Rnai agents for inhibiting expression of androgen receptor (AR), compositions thereof, and methods of use

Abstract

Described are RNAi agents, compositions that include RNAi agents, and methods for inhibition of an Androgen Receptor (AR) gene. The AR RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of an AR gene. Pharmaceutical compositions that include one or more AR RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described AR RNAi agents to central nervous system (CNS) tissue and / or skeletal muscle tissue, in vivo, provides for inhibition of AR gene expression and a reduction in AR activity, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases including spinal and bulbar muscular atrophy (SBMA).

Description

Cross Reference to Related Applications

[0001] This application claims priority from United States Provisional Patent Application Serial No. 63 / 624,417, filed on January 24, 2024, United States Provisional Patent Application Serial No. 63 / 573,151, filed April 2,2024. United States Provisional Patent Application Serial No. 63 / 662,243, filed June 20, 2024, United States Provisional Patent Application Serial No. 63 / 718,062, filed November 8, 2024, and United States Provisional Patent Application Serial No. 63 / 724,015, filed November 22, 2024, the contents of each of which are incorporated herein by reference in their entirety. Sequence Listing

[0002] This application contains a Sequence Listing (in compliance with Standard ST26), which has been submitted in xml format and is hereby incorporated by reference in its entirety. The xml sequence listing file is named 30710-WO SeqListing.xml, created January 23, 2025, and is 3922 kb in size. Field of the Invention

[0003] The present disclosure relates to RNA interference (RNAi) agents, e.g., double stranded RNAi agents, for inhibition of Androgen Receptor (“AR”) gene expression, compositions that include AR RNAi agents, and methods of use thereof. Background

[0004] The androgen receptor (“AR”) is a type of nuclear receptor activated by binding of androgenic hormones, such as testosterone. In some males, trinucleotide CAG repeat expansions in exon 1 of the androgen receptor gene results in loss of AR function and a toxic gain of function related to lower motor neuron disease, called spinal and bulbar muscular atrophy (“SBMA”), also known as Kennedy’s disease.

[0005] SBMA is an adult-onset disease that slowly progresses over several years, causing bulbar and lower motor neuron loss, and muscle denervation. The loss of bulbar neurons may cause dysarthria and dysphagia. There is currently no cure for SBMA, and current treatment focuses on preventing disease complications. Therefore there exists a need for treatments that reduce mutant AR gene production. Summary

[0006] There exists a need for novel RNA interference (RNAi) agents (termed RNAi agents, RNAi triggers, or triggers), e.g., double stranded RNAi agents, that are able to selectively and efficiently inhibit the expression of an AR gene, including for use as a therapeutic or medicament. Further, there exists a need for compositions of novel AR-specific RNAi agents for the treatment of diseases or disorders associated mutant AR expression and / or disorders that can be mediated at least in part by a reduction in AR gene expression and / or AR receptor expression.

[0007] The nucleotide sequences and chemical modifications of the AR RNAi agents disclosed herein, as well as their combination with certain specific targeting ligands suitable for selectively and efficiently delivering the AR RNAi agents to relevant CNS and / or skeletal muscle cells in vivo, differ from those previously disclosed or known in the art. The AR RNAi agents disclosed herein provide for highly potent and efficient inhibition of the expression of an AR gene.

[0008] The nucleotide sequences and chemical modifications of the AR RNAi agents disclosed herein, as well as their combination with certain specific antigen binding proteins suitable for selectively and efficiently delivering the AR RNAi agents to relevant CNS cells in vivo, differ from those previously disclosed or known in the art. The AR RNAi agents disclosed herein provide for highly potent and efficient inhibition of the expression of an AR gene.

[0009] In general, the present disclosure features AR gene-specific RNAi agents, compositions that include AR RNAi agents, and methods for inhibiting expression of an AR gene in vitro and / or in vivo using the AR RNAi agents and compositions that include AR RNAi agents described herein. The AR RNAi agents described herein are able to selectively and efficiently decrease expression of an AR gene, and thereby reduce the expression of the androgen receptor.

[0010] The described AR RNAi agents can be used in methods for therapeutic treatment (including preventative or prophylactic treatment) of symptoms and diseases including, but not limited to various neuromuscular diseases (including SBMA or Kennedy’s disease.)

[0011] In one aspect, the disclosure features RN Ai agents for inhibiting expression of an AR (or AR) gene, wherein the RNAi agent includes a sense strand (also referred to as a passenger strand) and an antisense strand (also referred to as a guide strand). The sense strand and the antisense strand can be partially, substantially, or fully complementary to each other. The length of the RNAi agent sense and antisense strands described herein each can be 16 to 49 nucleotides in length. In some embodiments, the sense and antisense strands are independently 17 to 26 nucleotides in length. The sense and antisense strands can be either the same length or different lengths. In some embodiments, the sense and antisense strands are independently 21 to 26 nucleotides in length. In some embodiments, the sense and antisense strands are independently 21 to 24 nucleotides in length. In some embodiments, both the sense strand and the antisense strand are 21 nucleotides in length. In some embodiments, the antisense strands are independently 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, the sense strands are independently 16, 17. 18. 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49 nucleotides in length. The RNAi agents described herein, upon deliver to a cell expressing AR such as endothelial cells, neurons, microglia, and astrocytes, inhibit the expression of one or more AR gene variants in vivo and / or in vitro.

[0012] The AR RNAi agents disclosed herein target a human AR gene (see, e.g. SEQ ID NO: 1). In some embodiments, the AR RNAi agents disclosed herein target a portion of an AR gene ha ving the sequence of any of the sequences disclosed in Table 1.

[0013] In another aspect, the disclosure features compositions, including pharmaceutical compositions, that include one or more of the disclosed AR RNAi agents that are able to selectively and efficiently decrease expression of an AR gene. The compositions that include one or more AR RNAi agents described herein can be administered to a subject, such as a human or animal subject, for the treatment (including prophylactic treatment or inhibition) of symptoms and diseases associated with AR receptor activity.

[0014] Examples of AR RNAi agent sense strands and antisense strands that can be used in an AR RNAi agent are provided in Tables 3, 4, 5, and 6. Examples of AR RNAi agent duplexes are provided in Tables 7, 8, 9, and 10. Examples of 19-nucleotide core stretch sequences that may consist of or may be included in the sense strands and antisense strands of certain AR RNAi agents disclosed herein, are provided in Table 2.

[0015] In another aspect, the disclosure features methods for delivering AR RNAi agents to neurons, astrocytes, microglia and endothelial cells in a subject, such as a mammal, in vivo. Also described herein are compositions for use in such methods. In some embodiments, disclosed herein are methods for delivering AR RNAi agents to central nervous system cells (neurons, astrocytes, microglia and endothelial cells) to a subject in vivo. In some embodiments, the subject is a human subject

[0016] The methods disclosed herein include the administration of one or more AR RNAi agents to a subject, e.g., a human or animal subject, by any suitable means known in the art. The pharmaceutical compositions disclosed herein that include one or more AR RNAi agents can be administered m a number of ways depending upon whether local or systemic treatment is desired. Administration can be, but is not limited to, for example, intravenous, intraarterial, subcutaneous, intraperitoneal, subdermal (e.g., via an implanted device), and intraparenchymal administration. In some embodiments, the pharmaceutical compositions described herein are administered by intrathecal injection or intracerebroventricular injection.

[0017] In some embodiments, it is desired that the AR RNAi agents described herein inhibit the expression of an AR gene in central nervous system cells.

[0018] The one or more AR RNAi agents can be delivered to target cells or tissues using any oligonucleotide delivery technology known in the art. In some embodiments, an AR RNAi agent is delivered to cells or tissues by covalently linking the RNAi agent to a targeting group, lipid moiety, or antigen binding protein.

[0019] A targeting group can be linked to the 3' or 5' end of a sense strand or an antisense strand of an AR RNAi agent. In some embodiments, a targeting group is linked to the 3' or 5' end of the sense strand. In some embodiments, a targeting group is linked to the 5' end of the sense strand. In some embodiments, a targeting group is linked internally to a nucleotide on the sense strand and / or the antisense strand of the RNAi agent. In some embodiments, a targeting group is linked to the RNAi agent via a linker.

[0020] In another aspect, the disclosure features compositions that include one or more AR RNAi agents that have the duplex structures disclosed in Tables 7, 8, 9. and 10.

[0021] In some embodiments, an AR RNAi agent is linked to one or more linking groups or other non-nucleotide groups or compounds, such as pharmacokinetic / pharmacodynamic (PK / PD) modulators. PK / PD modulators can increase circulation time of the conjugated drug and / or increase the activity of the RNAi agent through improved cell receptor binding, improved cellular uptake, and / or other means. Examples of PK / PD modulators suitable for use with the AR RNAi agents disclosed herein can be found in Table 11, herein.

[0022] In some embodiments, an AR RNAi agent is conjugated to a targeting group, a linking group, a PK / PD modulator, and / or another non-nucleotide group. In some embodiments, an AR RNAi agent is conjugated to a targeting group and a PK / PD modulator.

[0023] The use of AR RNAi agents provides methods for therapeutic (including prophylactic) treatment of diseases or disorders for which a reduction in AR receptor activity can provide a therapeutic benefit. The AR RNAi agents disclosed herein can be used to treat various neurodegenerative diseases, including SBMA. Such methods of treatment include administration of an AR RNAi agent to a human being or animal having mutant androgen receptor or androgen receptor activity beyond desirable levels.

[0024] The one or more AR RNAi agents can be delivered to target cells or tissues using any oligonucleotide delivery technology known in the art. In some embodiments, an AR RNAi agent is delivered to cells or tissues by covalently linking the RNAi agent to a targeting group or an antigen binding protein.

[0025] The one or more AR RNAi agents can be delivered to target cells or tissues using any oligonucleotide delivery technology known in the art. In some embodiments, an AR RNAi agent is delivered to cells or tissues by covalently linking the RNAi agent to a targeting group. In some embodiments, the targeting group can include a cell receptor ligand. A targeting group can be linked to the 3' or 5' end of a sense strand or an antisense strand of an AR RNAi agent, or can be linked via one or more internal nucleotides of the sense strand or the antisense strand. In some embodiments, a targeting group is linked to the 3' or 5' end of the sense strand. In some embodiments, a targeting group is linked to the 5' end of the sense strand. In some embodiments, a targeting group is linked internally to a nucleotide on the sense strand and / or the antisense strand of the RNAi agent. In some embodiments, a targeting group is linked to the RNAi agent via a linker. Example targeting ligands suitable for use that have affinity for skeletal muscle cells and / or receptors present on skeletal muscle cells (e.g., integrin alpha-v-beta-6 (av|36)), are shown in Table 11 herein.

[0026] An antigen binding protein can be linked to the 3' or 5' end of a sense strand or an antisense strand of an AR RNAi agent. In some embodiments, an antigen binding protein is linked to the 3' or 5' end of the sense strand. In some embodiments, an antigen binding protein is linked to the 5' end of the sense strand. In some embodiments, an antigen binding protein is linked internally to a nucleotide on the sense strand and / or the antisense strand of the RNAi agent. In some embodiments, an antigen binding protein is linked to the RNAi agent via a linker. Definitions

[0027] As used herein, the terms ‘’oligonucleotide” and ‘’polynucleotide” mean a polymer of linked nucleosides each of which can be independently modified or unmodified.

[0028] As used herein, an “RNAi agent" (also referred to as an “RNAi trigger”) means a composition that contains an RNA or RNA-like (e.g., chemically modified RNA) oligonucleotide molecule that is capable of degrading or inhibiting (e.g., degrades or inhibits under appropriate conditions) translation of messenger RNA (mRNA) transcripts of a target mRNA in a sequence specific manner. As used herein, RNAi agents may operate through the RNA interference mechanism (i.e., inducing RNA interference through interaction with the RNA interference pathway machinery (RNA-induced silencing complex or RISC) of mammalian cells), or by any alternative mechanism(s) or pathway(s). While it is believed that RNAi agents, as that term is used herein, operate primarily through the RNA interference mechanism, the disclosed RNAi agents are not bound by or limited to any particular pathway or mechanism of action. RNAi agents disclosed herein are comprised of a sense strand and an antisense strand, and include, but are not limited to: short (or small) interfering RNAs (siRNAs), double stranded RNAs (dsRNA), micro RNAs (miRNAs), short hairpin RNAs (shRNA), and dicer substrates. The antisense strand of the RNAi agents described herein is at least partially complementary to the mRNA being targeted (i.e. AR mRNA). RNAi agents can include one or more modified nucleotides and / or one or more non-phosphodiester linkages.

[0029] As used herein, the terms “silence,” “reduce,” “inhibit,” “down-regulate,” or “knockdown” when referring to expression of a given gene, mean that the expression of the gene, as measured by the level of RNA transcribed from the gene or the level of polypeptide, protein, or protein subunit translated from the mRNA in a cell, group of cells, tissue, organ, or subject in which the gene is transcribed, is reduced when the cell, group of cells, tissue, organ, or subject is treated with the RNAi agents described herein as compared to a second cell, group of cells, tissue, organ, or subject that has not or have not been so treated.

[0030] As used herein, the terms “sequence” and “nucleotide sequence” mean a succession or order of nucleobases or nucleotides, described with a succession of letters using standard nomenclature.

[0031] As used herein, a “base,” “nucleotide base,” or “nucleobase,” is a heterocyclic pyrimidine or purine compound that is a component of a nucleotide, and includes the primary purine bases adenine and guanine, and the primary' pyrimidine bases cytosine, thymine, and uracil. A nucleobase may further be modified to include, without limitation, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. (See. e.g., Modified Nucleosides in Biochemistry, Biotechnology' and Medicine, Herdewijn, P. ed. Wiley-VCH, 2008). The synthesis of such modified nucleobases (including phosphoramidite compounds that include modified nucleobases) is known in the art.

[0032] As used herein, and unless otherwise indicated, the term “complementary,’' when used to describe a first nucleobase or nucleotide sequence (e.g.. RNAi agent sense strand or targeted mRNA) in relation to a second nucleobase or nucleotide sequence (e.g., RN Ai agent antisense strand or a single-stranded antisense oligonucleotide), means the ability of an oligonucleotide or polynucleotide including the first nucleotide sequence to hybridize (form base pair hydrogen bonds under mammalian physiological conditions (or otherwise suitable in vivo or in vitro conditions) and form a duplex or double helical structure under certain standard conditions with an oligonucleotide that includes the second nucleotide sequence. The person of ordinary skill in the art would be able to select the set of conditions most appropriate for a hybridization test. Complementary sequences include Watson-Crick base pairs or non-Watson-Crick base pairs and include natural or modified nucleotides or nucleotide mimics, at least to the extent that the above hybridization requirements are fulfilled. Sequence identity or complementarity is independent of modification. For example, a and Af, as defined herein, are complementary to U (or T) and identical to A for the purposes of determining identity or complementarity.

[0033] As used herein, “perfectly complementary” or “fully complementary” means that in a hybridized pair of nucleobase or nucleotide sequence molecules, all (100%) of the bases in a contiguous sequence of a first oligonucleotide will hybridize with the same number of bases in a contiguous sequence of a second oligonucleotide. The contiguous sequence may comprise all or a part of a first or second nucleotide sequence.

[0034] As used herein, “partially complementary ” means that in a hybridized pair of nucleobase or nucleotide sequence molecules, at least 70%, but not all, of the bases in a contiguous sequence of a first oligonucleotide will hy bridize with the same number of bases in a contiguous sequence of a second oligonucleotide. The contiguous sequence may comprise all or a part of a first or second nucleotide sequence.

[0035] As used herein, “substantially complementary” means that in a hybridized pair of nucleobase or nucleotide sequence molecules, at least 85%, but not all, of the bases in a contiguous sequence of a first oligonucleotide will hybridize with the same number of bases in a contiguous sequence of a second oligonucleotide. The contiguous sequence may comprise all or a part of a first or second nucleotide sequence.

[0036] As used herein, the terms “complementary,” “fully complementary ,” “partially complementary',” and “substantially complementary ” are used with respect to the nucleobase or nucleotide matching between the sense strand and the antisense strand of an RNAi agent, or between the antisense strand of an RNAi agent and a sequence of an AR mRNA.

[0037] As used herein, the term “substantially identical’" or “substantial identity,” as applied to a nucleic acid sequence means the nucleotide sequence (or a portion of a nucleotide sequence) has at least about 85% sequence identity or more, e.g., at least 90%, at least 95%, or at least 99% identity’, compared to a reference sequence. Percentage of sequence identity is determined by comparing two optimally aligned sequences over a comparison window. The percentage is calculated by determining the number of positions at which the same type of nucleic acid base occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions m the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity. The inventions disclosed herein encompass nucleotide sequences substantially identical to those disclosed herein.

[0038] As used herein, the terms “treat,"’ “treatment,” and the like, mean the methods or steps taken to provide relief from or alleviation of the number, severity', and / or frequency of one or more symptoms of a disease in a subject. As used herein, “treat” and “treatment” may include the prevention, management, prophylactic treatment, and / or inhibition or reduction of the number, severity, and / or frequency of one or more symptoms of a disease in a subject.

[0039] As used herein, the phrase “introducing into a cell,” when referring to an RNAi agent, means functionally delivering the RNAi agent into a cell. The phrase “functional delivery,” means delivering the RNAi agent to the cell in a manner that enables the RNAi agent to have the expected biological activity, e.g., sequence-specific inhibition of gene expression.

[0040] Unless stated otherwise, use of the symbol as used herein means that any group or groups may be linked thereto that is in accordance with the scope of the inventions described herein.

[0041] As used herein, the term “isomers” refers to compounds that have identical molecular formulae, but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,"’ and stereoisomers that are non-superimposable mirror images are termed “enantiomers,” or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is termed a “chiral center.”

[0042] As used herein, unless specifically identified in a structure as having a particular conformation, for each structure in which asymmetric centers are present and thus give rise to enantiomers, diastereomers, or other stereoisomeric configurations, each structure disclosed herein is intended to represent all such possible isomers, including their optically pure and racemic forms. For example, the structures disclosed herein are intended to cover mixtures of diastereomers as well as single stereoisomers.

[0043] As used in a claim herein, the phrase “consisting of’ excludes any element, step, or ingredient not specified in the claim. When used in a claim herein, the phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claimed invention.

[0044] The person of ordinary' skill in the art would readily understand and appreciate that the compounds and compositions disclosed herein may have certain atoms (e.g., N, O, or S atoms) in a protonated or deprotonated state, depending upon the environment in which the compound or composition is placed. Accordingly, as used herein, the structures disclosed herein envisage that certain functional groups, such as, for example, OH, SH, or NH, may be protonated or deprotonated. The disclosure herein is intended to cover the disclosed compounds and compositions regardless of their state of protonation based on the environment (such as pH), as would be readily understood by the person of ordinary skill in the art. Correspondingly, compounds described herein with labile protons or basic atoms should also be understood to represent salt forms of the corresponding compound. Compounds described herein may be in a free acid, free base, or salt form. Pharmaceutically acceptable salts of the compounds described herein should be understood to be within the scope of the invention.

[0045] As used herein, the term “linked” or “conjugated” when referring to the connection between two compounds or molecules means that two compounds or molecules are joined by a covalent bond. Unless stated, the terms “linked” and “conjugated” as used herein may refer to the connection between a first compound and a second compound either with or without any intervening atoms or groups of atoms.

[0046] As used herein, the term “including” is used to herein mean, and is used interchangeably with, the phrase “including but not limited to.” The term “or” is used herein to mean, and is used interchangeably with, the term “and / or,” unless the context clearly indicates otherwise.

[0047] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary' skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below'. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0048] Other objects, features, aspects, and advantages of the invention will be apparent from the following detailed description, accompanying figures, and from the claims. Detailed Description RNAi Agents

[0049] Described herein are RNAi agents for inhibiting expression of the AR gene (referred to herein as AR RNAi agents or AR RNAi triggers). Each AR RNAi agent disclosed herein comprises a sense strand and an antisense strand. The sense strand and the antisense strand each can be 16 to 49 nucleotides in length. The sense and antisense strands can be either the same length or they can be different lengths. In some embodiments, the sense and antisense strands are each independently 18 to 27 nucleotides in length. In some embodiments, both the sense and antisense strands are each 21-26 nucleotides in length. In some embodiments, the sense and antisense strands are each 21-24 nucleotides in length. In some embodiments, the sense and antisense strands are each independently 19-21 nucleotides in length. In some embodiments, the sense strand is about 19 nucleotides in length while the antisense strand is about 21 nucleotides in length. In some embodiments, the sense strand is about 21 nucleotides in length while the antisense strand is about 23 nucleotides in length. In some embodiments, a sense strand is 23 nucleotides in length and an antisense strand is 21 nucleotides in length. In some embodiments, both the sense and antisense strands are each 21 nucleotides in length. In some embodiments, the RNAi agent sense and antisense strands are each independently 16.17. 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32. 33, 34, 35, 36, 37, 38, or 39 nucleotides in length. In some embodiments, a double-stranded RNAi agent has a duplex length of about 16, 17, 18, 19, 20, 21, 22, 23 or 24 nucleotides.

[0050] Examples of nucleotide sequences used in forming AR RNAi agents are provided in Tables 2, 3, 4, 5, 6. and 10. Examples of RNAi agent duplexes, that include the sense strand and antisense strand sequences in Tables 2, 3,4, 5, 6, are shown in Tables 7, 8, 9, and 10.

[0051] In some embodiments, the region of perfect, substantial, or partial complementarity between the sense strand and the antisense strand is 16-26 (e.g., 16, 17. 18. 19. 20. 21, 22, 23, 24, 25, or 26) nucleotides in length and occurs at or near the 5' end of the antisense strand (e.g., this region may be separated from the 5' end ofthe antisense strand by 0,1,2. 3, or 4 nucleotides that are not perfectly, substantially, or partially complementary).

[0052] A sense strand of the AR RNAi agents described herein includes at least 16 consecutive nucleotides that have at least 85% identity to a core stretch sequence (also referred to herein as a “core stretch” or “core sequence”) of the same number of nucleotides in an AR mRNA. In some embodiments, a sense strand core stretch sequence is 100% (perfectly) complementary or at least about 85% (substantially) complementary to a core stretch sequence in the antisense strand, and thus the sense strand core stretch sequence is typically perfectly identical or at least about 85% identical to a nucleotide sequence of the same length (sometimes referred to, e.g. as a target sequence) present in the AR mRNA target. In some embodiments, this sense strand core stretch is 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides in length. In some embodiments, this sense strand core stretch is 17 nucleotides in length. In some embodiments, this sense strand core stretch is 19 nucleotides in length.

[0053] An antisense strand of an AR RNAi agent described herein includes at least 16 consecutive nucleotides that have at least 85% complementarity to a core stretch of the same number of nucleotides in an AR mRNA and to a core stretch of the same number of nucleotides in the corresponding sense strand. In some embodiments, an antisense strand core stretch is 100% (perfectly) complementary or at least about 85% (substantially) complementary to a nucleotide sequence (e.g, target sequence) of the same length present in the AR mRNA target. In some embodiments, this antisense strand core stretch is 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides in length. In some embodiments, this antisense strand core stretch is 19 nucleotides in length. In some embodiments, this antisense strand core stretch is 17 nucleotides in length. A sense strand core stretch sequence can be the same length as a corresponding antisense core sequence or it can be a different length.

[0054] The AR RNAi agent sense and antisense strands anneal to form a duplex. A sense strand and an antisense strand of an AR RNAi agent can be partially, substantially, or fully complementary to each other. Within the complementary duplex region, the sense strand core stretch sequence is at least 85% complementary or 100% complementary to the antisense core stretch sequence. In some embodiments, the sense strand core stretch sequence contains a sequence of at least 16, at least 17. at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 nucleotides that is at least 85% or 100% complementary to a corresponding 16. 17. 18, 19, 20, 21,22, or 23 nucleotide sequence of the antisense strand core stretch sequence (i.e., the sense and antisense core stretch sequences of an AR RNAi agent have a region of at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 nucleotides that is at least 85% base paired or 100% base paired.)

[0055] In some embodiments, the antisense strand of an AR RNAi agent disclosed herein differs by 0, 1.2. or 3 nucleotides from any of the antisense strand sequences in Table 2 or Table 3. In some embodiments, the sense strand of an AR RNAi agent disclosed herein differs by 0, 1, 2, or 3 nucleotides from any of the sense strand sequences in Table 2, Table 4, Table 5, Table 6, or Table 10.

