The method of any one of the preceding claims, wherein when a single subcutaneous dose equivalentto about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, M-AAT level of about 6.9 micromolar or more in plasma is observed, optionally about two weeks after administration, or wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, M-AAT level of about 4.0 or 4.8 micromolar or more in plasma is observed; and / or wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean M-AAT level of about 6.9 micromolar in plasma is observed, optionally about two weeks after administration, or wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean M-AAT level of about 4.0 or 4.8 micromolar in plasma is observed.

86. The method of any one of the preceding claims, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient, decrease of Z-AAT level of about or at least about 47.3% or 48.8% in plasma is observed; and / or wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean decrease of Z-AAT level of about or at least about 47.3% or 48.8% in plasma is observed.

87. The method of any one of the preceding claims, wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient, increase of total AAT from baseline is observed about two days after administration and / or about 8 weeks after administration and / or about 12 weeks after administration; and / or wherein when a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient, M-AAT is observed about two days after administration and / or about 8 weeks after administration and / or about 12 weeks after administration.

88. The method of any one of the preceding claims, wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to a Pi*ZZ AATD subject, total AAT level of about 11.9 micromolar or more in plasma is observed, optionally wherein the baseline total AAT level is below a level of quantification; and / or when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to Pi*ZZ AATD subjects, mean total AAT level of about 11.9 micromolar in plasma is observed, optionally wherein mean total AAT protein increases from below a level of quantification at baseline to about 11.9 micromolar.

89. The method of any one of the preceding claims, wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to a Pi*ZZ AATD patient, M-AAT representing about or more than about 64.4% of total AAT in plasma is observed; and / orwherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to Pi*ZZ AATD patients, mean M-AAT representing about or more than about 64.4% of total AAT in plasma is observed.

90. The method of any one of the preceding claims, wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to a Pi*ZZ AATD patient, M-AAT representing about or more than about 50% of total AAT in plasma is observed for at least about two months following last dose; and / or wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to Pi*ZZ AATD patients, mean M-AAT representing about or more than about 50% of total AAT in plasma is observed for at least about two months following last dose.

91. The method of any one of the preceding claims, wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to a Pi*ZZ AATD subject, M-AAT level of about 7.2 micromolar or more in plasma is observed; and / or wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to Pi*ZZ AATD patients, mean M-AAT level of about 7.2 micromolar in plasma is observed.

92. The method of any one of the preceding claims, wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to a Pi*ZZ AATD subject, decrease of Z-AAT level of about or at least about 60.3% in plasma is observed; and / or wherein when 7 subcutaneous doses equivalent to about 200 mg WV-49090 free acid form are administered about every two weeks to Pi*ZZ AATD patients, mean decrease of Z-AAT level of about or at least about 60.3% in plasma is observed.

93. The method of any one of the preceding claims, wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, total AAT level of about 12.8 micromolar or more in plasma is observed, optionally wherein the baseline total AAT level is below a level of quantification; and / or wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to Pi*ZZ AATD subjects, mean total AAT level of about 12.8 micromolar in plasma is observed, optionally wherein mean total AAT protein increases from below a level of quantification at baseline to about 12.8 micromolar.

94. The method of any one of the preceding claims, wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient, M-AAT representing about or more than about 47.2% of total AAT in plasma is observed; and / or wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean M-AAT representing about or more than about 47.2% of total AAT in plasma is observed.

95. The method of any one of the preceding claims, wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, M-AAT level of about 5.3 micromolar or more in plasma is observed; and / or wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean M-AAT level of about 5.3 micromolar in plasma is observed.

96. The method of any one of the preceding claims, wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to a Pi*ZZ AATD subject, decrease of Z-AAT level of about or at least about 49.0% in plasma is observed; and / or wherein when a single subcutaneous dose equivalent to about 400 mg WV-49090 free acid form is administered to Pi*ZZ AATD patients, mean decrease of Z-AAT level of about or at least about 49.0% in plasma is observed.

97. The method of any one of the preceding claims, comprising assessing level of neutrophil elastase inhibition and / or wherein an increase in neutrophil elastase inhibition from baseline is observed.

98. The method of any one of the preceding claims, wherein a subject exhibits acute phase response production of AAT polypeptide and / or M-AAT polypeptide and / or wherein a subject exhibits increased production of AAT polypeptide and / or M-AAT polypeptide in response to an inflammatory event, optionally wherein the inflammatory event is a non-drug-related inflammatory event.

99. The method of any one of the preceding claims, wherein WV-49090 administration is well-tolerated and / or wherein no serious adverse events are observed.

100. The method of any one of the preceding claims, wherein no serious adverse events is observed in at least 57 days after a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to a Pi*ZZ AATD patient; and / or wherein no serious adverse events is observed in at least 57 days after a single subcutaneous dose equivalent to about 200 mg WV-49090 free acid form is administered to two or more Pi*ZZ AATD patients.

101. A composition comprising WV-49090.

102. The composition of claim 101, wherein: (i) a form of WV-49090 in the composition is a pharmaceutically acceptable salt form; (ii) a form of WV-49090 in the composition is a sodium salt; (iii) each form of WV-49090 in the composition is independently a salt form; and / or (iv) each form of WV-49090 in the composition is independently a pharmaceutically acceptable salt form.

103. The composition of claim 101 or 102, wherein the composition has a WV-49090 purity of about 65%- 90%, about 65%-85%, about 65%-80%, or about 65%-75%, optionally wherein the purity is measured by IP-RP-UPLC using area % at 260 nm or the purity is measured by an IP-RP-UPLC method for purity as described herein, optionally wherein the purity is assessed by an IP-RP-UPLC method comprising one or more parameters from Table 1 or purity is assessed by an IP-RP-UPLC method using parameters from Table 1.