[0056] In some embodiments, the sense strand and / or the antisense strand can optionally and independently contain an additional 1. 2, 3, 4. 5, or 6 nucleotides (extension) at the 3' end. the 5' end, or both the 3' and 5' ends of the core stretch sequences. The antisense strand additional nucleotides, if present, may or may not be complementary' to the corresponding sequence in the AR mRNA The sense strand additional nucleotides, if present, may or may not be identical to the corresponding sequence in the AR mRNA. The antisense strand additional nucleotides, if present, may or may not be complementary to the corresponding sense strand’s additional nucleotides, if present.

[0057] As used herein, an extension comprises 1, 2, 3, 4, 5, or 6 nucleotides at the 5' and / or 3' end of the sense strand core stretch sequence and / or antisense strand core stretch sequence. The extension nucleotides on a sense strand may or may not be complementary to nucleotides, either core stretch sequence nucleotides or extension nucleotides, in the corresponding antisense strand. Conversely, the extension nucleotides on an antisense strand may or may not be complementary to nucleotides, either core stretch nucleotides or extension nucleotides, in the corresponding sense strand. In some embodiments, both the sense strand and the antisense strand of an RNAi agent contain 3' and 5' extensions. In some embodiments, one or more of the 3' extension nucleotides of one strand base pairs with one or more 5' extension nucleotides of the other strand. In other embodiments, one or more of 3' extension nucleotides of one strand do not base pair with one or more 5' extension nucleotides of the other strand. In some embodiments, an AR RNAi agent has an antisense strand having a 3' extension and a sense strand having a 5' extension. In some embodiments, the extension nucleotide(s) are unpaired and form an overhang. As used herein, an “overhang” refers to a stretch of one or more unpaired nucleotides located at a terminal end of either the sense strand or the antisense strand that does not form part of the hybridized or duplexed portion of an RNAi agent disclosed herein.

[0058] In some embodiments, an AR RNAi agent comprises an antisense strand having a 3' extension of 1, 2, 3, 4, 5, or 6 nucleotides in length. In other embodiments, an AR RNAi agent comprises an antisense strand having a 3' extension of I, 2, or 3 nucleotides in length. In some embodiments, one or more of the antisense strand extension nucleotides comprise nucleotides that are complementary to the corresponding AR mRNA sequence. In some embodiments, one or more of the antisense strand extension nucleotides comprise nucleotides that are not complementary to the corresponding AR mRNA sequence.

[0059] In some embodiments, an AR RNAi agent comprises a sense strand having a 3' extension of 1, 2, 3, 4, or 5 nucleotides in length. In some embodiments, one or more of the sense strand extension nucleotides comprises adenosine, uracil, or thymidine nucleotides, AT dinucleotide, or nucleotides that correspond to or are the identical to nucleotides in the AR mRNA sequence. In some embodiments, the 3' sense strand extension includes or consists of one of the following sequences, but is not limited to: T, UT, TT, UU, UUT, TTT, or TTTT (each listed 5' to 3').

[0060] A sense strand can have a 3' extension and / or a 5' extension. In some embodiments, an AR RNAi agent comprises a sense strand having a 5' extension of 1, 2, 3, 4. 5, or 6 nucleotides in length. In some embodiments, one or more of the sense strand extension nucleotides comprise nucleotides that correspond to or are identical to nucleotides in the AR mRNA sequence.

[0061] Examples of sequences used in forming AR RNAi agents are provided in Tables 2, 3, 4, 5, 6. and 10. In some embodiments, an AR RNAi agent antisense strand includes a sequence of any of the sequences in Tables 2, 3, or 10. In certain embodiments, an AR RNAi agent antisense strand comprises or consists of any one of the modified sequences in Table 3. In some embodiments, an AR RNAi agent antisense strand includes the sequence of nucleotides (from 5' end -» 3' end) 1-17. 2-15. 2-17. 1-18. 2-18. 1-19. 2-19, 1-20, 2-20, 1-21, or 2-21, of any of the sequences in Tables 2 or 3. In some embodiments, an AR RNAi agent sense strand includes the sequence of any of the sequences in Tables 2, 4. 5, or 6. In some embodiments, an AR RNAi agent sense strand includes the sequence of nucleotides (from 5' end -> 3' end) 1-18, 119, 1-20, 1-21. 2-19. 2-20. 2-21. .3-20. 3-21. or 4-21 of any of the sequences in Tables 2, 4, 5, or 6. In certain embodiments, an AR RNAi agent sense strand comprises or consists of a modified sequence of any one of the modified sequences in Table 4, 5, 6, or 10.

[0062] In some embodiments, the sense and antisense strands of the RNAi agents described herein contain the same number of nucleotides. In some embodiments, the sense and antisense strands of the RNAi agents described herein contain different numbers of nucleotides. In some embodiments, the sense strand 5' end and the antisense strand 3' end of an RNAi agent form a blunt end. In some embodiments, the sense strand 3' end and the antisense strand 5' end of an RNAi agent form a blunt end. In some embodiments, both ends of an RNAi agent form blunt ends. In some embodiments, neither end of an RNAi agent is blunt-ended. As used herein a “blunt end” refers to an end of a double stranded RNAi agent in which the terminal nucleotides of the two annealed strands are complementary (form a complementary base-pair).

[0063] In some embodiments, the sense strand 5' end and the antisense strand 3' end of an RNAi agent form a frayed end. In some embodiments, the sense strand 3' end and the antisense strand 5' end of an RNAi agent form a fray ed end. In some embodiments, both ends of an RNAi agent form a frayed end. In some embodiments, neither end of an RNAi agent is a frayed end. As used herein a frayed end refers to an end of a double stranded RNAi agent in which the terminal nucleotides of the two annealed strands form a pair (i.e., do not form an overhang) but are not complementary (i.e. form a non-complementary pair). In some embodiments, one or more unpaired nucleotides at the end of one strand of a double stranded RNAi agent form an overhang. The unpaired nucleotides may be on the sense strand or the antisense strand, creating either 3’ or 5' overhangs. In some embodiments, the RNAi agent contains: a blunt end and a frayed end, a blunt end and 5' overhang end, a blunt end and a 3' overhang end, a frayed end and a 5' overhang end, a frayed end and a 3' overhang end, two 5' overhang ends, two 3' overhang ends, a 5' overhang end and a 3' overhang end, two frayed ends, or two blunt ends. Typically, when present, overhangs are located at the 3’ terminal ends of the sense strand, the antisense strand, or both the sense strand and the antisense strand.

[0064] The AR RNAi agents disclosed herein may also be comprised of one or more modified nucleotides. In some embodiments, substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand of the AR RNAi agent are modified nucleotides. The AR RNAi agents disclosed herein may further be comprised of one or more modified intemucleoside linkages, e.g., one or more phosphorothioate linkages. In some embodiments, an AR RNAi agent contains one or more modified nucleotides and one or more modified intemucleoside linkages. In some embodiments, a 2'-modified nucleotide is combined with modified intemucleoside linkage.

[0065] In some embodiments, an AR RNAi agent is prepared or provided as a salt, mixed salt, or a free-acid. In some embodiments, an AR RNAi agent is prepared as a pharmaceutically acceptable salt. In some embodiments, an AR RNAi agent is prepared as a pharmaceutically acceptable sodium salt. Such forms that are well known in the art are within the scope of the inventions disclosed herein. Modified Nucleotides

[0066] Modified nucleotides, when used in various oligonucleotide constructs, can preserve activity of the compound in cells while at the same time increasing the serum stability of these compounds, and can also minimize the possibility of activating interferon activity in humans upon admini stration of the oligonucleotide construct.

[0067] In some embodiments, an AR RNAi agent contains one or more modified nucleotides. As used herein, a “modified nucleotide” is a nucleotide other than a ribonucleotide (2'-hydroxyl nucleotide). In some embodiments, at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100%) of the nucleotides are modified nucleotides. As used herein, modified nucleotides can include, but are not limited to, deoxyribonucleotides, nucleotide mimics, abasic nucleotides, 2'-modified nucleotides, inverted nucleotides, modified nucleobase-comprising nucleotides, bridged nucleotides, peptide nucleic acids (PNAs), 2',3'-seco nucleotide mimics (unlocked nucleobase analogues), locked nucleotides, 3'-O-methoxy (2' intemucleoside linked) nucleotides, 2'-F-Arabino nucleotides, 5'-Me, 2'-fluoro nucleotide, morpholino nucleotides, vinyl phosphonate deoxyribonucleotides, vinyl phosphonate containing nucleotides, and cyclopropyl phosphonate containing nucleotides. 2'-modified nucleotides (i.e., a nucleotide with a group other than a hydroxyl group at the 2' position of the five-membered sugar ring) include, but are not limited to. 2'-O-inethyl nucleotides (also referred to as 2'-methoxy nucleotides), 2'-fluoro nucleotides (also referred to herein as 2'-deoxy-2'-fluoro nucleotides), 2'-deoxy nucleotides, 2'-methoxyethyl (2'-O-2-methoxylethyl) nucleotides (also referred to as 2'-MOE), 2'-amino nucleotides, and 2'-alkyl nucleotides. It is not necessary for all positions in a given compound to be uniformly modified. Conversely, more than one modification can be incorporated in a single AR RNAi agent or even in a single nucleotide thereof. The AR RNAi agent sense strands and antisense strands can be synthesized and / or modified by methods known in the art. Modification at one nucleotide is independent of modification at another nucleotide.

[0068] Modified nucleobases include synthetic and natural nucleobases, such as 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted punnes, (e.g., 2-aminopropyladenine, 5-propynyluracil, or 5-propynylcytosine), 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, inosine, xanthine, hypoxanthine, 2-aminoadenine, 6-alkyl (e.g., 6-methyl, 6-ethyl, 6-isopropyl. or 6-n-butyl) derivatives of adenine and guanine, 2-alkyl (e.g., 2-methyl, 2-ethyl, 2-isopropyl, or 2-n-butyl) and other alkyl derivatives of adenine and guanine. 2-thiouracil, 2-thiothymine, 2-thiocytosine, 5-halouracil, cytosine, 5-propynyl uracil, 5-propynyl cytosine, 6-azo uracil, 6-azo cytosine, 6-azo thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-sulfhydryl, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo (e.g.. 5-bromo), 5-trifluoromethyl, and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, and 3-deazaadenine.

[0069] In some embodiments, the 5’ and / or 3' end of the antisense strand can include abasic residues (Ab), which can also be referred to as an “abasic site” or “abasic nucleotide.” An abasic residue (Ab) is a nucleotide or nucleoside that lacks a nucleobase at the 1' position of the sugar moiety. (See, e.g., U.S. Patent No. 5,998.203). In some embodiments, an abasic residue can be placed internally in a nucleotide sequence. In some embodiments. Ab or AbAb can be added to the 3' end of the antisense strand. In some embodiments, the 5' end of the sense strand can include one or more additional abasic residues (e.g., (Ab) or (AbAb)). In some embodiments, UUAb, UAb, or Ab are added to the 3' end of the sense strand. In some embodiments, an abasic (deoxyribose) residue can be replaced with a ribitol (abasic ribose) residue.

[0070] In some embodiments, all or substantially all of the nucleotides of an RNAi agent are modified nucleotides. As used herein, an RNAi agent wherein substantially all of the nucleotides present are modified nucleotides is an RNAi agent having four or fewer (i.e., 0, 1, 2, 3, or 4) nucleotides in both the sense strand and the antisense strand being ribonucleotides (i.e., unmodified). As used herein, a sense strand wherein substantially all of the nucleotides present are modified nucleotides is a sense strand having two or fewer (i.e., 0, 1, or 2) nucleotides in the sense strand being unmodified ribonucleotides. As used herein, an antisense sense strand wherein substantially all of the nucleotides present are modified nucleotides is an antisense strand having two or fewer (i.e., 0, 1, or 2) nucleotides in the sense strand being unmodified ribonucleotides. In some embodiments, one or more nucleotides of an RNAi agent is an unmodified ribonucleotide. Chemical structures for certain modified nucleotides are set forth in Table 11 herein. Modified Intemucleoside Linkages

[0071] In some embodiments, one or more nucleotides of an AR RNAi agent are linked by non-standard linkages or backbones (i.e., modified intemucleoside linkages or modified backbones). Modified intemucleoside linkages or backbones include, but are not limited to, phosphorothioate groups (represented herein as a lower case “s”). chiral phosphorothioates, thiophosphates, phosphorodithioates, phosphotri esters, aminoalkyl-phosphotriesters, alkyl phosphonates (e.g.. methyl phosphonates or 3'-alkylene phosphonates), chiral phosphonates, phosphinates, phosphoramidates (e.g., 3'-amino phosphoramidate, aminoalkylphosphoramidates, or thionophosphoramidates), thionoalkyl-phosphonates, thionoalkylphosphotriesters, morpholino linkages, boranophosphates having normal 3'-5' linkages, 2'-5' linked analogs of boranophosphates, or boranophosphates having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'. In some embodiments, a modified intemucleoside linkage or backbone lacks a phosphorus atom. Modified intemucleoside linkages lacking a phosphorus atom include, but are not limited to, short chain alkyl or cycloalkyl inter-sugar linkages, mixed heteroatom and alkyl or cycloalkyl inter-sugar linkages, or one or more short chain heteroatomic or heterocyclic intersugar linkages. In some embodiments, modified intemucleoside backbones include, but are not limited to, siloxane backbones, sulfide backbones, sulfoxide backbones, sulfone backbones, formacetyl and thioformacetyl backbones, methylene formacetyl and thioformacetyl backbones, alkene-containing backbones, sulfamate backbones, methyleneimino and methylenehydrazino backbones, sulfonate and sulfonamide backbones, amide backbones, and other backbones having mixed N, O, S, and CH2 components.

[0072] In some embodiments, a sense strand of an AR RNAi agent can contain 1, 2, 3, 4. 5, or 6 phosphorothioate linkages, an antisense strand of an AR RNAi agent can contain 1, 2, 3, 4, 5, or 6 phosphorothioate linkages, or both the sense strand and the antisense strand independently can contain 1, 2, 3, 4, 5, or 6 phosphorothioate linkages. In some embodiments, a sense strand of an AR RNAi agent can contain 1, 2, 3, or 4 phosphorothioate linkages, an antisense strand of an AR RNAi agent can contain 1. 2, 3, or 4 phosphorothioate linkages, or both the sense strand and the antisense strand independently can contain 1, 2, 3, or 4 phosphorothioate linkages.

[0073] In some embodiments, an AR RNAi agent sense strand contains at least two phosphorothioate intemucleoside linkages. In some embodiments, the phosphorothioate intemucleoside linkages are between the nucleotides at positions 1-3 from the 3’ end of the sense strand. In some embodiments, one phosphorothioate intemucleoside linkage is at the 5’ end of the sense strand nucleotide sequence, and another phosphorothioate linkage is at the 3’ end of the sense strand nucleotide sequence. In some embodiments, two phosphorothioate intemucleoside linkage are located at the 5’ end of the sense strand, and another phosphorothioate linkage is at the 3' end of the sense strand. In some embodiments, the sense strand does not include any phosphorothioate intemucleoside linkages between the nucleotides, but contains one, two, or three phosphorothioate linkages between the terminal nucleotides on both the 5’ and 3’ ends and the optionally present inverted abasic residue terminal caps. In some embodiments, the targeting ligand is linked to the sense strand via a phosphorothioate linkage.

[0074] In some embodiments, an AR RNAi agent antisense strand contains four phosphorothioate intemucleoside linkages. In some embodiments, the four phosphorothioate internucleoside linkages are between the nucleotides at positions 1-3 from the 5' end of the antisense strand and between the nucleotides at positions 19-21,20-22, 21-23, 22-24, 23-25, or 24-26 from the 5' end. In some embodiments, three phosphorothioate intemucleoside linkages are located between positions 1-4 from the 5’ end of the antisense strand, and a fourth phosphorothioate intemucleoside linkage is located between positions 20-21 from the 5’ end of the antisense strand. In some embodiments, an AR RNAi agent contains at least three or four phosphorothioate intemucleoside linkages in the antisense strand. Capping Residues or Moieties

[0075] In some embodiments, the sense strand may include one or more capping residues or moieties, sometimes referred to in the art as a “cap,’’ a ‘■‘terminal cap,” or a “capping residue.” As used herein, a “capping residue” is a non-nucleotide compound or other moiety that can be incorporated at one or more termini of a nucleotide sequence of an RNAi agent disclosed herein. A capping residue can provide the RNAi agent, in some instances, with certain beneficial properties, such as, for example, protection against exonuclease degradation. In some embodiments, inverted abasic residues (invAb) (also referred to in the art as “inverted abasic sites”) are added as capping residues (see Table 11). (See, e.g., F. Czaudema. Nucleic Acids Res., 2003, 31(11), 2705-16). Capping residues are generally known in the art, and include, for example, inverted abasic residues as well as carbon chains such as a terminal C3H7 (propyl), CsHb (hexyl), or C12H25 (dodecyl) groups. In some embodiments, a capping residue is present at either the 5' terminal end, the 3' terminal end, or both the 5' and 3' terminal ends of the sense strand. In some embodiments, the 5’ end and / or the 3' end of the sense strand may include more than one inverted abasic deoxyribose moiety as a capping residue.

[0076] In some embodiments, one or more inverted abasic residues (invAb) are added to the 3' end of the sense strand. In some embodiments, one or more inverted abasic residues (invAb) are added to the 5' end of the sense strand. In some embodiments, one or more inverted abasic residues or inverted abasic sites are inserted between the targeting ligand and the nucleotide sequence of the sense strand of the RNAi agent. In some embodiments, the inclusion of one or more inverted abasic residues or inverted abasic sites at or near the terminal end or terminal ends of the sense strand of an RNAi agent allows for enhanced activity or other desired properties of an RN Ai agent.

[0077] In some embodiments, one or more inverted abasic residues (invAb) are added to the 3' end of the sense strand. In some embodiments, one or more inverted abasic residues (invAb) are added to the 5' end of the sense strand. In some embodiments, one or more inverted abasic residues or inverted abasic sites are inserted between the targeting ligand and the nucleotide sequence of the sense strand of the RNAi agent. In some embodiments, one or more inverted abasic residues or inverted abasic sites are inserted between the PK / PD modulator and the nucleotide sequence of the sense strand of the RNAi agent. In some embodiments, the inclusion of one or more inverted abasic residues or inverted abasic sites at or near the terminal end or terminal ends of the sense strand of an RNAi agent allows for enhanced activity or other desired properties of an RNAi agent.

[0078] In some embodiments, one or more inverted abasic residues (invAb) are added to the 5' end of the sense strand. In some embodiments, one or more inverted abasic residues can be inserted between the targeting ligand and the nucleotide sequence of the sense strand of the RNAi agent. The inverted abasic residues may be linked via phosphate, phosphorothioate (e.g.. shown herein as (invAb)s)), or other intemucl eoside linkages. In some embodiments, the inclusion of one or more inverted abasic residues at or near the terminal end or terminal ends of the sense strand of an RNAi agent may allow for enhanced activity or other desired properties of an RNAi agent. In some embodiments, an inverted abasic (deoxyribose) residue can be replaced with an inverted ribitol (abasic ribose) residue. In some embodiments, the 3' end of the antisense strand core stretch sequence, or the 3' end of the antisense strand sequence, may include an inverted abasic residue. The chemical structures for inverted abasic deoxyribose residues are shown in Table 11 below. AR RNAi Agents

[0079] The AR RNAi agents disclosed herein are designed to target specific positions on an AR gene (e.g., SEQ ID NO: 1 (NM 000044.6)). As defined herein, an antisense strand sequence is designed to target an AR gene at a given position on the gene when the 5' terminal nucleobase of the antisense strand is aligned with a position that is 21 nucleotides downstream (towards the 3' end) from the position on the gene when base pairing to the gene. For example, as illustrated in Tables 1 and 2 herein, an antisense strand sequence designed to target an AR gene at position 304 requires that when base pairing to the gene, the 5' terminal nucleobase of the antisense strand is aligned with position 324 of an AR gene.

[0080] As provided herein, an AR RNAi agent does not require that the nucleobase at position 1 (5'   3') of the antisense strand be complementary to the gene, provided that there is at least 85% complementarity (e.g., at least 85, 86. 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% complementarity) of the antisense strand and the gene across a core stretch sequence of at least 16 consecutive nucleotides. For example, for an AR RNAi agent disclosed herein that is designed to target position 304 of an AR gene, the 5' terminal nucleobase of the antisense strand of the of the AR RNAi agent must be aligned with position 324 of the gene; however, the 5' terminal nucleobase of the antisense strand may be, but is not required to be, complementary' to position 324 of an AR gene, provided that there is at least 85% complementarity (e.g., at least 85, 86, 87, 88, 89, 90. 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% complementarity) of the antisense strand and the gene transcript across a core stretch sequence of at least 16 consecutive nucleotides. As shown by, among other things, the various examples disclosed herein, the specific site of binding of the gene by the antisense strand of the AR RNAi agent (e.g., whether the AR RNAi agent is designed to target an AR gene at position 127, at position 130. at position 136, or at some other position) is an important factor to the level of inhibition achieved by the AR RNAi agent. (See, e.g., Kamola et al., The siRNA Non-seed Region and Its Target Sequences are Auxiliary Determinants of Off-Target Effects, PLOS Computational Biology, 11(12), Figure 1 (2015)).

[0081] In some embodiments, the AR RNAi agents disclosed herein target an AR gene al or near the positions of the AR sequence shown in Table 1. In some embodiments, the antisense strand of an AR RNAi agent disclosed herein includes a core stretch sequence that is fully, substantially, or at least partially complementary to a target AR 19-mer sequence disclosed in Table 1. Table 1. AR 19-mer mRNA Target Sequences (taken from homo sapiens Androgen Receptor (AR) transcript, GenBank NM_000044.6 (SEQ ID NO: 1)) SEQ ID No. AR 19-mer Target Sequences (5'^3') Corresponding Positions of Sequence on SEQ ID NO: 1 Targeted Gene Position (as referred to herein) 2 AGCUUUCCAGAAUCUGUUC 1189- 1207 1187 3 CCUCCAAGGACAAUUACUU 1785 - 1803 1783 4 CUUCGACCAUUUCUGACAA 1812-1830 1810 5 UGAAGAUACUGCUGAGUAU 2035 - 2053 2033 6 UUUCAAGGGAGGUUACACC 2059 - 2077 2057 7 CCCUGUCUCUCUACAAGUC 2157-2175 2155 8 GCGACUACUACAACUUUCC 2211 -2229 2209 SEQ ID No. AR 19-mer Target Sequences (5'^3') Corresponding Positions of Sequence on SEQ ID NO: 1 Targeted Gene Position (as referred to herein) 9 GUCCCACUUGUGUCAAAAG 2673 - 2691 2671 10 CUGGAUGGAUAGCUACUCC 2704 - 2722 2702 11 CAUUGACUAUUACUUUCCA 2773 - 2791 2771 12 AAGGUCUUCUUCAAAAGAG 2867 - 2885 2865 13 CUGAAGGGAAACAGAAGUA 2889 - 2907 2887 14 AAUGAUUGCACUAUUGAUA 2924 - 2942 2922 15 UCCGAAGGAAAAAUUGUCC 2946 - 2964 2944 16 GAAAAAUUGUCCAUCUUGU 2953 - 2971 2951 17 CGUCUUCGGAAAUGUUAUG 2972 - 2990 2970 18 UC GGAAAUGUUAUGAAGCA 2977 - 2995 2975 19 GAAGAAACUUGGUAAUCUG 3022 - 3040 3020 20 GACAGUGUCACACAUUGAA 3106-3124 3104 21 CACAUUGAAGGCUAUGAAU 3116-3134 3114 22 UGCUCUCUAGCCUCAAUGA 3228 - 3246 3226 23 AGAGCUGCAUCAGUUCACU 3742 - 3760 3740 24 GCAUCAGUUCACUUUUGAC 3748 - 3766 3746 25 CAUCAGUUCACUUUUGACC 3749 - 3767 3747 26 CUUUUGACCUGCUAAUCAA 3759 - 3777 3757 27 UGACCUGCUAAUCAAGUCA 3763 - 3781 3761 28 GACCUGCUAAUCAAGUCAC 3764 - 3782 3762 29 UGGUGAGCGUGGACUUUCC 3786 - 3804 3784 30 AAUGAUGGCAGAGAUCAUC 3808 - 3826 3806 31 GAUCAUCUCUGUGCAAGUG 3820 - 3838 3818 32 AUCCUUUCUGGGAAAGUCA 3845 - 3863 3843 33 ACCCAGUGAAGCAUUGGAA 3881 - 3899 3879

[0082] Homo sapiens Androgen Receptor (AR), GenBank NM_000044.6 (SEQ ID NO:1), gene transcript (10667 bases): 1 agcgccccct ccgagatccc ggggagccag cttgctggga gagcgggacg gtccggagca 61 agcccagagg cagaggaggc gacagaggga aaaagggccg agctagccgc tccagtgctg 121 tacaggagcc gaagggacgc accacgccag ccccagcccg gctccagcga cagccaacgc 181 ctcttgcagc gcggcggctt cgaagccgcc gcccggagct gccctttcct cttcggtgaa 241 gtttttaaaa gctgctaaag actcggagga agcaaggaaa gtgcctggta ggactgacgg 301 ctgcctttgt cctcctcctc tccaccccgc ctccccccac cctgccttcc ccccctcccc 361 cgtcttctct cccgcagctg cctcagtcgg ctactctcag ccaacccccc tcaccaccct 421 tctccccacc cgcccccccg cccccgtcgg cccagcgctg ccagcccgag tttgcagaga 481 ggtaactccc tttggctgcg agcgggcgag ctagctgcac attgcaaaga aggctcttag 541 gagccaggcg actggggagc ggcttcagca ctgcagccac gacccgcctg gttaggctgc 601 acgcggagag aaccctctgt tttcccccac tctctctcca cctcctcctg ccttccccac 661 cccgagtgcg gagccagaga tcaaaagatg aaaaggcagt caggtcttca gtagccaaaa 721 aacaaaacaa acaaaaacaa aaaagccgaa ataaaagaaa aagataataa ctcagttctt 781 atttgcacct acttcagtgg acactgaatt tggaaggtgg aggattttgt ttttttcttt 841 taagatctgg gcatcttttg aatctaccct tcaagtatta agagacagac tgtgagccta 901 gcagggcaga tcttgtccac cgtgtgtctt cttctgcacg agactttgag gctgtcagag 961 cgctttttgc gtggttgctc ccgcaagttt ccttctctgg agcttcccgc aggtgggcag 1021 ctagctgcag cgactaccgc atcatcacag cctgttgaac tcttctgagc aagagaaggg 1081 gaggcggggt aagggaagta ggtggaagat tcagccaagc tcaaggatgg aagtgcagtt 1141 agggctggga agggtctacc ctcggccgcc gtccaagacc taccgaggag ctttccagaa 1201 tctgttccag agcgtgcgcg aagtgatcca gaacccgggc cccaggcacc cagaggccgc 1261 gagcgcagca cctcccggcg ccagtttgct gctgctgcag cagcagcagc agcagcagca 1321 gcagcagcag cagcagcagc agcagcagca gcagcagcag cagcaagaga ctagccccag 1381 gcagcagcag cagcagcagg gtgaggatgg ttctccccaa gcccatcgta gaggccccac 1441 aggctacctg gtcctggatg aggaacagca accttcacag ccgcagtcgg ccctggagtg 1501 ccaccccgag agaggttgcg tcccagagcc tggagccgcc gtggccgcca gcaaggggct 1561 gccgcagcag ctgccagcac ctccggacga ggatgactca gctgccccat ccacgttgtc 1621 cctgctgggc cccactttcc ccggcttaag cagctgctcc gctgacctta aagacatcct 1681 gagcgaggcc agcaccatgc aactccttca gcaacagcag caggaagcag tatccgaagg 1741 cagcagcagc gggagagcga gggaggcctc gggggctccc acttcctcca aggacaatta 1801 cttagggggc acttcgacca tttctgacaa cgccaaggag ttgtgtaagg cagtgtcggt 1861 gtccatgggc ctgggtgtgg aggcgttgga gcatctgagt ccaggggaac agcttcgggg 1921 ggattgcatg tacgccccac ttttgggagt tccacccgct gtgcgtccca ctccttgtgc 1981 cccattggcc gaatgcaaag gttctctgct agacgacagc gcaggcaaga gcactgaaga 2041 tactgctgag tattcccctt tcaagggagg ttacaccaaa gggctagaag gcgagagcct 2101 aggctgctct ggcagcgctg cagcagggag ctccgggaca cttgaactgc cglctaccct 2161 gtctctctac aagtccggag cactggacga ggcagctgcg taccagagtc gcgactacta 2221 caactttcca ctggctctgg ccggaccgcc gccccctccg ccgcctcccc atccccacgc 2281 tcgcatcaag ctggagaacc cgctggacta cggcagcgcc tgggcggctg cggcggcgca 2341 gtgccgctat ggggacctgg cgagcctgca tggcgcgggt gcagcgggac ccggttctgg 2401 gtcaccctca gccgccgctt cctcatcctg gcacactctc ttcacagccg aagaaggcca 2461 gttgtatgga ccgtgtggtg gtggtggggg tggtggcggc ggcggcggcg gcggcggcgg 2521 cggcggcggc ggcggcggcg gcggcgaggc gggagctgta gccccctacg gctacactcg 2581 gccccctcag gggctggcgg gccaggaaag cgacttcacc gcacctgatg tgtggtaccc tggcggcatg gtgagcagag tgccctatcc cagtcccact tgtgtcaaaa gcgaaatggg cccctggatg gatagctact ccggacctta cggggacatg cgtttggaga ctgccaggga ccatgttttg cccattgact attactttcc accccagaag acctgcctga tctgtggaga tgaagcttct gggtgtcact atggagctct cacatgtgga agctgcaagg tcttcttcaa aagagccgct gaagggaaac agaagtacct gtgcgccagc agaaatgatt gcactattga taaattccga aggaaaaatt gtccatcttg tcgtcttcgg aaatgttatg aagcagggat gactctggga gcccggaagc tgaagaaact tggtaatctg aaactacagg aggaaggaga ggcttccagc accaccagcc ccactgagga gacaacccag aagctgacag tgtcacacat tgaaggctat gaatgtcagc ccatclttct gaatgtcctg gaagccaltg agccaggtgt agtgtgtgct ggacacgaca acaaccagcc cgactccttt gcagccttgc tctctagcct caatgaactg ggagagagac agcttgtaca cgtggtcaag tgggccaagg ccttgcctgg cttccgcaac ttacacgtgg acgaccagat ggctgtcatt cagtactcct ggatggggct catggtgttt gccatgggct ggcgatcctt caccaatgtc aactccagga tgctctactt cgcccctgat ctggttttca atgagtaccg catgcacaag tcccggatgt acagccagtg tgtccgaatg aggcacctct ctcaagagtt tggatggctc caaatcaccc cccaggaatt cctgtgcatg aaagcactgc tactcttcag cattattcca gtggatgggc tgaaaaatca aaaattcttt gatgaacttc gaatgaacta catcaaggaa ctcgatcgta tcattgcatg caaaagaaaa aatcccacat cctgctcaag acgcttctac cagctcacca agctcctgga ctccglgcag cctattgcga gagagctgca tcagltcact ttlgacctgc taatcaagtc acacatggtg agcgtggact ttccggaaat gatggcagag atcatctctg tgcaagtgcc caagatcctt tctgggaaag tcaagcccat ctatttccac acccagtgaa gcattggaaa ccctatttcc ccaccccagc tcatgccccc tttcagatgt cttctgcctg ttataactct gcactactcc tctgcagtgc cttggggaat ttcctctatt gatgtacagt ctgtcatgaa catgttcctg aattctattt gctgggcttt ttttt tctct ttctctcctt tctttttctt cttccctccc tatctaaccc tcccatggca ccttcagact ttgcttccca ttgtggctcc tatctgtgtt ttgaatggtg ttgtatgcct ttaaatctgt gatgatcctc atatggccca gtgtcaagtt gtgcttgttt acagcactac tctgtgccag ccacacaaac gtttacttat cttatgccac gggaagttta gagagctaag attatctggg gaaatcaaaa caaaaacaag caaacaaaaa aaaaaagcaa aaacaaaaca aaaaataagc caaaaaacct tgctagtgtt ttttcctcaa aaataaataa ataaataaat aaatacgtac atacatacac acatacatac aaacatatag aaatccccaa agaggccaat agtgacgaga aggtgaaaat tgcaggccca tggggagtta ctgatttttt catctcctcc ctccacggga gactttattt tctgccaatg gctattgcca ttagagggca gagtgacccc agagctgagt tgggcagggg ggtggacaga gaggagagga caaggagggc aatggagcat cagtacctgc ccacagcctt ggtccctggg ggctagactg ctcaactgtg gagcaattca ttatactgaa aatgtgcttg ttgttgaaaa tttgtctgca tgttaatgcc tcacccccaa acccttttct ctctcactct ctgcctccaa cttcagattg actttcaata gtttttctaa gacctttgaa ctgaatgttc tcttcagcca aaacttggcg acttccacag aaaagtctga ccactgagaa gaaggagagc agagatttaa ccctttgtaa ggccccattt ggatccaggt ctgctttctc atgtgtgagt cagggaggag ctggagccag aggagaagaa aatgatagct tggctgttct cctgcttagg acactgactg aatagttaaa ctctcactgc cactaccttt tccccacctt taaaagacct gaatgaagtt ttctgccaaa ctccgtgaag ccacaagcac cttatgtcct cccttcagtg ttttgtgggc ctgaatttca tcacactgca tttcagccat ggtcatcaag cctgtttgct tcttttgggc atgttcacag attctctgtt aagagccccc accaccaaga aggttagcag gccaacagct ctgacatcta tctgtagatg ccagtagtca caaagatttc ttaccaactc tcagatcgct ggagccctta gacaaactgg aaagaaggca tcaaagggat caggcaagct gggcgtcttg cccttgtccc ccagagatga taccctccca gcaagtggag aagttctcac ttccttcttt agagcagcta aaggggctac ccagatcagg gttgaagaga aaactcaatt accagggtgg gaagaatgaa ggcactagaa ccagaaaccc tgcaaatgct cttcttgtca cccagcatat ccacctgcag aagtcatgag aagagagaag gaacaaagag gagactctga ctactgaatt aaaatcttca gcggcaaagc ctaaagccag atggacacca tctggtgagt ttactcatca tcctcctctg ctgctgattc tgggctctga cattgcccat actcactcag attccccacc tttgtlgclg cctcltagtc agagggaggc caaaccallg agactttcta cagaaccatg gcttctttcg gaaaggtctg gttggtgtgg ctccaatact ttgccaccca tgaactcagg gtgtgccctg ggacactggt tttatatagt cttttggcac acctgtgttc tgttgacttc gttcttcaag cccaagtgca agggaaaatg tccacctact ttctcatctt ggcctctgcc tccttactta gctcttaatc tcatctgttg aactcaagaa atcaagggcc agtcatcaag ctgcccattt taattgattc actctgtttg ttgagaggat agtttctgag tgacatgata tgatccacaa gggtttcctt ccctgatttc tgcattgata ttaatagcca aacgaacttc aaaacagctt taaataacaa gggagagggg aacctaagat gagtaatatg ccaatccaag actgctggag aaaactaaag ctgacaggtt ccctttttgg ggtgggatag acatgttctg gttttcttta ttattacaca atctggctca tgtacaggat cacttttagc tgttttaaac agaaaaaaat atccaccact cttttcagtt acactaggtt acattttaat aggtccttta catctgtttt ggaatgattt tcatcttttg tgatacacag attgaattat atcattttca tatctctcct tgtaaatact agaagctctc ctttacattt ctctatcaaa tttttcatct ttatgggttt cccaattgtg actcttgtct tcatgaatat atgtttttca tttgcaaaag ccaaaaatca gtgaaacagc agtgtaatta aaagcaacaa ctggattact ccaaatttcc aaatgacaaa actagggaaa aatagcctac acaagccttt aggcctactc tttctgtgct tgggtttgag tgaacaaagg agattttagc ttggctctgt tctcccatgg atgaaaggag gaggattttt tttttctttt ggccattgat gttctagcca atgtaattga cagaagtctc attttgcatg cgctctgctc tacaaacaga gttggtatgg ttggtatact gtactcacct gtgagggact ggccactcag acccacttag ctggtgagct agaagatgag gatcactcac tggaaaagtc acaaggacca tctccaaaca agttggcagt gctcgatgtg gacgaagagt gaggaagaga aaaagaagga gcaccaggga gaaggctccg tctgtgctgg gcagcagaca gctgccagga tcacgaactc tgtagtcaaa gaaaagagtc gtgtggcagt ttcagctctc gttcattggg cagctcgcct aggcccagcc tctgagctga catgggagtt gttggattct ttgtttcata gctttttcta tgccataggc aatattgttg ttcttggaaa gtttattatt tttttaactc ccttactctg agaaagggat attttgaagg actgtcatat atctttgaaa aaagaaaatc tgtaatacat atatttttat gtatgttcac tggcactaaa aaatatagag agcttcattc tgtcctttgg gtagttgctg aggtaattgt ccaggttgaa aaataatgtg ctgatgctag agtccctctc tgtccatact ctacttctaa atacatatag gcatacatag caagttttat ttgacttgta ctttaagaga aaatatgtcc accatccaca tgatgcacaa atgagctaac attgagcttc aagtagcttc taagtgtttg tttcattagg cacagcacag atgtggcctt tccccccttc tctcccttga tatctggcag ggcataaagg cccaggccac ttcctctgcc ccttcccagc cctgcaccaa agctgcattt caggagactc tctccagaca gcccagtaac tacccgagca tggcccctgc atagccctgg aaaaataaga ggctgactgt ctacgaatla tcttgtgcca gttgcccagg tgagagggca ctgggccaag ggagtggttl tcatgtttga cccactacaa ggggtcatgg gaatcaggaa tgccaaagca ccagatcaaa tccaaaactt aaagtcaaaa taagccattc agcatgttca gtttcttgga aaaggaagtt tctacccctg atgcctttgt aggcagatct gttctcacca ttaatctttt tgaaaatctt ttaaagcagt tttlaaaaag agagatgaaa gcatcacatt atataaccaa agattacatt gtacctgcta agataccaaa attcataagg gcaggggggg agcaagcatt agtgcctctt tgataagctg tccaaagaca gactaaagga ctctgctggt gactgactta taagagcttt gtgggttttt tttlccctaa taatatacat gtttagaaga attgaaaata atttcgggaa aatgggatta tgggtccttc actaagtgat tttataagca gaactggctt tccttttctc tagtagttgc tgagcaaatt gttgaagctc catcattgca tggttggaaa tggagctgtt cttagccact gtgtttgcta gtgcccatgt tagcttatct gaagatgtga aacccttgct gataagggag catttaaagt actagatttt gcactagagg gacagcaggc agaaatcctt atttctgccc actttggatg gcacaaaaag ttatctgcag ttgaaggcag aaagttgaaa tacattgtaa atgaatattt gtatccatgt ttcaaaattg aaatatatat atatatatat atatatatat atatatatat atagtgtgtg tgtgtgttct gatagcttta actttctctg catctttata tttggttcca gatcacacct gatgccatgt acttgtgaga gaggatgcag 8761 ttttgttttg gaagctctct cagaacaaac aagacacctg gattgatcag ttaactaaaa 8821 gttttctccc ctattgggtt tgacccacag gtcctgtgaa ggagcagagg gataaaaaga 8881 gtagaggaca tgatacattg tactttacta gttcaagaca gatgaatgtg gaaagcataa 8941 aaactcaatg gaactgactg agatttacca cagggaaggc ccaaacttgg ggccaaaagc 9001 ctacccaagt gattgaccag tggcccccta atgggacctg agctgttgga agaagagaac 9061 tgttccttgg tcttcaccat ccttgtgaga gaagggcagt ttcctgcatt ggaacctgga 9121 gcaagcgctc tatctttcac acaaattccc tcacctgaga ttgaggtgct cttgttactg 9181 ggtgtctgtg tgctgtaatt ctggttttgg atatgttctg taaagatttt gacaaatgaa 9241 aatgtgtttt tctctgttaa aacttgtcag agtactagaa gttgtatctc tgtaggtgca 9301 ggtccatttc tgcccacagg tagggtgttt ttctttgatt aagagattga cacttctgtt 9361 gcctaggacc tcccaactca accatttcta ggtgaaggca gaaaaatcca cattagttac 9421 tcctcttcag acatttcagc tgagataaca aatcttttgg aattttttca cccatagaaa 9481 gagtggtaga tatttgaatt tagcaggtgg agtttcatag taaaaacagc ttttgactca 9541 gctttgattt atcctcattt gatttggcca gaaagtaggt aatatgcatt gattggcttc 9601 tgattccaat tcagtatagc aaggtgctag gttttttcct ttccccacct gtctcttagc 9661 ctggggaatt aaatgagaag ccttagaatg ggtggccctt gtgacctgaa acacttccca 9721 cataagctac ttaacaagat tgtcatggag ctgcagattc cattgcccac caaagactag 9781 aacacacaca tatccataca ccaaaggaaa gacaattctg aaatgctgtt tctctggtgg 9841 ttccclctct ggctgctgcc tcacagtatg ggaacclgta ctctgcagag gtgacaggcc 9901 agatttgcat tatctcacaa ccttagccct tggtgctaac tgtcctacag tgaagtgcct 9961 ggggggttgt cctatcccat aagccacttg gatgctgaca gcagccacca tcagaatgac 10021 ccacgcaaaa aaaagaaaaa aaaaattaaa aagtcccctc acaacccagt gacacctttc 10081 tgctttcctc tagactggaa cattgattag ggagtgcctc agacatgaca ttcttgtgct 10141 gtccttggaa ttaatctggc agcaggaggg agcagactat gtaaacagag ataaaaatta 10201 attttcaata ttgaaggaaa aaagaaataa gaagagagag agaaagaaag catcacacaa 10261 agattttctt aaaagaaaca attttgcttg aaatctcttt agatggggct catttctcac 10321 ggtggcactt ggcctccact gggcagcagg accagctcca agcgctagtg ttctgttctc 10381 tttttgtaat cttggaatct tttgttgctc taaatacaat taaaaatggc agaaacttgt 10441 ttgttggact acatgtgtga ctttgggtct gtctctgcct ctgctttcag aaatgtcatc 10501 cattgtgtaa aatattggct tactggtctg ccagctaaaa cttggccaca tcccctgtla 10561 tggctgcagg atcgagttat tgttaacaaa gagacccaag aaaagctgct aatgtcctct 10621 tatcattgtt gttaatttgt taaaacataa agaaatctaa aatttca

[0083] In some embodiments, an AR RNAi agent includes an antisense strand wherein position 19 of the antisense strand (5'3') is capable of forming a base pair with position 1 of a 19-mer target sequence disclosed in Table 1. In some embodiments, an AR agent includes an antisense strand wherein position 1 of the antisense strand (5' 3') is capable of forming a base pair with position 19 of a 19-mer target sequence disclosed in Table 1.

[0084] In some embodiments, an AR agent includes an antisense strand wherein position 2 of the antisense strand (5' -> 3’) is capable of forming a base pair with position 18 of a 19-mer target sequence disclosed in Table 1. In some embodiments, an AR agent includes an antisense strand wherein positions 2 through 18 of the antisense strand (5' -> 3') are capable of forming base pairs with each of the respective complementary bases located at positions 18 through 2 of the 19-mer target sequence disclosed in Table 1.

[0085] For the RNAi agents disclosed herein, the nucleotide at position 1 of the antisense strand (from 5' end -> 3' end) can be perfectly complementary to an AR gene, or can be non-complementary to an AR gene. In some embodiments, the nucleotide at position 1 of the antisense strand (from 5' end 3' end) is a U, A, or dT. In some embodiments, the nucleotide at position 1 of the antisense strand (from 5' end -> 3' end) forms an A:U or U:A base pair with the sense strand.

[0086] In some embodiments, an AR RNAi agent antisense strand comprises the sequence of nucleotides (from 5' end -> 3' end) 2-18 or 2-19 of any of the antisense strand sequences in Table 2 or Table 3. In some embodiments, an AR RNAi sense strand comprises the sequence of nucleotides (from 5' end -> 3' end) 1-17, 1 -18, or 2-18 of any of the sense strand sequences in Table 2, Table 4, Table 5, or Table 6.

[0087] In some embodiments, an AR RNAi agent comprises of (i) an antisense strand comprising the sequence of nucleotides (from 5' end -> 3' end) 2-18 or 2-19 of any of the antisense strand sequences in Table 2 or Table 3, and (li) a sense strand comprising the sequence of nucleotides (from 5' end 3' end) 1-17 or 1-18 of any of the sense strand sequences in Table 2, Table 4, Table 5, or Table 6.