104. The composition of any one of claims 101-103, wherein stereochemical purity of WV-49090 is about 80% or 85% or more or about 80%-90%; and / or wherein stereochemical purity is assessed by dimer modeling.

105. The composition of any one of claims 101-104, wherein the composition is a liquid composition wherein WV-49090 is dissolved.

106. The composition of any one of claims 101-105, wherein the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier, optionally wherein the pharmaceutically acceptable carrier is or comprises a phosphate buffered solution.

107. The composition of any one of claims 101-106, wherein the composition has a pH of about 7, a pH of about 6-8, or a pH of about 6.7 ± 1.

0.

108. The composition of any one of claims 101-107, wherein the concentration of WV-49090 is equivalent to about 25 mg / mL WV-49090 free acid form, optionally wherein the composition is packaged into a vial, wherein the volume of the composition in the vial is about 3.2 mL.

109. The composition of any one of claims 101-108, wherein the composition is packaged into a vial, wherein the amount of WV-49090 in the vial is equivalent to about 80 mg WV-49090 free acid form.

110. The composition of any one of claims 101-109, wherein the amount of WV-49090 is measured by UV at 260 nm, optionally UV at 260 nm and 22.1 OD / mg.

111. The composition of any one of claims 101-104, wherein the composition is a WV-49090 drug substance, optionally wherein the WV-49090 drug substance in the composition is manufactured, characterized, released, or stored by a process or one or more methods described herein; and / or the WV-49090 drug substance is sodium salt.

112. The composition of any one of claims 101-104, wherein the composition is a WV-49090 drug product, optionally wherein the WV-49090 drug product is manufactured, characterized, released, or stored by a process or one or more methods described herein.

113. The composition of any one of claims 101-104, wherein a pharmaceutical composition is manufactured, characterized, released, or stored by a process or one or more methods described herein.

114. The composition of any one of claims 101-113, wherein the composition is or delivers a dose of WV- 49090 of any one of claims 1-100.

115. The composition of any one of claims 103-114, wherein about is ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9%, or ±10%.

116. The composition of any one of claims 101-115, for use in a method of any one of claims 1-100.

117. A method for manufacturing a WV-49090 composition according to a method described in the specification.

118. The method of claim 117, comprising utilizing IP-RP-UPLC to assess purity and / or impurities in the manufactured WV-49090 composition and release the preparation if the purity and / or impurities meet certaincriteria.

119. The method of claim 117 or 118, wherein the composition is a drug substance or a drug product.

120. A method for releasing a WV-49090 preparation, comprising utilizing IP-RP-UPLC to assess purity and / or impurities in the WV-49090 preparation and release the preparation if the purity and / or impurities meet certain criteria.

121. A method for assessing purity of WV-49090 utilizing IP-RP-UPLC.

122. The method of any one of claim 118-121, wherein the IP-RP-UPLC utilized one or more parameters described in the specification, optionally wherein the IP-RP-UPLC method comprises one or more parameters in Table 1.

123. The method of any one of claims 117-119, comprising a method of any one of claims 120-122.

124. A method for confirming stereochemical identity of WV-49090 utilizing IP-RP-UPLC.

125. The method of any one of claims 117-124, wherein stereochemical identity of WV-49090 is confirmed by an IP-RP-UPLC method for stereochemical identity as described herein, optionally wherein the IP-RP-UPLC method comprises one or more parameters in Table 2 or wherein the IP-RP-UPLC method uses parameters in Table 2.

126. The method of any one of claims 117-123, comprising a method of claim 124 or 125.

127. The method of any one of claims 117-126, wherein the composition is a composition in any one of claims 101-116.

128. A vial comprising a composition of any one of claims 101-116.

129. A device comprising a composition of any one of claims 101-116.

130. The device of claim 129, wherein: (i) the device is for subcutaneous administration; (ii) the device is or comprises a syringe or an autoinjector; and / or (iii) the device contains or delivers a dose of WV-49090 of any one of claims 1-100.

131. Use of a composition of any one of claims 101-116 in the manufacture of a medicament for a method of any one of claims 1-100.

132. WV-49090, for use in a method of any one of claims 1-100.

133. Use of WV-49090 in the manufacture of a medicament for a method of any one of claims 1-100.

134. A method of providing acute phase response production of a polypeptide in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript; or a method for modulating level of an acute phase protein in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript; a method for providing an increased acute phase response AAT level in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a targetadenosine in a target transcript; or a method for providing an increased acute phase response M-AAT level in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript; or a method for providing an increased acute phase response Z-AAT level in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript.

135. A method of providing increased production of a polypeptide in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript; or a method of providing an increased AAT level in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript; or a method of providing an increased M-AAT level in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript; or a method of providing an increased Z-AAT level in response to an inflammatory event in a subject, comprising administering or delivering to the subject an oligonucleotide or oligonucleotide composition for editing a target adenosine in a target transcript; or.

136. The method of claim 135, wherein the inflammatory event is a non-drug-related inflammatory event and / or the increased production is higher than a baseline production, optionally wherein the baseline production is prior to the inflammatory event.

137. The method of any one of claims 134-136, wherein the target transcript is a mRNA, a SERPINA1 transcript, and / or a SERPINA1 mRNA; and / or wherein the polypeptide is an AAT polypeptide and / or a M- AAT polypeptide.

138. A compound, oligonucleotide, composition, method, process, use, device, sample, dose or dosing regimen of any one of Embodiments 1-394.

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