[0088] In some embodiments, the AR RNAi agents include core 19-mer nucleotide sequences shown in the following Table 2. Table 2. AR RNAi Agent Antisense Strand and Sense Strand Core Stretch Base Sequences (N=any nucleobase; I = inosine (hypoxanthine nucleobase) SEQ ID NO:. Antisense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO:. Sense Strand Base Sequence (5'    3') (Shown as an Unmodified Nucleotide Sequence) Corresponding Positions of Identified Sequence on SEQ ID NO: 1 Targeted Gene Position 34 UAACAGAUUCUGGAAAGCU 178 AGCUUUCCAGAAUCUGUUA 1189- 1207 1187 35 AAACAGAUUCUGGAAAGCU 179 AGCUUUCCAGAAUCUGUUU 1189- 1207 1187 36 GAACAGAUUCUGGAAAGCU 180 AGCUUUCCAGAAUCUGUUC 1189- 1207 1187 37 NAACAGAUUCUGGAAAGCU 181 AGCUUUCCAGAAUCUGUUN 1189- 1207 1187 38 NAACAGAUUCUGGAAAGCN 182 NGCUUUCCAGAAUCUGUUN 1189- 1207 1187 39 UAGUAAUUGUCCUUGGAGG 183 CCUCCAAGGACAAUUACUA 1785 - 1803 1783 40 AAGUAAUUGUCCUUGGAGG 184 CCUCCAAGGACAAUUACUU 1785 - 1803 1783 41 NAGUAAUUGUCCUUGGAGG 185 CCUCCAAGGACAAUUACUN 1785 - 1803 1783 42 NAGUAAUUGUCCUUGGAGN 186 NCUCCAAGGACAAUUACUN 1785 - 1803 1783 43 AUGUCAGAAAUGGUCGAAG 187 CUUCGACCAUUUCUGACAU 1812-1830 1810 44 UUGUCAGAAAUGGUCGAAG 188 CUUCGACCAUUUCUGACAA 1812-1830 1810 WO 2025 / 160224                                   PCT / US2025 / 012678 SEQ ID NO:. Antisense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO:. Sense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) Corresponding Positions of Identified Sequence on SEQ ID NO: 1 Targeted Gene Position 45 NUGUCAGAAAUGGUCGAAG 189 CUUCGACCAUUUCUGACAN 1812-1830 1810 46 NUGUCAGAAAUGGUCGAAN 190 NUUCGACCAUUUCUGACAN 1812-1830 1810 47 UUACUCAGCAGUAUCUUCA 191 UGAAGAUACUGCUGAGUAA 2035 - 2053 2033 48 AUACUCAGCAGUAUCUUCA 192 UGAAGAUACUGCUGAGUAU 2035 - 2053 2033 49 NUACUCAGCAGUAUCUUCA 193 UGAAGAUACUGCUGAGUAN 2035 - 2053 2033 50 NUACUCAGCAGUAUCUUCN 194 NGAAGAUACUGCUGAGUAN 2035 - 2053 2033 51 UGUGUAACCUCCCUUGAAA 195 UUUCAAGGGAGGUUACACA 2059 - 2077 2057 52 AGUGUAACCUCCCUUGAAA 196 UUUCAAGGGAGGUUACACU 2059 - 2077 2057 53 GGUGUAACCUCCCUUGAAA 197 UUUCAAGGGAGGUUACACC 2059 - 2077 2057 54 NGUGUAACCUCCCUUGAAA 198 UUUCAAGGGAGGUUACACN 2059 - 2077 2057 55 NGUGUAACCUCCCUUGAAN 199 NUUCAAGGGAGGUUACACN 2059 - 2077 2057 56 UACUUGUAGAGAGACAGGG 200 CCCUGUCUCUCUACAAGUA 2157-2175 2155 WO 2025 / 160224                                   PCT / US2025 / 012678 SEQ ID NO:. Antisense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO:. Sense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) Corresponding Positions of Identified Sequence on SEQ ID NO: 1 Targeted Gene Position 57 AACUUGUAGAGAGACAGGG 201 CCCUGUCUCUCUACAAGUU 2157-2175 2155 58 GACUUGUAGAGAGACAGGG 202 CCCUGUCUCUCUACAAGUC 2157-2175 2155 59 NACUUGUAGAGAGACAGGG 203 CCCUGUCUCUCUACAAGUN 2157-2175 2155 60 NACUUGUAGAGAGACAGGN 204 NCCUGUCUCUCUACAAGUN 2157-2175 2155 61 UGAAAGUUGUAGUAGUCGC 205 GCGACUACUACAACUUUCA 2211 -2229 2209 62 AGAAAGUUGUAGUAGUCGC 206 GCGACUACUACAACUUUCU 2211 -2229 2209 63 GGAAAGUUGUAGUAGUCGC 207 GCGACUACUACAACUUUCC 2211 -2229 2209 64 NGAAAGUUGUAGUAGUCGC 208 GCGACUACUACAACUUUCN 2211 -2229 2209 65 NGAAAGUUGUAGUAGUCGN 209 NCGACUACUACAACUUUCN 2211 -2229 2209 66 UUUUUGACACAAGUGGGAC 210 GUCCCACUUGUGUCAAAAA 2673 -2691 2671 67 AUUUUGACACAAGUGGGAC 211 GUCCCACUUGUGUCAAAAU 2673 -2691 2671 68 CUUUUGACACAAGUGGGAC 212 GUCCCACUUGUGUCAAAAG 2673 -2691 2671 WO 2025 / 160224                                   PCT / US2025 / 012678 SEQ ID NO:. Antisense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO:. Sense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) Corresponding Positions of Identified Sequence on SEQ ID NO: 1 Targeted Gene Position 69 NUUUUGACACAAGUGGGAC 213 GUCCCACUUGUGUCAAAAN 2673 - 2691 2671 70 NUUUUGACACAAGUGGGAN 214 NUCCCACUUGUGUCAAAAN 2673 - 2691 2671 71 UGAGUAGCUAUCCAUCCAG 215 CUGGAUGGAUAGCUACUCA 2704 - 2722 2702 72 AGAGUAGCUAUCCAUCCAG 216 CUGGAUGGAUAGCUACUCU 2704 - 2722 2702 73 GGAGUAGCUAUCCAUCCAG 217 CUGGAUGGAUAGCUACUC C 2704 - 2722 2702 74 NGAGUAGCUAUCCAUCCAG 218 CUGGAUGGAUAGCUACUCN 2704 - 2722 2702 75 NGAGUAGCUAUCCAUCCAN 219 NUGGAUGGAUAGCUACUCN 2704 - 2722 2702 76 AGGAAAGUAAUAGUCAAUG 220 CAUUGACUAUUACUUUCCU 2773 -2791 2771 77 UGGAAAGUAAUAGUCAAUG 221 CAUUGACUAUUACUUUCCA 2773 -2791 2771 78 NGGAAAGUAAUAGUCAAUG 222 CAUUGACUAUUACUUUCCN 2773 -2791 2771 79 NGGAAAGUAAUAGUCAAUN 223 NAUUGACUAUUACUUUCCN 2773 - 2791 2771 80 UUCUUUUGAAGAAGACCUU 224 AAGGUCUUCUUCAAAAGAA 2867 - 2885 2865 WO 2025 / 160224                                   PCT / US2025 / 012678 SEQ ID NO:. Antisense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO:. Sense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) Corresponding Positions of Identified Sequence on SEQ ID NO: 1 Targeted Gene Position 81 AUCUUUUGAAGAAGACCUU 225 AAGGUCUUCUUCAAAAGAU 2867 - 2885 2865 82 CUCUUUUGAAGAAGACCUU 226 AAGGUCUUCUUCAAAAGAG 2867 - 2885 2865 83 NUCUUUUGAAGAAGACCUU 227 AAGGUCUUCUUCAAAAGAN 2867 - 2885 2865 84 NUCUUUUGAAGAAGACCUN 228 NAGGUCUUCUUCAAAAGAN 2867 - 2885 2865 85 AACUUCUGUUUCCCUUCAG 229 CUGAAGGGAAACAGAAGUU 2889 - 2907 2887 86 UACUUCUGUUUCCCUUCAG 230 CUGAAGGGAAACAGAAGUA 2889 - 2907 2887 87 NACUUCUGUUUCCCUUCAG 231 CUGAAGGGAAACAGAAGUN 2889 - 2907 2887 88 NACUUCUGUUUCCCUUCAN 232 NUGAAGGGAAACAGAAGUN 2889 - 2907 2887 89 AAUCAAUAGUGCAAUCAUU 233 AAUGAUUGCACUAUUGAUU 2924 - 2942 2922 90 UAUCAAUAGUGCAAUCAUU 234 AAUGAUUGCACUAUUGAUA 2924 - 2942 2922 91 NAUCAAUAGUGCAAUCAUU 235 AAUGAUUGCACUAUUGAUN 2924 - 2942 2922 92 NAUCAAUAGUGCAAUCAUN 236 NAUGAUUGCACUAUUGAUN 2924 - 2942 2922 WO 2025 / 160224                                   PCT / US2025 / 012678 SEQ ID NO:. Antisense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO:. Sense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) Corresponding Positions of Identified Sequence on SEQ ID NO: 1 Targeted Gene Position 93 UGACAAUUUUUCCUUCGGA 237 UCCGAAGGAAAAAUUGUCA 2946 - 2964 2944 94 AGACAAUUUUUCCUUCGGA 238 UCCGAAGGAAAAAUUGUCU 2946 - 2964 2944 95 GGACAAUUUUUCCUUCGGA 239 UCCGAAGGAAAAAUUGUCC 2946 - 2964 2944 96 NGACAAUUUUUCCUUCGGA 240 UCCGAAGGAAAAAUUGUCN 2946 - 2964 2944 97 NGACAAUUUUUCCUUCGGN 241 NCCGAAGGAAAAAUUGUCN 2946 - 2964 2944 98 UCAAGAUGGACAAUUUUUC 242 GAAAAAUUGUCCAUCUUGA 2953 -2971 2951 99 ACAAGAUGGACAAUUUUUC 243 GAAAAAUUGUCCAUCUUGU 2953 -2971 2951 100 NCAAGAUGGACAAUUUUUC 244 GAAAAAUUGUCCAUCUUGN 2953 -2971 2951 101 NCAAGAUGGACAAUUUUUN 245 NAAAAAUUGUCCAUCUUGN 2953 -2971 2951 102 UAUAACAUUUCCGAAGACG 246 CGUCUUCGGAAAUGUUAUA 2972 - 2990 2970 103 AAUAACAUUUCCGAAGACG 247 CGUCUUCGGAAAUGUUAUU 2972 - 2990 2970 104 CAUAACAUUUCCGAAGACG 248 CGUCUUCGGAAAUGUUAUG 2972 - 2990 2970 WO 2025 / 160224                                   PCT / US2025 / 012678 SEQ ID NO:. Antisense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO:. Sense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) Corresponding Positions of Identified Sequence on SEQ ID NO: 1 Targeted Gene Position 105 NAUAACAUUUCCGAAGACG 249 CGUCUUCGGAAAUGUUAUN 2972 - 2990 2970 106 NAUAACAUUUC CGAAGACN 250 NGUCUUCGGAAAUGUUAUN 2972 - 2990 2970 107 AGCUUCAUAACAUUUCCGA 251 UCGGAAAUGUUAUGAAGCU 2977 - 2995 2975 108 UGCUUCAUAACAUUUCCGA 252 UCGGAAAUGUUAUGAAGCA 2977 - 2995 2975 109 NGCUUCAUAACAUUUCCGA 253 UCGGAAAUGUUAUGAAGCN 2977 - 2995 2975 110 NGCUUCAUAACAUUUCCGN 254 NCGGAAAUGUUAUGAAGCN 2977 - 2995 2975 111 UAGAUUACCAAGUUUCUUC 255 GAAGAAACUUGGUAAUCUA 3022 - 3040 3020 112 AAGAUUACCAAGUUUCUUC 256 GAAGAAACUUGGUAAUCUU 3022 - 3040 3020 113 CAGAUUACCAAGUUUCUUC 257 GAAGAAACUUGGUAAUCUG 3022 - 3040 3020 114 NAGAUUACCAAGUUUCUUC 258 GAAGAAACUUGGUAAUCUN 3022 - 3040 3020 115 NAGAUUACCAAGUUUCUUN 259 NAAGAAACUUGGUAAUCUN 3022 - 3040 3020 116 AUCAAUGUGUGACACUGUC 260 GACAGUGUCACACAUUGAU 3106-3124 3104 WO 2025 / 160224                                   PCT / US2025 / 012678 SEQ ID NO:. Antisense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO:. Sense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) Corresponding Positions of Identified Sequence on SEQ ID NO: 1 Targeted Gene Position 117 UUCAAUGUGUGACACUGUC 261 GACAGUGUCACACAUUGAA 3106-3124 3104 118 NUCAAUGUGUGACACUGUC 262 GACAGUGUCACACAUUGAN 3106-3124 3104 119 NUCAAUGUGUGACACUGUN 263 NACAGUGUCACACAUUGAN 3106-3124 3104 120 UUUCAUAGCCUUCAAUGUG 264 CACAUUGAAGGCUAUGAAA 3116-3134 3114 121 AUUCAUAGCCUUCAAUGUG 265 CACAUUGAAGGCUAUGAAU 3116-3134 3114 122 NUUCAUAGCCUUCAAUGUG 266 CACAUUGAAGGCUAUGAAN 3116-3134 3114 123 NUUCAUAGCCUUCAAUGUN 267 NACAUUGAAGGCUAUGAAN 3116-3134 3114 124 ACAUUGAGGCUAGAGAGCA 268 UGCUCUCUAGCCUCAAUGU 3228 - 3246 3226 125 UCAUUGAGGCUAGAGAGCA 269 UGCUCUCUAGCCUCAAUGA 3228 - 3246 3226 126 NCAUUGAGGCUAGAGAGCA 270 UGCUCUCUAGCCUCAAUGN 3228 - 3246 3226 127 NCAUUGAGGCUAGAGAGCN 271 NGCUCUCUAGCCUCAAUGN 3228 - 3246 3226 128 UGUGAACUGAUGCAGCUCU 272 AGAGCUGCAUCAGUUCACA 3742 - 3760 3740 WO 2025 / 160224                                   PCT / US2025 / 012678 SEQ ID NO:. Antisense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO:. Sense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) Corresponding Positions of Identified Sequence on SEQ ID NO: 1 Targeted Gene Position 129 AGUGAACUGAUGCAGCUCU 273 AGAGCUGCAUCAGUUCACU 3742 - 3760 3740 130 NGUGAACUGAUGCAGCUCU 274 AGAGCUGCAUCAGUUCACN 3742 - 3760 3740 131 NGUGAACUGAUGCAGCUCN 275 NGAGCUGCAUCAGUUCACN 3742 - 3760 3740 132 UUCAAAAGUGAACUGAUGC 276 GCAUCAGUUCACUUUUGAA 3748 - 3766 3746 133 AUCAAAAGUGAACUGAUGC 277 GCAUCAGUUCACUUUUGAU 3748 - 3766 3746 134 GUCAAAAGUGAACUGAUGC 278 GCAUCAGUUCACUUUUGAC 3748 - 3766 3746 135 NUCAAAAGUGAACUGAUGC 279 GCAUCAGUUCACUUUUGAN 3748 - 3766 3746 136 NUCAAAAGUGAACUGAUGN 280 NCAUCAGUUCACUUUUGAN 3748 - 3766 3746 137 UGUCAAAAGUGAACUGAUG 281 CAUCAGUUCACUUUUGACA 3749 - 3767 3747 138 AGUCAAAAGUGAACUGAUG 282 CAUCAGUUCACUUUUGACU 3749 - 3767 3747 139 GGUCAAAAGUGAACUGAUG 283 CAUCAGUUCACUUUUGACC 3749 - 3767 3747 140 NGUCAAAAGUGAACUGAUG 284 CAUCAGUUCACUUUUGACN 3749 - 3767 3747 WO 2025 / 160224                                   PCT / US2025 / 012678 SEQ ID NO:. Antisense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO:. Sense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) Corresponding Positions of Identified Sequence on SEQ ID NO: 1 Targeted Gene Position 141 NGUCAAAAGUGAACUGAUN 285 NAUCAGUUCACUUUUGACN 3749 - 3767 3747 142 AUGAUUAGCAGGUCAAAAG 286 CUUUUGACCUGCUAAUCAU 3759 - 3777 3757 143 UUGAUUAGCAGGUCAAAAG 287 CUUUUGACCUGCUAAUCAA 3759 - 3777 3757 144 NUGAUUAGCAGGUCAAAAG 288 CUUUUGACCUGCUAAUCAN 3759 - 3777 3757 145 NUGAUUAGCAGGUCAAAAN 289 NUUUUGACCUGCUAAUCAN 3759 - 3777 3757 146 AGACUUGAUUAGCAGGUCA 290 UGACCUGCUAAUCAAGUCU 3763 - 3781 3761 147 UGACUUGAUUAGCAGGUCA 291 UGACCUGCUAAUCAAGUCA 3763 - 3781 3761 148 NGACUUGAUUAGCAGGUCA 292 UGACCUGCUAAUCAAGUCN 3763 - 3781 3761 149 NGACUUGAUUAGCAGGUCN 293 NGACCUGCUAAUCAAGUCN 3763 - 3781 3761 150 UUGACUUGAUUAGCAGGUC 294 GACCUGCUAAUCAAGUCAA 3764 - 3782 3762 151 AUGACUUGAUUAGCAGGUC 295 GACCUGCUAAUCAAGUCAU 3764 - 3782 3762 152 GUGACUUGAUUAGCAGGUC 296 GACCUGCUAAUCAAGUCAC 3764 - 3782 3762 WO 2025 / 160224                                   PCT / US2025 / 012678 SEQ ID NO:. Antisense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO:. Sense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) Corresponding Positions of Identified Sequence on SEQ ID NO: 1 Targeted Gene Position 153 NUGACUUGAUUAGCAGGUC 297 GACCUGCUAAUCAAGUCAN 3764 - 3782 3762 154 NUGACUUGAUUAGCAGGUN 298 NACCUGCUAAUCAAGUCAN 3764 - 3782 3762 155 UGAAAGUCCACGCUCACCA 299 UGGUGAGCGUGGACUUUCA 3786 - 3804 3784 156 AGAAAGUCCACGCUCACCA 300 UGGUGAGC GUGGACUUUCU 3786 - 3804 3784 157 GGAAAGUCCACGCUCACCA 301 UGGUGAGC GUGGACUUUCC 3786 - 3804 3784 158 NGAAAGUCCACGCUCACCA 302 UGGUGAGC GUGGACUUUCN 3786 - 3804 3784 159 NGAAAGUCCACGCUCACCN 303 NGGUGAGC GUGGACUUUCN 3786 - 3804 3784 160 UAUGAUCUCUGCCAUCAUU 304 AAUGAUGGCAGAGAUCAUA 3808 - 3826 3806 161 AAUGAUCUCUGCCAUCAUU 305 AAUGAUGGCAGAGAUCAUU 3808 - 3826 3806 162 GAUGAUCUCUGCCAUCAUU 306 AAUGAUGGCAGAGAUCAUC 3808 - 3826 3806 163 NAUGAUCUCUGCCAUCAUU 307 AAUGAUGGCAGAGAUCAUN 3808 - 3826 3806 164 NAUGAUCUCUGCCAUCAUN 308 NAUGAUGGCAGAGAUCAUN 3808 - 3826 3806 WO 2025 / 160224                                   PCT / US2025 / 012678 SEQ ID NO:. Antisense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO:. Sense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) Corresponding Positions of Identified Sequence on SEQ ID NO: 1 Targeted Gene Position 165 UACUUGCACAGAGAUGAUC 309 GAUCAUCUCUGUGCAAGUA 3820 - 3838 3818 166 AACUUGCACAGAGAUGAUC 310 GAUCAUCUCUGUGCAAGUU 3820 - 3838 3818 167 CACUUGCACAGAGAUGAUC 311 GAUCAUCUCUGUGCAAGUG 3820 - 3838 3818 168 NACUUGCACAGAGAUGAUC 312 GAUCAUCUCUGUGCAAGUN 3820 - 3838 3818 169 NACUUGCACAGAGAUGAUN 313 NAUCAUCUCUGUGCAAGUN 3820 - 3838 3818 170 AGACUUUCCCAGAAAGGAU 314 AUCCUUUCUGGGAAAGUCU 3845 - 3863 3843 171 UGACUUUCCCAGAAAGGAU 315 AUCCUUUCUGGGAAAGUCA 3845 - 3863 3843 172 NGACUUUCCCAGAAAGGAU 316 AUCCUUUCUGGGAAAGUCN 3845 - 3863 3843 173 NGACUUUCCCAGAAAGGAN 317 NUCCUUUCUGGGAAAGUCN 3845 - 3863 3843 174 AUCCAAUGCUUCACUGGGU 318 ACCCAGUGAAGCAUUGGAU 3881 - 3899 3879 175 UUCCAAUGCUUCACUGGGU 319 ACCCAGUGAAGCAUUGGAA 3881 - 3899 3879 176 NUCCAAUGCUUCACUGGGU 320 ACCCAGUGAAGCAUUGGAN 3881 - 3899 3879 WO 2025 / 160224                                   PCT / US2025 / 012678 SEQ ID NO:. Antisense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO:. Sense Strand Base Sequence (5' - 3') (Shown as an Unmodified Nucleotide Sequence) Corresponding Positions of Identified Sequence on SEQ ID NO: 1 Targeted Gene Position 177 NUCCAAUGCUUCACUGGGN 321 NCCCAGUGAAGCAUUGGAN 3881 - 3899 3879 WO 2025 / 160224                                   PCT / US2025 / 012678

[0089] The AR RNAi agent sense strands and antisense strands that comprise or consist of the nucleotide sequences in Table 2 can be modified nucleotides or unmodified nucleotides. In some embodiments, the AR RNAi agents having the sense and antisense strand sequences that comprise or consist of any of the nucleotide sequences in Table 2 are all or substantially all modified nucleotides.

[0090] In some embodiments, the antisense strand of an AR RNAi agent disclosed herein differs by 0, 1, 2, or 3 nucleotides from any of the antisense strand sequences in Table 2. In some embodiments, the sense strand of an AR RNAi agent disclosed herein differs by 0, 1,2, or 3 nucleotides from any of the sense strand sequences in Table 2.

[0091] As used herein, each N listed in a sequence disclosed in Table 2 may be independently selected from any and all nucleobases (including those found on both modified and unmodified nucleotides). In some embodiments, an N nucleotide listed in a sequence disclosed in Table 2 has a nucleobase that is complementary to the N nucleotide at the corresponding position on the other strand. In some embodiments, an N nucleotide listed in a sequence disclosed in Table 2 has a nucleobase that is not complementary to the N nucleotide at the corresponding position on the other strand. In some embodiments, an N nucleotide listed in a sequence disclosed in Table 2 has a nucleobase that is the same as the N nucleotide at the corresponding position on the other strand. In some embodiments, an N nucleotide listed in a sequence disclosed in Table 2 has a nucleobase that is different from the N nucleotide al the corresponding position on the other strand.

[0092] Certain modified AR RNAi agent sense and antisense strands are provided in Table 3, Table 4, Table 5, Table 6, and Table 10. Certain modified AR RNAi agent antisense strands, as well as their underlying unmodified nucleobase sequences, are provided in Table 3. Certain modified AR RNAi agent sense strands, as well as their underlying unmodified nucleobase sequences, are provided in Tables 4. 5, and 6. In forming AR RNAi agents, each of the nucleotides in each of the underlying base sequences listed in Tables 3, 4, 5, and 6, as well as in Table 2, above, can be a modified nucleotide.

[0093] The AR RNAi agents described herein are formed by annealing an antisense strand with a sense strand. A sense strand containing a sequence listed in Table 2, Table 4, Table 5, or Table 6 can be hybridized to any antisense strand containing a sequence listed in Table 2 or Table 3, provided the two sequences have a region of at least 85% complementarity over a contiguous 16, 17, 18, 19, 20, or 21 nucleotide sequence.

[0094] In some embodiments, an AR RNAi agent antisense strand comprises a nucleotide sequence of any of the sequences in Table 2 or Table 3.

[0095] In some embodiments, an AR RNAi agent comprises or consists of a duplex having the nucleobase sequences of the sense strand and the antisense strand of any of the sequences in Table 2, Table 3, Table 4, Table 5, Table 6, or Table 10.

[0096] Examples of antisense strands containing modified nucleotides are provided in Table 3. Examples of sense strands containing modified nucleotides are provided in Tables 4, 5 and 6.

[0097] As used in Tables 3, 4. 5, 6. and 10, the following notations are used to indicate modified nucleotides, targeting groups, and linking groups: A        =  adenosine-3'-phosphate C         =  cytidine-3'-phosphate G        =  guanosine-3'-phosphate U         =  uridine-3'-phosphate I          =  inosine-3'-phosphate a         =  2'-O-methyladenosine-3'-phosphate as        =  2'-O-methyladenosine-3'-phosphorothioate c         =  2'-O-methylcytidine-3 '-phosphate cs        =  2'-O-methylcytidine-3'-phosphorothioate g         =  2'-O-methylguanosine-3'-phosphate gs        =  2'-O-methylguanosine-3'-phosphorothioate i          =  2'-O-methylinosine-3’-phosphate is         =  2'-O-methylinosine-3’-phosphorothioate t          =  2'-O-methyl-5-methyluridine-3'-phosphate ts         =  2'-O-methyl-5-methyluridine-3'-phosphorothioate u         =  2'-O-methyluridine-3'-phosphate us        =  2'-O-methyluridine-3'-phosphorothioate Af       =  2'-fluoroadenosine-3'-phosphate Afs       =  2'-fluoroadenosine-3'-phosporothioate Cf        =  2'-fluorocytidine-3'-phosphate Cfs       =  2'-fluorocytidine-3'-phosphorothioate Gf        =  2'-fluoroguanosine-3'-phosphate Gfs       =  2'-fluoroguanosine-3'-phosphorothioate Tf        =  2'-fluoro-5'-methyluridine-3'-phosphate Tfs       =  2'-fluoro-5'-methyluridine-3'-phosphorothioate Uf        =  2'-fluorouridine-3'-phosphate Ufs       =  2'-fluorouridine-3'-phosphorothioate dT       =  2'-deoxythymidine-3 '-phosphate Auna     =  2'.3'-seco-adenosine-3'-phosphate (See Table 11) Aunas    =  2'.3'-seco-adenosine-3'-phosphorothioate (See Table 11) Cuna     =  2',3'-seco-cytidine-3'-phosphate (SeeTable 11) Cunas = 2'.3'-seco-cytidine-3'-phosphorothioate (See Table 11) Guna = 2',3'-seco-guanosine-3'-phosphate (See Table 11) Gunas = 2',3'-seco-guanosine-3'-phosphorothioate (See Table 11) Uuna     =  2',3'-seco-uridine-3'-phosphate (See Table 11) Uunas = 2',3'-seco-uridine-3'-phosphorothioate (See Table 11) a_2N     =  see Table 11 a_2Ns    =  see Table 11 (invAb) = inverted abasic deoxyribonucleotide-5'- phosphate, see Table 11 (invAb)s = inverted abasic deoxyribonucleotide-5'- phosphorothioate, see Table 11 s          = phosphorothioate linkage p         =  terminal phosphate (as synthesized) vpdN     =  vinyl phosphonate deoxyribonucleotide cPrpa     =  5’-cyclopropyl phosphonate-2'-O-methyladenosine-3'-phosphate (see Table 11) cPrpas    =  5’-cyclopropyl            phosphonate-2'-O-methyladenosine-3'- phosphorothioate (see Table 11) cPrpu    =  5’-cyclopropyl phosphonate-2'-O-methyluridine-3'-phosphate (see Table 11) cPrpus    =  5’-cyclopropyl                phosphonate-2'-O-methyluridine-3'- phosphorothioate (see Table 11) (Alk-SS-C6) = see Table 11 (C6-SS-Alk) = see Table 11 (C6-SS-C6) = see Table 11 (6-SS-6)     = see Table 11 (C6-SS-Alk-Me) = see Table 11 (NH2-C6)   =  see Table 11 -C6-        =   see Table 11 -C6s-        =   see Table 11 -L6-C6-     =   see Table 11 -L6-C6s-    =   see Table 11 LP183s     =  seeTablell LP183rs    =  seeTablell LP409s = see Table 11 cC16       =  seeTablell aC16       =  seeTablell gC16      =  seeTablell uC16      =  seeTablell ALNA     =  see Table 11 cl 6s        =  seeTablell C22s = see Table 11 H0-C16s (2C8C12)s (2C6C10)s LP283 LP293 LP294 LP310 LP383 LP395 LP395s LP396 aAlk uAlk cAlk gAlk (NAG37) (NAG37)s [NEM] FabOOOl =   see Table 11 =   see Table 11 =   see Table 11 =   see Table 11 =   see Table 11 =   see Table 11 =   see Table 11 =   see Table 11 =   see Table 11 =   see Table 11 =   see Table 11 =   see Table 11 =   see Table 11 =   see Table 11 =   see Table 11 =   see Table 11 =   see Table 11 =   see Table 11 = see Antigen Binding Proteins, infra Fab0002 = see Antigen Binding Proteins, infra Fab0044 = see Antigen Binding Proteins, infra Fab0046 = see Antigen Binding Proteins, infra Fab0056 = see Antigen Binding Proteins, infra Fab0058 = see Antigen Binding Proteins, infra Fab0060 = see Antigen Binding Proteins, infra Fab0061 = see Antigen Binding Proteins, infra Fab0062 = see Antigen Binding Proteins, infra Fab0063 = see Antigen Binding Proteins, infra Fab0064 = see Antigen Binding Proteins, infra Fab0065 = see Antigen Binding Proteins, infra Fab0066 = see Antigen Binding Proteins, infra Fab0067 = see Antigen Binding Proteins, infra Fab0068 = see Antigen Binding Proteins, infra Fab0069 = see Antigen Binding Proteins, infra Fab0070 = see Antigen Binding Proteins, infra Fab0071 = see Antigen Binding Proteins, infra Fab0072 = see Antigen Binding Proteins, infra Fab0073 = see Antigen Binding Proteins, infra Fab0074 = see Antigen Binding Proteins, infra Fab0165 = see Antigen Binding Proteins, infra Fab0166    = see Antigen Binding Proteins, infra Fab0167    =   see Antigen Binding Proteins, infra Fab0168    =   see Antigen Binding Proteins, infra xAb000293 = see Antigen Binding Proteins, infra LP-29       =   see Table 11 LP-238b    =  see Table 11 avP6-pepl = see Table 11, also referred to as "avp6 peptide 1”

[0098] As the person of ordinary skill in the art would readily understand, unless otherwise indicated by the sequence (such as, for example, by a phosphorothioate linkage “s”), when present in an oligonucleotide, the nucleotide monomers are mutually linked by 5’-3’-phosphodiester bonds. As the person of ordinary skill in the art would dearly understand, the inclusion of a phosphorothioate linkage as shown in the modified nucleotide sequences disclosed herein replaces the phosphodiester linkage typically present in oligonucleotides. Further, the person of ordinary skill in the art would readily understand that the terminal nucleotide at the 3’ end of a given oligonucleotide sequence would typically have a hydroxyl (-OH) group at the respective 3’ position of the given monomer instead of a phosphate moiety ex vivo. Additionally, for the embodiments disclosed herein, when viewing the respective strand 5’ -> 3’, the inverted abasic residues are inserted such that the 3’ position of the deoxyribose is linked at the 3’ end of the preceding monomer on the respective strand (see, e.g., Table 11). Moreover, as the person of ordinary skill would readily understand and appreciate, while the phosphorothioate chemical structures depicted herein typically show the anion on the sulfur atom, the inventions disclosed herein encompass all phosphorothioate tautomers (e.g., where the sulfur atom has a double-bond and the anion is on an oxygen atom). Unless expressly indicated otherwise herein, such understandings of the person of ordinary skill in the art are used when describing the AR RNAi agents and compositions of AR RNAi agents disclosed herein.

[0099] Certain examples of targeting groups and linking groups used with the AR RN Ai agents disclosed herein are included in the chemical structures provided below in Table 11. Each sense strand and / or antisense strand can have any targeting groups or linking groups listed herein, as well as other targeting or linking groups, conjugated to the 5' and / or 3' end of the sequence.

[0100] Certain examples of antigen binding proteins and linking groups used with the AR RNAi agents disclosed herein are included in the chemical structures provided below in Table 11. Each sense strand and / or antisense strand can have any antigen binding protein or linking group listed herein, as well as other targeting groups, antigen binding proteins, linking groups, conjugated to the 5' and / or 3' end of the sequence Table 3. AR RNAi Agent Antisense Strand Sequences AS Strand ID Modified Antisense Strand (5' —> 3’) SEQ ID NO. Underlying Base Sequence (5' —► 3’) (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CA002712 usGfsasAfaGfuuguaGfuAfgUfcGfcgsa 322 UGAAAGUUGUAGUAGUCGCGA 658 CA002714 usUfscsUfuUfugaagAfaGfaCfcUfugsc 323 UUCUUUUGAAGAAGACCUUGC 659 CA002716 asUfsusCfaUfagccuUfcAfaUfgUfgusg 324 AUUCAUAGCCUUCAAUGUGUG 660 CA002718 usGfsusCfaAfaagugAfaCfuGfaUfgcsa 325 UGUCAAAAGUGAACUGAUGCA 661 CA002720 usAfsusGfaUfcucugCfcAfuCfaUfuusc 326 UAUGAUCUCUGCCAUCAUUUC 662 CA003818 cPrpusGfsuCfaaaagugAfaCfuGfaugscsg 327 UGUCAAAAGUGAACUGAUGCG 663 CA003820 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 UUGAUUAGCAGGUCAAAAGUG 664 CA004048 cPrpusGfsusCfaaaagugAfaCfuGfaugcsg 329 UGUCAAAAGUGAACUGAUGCG 663 CA004294 cPrpusGfsasAfaGfuuguaGfuAfgUfcGfcgsa 330 UGAAAGUUGUAGUAGUCGCGA 658 CA004296 cPrpasGfsusGfaAfcugauGfcAfgCfuCfucsu 331 AGUGAACUGAUGCAGCUCUCU 665 CA004298 cPrpusGfsusCfaAfaagugAfaCfuGfaUfgcsa 332 UGUCAAAAGUGAACUGAUGCA 661 CA004299 cPrpusUfsgsAfuUfagcagGfuCfaAfaAfgusg 333 UUGAUUAGCAGGUCAAAAGUG 664 CA004301 cPrpusGfsasCfuUfgauuaGfcAfgGfuCfaasg 334 UGAC UUGAUUAGCAGGUCAAG 666 CA004303 cPrpusGfsasAfaGfuccacGfcUfcAfcCfausg 335 UGAAAGUCCACGCUCACCAUG 667 CA005484 cPrpusUfsgauuAfgcagGfuCfaAfasasg 336 UUGAUUAGCAGGUCAAAAG 668 CA006133 cPrpusUfsgsAfuuagcagGfuCfaAfaAfgUfsg 337 UUGAUUAGCAGGUCAAAAGUG 664 CA008104 cPrpusGfsasAfaGfuuguaGfuAfgUfcGfsc 338 UGAAAGUUGUAGUAGUCGC 669 CA008106 cPrpusUfscsAfaAfagugaAfcUfgAfuGfsc 339 UUCAAAAGUGAACUGAUGC 670 CA008108 cPrpusGfsusCfaAfaagugAfaCfuGfaUfsg 340 UGUCAAAAGUGAACUGAUG 671 CA008110 cPrpusUfsgsAfuUfagcagGfuCfaAfaAfsg 341 UUGAUUAGCAGGUCAAAAG 668 CA008112 cPrpusGfsasAfaGfuccacGfcUfcAfcCfsa 342 UGAAAGUCCACGCUCACCA 672 CA014806 cPrpusGfsasAfaGfuugcaGfuAfgUfcGfcgsa 343 UGAAAGUUGCAGUAGUCGCGA 673 CA015225 cPrpusUfsgauuAfgcagGfuCfaAfaagusg 344 UUGAUUAGCAGGUCAAAAGUG 664 CA015234 cPrpusUfsgauuAfgcagGfuCfaAfaagusa 345 UUGAUUAGCAGGUCAAAAGUA 674 CA911017 usAfscsUfuCfuguuuCfcCfuUfcAfgcsg 346 UACUUCUGUUUCCCUUCAGCG 675 CA911038 usAfscsUfuGfcacagAfgAfuGfaUfcusc 347 UACUUGCACAGAGAUGAUCUC 676 WO 2025 / 160224                                   PCT / US2025 / 012678 AS Strand ID Modified Antisense Strand (5'   3’) SEQ ID NO. Underlying Base Sequence (5' —> 3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CA911040 usGfsasCfuUfucccaGfaAfaGfgAfucsu 348 UGAC UUUCCCAGAAAGGAU CU 677 CA912288 cPrpusGfscsUfuCfauaacAfuUfuCfcGfaasg 349 UGCUUCAUAACAUUUCCGAAG 678 CA912291 cPrpusUfscsAfaAfagugaAfcUfg AfuGfcasg 350 UUCAAAAGUGAACUGAUGCAG 679 CA912644 cPrpusGfsasAfaguuguaGfuAfgUfcgcgsa 351 UGAAAGUUGUAGUAGUCGCGA 658 CA912645 cPrpus Gfs aAfaguuguaGfu AfgUfcgcgs a 352 UGAAAGUUGUAGUAGUCGCGA 658 CA912646 cPrpus Gfs aAfaguuguaGfuAfgUfcgcgs sa 353 UGAAAGUUGUAGUAGUCGCGA 658 CA912647 cPrpusGfsaAfaguuguaGfuAfgUfcgcsgsa 354 UGAAAGUUGUAGUAGUCGCGA 658 CA912648 cPrpuGfaAfaguuguaGfuAfgUfcgcsgsa 355 UGAAAGUUGUAGUAGUCGCGA 658 CA912649 cPrpusGfsaaagUfuguaGfuAfgUfcgcsgsa 356 UGAAAGUUGUAGUAGUCGCGA 658 CA912650 cPrpusGfsaaaguuGfuaGfuAfgUfcgcsgsa 357 UGAAAGUUGUAGUAGUCGCGA 658 CA912652 cPrpusGfsaAfagUuNAUguaGfuAfgUfcgcsgsa 358 UGAAAGUUGUAGUAGUCGCGA 658 CA912653 cPrpus Gfs aaaguuguaGfuAfgU fcgcsgsa 359 UGAAAGUUGUAGUAGUCGCGA 658 CA912654 cPrpusGfsaaaguuguaguAfgUfcgcsgsa 360 UGAAAGUUGUAGUAGUCGCGA 658 CA912668 cPrpusUfsgsUfcAfgaaauGfgUfcGfaAfgusg 361 UUGUCAGAAAUGGUCGAAGUG 680 CA912670 cPrpusGfsasGfuAfgcuauCfcAfuCfcAfggsg 362 UGAGUAGCUAUCCAUCCAGGG 681 CA912672 cPrpusGfsgsAfaAfguaauAfgUfcAfaUfggsg 363 UGGAAAGUAAUAGUCAAUGGG 682 CA912674 cPrpus AfsusCfaAfuagugCfaAfuCfaUfuusc 364 UAUCAAUAGUGCAAUCAUUUC 683 CA912676 cPrpus AfsgsAfuUfaccaaGfuUfuCfuUfcasg 365 UAGAUUACCAAGUUUCUUCAG 684 CA912753 cPrpusGfsusCfaaaagugAfaCfuGfaugcsa 366 UGUCAAAAGUGAACUGAUGCA 661 CA912756 cPrpusGfsusCfaaaagugAfaCfuGfaugcsc 367 UGUCAAAAGUGAACUGAUGCC 685 CA912757 cPrpusGfsuCfaaaagugAfaCfuGfaugcsa 368 UGUCAAAAGUGAACUGAUGCA 661 CA912758 cPrpusGfsuCfaaaagugAfaCfuGfaugcssa 369 UGUCAAAAGUGAACUGAUGCA 661 CA912759 cPrpusGfsuCfaaaagugAfaCfuGfaugscsa 370 UGUCAAAAGUGAACUGAUGCA 661 CA912760 cPrpuGfuCfaaaagugAfaCfuGfaugscsa 371 UGUCAAAAGUGAACUGAUGCA 661 CA912764 cPrpusGfsuscaaAfagugAfaCfuGfaugcsa 372 UGUCAAAAGUGAACUGAUGCA 661 CA912765 cPrpusGfsuscaaaaGfugAfaCfuGfaugcsa 373 UGUCAAAAGUGAACUGAUGCA 661 CA912766 cPrpusGfsuscaaaagugaaCfuGfaugcsa 374 UGUCAAAAGUGAACUGAUGCA 661 WO 2025 / 160224                                   PCT / US2025 / 012678 AS Strand ID Modified Antisense Strand (5'   3’) SEQ ID NO. Underlying Base Sequence (5' —> 3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CA912767 cPrpusGfsusCfaaAuNAagug AfaCfuGfaugcsa 375 UGUCAAAAGUGAACUGAUGCA 661 CA913048 usUfsgsAfuUfagcagGfuCfaAfaAfgusg 376 UUGAUUAGCAGGUCAAAAGUG 664 CA913049 cPrpusUfsgsAfuuagcagGfuCfaAfaagusg 377 UUGAUUAGCAGGUCAAAAGUG 664 CA913050 cPrpusUfsgAfuuagcagGfuCfaAfaagusg 378 UUGAUUAGCAGGUCAAAAGUG 664 CA913051 cPrpusUfsgAfuuagcagGfuCfaAfaagussg 379 UUGAUUAGCAGGUCAAAAGUG 664 CA913052 cPrpusUfsgAfuuagcagGfuCfaAfaagsusg 380 UUGAUUAGCAGGUCAAAAGUG 664 CA913053 cPrpusUfsgsAfuuagcagGfuCfaAfaagsusg 381 UUGAUUAGCAGGUCAAAAGUG 664 CA913055 cPrpusUfsgauuagCfagGfuCfaAfaagsusg 382 UUGAUUAGCAGGUCAAAAGUG 664 CA913056 cPrpusUfsgauuagcagGfuCfaAfaagsusg 383 UUGAUUAGCAGGUCAAAAGUG 664 CA913057 cPrpusUfsgauuagcagguCfaAfaagsusg 384 UUGAUUAGCAGGUCAAAAGUG 664 CA913058 cPrpusUfsgAfuUuNAagcagGfuCfaAfaagsusg 385 UUGAUUAGCAGGUCAAAAGUG 664 CA913059 cPrpusUfsgAfuuAuNAgcagGfuCfaAfaagsusg 386 UUGAUUAGCAGGUCAAAAGUG 664 CA913201 cPrpus Gfs aAfaguuguaGfuAfgUfcgcsgsg 387 UGAAAGUUGUAGUAGUCGCGG 686 CA913210 cPrpusGfsucaaAfagugAfaCfuGfaugscsg 388 UGUCAAAAGUGAACUGAUGCG 663 CA916238 cPrpusUfsgAfuUfagcagGfuCfaAfaAfgusg 389 UUGAUUAGCAGGUCAAAAGUG 664 WO 2025 / 160224                                   PCT / US2025 / 012678 Table 4. AR Agent Sense Strand Sequences (Shown Without Linkers, Conjugates, or Capping Moieties) Strand ID Modified Sense Strand (5'   3’) SEQ ID NO. Underlying Base Sequence (5' —► 3’) (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CS002711-NL ucgcgacuAfCfUfacaacuuuca 390 UCGCGACUACUACAACUUUCA 687 CS002713-NL gcaaggucUfUfCfuucaaaagaa 391 GCAAGGUCUUCUUCAAAAGAA 688 CS002715-NL cacacauuGfAfAfggcuaugaau 392 CACACAUUGAAGGCUAUGAAU 689 CS002717-NL ugcaucagUfUfCfacuuuugaca 393 UGCAUCAGUUCACUUUUGACA 690 CS002719-NL ga_2N aaugauGfGfCfagagaucaua 394 G(A2N)AAUGAUGGCAGAGAUCAUA 691 CS003817-NL cgcaucagUfuCfaCfuuuugaca 395 CGCAUCAGUUCACUUUUGACA 692 CS003819-NL cacuuuugAfcCfuGfcuaaucaa 396 CACUUUUGACCUGCUAAUCAA 693 CS004146-NL cacuuuugAfCfCfugcuaaucaa 397 CACUUUUGACCUGCUAAUCAA 693 CS005480-NL cacuuuugAfcCfuGfcuaaucaa 398 CACUUUUGACCUGCUAAUCAA 693 CS005483-NL cuuuug AfcC fuGfcuaaucaa 399 CUUUUGACCUGCUAAUCAA 694 CS005797-NL cacuuuugAfCfCfugcuaaucaa 400 CACUUUUGACCUGCUAAUCAA 693 CS005798-NL cacuuuugAfCfCfugcuaaucaa 401 CACUUUUGACCUGCUAAUCAA 693 CS005799-NL cacuuuugAfCfCfugcuaaucaa 402 CACUUUUGACCUGCUAAUCAA 693 CS005800-NL cacuuuugAfCfCfugcuaaucaa 403 CACUUUUGACCUGCUAAUCAA 693 CS005801-NL cacuuuugAfCfCfugcuaaucaa 404 CACUUUUGACCUGCUAAUCAA 693 CS005917-NL cacuuuugAfCfCfugcuaaucaa 405 CACUUUUGACCUGCUAAUCAA 693 CS005918-NL cacuuuugAfCfCfugcuaaucaa 406 CACUUUUGACCUGCUAAUCAA 693 CS005919-NL cacuuuugAfCfCfugcuaaucaa 407 CACUUUUGACCUGCUAAUCAA 693 CS005920-NL cacuuuugAfCfCfugcuaaucaa 408 CACUUUUGACCUGCUAAUCAA 693 CS005921-NL cacuuuugAfCfCfugcuaaucaa 409 CACUUUUGACCUGCUAAUCAA 693 CS005922-NL cacuuuugAfCfCfugcuaaucaa 410 CACUUUUGACCUGCUAAUCAA 693 CS005923-NL cacuuuugAfCfCfugcuaaucaa 411 CACUUUUGACCUGCUAAUCAA 693 CS005924-NL cacuuuugAfCfCfugcuaaucaa 412 CACUUUUGACCUGCUAAUCAA 693 CS005925-NL cacuuuugAfCfCfugcuaaucaa 413 CACUUUUGACCUGCUAAUCAA 693 WO 2025 / 160224                                   PCT / US2025 / 012678 Strand ID Modified Sense Strand (5' —► 3’) SEQ ID NO. Underlying Base Sequence (5' —» 3’) (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CS005926-NL cacuuuugAfCfCfugcuaaucaa 414 CACUUUUGACCUGCUAAUCAA 693 CS006134-NL cacuuuugAfCfCfugcuaaucaa 415 CACUUUUGACCUGCUAAUCAA 693 CS006139-NL cacuuuugAfCfCfugcuaaucaa 416 CACUUUUGACCUGCUAAUCAA 693 CS006143-NL cacuuuugAfCfCfugcuaaucaa 417 CACUUUUGACCUGCUAAUCAA 693 CS006144-NL cacuuuugAfCfCfugcuaaucaa 418 CACUUUUGACCUGCUAAUCAA 693 CS006686-NL cacuuuugAfCfCfugcuaaucaa 419 CACUUUUGACCUGCUAAUCAA 693 CS006687-NL cacuuuugAfCfCfugcuaaucaa 420 CACUUUUGACCUGCUAAUCAA 693 CS006688-NL cacuuuugAfCfCfugcuaaucaa 421 CACUUUUGACCUGCUAAUCAA 693 CS007540-NL cacuuuugAfCfCfugcuaaucaa 422 CACUUUUGACCUGCUAAUCAA 693 CS007547-NL cacuuuugAfCfCfugcuaaucaa 423 CACUUUUGACCUGCUAAUCAA 693 CS007653-NL cacuuuugAfCfCfugcuaaucaa 424 CACUUUUGACCUGCUAAUCAA 693 CS007720-NL cacuuuugAfCfCfugcuaaucaa 425 CACUUUUGACCUGCUAAUCAA 693 CS007721-NL cacuuuugAfCfCfugcuaaucaa 426 CACUUUUGACCUGCUAAUCAA 693 CS007722-NL cacuuuugAfCfCfugcuaaucaa 427 CACUUUUGACCUGCUAAUCAA 693 CS007724-NL cacuuuugAfCfCfugcuaaucaa 428 CACUUUUGACCUGCUAAUCAA 693 CS007725-NL cacuuuugAfCfCfugcuaaucaa 429 CACUUUUGACCUGCUAAUCAA 693 CS007920-NL cacuuuugAfCfCfugcuaaucaa 430 CACUUUUGACCUGCUAAUCAA 693 CS008103-NL gcgacuAfCfUfacaacuuuca 431 GCGACUACUACAACUUUCA 695 CS008105-NL gcaucaGfUfUfcacuuuugaa 432 GCAUCAGUUCACUUUUGAA 696 CS008107-NL caucagUfUfCfacuuuugaca 433 CAUCAGUUCACUUUUGACA 697 CS008109-NL cuuuugAfCfCfugcuaaucaa 434 CUUUUGACCUGCUAAUCAA 694 CS008111-NL uggugaGfCfGfuggacuuuca 435 UGGUGAGCGUGGACUUUCA 698 CS008239-NL cacuuuugAfCfCfugcuaaucaa 436 CACUUUUGACCUGCUAAUCAA 693 CS008240-NL cacuuuugAfCfCfugcuaaucaa 437 CACUUUUGACCUGCUAAUCAA 693 CS008241-NL cacuuuugAfCfCfugcuaaucaa 438 CACUUUUGACCUGCUAAUCAA 693 WO 2025 / 160224                                   PCT / US2025 / 012678 Strand ID Modified Sense Strand (5' —► 3’) SEQ ID NO. Underlying Base Sequence (5' —» 3’) (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CS008243-NL cacuuuugAfCfCfugcuaaucaa 439 CACUUUUGACCUGCUAAUCAA 693 CS010925-NL cacuuuugAfCfCfugcuaaucaa 440 CACUUUUGACCUGCUAAUCAA 693 CS010926-NL cacuuuugAfCfCfugcuaaucaa 441 CACUUUUGACCUGCUAAUCAA 693 CS010949-NL cacuuuugAfCfCfugcuaaucaa 442 CACUUUUGACCUGCUAAUCAA 693 CS011048-NL cacuuuugAfCfCfugcuaaucaa 443 CACUUUUGACCUGCUAAUCAA 693 CS011508-NL gcgacuAfCfUfacaacuuuca 444 GCGACUACUACAACUUUCA 695 CS011509-NL cuuuugAfCfCfugcuaaucaa 445 CUUUUGACCUGCUAAUCAA 694 CS011510-NL ucgcgacuAfCfUfacaacuuuca 446 UCGCGACUACUACAACUUUCA 687 CS011511-NL gcgacuAfCfUfacaacuuuca 447 GCGACUACUACAACUUUCA 695 CS012343-NL cacuuuugAfcCfuGfcuaaucaa 448 CACUUUUGACCUGCUAAUCAA 693 CS014012-NL cacuuuugAfCfCfugcuaaucaa 449 CACUUUUGACCUGCUAAUCAA 693 CS014805-NL ucgcgacuAfCfUfgcaacuuuca 450 UCGCGACUACUGCAACUUUCA 699 CS015226-NL cacuuuugAfCfCfugcuaaucasa 451 CACUUUUGACCUGCUAAUCAA 693 CS015233-NL uacuuuugAfCfCfugcuaaucaa 452 UACUUUUGACCUGCUAAUCAA 700 CS015235-NL uacuuuugAfCfCfugcuaaucaa 453 UACUUUUGACCUGCUAAUCAA 700 CS911008-NL ucgcgacuAfCfUfacaacuuuca 454 UCGCGACUACUACAACUUUCA 687 CS911015-NL gcaaggucUfUfCfuucaaaagaa 455 GCAAGGUCUUCUUCAAAAGAA 688 CS911016-NL cgcugaagGfGfAfaacagaagua 456 CGCUGAAGGGAAACAGAAGUA 701 CS911030-NL cacacauuGfAfAfggcuaugaau 457 CACACAUUGAAGGCUAUGAAU 689 CS911033-NL ugcaucagUfUfCfacuuuugaca 458 UGCAUCAGUUCACUUUUGACA 690 CS911036-NL ga_2N aaugauGfGfC fagagaucaua 459 G(A2N)AAUGAUGGCAGAGAUCAUA 691 CS911037-NL gagaucauCfUfCfugugcaagua 460 GAGAUCAUCUCUGUGCAAGUA 702 CS911039-NL agauccuuUfCfUfgggaaaguca 461 AGAUCCUUUCUGGGAAAGUCA 703 CS911410-NL ucgcgacuAfCfUfacaacuuuca 462 UCGCGACUACUACAACUUUCA 687 CS911411-NL gcaaggucUfUfCfuucaaaagaa 463 GCAAGGUCUUCUUCAAAAGAA 688 WO 2025 / 160224                                   PCT / US2025 / 012678 Strand ID Modified Sense Strand (5' —► 3’) SEQ ID NO. Underlying Base Sequence (5' —» 3’) (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CS911412-NL cacacauuGfAfAfggcuaugaau 464 CACACAUUGAAGGCUAUGAAU 689 CS911413-NL ugcaucagUfUfCfacuuuugaca 465 UGCAUCAGUUCACUUUUGACA 690 CS911414-NL ga_2NaaugauGfGfCfagagaucaua 466 G(A2N)AAUGAUGGCAGAGAUCAUA 691 CS912286-NL ucgcgacuAfCfUfacaacuuuca 467 UCGCGACUACUACAACUUUCA 687 CS912287-NL cuucggaaAfUfGfuuaugaagca 468 CUUCGGAAAUGUUAUGAAGCA 704 CS912289-NL agagagcuGfCfAfucaguucacu 469 AGAGAGCUGCAUCAGUUCACU 705 CS912290-NL cugcaucaGfUfUfcacuuuugaa 470 CUGCAUCAGUUCACUUUUGAA 706 CS912292-NL ugcaucagUfUfCfacuuuugaca 471 UGCAUCAGUUCACUUUUGACA 690 CS912293-NL cacuuuugAfCfCfugcuaaucaa 472 CACUUUUGACCUGCUAAUCAA 693 CS912294-NL cuugaccuGfCfUfaaucaaguca 473 CUUGACCUGCUAAUCAAGUCA 707 CS912295-NL cauggugaGfCfGfuggacuuuca 474 CAUGGUGAGCGUGGACUUUCA 708 CS912667-NL cacuucgaC fCfAfuuucugacaa 475 CACUUCGACCAUUUCUGACAA 709 CS912669-NL cccuggauGfGfAfuagcuacuca 476 CCCUGGAUGGAUAGCUACUCA 710 CS912671-NL cccauugaCfUfAfuuacuuucca 477 CCCAUUGACUAUUACUUUCCA 711 CS912673-NL ga_2NaaugauUfGfCfacuauugaua 478 G(A2N)AAUGAUUGCACUAUUGAUA 712 CS912675-NL cugaagaaAfCfUfugguaaucua 479 CUGAAGAAACUUGGUAAUCUA 713 CS912754-NL cgcaucagUfUfCfacuuuugaca 480 CGCAUCAGUUCACUUUUGACA 692 CS912755-NL ggcaucagUfUfCfacuuuugaca 481 GGCAUCAGUUCACUUUUGACA 714 CS912761-NL ugcaucagUfuCfaCfuuuugaca 482 UGCAUCAGUUCACUUUUGACA 690 CS912762-NL ugcaucAfgUfuCfacuuuugaca 483 UGCAUCAGUUCACUUUUGACA 690 CS912763-NL ugcaucagUfUfCfAfcuuuugaca 484 UGCAUCAGUUCACUUUUGACA 690 CS912776-NL ucgcgacuAfcUfaCfaacuuuca 485 UCGCGACUACUACAACUUUCA 687 CS913054-NL cacuuuugAfcCfuGfcuaaucaa 486 CACUUUUGACCUGCUAAUCAA 693 CS913197-NL ucgcgaCfuAfcUfacaacuuuca 487 UCGCGACUACUACAACUUUCA 687 CS913198-NL ucgcgacuAfCfUfAfcaacuuuca 488 UCGCGACUACUACAACUUUCA 687 WO 2025 / 160224                                   PCT / US2025 / 012678 Strand ID Modified Sense Strand (5' —► 3’) SEQ ID NO. Underlying Base Sequence (5' —» 3’) (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CS913199-NL ucgcgacuAfcUfAfcaacuuuca 489 UCGCGACUACUACAACUUUCA 687 CS913200-NL ccgcgacuAfCfU facaacuuuca 490 CCGCGACUACUACAACUUUCA 715 CS913206-NL cgcaucagUfUfCfAfcuuuugaca 491 CGCAUCAGUUCACUUUUGACA 692 CS913207-NL cgcaucagUfuCfAfcuuuugaca 492 CGCAUCAGUUCACUUUUGACA 692 CS913208-NL cgcaucagUfuCfacuuuugaca 493 CGCAUCAGUUCACUUUUGACA 692 CS913209-NL cgcaucagUfuC faC fuuuugaca 494 CGCAUCAGUUCACUUUUGACA 692 CS914381-NL cgcaucagUfuCfaCfuuuugaca 495 CGCAUCAGUUCACUUUUGACA 692 CS914382-NL cacuuuugAfcCfuGfcuaaucaa 496 CACUUUUGACCUGCUAAUCAA 693 CS915295-NL cacuuuugAfcCfuGfcuaaucaa 497 CACUUUUGACCUGCUAAUCAA 693 CS915332-NL cacuuuugAfCfCfugcuaaucaa 498 CACUUUUGACCUGCUAAUCAA 693 CS915333-NL cgcaucagUfUfCfacuuuugaca 499 CGCAUCAGUUCACUUUUGACA 692 CS915702-NL agagagcuGfCfAfucaguucacu 500 AGAGAGCUGCAUCAGUUCACU 705 CS915703-NL cuugaccuGfCfUfaaucaaguca 501 CUUGACCUGCUAAUCAAGUCA 707 CS915704-NL cauggugaGfCfGfuggacuuuca 502 CAUGGUGAGCGUGGACUUUCA 708 CS916239-NL csacuuuugAfCfCfugcuaaucaa 503 CACUUUUGACCUGCUAAUCAA 693 CS916240-NL csascuuuugAfCfCfugcuaaucaa 504 CACUUUUGACCUGCUAAUCAA 693 CS916241-NL csacuuuugAfCfCfugcuaaucaa 505 CACUUUUGACCUGCUAAUCAA 693 CS916242-NL csascuuuugAfCfCfugcuaaucaa 506 CACUUUUGACCUGCUAAUCAA 693 CS916243-NL cs a_2N scuuuug AfCfCfugcuaaucaa 507 C(A2N)CUUUUGACCUGCUAAUCAA 716 a_2N=2-aminoadenosine nucleotide, (A2N) = 2-aminoadenine nucleotide WO 2025 / 160224                                   PCT / US2025 / 012678 Table 5. AR Agent Sense Strand Sequences (Shown With (NH2-C6) Linker or (NAG37)s ligand (see Table 11 for structure information.)) a 2N=2-aminoadenosine nucleotide Strand ID Modified Sense Strand (5' —► 3’) SEQ ID NO. Underlying Base Sequence (5' —► 3’) (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CS011508 (NH2-C6)s(invAb)sgcgacuAfCfUfacaacuuucas(invAb) 508 GCGACUACUACAACUUUCA 695 CS011509 (NH2-C6)s(invAb)scuuuugAfCfCfugcuaaucaas(invAb) 509 CUUUUGACCUGCUAAUCAA 694 CS012343 (invAb)scacuuuugAfcCfuGfcuaaucaas(invAb) 510 CACUUUUGACCUGCUAAUCAA 693 CS015226 (NH2-C6)s(invAb)scacuuuugAfCfCfugcuaaucasa 511 CACUUUUGACCUGCUAAUCAA 693 CS015233 (NH2-C6)s(invAb)suacuuuugAfCfCfugcuaaucaas(invAb) 512 UACUUUUGACCUGCUAAUCAA 700 CS015235 (NH2-C6)suacuuuugAfCfCfugcuaaucaas(invAb) 513 UACUUUUGACCUGCUAAUCAA 700 CS911008 (NAG37)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 514 UCGCGACUACUACAACUUUCA 687 CS911015 (NAG37)s(invAb)sgcaaggucUfUfCfuucaaaagaas(invAb) 515 GC AAGGU CUUCUUC AAAAGAA 688 CS911016 (NAG37)s(invAb)scgcugaagGfGfAfaacagaaguas(invAb) 516 CGCUGAAGGGAAACAGAAGUA 701 CS911030 (NAG37)s(invAb)scacacauuGfAfAfggcuaugaaus(invAb) 517 CACACAUUGAAGGCUAUGAAU 689 CS911033 (NAG37)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 518 UGCAUCAGUUCACUUUUGACA 690 CS911036 (NAG37)s(invAb)sga_2NaaugauGfGfCfagagaucauas(invAb) 519 G(A2N)AAUGAUGGCAGAGAUCAUA 691 CS911037 (NAG37)s(invAb)sgagaucauCfUfCfugugcaaguas(invAb) 520 GAGAUCAUCUCUGUGCAAGUA 702 CS911039 (NAG37)s(invAb)sagauccuuUfCfUfgggaaagucas(invAb) 521 AGAUCCUUUCUGGGAAAGUCA 703 CS911410 (NH2-C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 522 UCGCGACUACUACAACUUUCA 687 CS911411 (NH2-C6)s(invAb)sgcaaggucUfUfCfuucaaaagaas(invAb) 523 GCAAGGUCUUCUUCAAAAGAA 688 CS911412 (NH2-C6)s(invAb)scacacauuGfAfAfggcuaugaaus(invAb) 524 CACACAUUGAAGGCUAUGAAU 689 CS911413 (NH2-C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 525 UGCAUCAGUUCACUUUUGACA 690 CS911414 (NH2-C6)s(invAb)sga_2NaaugauGfGfCfagagaucauas(invAb) 526 G(A2N)AAUGAUGGCAGAGAUCAUA 691 CS915295 (NH2-C6)s(invAb)scacuuuugAfcCfuGfcuaaucaas(invAb) 527 CACUUUUGACCUGCUAAUCAA 693 CS915332 (NH2-C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 528 CACUUUUGACCUGCUAAUCAA 693 CS915333 (NH2-C6)s(invAb)scgcaucagUfUfCfacuuuugacas(invAb) 529 CGCAUCAGUUCACUUUUGACA 692 WO 2025 / 160224                                   PCT / US2025 / 012678 Strand ID Modified Sense Strand (5' —► 3’) SEQ ID NO. Underlying Base Sequence (5'   3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CS915702 (NH2-C6)s(invAb)sagagagcuGfCfAfucaguucacus(invAb) 530 AGAGAGCUGCAUCAGUUCACU 705 CS915703 (NH2-C6)s(invAb)scuugaccuGfCfUfaaucaagucas(invAb) 531 CUUGACCUGCUAAUCAAGUCA 707 CS915704 (NH2-C6)s(invAb)scauggugaGfCfGfuggacuuucas(invAb) 532 CAUGGUGAGCGUGGACUUUCA 708 CS916239 (NH2-C6)s(invAb)scsacuuuugAfCfCfugcuaaucaas(invAb) 533 CACUUUUGACCUGCUAAUCAA 693 CS916240 (NH2-C6)s(invAb)scsascuuuugAfCfCfugcuaaucaas(invAb) 534 CACUUUUGACCUGCUAAUCAA 693 CS916241 (NH2-C 6)s csacuuuug AfCfCfugcuaaucaas (inv Ab) 535 CACUUUUGACCUGCUAAUCAA 693 CS916242 (NH2-C6)scsascuuuugAfCfCfugcuaaucaas(invAb) 536 CACUUUUGACCUGCUAAUCAA 693 CS916243 (NH2-C6)scsa_2NscuuuugAfCfCfugcuaaucaas(invAb) 537 C(A2N)CUUUUGACCUGCUAAUCAA 716 a_2N=2-aminoadenosine nucleotide, (A2N) = 2-aminoadenine nucleotide S            Table 6. AR Agent Sense Strand Sequences (Shown with lipid moiety or antigen binding moiety). The structures of the lipid moieties are shown in Table 11. Strand ID Modified Sense Strand (5' —> 3') SEQ ID NO. Underlying Base Sequence (5'   3’) (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CS002711 LP183-(NH-C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 568 UC GCGACUACUACAACUUUCA 687 CS002713 LP183-(NH-C6)s(invAb)sgcaaggucUfUfCfuucaaaagaas(invAb) 569 GCAAGGUCUUCUUCAAAAGAA 688 CS002715 LP183-(NH-C6)s(invAb)scacacauuGfAfAfggcuaugaaus(invAb) 570 CACACAUUGAAGGCUAUGAAU 689 CS002717 LP 183-(NH-C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 571 UGCAUCAGUUCACUUUUGACA 690 CS002719 LP183-(NH- C6)s(invAb)sga 2NaaugauGfGfCfagagaucauas(invAb) 572 G(A2N)AAUGAUGGCAGAGAUCAUA 691 CS003817 avP-pepl-(NH- C6)s(invAb)scgcaucagUfuCfaCfuuuugacas(invAb)C6-S-LP-238b 573 CGCAUCAGUUCACUUUUGACA 692 WO 2025 / 160224                                   PCT / US2025 / 012678 Strand ID Modified Sense Strand (5' —► 3’) SEQ ID NO. Underlying Base Sequence (5'   3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CS003819 av[3-pepl-(NH- C6)s(invAb)scacuuuugAfcCfuGfcuaaucaas(invAb)C6-S-LP-238b 574 CACUUUUGACCUGCUAAUCAA 693 CS004146 Fab0002[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 575 CACUUUUGACCUGCUAAUCAA 693 CS005480 LP293-(NH-C6)scacuuuugAfcCfuGfcuaaucaas(invAb) 576 CACUUUUGACCUGCUAAUCAA 693 CS005483 LP293-(NH-C6)scuuuugAfcCfuGfcuaaucaas(invAb) 577 CUUUUGACCUGCUAAUCAA 694 CS005797 Fab0064[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 578 CACUUUUGACCUGCUAAUCAA 693 CS005798 Fab0066[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 579 CACUUUUGACCUGCUAAUCAA 693 CS005799 Fab0067[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 580 CACUUUUGACCUGCUAAUCAA 693 CS005800 Fab0072[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 581 CACUUUUGACCUGCUAAUCAA 693 CS005801 Fab0073 [NEM] -L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 582 CACUUUUGACCUGCUAAUCAA 693 CS005917 Fab0060[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 583 CACUUUUGACCUGCUAAUCAA 693 CS005918 Fab0061 [NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 584 CACUUUUGACCUGCUAAUCAA 693 CS005919 Fab0062[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 585 CACUUUUGACCUGCUAAUCAA 693 CS005920 Fab0063 [NEM] -L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 586 CACUUUUGACCUGCUAAUCAA 693 CS005921 Fab0065 [NEM] -L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 587 CACUUUUGACCUGCUAAUCAA 693 WO 2025 / 160224                                   PCT / US2025 / 012678 Strand ID Modified Sense Strand (5' —► 3’) SEQ ID NO. Underlying Base Sequence (5'   3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CS005922 Fab0068[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 588 CACUUUUGACCUGCUAAUCAA 693 CS005923 Fab0069[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 589 CACUUUUGACCUGCUAAUCAA 693 CS005924 Fab0070[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 590 CACUUUUGACCUGCUAAUCAA 693 CS005925 Fab0071 [NEM] -L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 591 CACUUUUGACCUGCUAAUCAA 693 CS005926 Fab0074[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 592 CACUUUUGACCUGCUAAUCAA 693 CS006134 LP293-(NH-C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 593 CACUUUUGACCUGCUAAUCAA 693 CS006139 avP-pepl-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb)C6-S-LP-238b 594 CACUUUUGACCUGCUAAUCAA 693 CS006143 Fab0056[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 595 CACUUUUGACCUGCUAAUCAA 693 CS006144 Fab005 8 [NEM] -L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 596 CACUUUUGACCUGCUAAUCAA 693 CS006686 Fab0001-L-1026-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 597 CACUUUUGACCUGCUAAUCAA 693 CS006687 Fab0044[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 598 CACUUUUGACCUGCUAAUCAA 693 CS006688 Fab0046[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 599 CACUUUUGACCUGCUAAUCAA 693 CS007540 FabOOO 1 [CP-1113] -L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 600 CACUUUUGACCUGCUAAUCAA 693 CS007547 Fab0061 [CP-1113] -L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 601 CACUUUUGACCUGCUAAUCAA 693 WO 2025 / 160224                                   PCT / US2025 / 012678 Strand ID Modified Sense Strand (5' —► 3’) SEQ ID NO. Underlying Base Sequence (5'   3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CS007653 Fab0070-[CP-ll 13]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 602 CACUUUUGACCUGCUAAUCAA 693 CS007720 Fab0070-L-1026-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 603 CACUUUUGACCUGCUAAUCAA 693 CS007721 Fab0070-L-1045-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 604 CACUUUUGACCUGCUAAUCAA 693 CS007722 Fab0070[CP-1113]L-1063-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 605 CACUUUUGACCUGCUAAUCAA 693 CS007724 Fab0070[CP-l 154]L-1064-(NH- C6)s(invAb)scacuuuugAfCFCfugcuaaucaas(invAb) 606 CACUUUUGACCUGCUAAUCAA 693 CS007725 Fab0070-L-l 100-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 607 CACUUUUGACCUGCUAAUCAA 693 CS007920 Fab0070-L-l 176-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 608 CACUUUUGACCUGCUAAUCAA 693 CS008103 LP183-(NH-C6)s(invAb)sgcgacuAfCfUfacaacuuucas(invAb) 609 GCGACUACUACAACUUUCA 695 CS008105 LP183-(NH-C6)s(invAb)sgcaucaGfUfUfcacuuuugaas(invAb) 610 GCAUCAGUUCACUUUUGAA 696 CS008107 LP183-(NH-C6)s(invAb)scaucagUFUfCfacuuuugacas(invAb) 611 CAUCAGUUCACUUUUGACA 697 CS008109 LP183-(NH-C6)s(invAb)scuuuugAfCfCfugcuaaucaas(invAb) 612 CUUUUGACCUGCUAAUCAA 694 CS008111 LP183-(NH-C6)s(invAb)suggugaGfCfGfuggacuuucas(invAb) 613 UGGUGAGCGUGGACUUUCA 698 CS008239 FabO165-SMCC-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 614 CACUUUUGACCUGCUAAUCAA 693 CS008240 FabO166-SMCC-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 615 CACUUUUGACCUGCUAAUCAA 693 CS008241 FabO168-SMCC-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 616 CACUUUUGACCUGCUAAUCAA 693 CS008243 FabO167-SMCC-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 617 CACUUUUGACCUGCUAAUCAA 693 WO 2025 / 160224                                   PCT / US2025 / 012678 Strand ID Modified Sense Strand (5' —► 3’) SEQ ID NO. Underlying Base Sequence (5'   3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CS010925 Fab0070-L-1288L- 1307s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 618 CACUUUUGACCUGCUAAUCAA 693 CS010926 Fab0070-L-l 288L-1289-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 619 CACUUUUGACCUGCUAAUCAA 693 CS010949 Fab0070[CP-1113]L20- 1306s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 620 CACUUUUGACCUGCUAAUCAA 693 CS011048 Fab0070-L-1026- 1306s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 621 CACUUUUGACCUGCUAAUCAA 693 CS011508 (NH2-C6)s(invAb)sgcgacuAfCfUfacaacuuucas(invAb) 622 GCGACUACUACAACUUUCA 695 CS011509 (NH2-C6)s(invAb)scuuuugAfCfCfugcuaaucaas(invAb) 623 CUUUUGACCUGCUAAUCAA 694 CS011510 Fab0070-[CP-l 113]-L20-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 624 UCGCGACUACUACAACUUUCA 687 CS011511 Fab0070-[CP-l 113]-L20-(NH- C6)s(invAb)sgcgacuAfCfUfacaacuuucas(invAb) 625 GCGACUACUACAACUUUCA 695 CS014012 xAb000293-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 626 CACUUUUGACCUGCUAAUCAA 693 CS014805 LP293-(NH-C6)s(invAb)sucgcgacuAfCfUfgcaacuuucas(invAb) 627 UCGCGACUACUGCAACUUUCA 699 CS912286 LP183-(NH-C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 628 UCGCGACUACUACAACUUUCA 687 CS912287 LP18 3 -(NH-C 6)s(inv Ab)s cuucggaaAfU fGfuuaugaagcas (in v Ab) 629 CUUCGGAAAUGUUAUGAAGCA 704 CS912289 LP 183-(NH-C6)s(invAb)sagagagcuGfCfAfucaguucacus(invAb) 630 AGAGAGCUGCAUCAGUUCACU 705 CS912290 LP183-(NH-C6)s(invAb)scugcaucaGfUfUfcacuuuugaas(invAb) 631 CUGCAUCAGUUCACUUUUGAA 706 CS912292 LP183-(NH-C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 632 UGCAUCAGUUCACUUUUGACA 690 CS912293 LP 183-(NH-C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 633 CACUUUUGACCUGCUAAUCAA 693 CS912294 LP183-(NH-C6)s(invAb)scuugaccuGfCfUfaaucaagucas(invAb) 634 CUUGACCUGCUAAUCAAGUCA 707 CS912295 LP183-(NH-C6)s(invAb)scauggugaGfCfGfuggacuuucas(invAb) 635 CAUGGUGAGCGUGGACUUUCA 708 CS912667 LP 183-(NH-C6)s(invAb)scacuucgaCfCfAfuuucugacaas(invAb) 636 CACUUCGACCAUUUCUGACAA 709 WO 2025 / 160224                                   PCT / US2025 / 012678 Strand ID Modified Sense Strand (5' —► 3’) SEQ ID NO. Underlying Base Sequence (5'   3') (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CS912669 LP183-(NH-C6)s(invAb)scccuggauGfGfAfuagcuacucas(invAb) 637 CCCUGGAUGGAUAGCUACUCA 710 CS912671 LP183-(NH-C6)s(invAb)scccauugaCfUfAfuuacuuuccas(invAb) 638 CCCAUUGACUAUUACUUUCCA 711 CS912673 LP183-(NH- C6)s(invAb)sga 2NaaugauUfGfCfacuauugauas(invAb) 639 G(A2N)AAUGAUUGCACUAUUGAUA 712 CS912675 LP183-(NH-C6)s(invAb)scugaagaaAfCfUfugguaaucuas(invAb) 640 CUGAAGAAACUUGGUAAUCUA 713 CS912754 LP183-(NH-C6)s(invAb)scgcaucagUfUfCfacuuuugacas(invAb) 641 CGCAUCAGUUCACUUUUGACA 692 CS912755 LP 183-(NH-C6)s(invAb)sggcaucagUfUfCfacuuuugacas(invAb) 642 GGCAUCAGUUCACUUUUGACA 714 CS912761 LP183-(NH-C6)s(invAb)sugcaucagUfuCfaCfuuuugacas(invAb) 643 UGCAUCAGUUCACUUUUGACA 690 CS912762 LP 183-(NH-C6)s(invAb)sugcaucAfgUfuCfacuuuugacas(invAb) 644 UGCAUCAGUUCACUUUUGACA 690 CS912763 LP 183-(NH-C6)s(invAb)sugcaucagUfUfCfAfcuuuugacas(invAb) 645 UGCAUCAGUUCACUUUUGACA 690 CS912776 LP183-(NH-C6)s(invAb)sucgcgacuAfcUfaCfaacuuucas(invAb) 646 UCGCGACUACUACAACUUUCA 687 CS913054 LP183-(NH-C6)s(invAb)scacuuuugAfcCfuGfcuaaucaas(invAb) 647 CACUUUUGACCUGCUAAUCAA 693 CS913197 LP 183-(NH-C6)s(invAb)sucgcgaCfuAfcUfacaacuuucas(invAb) 648 UCGCGACUACUACAACUUUCA 687 CS913198 LP 183-(NH-C6)s(invAb)sucgcgacuAfCfUfAfcaacuuucas(invAb) 649 UCGCGACUACUACAACUUUCA 687 CS913199 LP183-(NH-C6)s(invAb)sucgcgacuAfcUfAfcaacuuucas(invAb) 650 UCGCGACUACUACAACUUUCA 687 CS913200 LP 183-(NH-C6)s(invAb)sccgcgacuAfCfUfacaacuuucas(invAb) 651 CCGCGACUACUACAACUUUCA 715 CS913206 LP183-(NH-C6)s(invAb)scgcaucagUfUfCfAfcuuuugacas(invAb) 652 CGCAUCAGUUCACUUUUGACA 692 CS913207 LP183-(NH-C6)s(invAb)scgcaucagUfuCfAfcuuuugacas(invAb) 653 CGCAUCAGUUCACUUUUGACA 692 CS913208 LP 183-(NH-C6)s(invAb)scgcaucagUfuCfacuuuugacas(invAb) 654 CGCAUCAGUUCACUUUUGACA 692 CS913209 LP183-(NH-C6)s(invAb)scgcaucagUfuCfaCfuuuugacas(invAb) 655 C GCAUCAGUUCACUUUUGACA 692 CS914381 LP293-(NH-C6)s(invAb)scgcaucagUfuCfaCfuuuugacas(invAb) 656 CGCAUCAGUUCACUUUUGACA 692 CS914382 LP293-(NH-C6)s(invAb)scacuuuugAfcCfuGfcuaaucaas(invAb) 657 CACUUUUGACCUGCUAAUCAA 693 WO 2025 / 160224                                   PCT / US2025 / 012678 0> bo Table 6.1. AR RNAi Agent Sense Strand Sequences Showing Targeting Ligand and / or PK / PD modulator Positions (Z = pharmacological moiety (e.g., targeting ligand, targeting group, and / or PK / PD modulator)). The structures of the lipid moieties are shown in Table 11. Strand ID Modified Sense Strand (5' —► 3’) SEQ ID NO. Underlying Base Sequence (5'   3’) (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CS003817-Z Z-(NH-C6)s(invAb)scgcaucagUfuCfaCfuuuugacas(invAb)C6-S-Z 764 CGCAUCAGUUCACUUUUGACA 692 CS003819-Z Z-(NH-C6)s(invAb)scacuuuugAfcCfuGfcuaaucaas(invAb)C6-S-Z 765 CACUUUUGACCUGCUAAUCAA 693 CS006139-Z Z-(NH-C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb)C6-S-Z 766 CACUUUUGACCUGCUAAUCAA 693 Table 6.2. AR RNAi Agent Sense Strand Sequences Showing Targeting Ligand linked at the 5’ terminal end and PK / PD modulator linked at the 3’ terminal end of the sense strand. (TL = targeting ligand; PK = PK / PD modulator)). Strand ID Modified Sense Strand (5' —► 3’) SEQ ID NO. Underlying Base Sequence (5' —> 3’) (Shown as an Unmodified Nucleotide Sequence) SEQ ID NO. CS003817-TP TL-(NH-C6)s(invAb)scgcaucagUfuCfaCfuuuugacas(invAb)C6-S-PK 767 CGCAUCAGUUCACUUUUGACA 692 CS003819-TP TL-(NH-C6)s(invAb)scacuuuugAfcCfuGfcuaaucaas(invAb)C6-S-PK 768 CACUUUUGACCUGCUAAUCAA 693 CS006139-TP TL-(NH-C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb)C6-S-PK 769 CACUUUUGACCUGCUAAUCAA 693 WO 2025 / 160224                                   PCT / US2025 / 012678

[0101] The AR RNAi agents disclosed herein are formed by annealing an antisense strand with a sense strand. A sense strand containing a sequence listed in Table 2. Table 4, Table 5. or Table 6 can be hybridized to any antisense strand containing a sequence listed in Table 2 or Table 3, provided the two sequences have a region of at least 85% complementarity over a contiguous 16, 17, 18, 19, 20, or 21 nucleotide sequence.

[0102] As shown in Table 5 above, certain of the example AR RNAi agent nucleotide sequences are shown to further include reactive linking groups at one or both of the 5’ terminal end and the 3’ terminal end of the sense strand. For example, many of the AR RNAi agent sense strand sequences shown in Table 5 above have a (NH2-C6) linking group at the 5’ end of the nucleotide sequence. Other linking groups, such as a (6-SS-6) linking group or a (C6-SS-C6) linking group, may be present as w ell or alternatively in certain embodiments. Such reactive linking groups are positioned to facilitate the linking of targeting ligands, targeting groups, and / or PK / PD modulators to the AR RNAi agents disclosed herein. Linking or conjugation reactions are well known in the art and provide for formation of covalent linkages between two molecules or reactants. Suitable conjugation reactions for use in the scope of the inventions herein include, but are not limited to. amide coupling reaction, Michael addition reaction, hydrazone formation reaction, inverse-demand Diels-Alder cycloaddition reaction, oxime ligation, and Copper (I)-catalyzed or strain-promoted azide-alkyne cycloaddition reaction cycloaddition reaction.

[0103] As shown in Table 5 above, certain of the example AR RNAi agent nucleotide sequences are show n to further include reactive linking groups at one or both of the 5’ terminal end and the 3’ terminal end of the sense strand. For example, many of the AR RNAi agent sense strand sequences shown in Table 5 above have a (NH2-C6) linking group at the 5’ end of the nucleotide sequence. Other linking groups, such as a (6-SS-6) linking group or a (C6-SS-C6) linking group, may be present as well or alternatively in certain embodiments. Such reactive linking groups are positioned to facilitate the linking of targeting ligands, targeting groups, and / or antigen binding proteins to the AR RNAi agents disclosed herein. Linking or conjugation reactions are well known in the art and provide for formation of covalent linkages between two molecules or reactants. Suitable conjugation reactions for use in the scope of the inventions herein include, but are not limited to, amide coupling reaction, Michael addition reaction, hydrazone formation reaction, inverse-demand Diels-Alder cycloaddition reaction, oxime ligation, and Copper (I)-catalyzed or strain-promoted azide-alkyne cycloaddition reaction cycloaddition reaction.

[0104] In some embodiments, targeting ligands, can be synthesized as activated esters, such as tetrafluorophenyl (TFP) esters, which can be displaced by a reactive amino group (e.g.. NIL-Ce) to attach the targeting ligand to the AR RNAi agents disclosed herein. In some embodiments, targeting ligands are synthesized as azides, which can be conjugated to a propargy l or DBCO group, for example, via Copper (1)- catalyzed or strain-promoted azide-alkyne cycloaddition reaction.

[0105] As shown in Table 5 and 6, above, the example AR RNAi agent sense strand nucleotide sequences are shown to further include, in some embodiments, reactive linking groups at both the 5? terminal end and the 3’ terminal end of the sense strand. For example, certain of the AR RNAi agent sense strand sequences shown in Table 5 or 6 above have an (NH2-C6) linking group at the 5’ end of the nucleotide sequence. Similarly, certain of the AR RNAi agent nucleotide sequences shown in Table 5 or 6 above have a (C6-SS-C6) linking group near the 3’ end of the nucleotide sequence. Such reactive linking groups are positioned to facilitate the linking of targeting ligands, targeting groups, and / or PK / PD modulators to the AR RNAi agents disclosed herein. Linking or conjugation reactions are well known in the art and provide for formation of covalent linkages between two molecules or reactants. Suitable conjugation reactions for use in the scope of the inventions herein include, but are not limited to. amide coupling reaction, Michael addition reaction, hydrazone formation reaction, and click chemistry cycloaddition reaction.

[0106] Additionally, certain of the nucleotide sequences can be synthesized with a dT nucleotide at the 3’ terminal end of the sense strand, followed by (3’ -> 5’) a linker (e.g., C6-SS-C6). The linker can, in some embodiments, facilitate the linkage to additional components, such as, for example, a lipid or one or more targeting ligands. As described herein, the disulfide bond of C6-SS-C6 is first reduced, removing the dT from the molecule, which can then facilitate the conj ugation of the desired component. The terminal dT nucleotide therefore is not a part of the fully conjugated construct.

[0107] Additionally, certain of the nucleotide sequences can be synthesized with a dT nucleotide at the 3’ terminal end of the sense strand, followed by (3’ -> 5’) a linker (e.g.. C6-SS-C6). The linker can, in some embodiments, facilitate the linkage to additional components, such as, for example, an antigen binding protein or one or more targeting ligands. As described herein, the disulfide bond of C6-SS-C6 is first reduced, removing the dT from the molecule, which can then facilitate the conjugation of the desired component. The terminal dT nucleotide therefore is not apart of the fully conjugated construct.

[0108] Additionally, the nucleotide sequences shown in Table 5 and 6 were synthesized with a dT nucleotide at the 3' terminal end of the sense strand, followed by (3’ -> 5’) a linker (e.g., C6-SS-C6). A suitable and commercially available dT-loaded resin can be used to initiate the synthesis of the oligonucleotide strand. The (C6-SS-C6) linker can. in some embodiments, then be used facilitate the linkage to additional components, such as, for example, a PK / PD modulator or one or more targeting ligands. As described herein, the C6-SS-C6 is first reduced cleaving among other things the dT residue off the molecule, which can then facilitate the conjugation of the desired PK / PD modulator.

[0109] As discussed herein, in some embodiments, one or more targeting ligands and / or PK / PD modulators are linked or conjugated to the RNAi agent. In some embodiments, a targeting ligand (or targeting group) and / or a PK / PD modulator is linked to the 5’ end of the sense strand, the 3’ end of the sense strand, and / or to one or more internal nucleotides. The synthesis of the sense strand and / or the antisense strand can be designed such that reactive groups are readily available to facilitate linkage to additional components, such as a targeting ligand or PK / PD modulator. Table 6.1 depicts the sense strand of the AR RNAi agents disclosed in Table 5 after linking to one or more targeting ligands and / or PK / PD modulators (collectively, shown below, as Z). Pharmacological moieties are linked to the AR RNAi agents using reactions described in Example 1. below. Following conjugation to targeting ligands, the linking groups may have the structure (NH-C6), (NH-C6)s, or (C6-S), the structure of each of which is shown in Table 11.

[0110] In some embodiments, the antisense strand of an AR RNAi agent disclosed herein differs by 0, 1, 2, or 3 nucleotides from any of the antisense strand sequences in Table 3 or Table 10. In some embodiments, the sense strand of an AR RNAi agent disclosed herein differs by 0, 1, 2, or 3 nucleotides from any of the sense strand sequences in Table 4, Table 5. Table 6, or Table 10.

[0111] In some embodiments, an AR RNAi agent antisense strand comprises a nucleotide sequence of any of the sequences in Table 2 or Table 3. In some embodiments, an AR RNAi agent antisense strand comprises the sequence of nucleotides (from 5’ end -> 3' end) 1-17, 2-17, 1-18,2-18, 1-19,2-19, 1-20, 2-20, 1-21,2-21, 1-22, 2-22, 1-23,2-23, 1-24, or 2-24 of any of the sequences in Table 2, Table 3, or Table 10. In certain embodiments, an AR RNAi agent antisense strand comprises or consists of a modified sequence of any one of the modified sequences in Table 3 or Table 10.

[0112] In some embodiments, an AR RNAi agent sense strand comprises the nucleotide sequence of any of the sequences in Table 2 or Table 4. In some embodiments, an AR RNAi agent sense strand comprises the sequence of nucleotides (from 5’ end 3’ end) 1-17, 2-17, 317, 4-17, 1-18, 2-18, 3-18, 4-18, 1-19, 2-19, 3-19, 4-19, 1-20, 2-20, 3-20, 4-20, 1 -21, 2-21, 3-21, 4-21, 1-22, 2-22, 3-22, 4-22, 1-23, 2-23, 3-23, 4-23, 1-24, 2-24, 3-24, or 4-24, of any of the sequences in Table 2, Table 4, Table 5. Table 6, or Table 10. In certain embodiments, an AR RNAi agent sense strand comprises or consists of a modified sequence of any one of the modified sequences in Table 3 or Table 10.

[0113] For the RNAi agents disclosed herein, the nucleotide at position 1 of the antisense strand (from 5' end -> 3' end) can be perfectly complementary to an AR gene, or can be non-complementary to an AR gene. In some embodiments, the nucleotide at position 1 of the antisense strand (from 5' end -> 3' end) is a U, A, or dT (or a modified version of U, A or dT). In some embodiments, the nucleotide at position 1 of the antisense strand (from 5’ end 3’ end) forms an AU or U:A base pair with the sense strand.

[0114] In some embodiments, an AR RNAi agent antisense strand comprises the sequence of nucleotides (from 5' end -> 3' end) 2-18 or 2-19 of any of the antisense strand sequences in Table 2, Table 3, or Table 10. In some embodiments, an AR RNAi sense strand comprises the sequence of nucleotides (from 5' end -> 3' end) 1-17 or 1-18 of any of the sense strand sequences in Table 2, Table 4, Table 5, Table 6, or Table 10.

[0115] In some embodiments, an AR RNAi agent includes (i) an antisense strand comprising the sequence of nucleotides (from 5' end -> 3' end) 2-18 or 2-19 of any of the antisense strand sequences in Table 2, Table 3, or Table 10, and (ii) a sense strand comprising the sequence of nucleotides (from 5' end -> 3' end) 1-17 or 1-18 of any of the sense strand sequences in Table 2, Table 4, Table 5, Table 6, or Table 10.

[0116] A sense strand containing a sequence listed in Table 2 or Table 4 can be hybridized to any antisense strand containing a sequence listed in Table 2 or Table 3 provided the two sequences have a region of at least 85% complementarity over a contiguous 16, 17, 18, 19, 20, or 21 nucleotide sequence. In some embodiments, the AR RNAi agent has a sense strand consisting of the modified sequence of any of the modified sequences in Table 4, Table 5, Table 6, or Table 10, and an antisense strand consisting of the modified sequence of any of the modified sequences in Table 3 or Table 10. Certain representative sequence pairings are exemplified by the Duplex ID Nos. shown in Tables 7, 8, and 9.

[0117] In some embodiments, an AR RNAi agent comprises, consists of. or consists essentially of a duplex represented by any one of the Duplex ID Nos. presented herein. In some embodiments, an AR RNAi agent consists of any of the Duplex ID Nos. presented herein. In some embodiments, an AR RNAi agent comprises the sense strand and antisense strand nucleotide sequences of any of the Duplex ID Nos. presented herein. In some embodiments, an AR RNAi agent comprises the sense strand and antisense strand nucleotide sequences of any of the Duplex ID Nos. presented herein and a targeting group, linking group, and / or other nonnucleotide group wherein the targeting group, linking group, and / or other non-nucleotide group is covalently linked (i.e., conjugated) to the sense strand or the antisense strand. In some embodiments, an AR RNAi agent includes the sense strand and antisense strand modified nucleotide sequences of any of the Duplex ID Nos. presented herein. In some embodiments, an AR RNAi agent comprises the sense strand and antisense strand modified nucleotide sequences of any of the Duplex ID Nos. presented herein and a targeting group, linking group, and / or other non-nucleotide group, wherein the targering group, linking group, and / or other non-nucleotide group is covalently linked to the sense strand or the antisense strand.

[0118] In some embodiments, an AR RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense strand / sense strand duplexes of Tables 2, 7, 8, 9, or 10, and comprises a targeting group. In some embodiments, an AR RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense strand / sense strand duplexes of Tables 2, 7, 8, 9, or 10, and comprises one or more lipid moieties.

[0119] In some embodiments, an AR RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense strand / sense strand duplexes of Tables 2. 7, 8, 9, or 10, and comprises a lipid moiety7 or antigen binding protein. In some embodiments, an AR RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense strand / sense strand duplexes of Tables 2, 7, 8. 9, or 10, and comprises one or more lipid moieties.

[0120] In some embodiments, an AR RNAi agent comprises an antisense strand and a sense strand having the modified nucleotide sequences of any of the antisense strand / sense strand duplexes of Tables 7, 8, 9, and 10.

[0121] In some embodiments, an AR RNAi agent comprises an antisense strand and a sense strand having the modified nucleotide sequences of any of the antisense strand / sense strand duplexes of Tables 7, 8, 9, and 10, and comprises a lipid moi ety or antigen binding protein .

[0122] In some embodiments, an AR RNAi agent comprises, consists of. or consists essentially of any of the duplexes of Tables 7, 8, 9, and 10.

[0123] In some embodiments, an AR RNAi agent comprises, consists of, or consists essentially of a duplex represented by any one of the Duplex ID Nos. presented herein. In some embodiments, an AR RNAi agent consists of any of the Duplex ID Nos. presented herein. In some embodiments, an AR RNAi agent comprises the sense strand and antisense strand nucleotide sequences of any of the Duplex ID Nos. presented herein. In some embodiments, an AR RNAi agent comprises the sense strand and antisense strand nucleotide sequences of any of the Duplex ID Nos. presented herein and a targeting group, linking group, antigen binding protein and / or other non-nucleotide group wherein the targeting group, linking group, antigen binding protein and / or other non-nucleotide group is covalently linked (i.e., conjugated) to the sense strand or the antisense strand. In some embodiments, an AR RNAi agent includes the sense strand and antisense strand modified nucleotide sequences of any of the Duplex ID Nos. presented herein. In some embodiments, an AR RNAi agent comprises the sense strand and antisense strand modified nucleotide sequences of any of the Duplex ID Nos. presented herein and a targeting group, linking group, and / or other non-nucleotide group, wherein the targeting group, linking group, antigen binding protein and / or other non-nucleotide group is covalently linked to the sense strand or the antisense strand.

[0124] In some embodiments, an AR RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense strand / sense strand duplexes of Tables 2. 7, 8, or 9, and comprises an antigen binding protein. In some embodiments, an AR RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense strand / sense strand duplexes of Tables 2, 7, 8, or 9, and comprises one or more antigen binding proteins.

[0125] In some embodiments, an AR RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense strand / sense strand duplexes of Tables 2, 7, 8, or 9, and comprises an antigen binding protein. In some embodiments, an AR RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense strand / sense strand duplexes of Tables 2, 7, 8, or 9, and comprises one or more antigen binding protein.

[0126] In some embodiments, an AR RNAi agent comprises an antisense strand and a sense strand having the modified nucleotide sequences of any of the antisense strand / sense strand duplexes of Tables 7, 8, and 9.

[0127] In some embodiments, an AR RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense strand / sense strand duplexes of Table 2 or Table 6, and further comprises a targeting group. In some embodiments, an AR RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense strand / sense strand duplexes of Table 6 (or Table 4, or Table 5), and further comprises an integrin receptor ligand targeting group.

[0128] In some embodiments, an AR RNAi agent comprises an antisense strand and a sense strand having the modified nucleotide sequences of any of the antisense strand / sense strand duplexes of Tables 7, 8, and 9, and comprises an antigen binding protein.

[0129] Table 7. AR RNAi Agent Duplexes with Corresponding Sense and Antisense Strand ID Numbers and Sequence ID numbers for the modified and unmodified nucleotide sequences. Duplex AS ID AS modified SEQID NO: AS unmodified SEQID NO: SS ID SS modified SEQ ID NO: SS unmodified SEQ ID NO: AC009786 CA008104 338 669 CS011508 508 695 AC009787 CA008110 341 668 CS011509 509 694 AC010606 CA003820 328 664 CS012343 510 693 AC012970 CAO 15225 344 664 CS915332 528 693 AC012971 CA015225 344 664 CS015226 511 693 AC012977 CA015234 345 674 CS015233 512 700 AC012978 CA015234 345 674 CS015235 513 700 AC908464 CA002712 322 658 CS911008 514 687 AC908468 CA002714 323 659 CS911015 515 688 AC908469 CA911017 346 675 CS911016 516 701 AC908476 CA002716 324 660 CS911030 517 689 AC908478 CA002718 325 661 CS911033 518 690 AC908480 CA002720 326 662 CS911036 519 691 AC908481 CA911038 347 676 CS911037 520 702 AC908482 CA911040 348 677 CS911039 521 703 AC908783 CA002712 322 658 CS911410 522 687 AC908784 CA002714 323 659 CS911411 523 688 AC908785 CA002716 324 660 CS911412 524 689 AC908786 CA002718 325 661 CS911413 525 690 AC908787 CA002720 326 662 CS911414 526 691 AC911885 CA003820 328 664 CS915295 527 693 AC911917 CA003820 328 664 CS915332 528 693 AC911918 CA004048 329 663 CS915333 529 692 AC912264 CA004294 330 658 CS911410 522 687 AC912265 CA004296 331 665 CS915702 530 705 AC912266 CA004298 332 661 CS911413 525 690 AC912267 CA004299 333 664 CS915332 528 693 AC912268 CA004301 334 666 CS915703 531 707 AC912269 CA004303 335 667 CS915704 532 708 AC912755 CA916238 389 664 CS915332 528 693 Duplex AS ID AS modified SEQID NO: AS unmodified SEQID NO: SS ID SS modified SEQ ID NO: SS unmodified SEQ ID NO: AC912756 CA916238 389 664 CS916239 533 693 AC912757 CA916238 389 664 CS916240 534 693 AC912758 CA916238 389 664 CS916241 535 693 AC912759 CA916238 389 664 CS916242 536 693 AC912760 CA916238 389 664 CS916243 537 716

[0130] Table 8. AR RNAi Agent Duplexes with Corresponding Sense and Antisense Strand ID Numbers and Sequence ID numbers for the modified and unmodified nucleotide sequences. (Shown with Targeting Ligand Conjugates) Duplex AS ID AS modified SEQ ID NO: AS unmodified SEQ ID NO: SS ID SS modified SEQ ID NO: SS unmodified SEQ ID NO: AC002143 CA002712 322 658 CS002711 568 687 AC002144 CA002714 323 659 CS002713 569 688 AC002145 CA002716 324 660 CS002715 570 689 AC002146 CA002718 325 661 CS002717 571 690 AC002147 CA002720 326 662 CS002719 572 691 AC003038 CA003818 327 663 CS003817 573 692 AC003039 CA003820 328 664 CS003819 574 693 AC003313 CA003820 328 664 CS004146 575 693 AC004444 CA003820 328 664 CS005480 576 693 AC004446 CA005484 336 668 CS005483 577 694 AC004691 CA003820 328 664 CS005797 578 693 AC004692 CA003820 328 664 CS005798 579 693 AC004693 CA003820 328 664 CS005799 580 693 AC004694 CA003820 328 664 CS005800 581 693 AC004695 CA003820 328 664 CS005801 582 693 AC004791 CA003820 328 664 CS005917 583 693 AC004792 CA003820 328 664 CS005918 584 693 AC004793 CA003820 328 664 CS005919 585 693 AC004794 CA003820 328 664 CS005920 586 693 AC004795 CA003820 328 664 CS005921 587 693 AC004796 CA003820 328 664 CS005922 588 693 AC004797 CA003820 328 664 CS005923 589 693 AC004798 CA003820 328 664 CS005924 590 693 AC004799 CA003820 328 664 CS005925 591 693 AC004800 CA003820 328 664 CS005926 592 693 Duplex AS ID AS modified SEQ ID NO: AS unmodified SEQ ID NO: SS ID SS modified SEQ ID NO: SS unmodified SEQ ID NO: AC004975 CA006133 337 664 CS006134 593 693 AC004982 CA006133 337 664 CS006139 594 693 AC004997 CA003820 328 664 CS006143 595 693 AC004998 CA003820 328 664 CS006144 596 693 AC005485 CA003820 328 664 CS006686 597 693 AC005487 CA003820 328 664 CS006687 598 693 AC005488 CA003820 328 664 CS006688 599 693 AC006262 CA003820 328 664 CS007540 600 693 AC006266 CA003820 328 664 CS007547 601 693 AC006372 CA003820 328 664 CS007653 602 693 AC006448 CA003820 328 664 CS007720 603 693 AC006449 CA003820 328 664 CS007721 604 693 AC006450 CA003820 328 664 CS007722 605 693 AC006452 CA003820 328 664 CS007724 606 693 AC006453 CA003820 328 664 CS007725 607 693 AC006597 CA003820 328 664 CS007920 608 693 AC006788 CA008104 338 669 CS008103 609 695 AC006789 CA008106 339 670 CS008105 610 696 AC006790 CA008108 340 671 CS008107 611 697 AC006791 CA008110 341 668 CS008109 612 694 AC006792 CA008112 342 672 CS008111 613 698 AC006894 CA003820 328 664 CS008239 614 693 AC006895 CA003820 328 664 CS008240 615 693 AC006896 CA003820 328 664 CS008241 616 693 AC006898 CA003820 328 664 CS008243 617 693 AC009014 CA003820 328 664 CS006134 593 693 AC009278 CA003820 328 664 CS010925 618 693 AC009279 CA003820 328 664 CSO10926 619 693 AC009310 CA003820 328 664 CS010949 620 693 AC009391 CA003820 328 664 CS011048 621 693 AC009786 CA008104 338 669 CS011508 622 695 AC009787 CA008110 341 668 CSO11509 623 694 AC009788 CA004294 330 658 CS011510 624 687 AC009789 CA008104 338 669 CS011511 625 695 AC011951 CA003820 328 664 CS014012 626 693 ACO 12606 CAO 14806 343 673 CS014805 627 699 AC013243 CA003820 328 664 CS006139 594 693 AC909551 CA002712 322 658 CS912286 628 687 Duplex AS ID AS modified SEQ ID NO: AS unmodified SEQ ID NO: SS ID SS modified SEQ ID NO: SS unmodified SEQ ID NO: AC909552 CA004294 330 658 CS912286 628 687 AC909553 CA912288 349 678 CS912287 629 704 AC909554 CA004296 331 665 CS912289 630 705 AC909555 CA912291 350 679 CS912290 631 706 AC909556 CA002718 325 661 CS912292 632 690 AC909557 CA004298 332 661 CS912292 632 690 AC909558 CA004299 333 664 CS912293 633 693 AC909559 CA004301 334 666 CS912294 634 707 AC909560 CA004303 335 667 CS912295 635 708 AC909838 CA002712 322 658 CS912286 628 687 AC909839 CA004294 330 658 CS912286 628 687 AC909840 CA912668 361 680 CS912667 636 709 AC909841 CA912670 362 681 CS912669 637 710 AC909842 CA912672 363 682 CS912671 638 711 AC909843 CA912674 364 683 CS912673 639 712 AC909844 CA912676 365 684 CS912675 640 713 AC909845 CA004298 332 661 CS912292 632 690 AC909894 CA002718 325 661 CS912292 632 690 AC909895 CA912753 366 661 CS912292 632 690 AC909896 CA004048 329 663 CS912754 641 692 AC909897 CA912756 367 685 CS912755 642 714 AC909898 CA912757 368 661 CS912292 632 690 AC909899 CA912758 369 661 CS912292 632 690 AC909900 CA912759 370 661 CS912292 632 690 AC909901 CA912760 371 661 CS912292 632 690 AC909902 CA912753 366 661 CS912761 643 690 AC909903 CA912753 366 661 CS912762 644 690 AC909904 CA912753 366 661 CS912763 645 690 AC909905 CA912764 372 661 CS912292 632 690 AC909906 CA912765 373 661 CS912292 632 690 AC909907 CA912766 374 661 CS912292 632 690 AC909908 CA912765 373 661 CS912761 643 690 AC909909 CA912759 370 661 CS912761 643 690 AC909910 CA912760 371 661 CS912761 643 690 AC909911 CA912767 375 661 CS912292 632 690 AC909919 CA912644 351 658 CS912286 628 687 AC909920 CA912645 352 658 CS912286 628 687 AC909921 CA912646 353 658 CS912286 628 687 Duplex AS ID AS modified SEQ ID NO: AS unmodified SEQ ID NO: SS ID SS modified SEQ ID NO: SS unmodified SEQ ID NO: AC909922 CA912647 354 658 CS912286 628 687 AC909923 CA912648 355 658 CS912286 628 687 AC909924 CA912649 356 658 CS912286 628 687 AC909925 CA912650 357 658 CS912286 628 687 AC909926 CA912647 354 658 CS912776 646 687 AC909927 CA912652 358 658 CS912286 628 687 AC909928 CA912653 359 658 CS912286 628 687 AC909929 CA912654 360 658 CS912286 628 687 AC910162 CA004299 333 664 CS912293 633 693 AC910163 CA913048 376 664 CS912293 633 693 AC910164 CA913049 377 664 CS912293 633 693 AC910165 CA913050 378 664 CS912293 633 693 AC910166 CA913051 379 664 CS912293 633 693 AC910167 CA913052 380 664 CS912293 633 693 AC910168 CA913053 381 664 CS912293 633 693 AC910169 CA913052 380 664 CS913054 647 693 AC910170 CA003820 328 664 CS912293 633 693 AC910171 CA913055 382 664 CS912293 633 693 AC910172 CA913056 383 664 CS912293 633 693 AC910173 CA913057 384 664 CS912293 633 693 AC910174 CA003820 328 664 CS913054 647 693 AC910175 CA913058 385 664 CS912293 633 693 AC910176 CA913059 386 664 CS912293 633 693 AC910274 CA912647 354 658 CS913197 648 687 AC910275 CA912647 354 658 CS913198 649 687 AC910276 CA912647 354 658 CS913199 650 687 AC910277 CA913201 387 686 CS913200 651 715 AC910278 CA912649 356 658 CS912776 646 687 AC910279 CA912650 357 658 CS912776 646 687 AC910280 CA912653 359 658 CS912776 646 687 AC910281 CA912654 360 658 CS912776 646 687 AC910286 CA003818 327 663 CS912754 641 692 AC910287 CA004048 329 663 CS913206 652 692 AC910288 CA003818 327 663 CS913206 652 692 AC910289 CA003818 327 663 CS913207 653 692 AC910290 CA003818 327 663 CS913208 654 692 AC910291 CA003818 327 663 CS913209 655 692 AC910292 CA913210 388 663 CS913208 654 692 Duplex AS ID AS modified SEQ ID NO: AS unmodified SEQ ID NO: SS ID SS modified SEQ ID NO: SS unmodified SEQ ID NO: AC911150 CA003818 327 663 CS914381 656 692 AC911151 CA003820 328 664 CS914382 657 693

[0131] Table 9, Conjugate Duplex ID Numbers Referencing Position Targeted On Androgen Receptor (AR) Gene AC Duplex ID AS ID SS ID Targeted AR Gene Position (Of SEQ ID NO:1) AC002143 CA002712 CS002711 2209 AC002144 CA002714 CS002713 2865 AC002145 CA002716 CS002715 3114 AC002146 CA002718 CS002717 3747 AC002147 CA002720 CS002719 3806 AC003038 CA003818 CS003817 3747 AC003039 CA003820 CS003819 3757 AC003313 CA003820 CS004146 3757 AC004444 CA003820 CS005480 3757 AC004446 CA005484 CS005483 3757 AC004691 CA003820 CS005797 3757 AC004692 CA003820 CS005798 3757 AC004693 CA003820 CS005799 3757 AC004694 CA003820 CS005800 3757 AC004695 CA003820 CS005801 3757 AC004791 CA003820 CS005917 3757 AC004792 CA003820 CS005918 3757 AC004793 CA003820 CS005919 3757 AC004794 CA003820 CS005920 3757 AC004795 CA003820 CS005921 3757 AC004796 CA003820 CS005922 3757 AC004797 CA003820 CS005923 3757 AC004798 CA003820 CS005924 3757 AC004799 CA003820 CS005925 3757 AC004800 CA003820 CS005926 3757 AC004975 CA006133 CS006134 3757 AC004982 CA006133 CS006139 3757 AC004997 CA003820 CS006143 3757 AC Duplex ID AS ID SS ID Targeted AR Gene Position (OfSEQID NO:1) AC004998 CA003820 CS006144 3757 AC005485 CA003820 CS006686 3757 AC005487 CA003820 CS006687 3757 AC005488 CA003820 CS006688 3757 AC006262 CA003820 CS007540 3757 AC006266 CA003820 CS007547 3757 AC006372 CA003820 CS007653 3757 AC006448 CA003820 CS007720 3757 AC006449 CA003820 CS007721 3757 AC006450 CA003820 CS007722 3757 AC006452 CA003820 CS007724 3757 AC006453 CA003820 CS007725 3757 AC006597 CA003820 CS007920 3757 AC006788 CA008104 CS008103 2209 AC006789 CA008106 CS008105 3746 AC006790 CA008108 CS008107 3747 AC006791 CA008110 CS008109 3757 AC006792 CA008112 CS008111 3784 AC006894 CA003820 CS008239 3757 AC006895 CA003820 CS008240 3757 AC006896 CA003820 CS008241 3757 AC006898 CA003820 CS008243 3757 AC009014 CA003820 CS006134 3757 AC009278 CA003820 CS010925 3757 AC009279 CA003820 CS010926 3757 AC009310 CA003820 CSO10949 3757 AC009391 CA003820 CS011048 3757 AC009786 CA008104 CS011508 2209 AC009787 CA008110 CS011509 3757 AC009788 CA004294 CS011510 2209 AC009789 CA008104 CS011511 2209 AC011951 CA003820 CS014012 3757 ACO 12606 CA014806 CS014805 2209 ACO 13243 CA003820 CS006139 3757 AC909551 CA002712 CS912286 2209 AC909552 CA004294 CS912286 2209 AC909553 CA912288 CS912287 2975 AC909554 CA004296 CS912289 3740 AC909555 CA912291 CS912290 3746 AC Duplex ID AS ID SS ID Targeted AR Gene Position (OfSEQID NO:1) AC909556 CA002718 CS912292 3747 AC909557 CA004298 CS912292 3747 AC909558 CA004299 CS912293 3757 AC909559 CA004301 CS912294 3761 AC909560 CA004303 CS912295 3784 AC909838 CA002712 CS912286 2209 AC909839 CA004294 CS912286 2209 AC909840 CA912668 CS912667 1810 AC909841 CA912670 CS912669 2702 AC909842 CA912672 CS912671 2771 AC909843 CA912674 CS912673 2922 AC909844 CA912676 CS912675 3020 AC909845 CA004298 CS912292 3747 AC909894 CA002718 CS912292 3747 AC909895 CA912753 CS912292 3747 AC909896 CA004048 CS912754 3747 AC909897 CA912756 CS912755 3747 AC909898 CA912757 CS912292 3747 AC909899 CA912758 CS912292 3747 AC909900 CA912759 CS912292 3747 AC909901 CA912760 CS912292 3747 AC909902 CA912753 CS912761 3747 AC909903 CA912753 CS912762 3747 AC909904 CA912753 CS912763 3747 AC909905 CA912764 CS912292 3747 AC909906 CA912765 CS912292 3747 AC909907 CA912766 CS912292 3747 AC909908 CA912765 CS912761 3747 AC909909 CA912759 CS912761 3747 AC909910 CA912760 CS912761 3747 AC909911 CA912767 CS912292 3747 AC909919 CA912644 CS912286 2209 AC909920 CA912645 CS912286 2209 AC909921 CA912646 CS912286 2209 AC909922 CA912647 CS912286 2209 AC909923 CA912648 CS912286 2209 AC909924 CA912649 CS912286 2209 AC909925 CA912650 CS912286 2209 AC909926 CA912647 CS912776 2209 AC Duplex ID AS ID SS ID Targeted AR Gene Position (OfSEQID NO:1) AC909927 CA912652 CS912286 2209 AC909928 CA912653 CS912286 2209 AC909929 CA912654 CS912286 2209 AC910162 CA004299 CS912293 3757 AC910163 CA913048 CS912293 3757 AC910164 CA913049 CS912293 3757 AC910165 CA913050 CS912293 3757 AC910166 CA913051 CS912293 3757 AC910167 CA913052 CS912293 3757 AC910168 CA913053 CS912293 3757 AC910169 CA913052 CS913054 3757 AC910170 CA003820 CS912293 3757 AC910171 CA913055 CS912293 3757 AC910172 CA913056 CS912293 3757 AC910173 CA913057 CS912293 3757 AC910174 CA003820 CS913054 3757 AC910175 CA913058 CS912293 3757 AC910176 CA913059 CS912293 3757 AC910274 CA912647 CS913197 2209 AC910275 CA912647 CS913198 2209 AC910276 CA912647 CS913199 2209 AC910277 CA913201 CS913200 2209 AC910278 CA912649 CS912776 2209 AC910279 CA912650 CS912776 2209 AC910280 CA912653 CS912776 2209 AC910281 CA912654 CS912776 2209 AC910286 CA003818 CS912754 3747 AC910287 CA004048 CS913206 3747 AC910288 CA003818 CS913206 3747 AC910289 CA003818 CS913207 3747 AC910290 CA003818 CS913208 3747 AC910291 CA003818 CS913209 3747 AC910292 CA913210 CS913208 3747 AC911150 CA003818 CS914381 3747 AC911151 CA003820 CS914382 3757

[0132] Table 10. Conjugate ID Numbers With Chemically Modified Antisense and Sense Strands (including Linkers and Conjugates) AC ID Number Sense Strand (Fully Modified with Conjugated Targeting Ligand) (S’ -> 3’) SEQ ID NO. Antisense Strand (5’ -> 3’) SEQ ID NO. AC002143 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 568 usGfsasAfaGfuuguaGfuAfgUfcGfcgsa 322 AC002144 LP183-(NH- C6)s(invAb)sgcaaggucUfUfCfuucaaaagaas(invAb) 569 usUfscsUfuUfugaagAfaGfaCfcUfugsc 323 AC002145 LP183-(NH- C6)s(invAb)scacacauuGfAfAfggcuaugaaus(invAb) 570 asUfs usCfaUfagccuUfcAfaUfgUfgusg 324 AC002146 LP183-(NH- C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 571 usGfsusCfaAfaagugAfaCfuGfaUfgcsa 325 AC002147 LP183-(NH- C6)s(invAb)sga 2NaaugauGfGfCfagagaucauas(invAb) 572 usAfsusGfaUfcucugCfcAfuCfaUfuusc 326 AC003038 avP-pepl-(NH- C6)s(invAb)scgcaucagUfuCfaCfuuuugacas(invAb)C6- S-LP-238b 573 cPrpusGfsuCfaaaagugAfaCfuGfaugscsg 327 AC003039 avP-pepl-(NH- C6)s(invAb)scacuuuugAfcCfuGfcuaaucaas(invAb)C6-S-LP-238b 574 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC003313 Fab0002[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 575 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004444 LP293-(NH-C6)scacuuuugAfcCfuGfcuaaucaas(invAb) 576 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004446 LP293-(NH-C6)scuuuugAfcCfuGfcuaaucaas(invAb) 577 cPrpusUfsgauuAfgcagGfuCfaAfasasg 336 AC004691 Fab0064[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 578 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004692 Fab0066[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 579 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004693 Fab0067[NEM]-L20-(NH- C6 )s (inv Ab)s cacuuuug AfCfCfugcuaaucaas (inv Ab) 580 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 WO 2025 / 160224                                   PCT / US2025 / 012678 AC ID Number Sense Strand (Fully Modified with Conjugated Targeting Ligand) (5’ -> 3’) SEQ ID NO. Antisense Strand (5’ -> 3’) SEQ ID NO. AC004694 Fab0072[NEM]-L20-(NH- C6)s(invAb)scacuuuug AfCfCfugcuaaucaas(invAb) 581 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004695 FabOO7 3 [NEM] -L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 582 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004791 Fab0060[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 583 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004792 Fab0061 [NEM] -L20-(NH- C6)s(invAb)scacuuuug AfCfCfugcuaaucaas(invAb) 584 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004793 Fab0062[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 585 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004794 Fab0063 [NEM] -L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 586 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004795 Fab0065 [NEM] -L20-(NH- C 6)s (inv Ab)s cacuuuug AfCfC fugcuaaucaas (inv Ab) 587 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004796 Fab0068[NEM]-L20-(NH- C 6)s (inv Ab)s cacuuuug AfCfC fugcuaaucaas (inv Ab) 588 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004797 Fab0069[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 589 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004798 Fab0070[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 590 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004799 Fab0071 [NEM]-L20-(NH- C6)s (inv Ab)s cacuuuug AfCfC fugcuaaucaas (inv Ab) 591 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004800 Fab0074[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 592 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004975 LP293-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 593 cPrpusUfsgsAfuuagcagGfuCfaAfaAfgUfsg 337 WO 2025 / 160224                                   PCT / US2025 / 012678 AC ID Number Sense Strand (Fully Modified with Conjugated Targeting Ligand) (5’ -> 3’) SEQ ID NO. Antisense Strand (5’ -> 3’) SEQ ID NO. AC004982 avP-pepl-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb)C6- S-LP-238b 594 cPrpusUfsgsAfuuagcagGfuCfaAfaAfgUfsg 337 AC004997 FabOO5 6[NEM] -L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 595 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC004998 FabOO5 8 [NEM] -L20-(NH- C6)s (inv Ab)s cacuuuug AfCfC fugcuaaucaas (inv Ab) 596 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC005485 Fab0001-L-1026-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 597 cPrpus U fsgauuAfgcagGfuCfaAfaagsusg 328 AC005487 Fab0044[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 598 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC005488 Fab0046[NEM]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 599 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC006262 FabOOO 1 [CP-1113] -L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 600 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC006266 Fab0061 [CP-1113] -L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 601 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC006372 Fab0070-[CP-l 113]-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 602 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC006448 Fab0070-L-1026-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 603 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC006449 Fab0070-L-1045-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 604 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC006450 Fab0070[CP-1113]L-1063-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 605 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC006452 FabOO7O[CP-l 154]L-1064-(NH- C6 )s (inv Ab)s cacuuuugAfCfC fugcuaaucaas (inv Ab) 606 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 WO 2025 / 160224                                   PCT / US2025 / 012678 AC ID Number Sense Strand (Fully Modified with Conjugated Targeting Ligand) (5’ -> 3’) SEQ ID NO. Antisense Strand (5’ -> 3’) SEQ ID NO. AC006453 Fab0070-L-1100-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 607 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC006597 FabOO7O-L-l 176-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 608 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC006788 LP183-(NH- C6)s(invAb)sgcgacuAfCfUfacaacuuucas(invAb) 609 cPrpusGfsasAfaGfuuguaGfuAfgUfcGfsc 338 AC006789 LP183-(NH- C6)s(invAb)sgcaucaGfUfUfcacuuuugaas(invAb) 610 cPrpusUfscsAfaAfagugaAfcUfgAfuGfsc 339 AC006790 LP183-(NH- C6)s(invAb)scaucagUfUfCfacuuuugacas(invAb) 611 cPrpusGfsusCfaAfaagugAfaCfuGfaUfsg 340 AC006791 LP183-(NH- C6)s(invAb)scuuuugAfCfCfugcuaaucaas(invAb) 612 cPrpusUfsgsAfuUfagcagGfuCfaAfaAfsg 341 AC006792 LP183-(NH- C6)s(invAb)suggugaGfCfGfuggacuuucas(invAb) 613 cPrpusGfsasAfaGfuccacGfcUfcAfcCfsa 342 AC006894 FabO165-SMCC-(NH- C 6)s (inv Ab)s cacuuuugAfCfC fugcuaaucaas (inv Ab) 614 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC006895 FabO166-SMCC-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 615 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC006896 FabO168-SMCC-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 616 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC006898 FabO167-SMCC-(NH- C6)s (inv Ab)s cacuuuugAfCfC fugcuaaucaas (inv Ab) 617 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC009014 LP293-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 593 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC009278 Fab0070-L-1288L- 1307s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 618 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC009279 Fab0070-L-1288L-1289-(NH- C6)s (inv Ab)s cacuuuugAfCfC fugcuaaucaas (inv Ab) 619 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 WO 2025 / 160224                                   PCT / US2025 / 012678 AC ID Number Sense Strand (Fully Modified with Conjugated Targeting Ligand) (5’ -> 3’) SEQ ID NO. Antisense Strand (5’ -> 3’) SEQ ID NO. AC009310 Fab0070[CP-1113]L20-L- 1306s(invAb)scacuuuug AfCfCfugcuaaucaas(invAb) 620 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC009391 Fab0070-L-1026-L- 1306s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 621 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC009786 (NH2-C6)s(invAb)sgcgacuAfCfUfacaacuuucas(invAb) 622 cPrpusGfsasAfaGfuuguaGfuAfgUfcGfsc 338 AC009787 (NH2-C6)s(invAb)scuuuugAfCfCfugcuaaucaas(invAb) 623 cPrpusUfsgsAfuUfagcagGfuCfaAfaAfsg 341 AC009788 Fab0070-[CP-1113]-L20-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 624 cPrpusGfsasAfaGfuuguaGfuAfgUfcGfcgsa 330 AC009789 Fab0070-[CP-1113]-L20-(NH- C6)s(invAb)sgcgacuAfCfUfacaacuuucas(invAb) 625 cPrpusGfsasAfaGfuuguaGfuAfgUfcGfsc 338 ACO 11951 xAb000293-L20-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 626 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 ACO 12606 LP293-(NH- C6)s(invAb)sucgcgacuAfCfUfgcaacuuucas(invAb) 627 cPrpusGfsasAfaGfuugcaGfuAfgUfcGfcgsa 343 ACO 13243 avP-pep 1 -(NH- C6)s (inv Ab)s cacuuuug AfCfC fugcuaaucaas (inv Ab)C 6-S-LP-238b 594 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC909551 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 628 usGfsasAfaGfuuguaGfuAfgUfcGfcgsa 322 AC909552 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 628 cPrpusGfsasAfaGfuuguaGfuAfgUfcGfcgsa 330 AC909553 LP183-(NH- C6)s(invAb)scuucggaaAfUfGfuuaugaagcas(invAb) 629 cPrpusGfscsUfuCfauaacAfuUfuCfcGfaasg 349 AC909554 LP183-(NH- C6)s(invAb)sagagagcuGfCfAfucaguucacus(invAb) 630 cPrpasGfsusGfaAfcugauGfcAfgCfuCfucsu 331 AC909555 LP183-(NH- C6)s(invAb)scugcaucaGfUfUfcacuuuugaas(invAb) 631 cPrpusUfscsAfaAfagugaAfcUfgAfuGfcasg 350 WO 2025 / 160224                                   PCT / US2025 / 012678 AC ID Number Sense Strand (Fully Modified with Conjugated Targeting Ligand) (5’ -> 3’) SEQ ID NO. Antisense Strand (5’ -> 3’) SEQ ID NO. AC909556 LP183-(NH- C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 632 usGfsusCfaAfaagugAfaCfuGfaUfgcsa 325 AC909557 LP183-(NH- C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 632 cPrpusGfsusCfaAfaagugAfaCfuGfaUfgcsa 332 AC909558 LP183-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 633 cPrpusUfsgsAfuUfagcagGfuCfaAfaAfgusg 333 AC909559 LP183-(NH- C6)s(invAb)scuugaccuGfCfUfaaucaagucas(invAb) 634 cPrpusGfsasCfuUfgauuaGfcAfgGfuCfaasg 334 AC909560 LP183-(NH- C6)s(invAb)scauggugaGfCfGfuggacuuucas(invAb) 635 cPrpusGfsasAfaGfuccacGfcUfcAfcCfausg 335 AC909838 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 628 usGfsasAfaGfuuguaGfuAfgUfcGfcgsa 322 AC909839 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 628 cPrpusGfsasAfaGfuuguaGfuAfgUfcGfcgsa 330 AC909840 LP183-(NH- C6)s(invAb)scacuucgaCfCfAfuuucugacaas(invAb) 636 cPrpusUfsgsUfcAfgaaauGfgUfcGfaAfgusg 361 AC909841 LP183-(NH- C6)s(invAb)scccuggauGfGfAfuagcuacucas(invAb) 637 cPrpusGfsasGfuAfgcuauCfcAfuCfcAfggsg 362 AC909842 LP183-(NH- C6)s(invAb)scccauugaCfUfAfuuacuuuccas(invAb) 638 cPrpusGfsgsAfaAfguaauAfgUfcAfaUfggsg 363 AC909843 LP183-(NH- C6)s(invAb)sga 2NaaugauUfGfCfacuauugauas(invAb) 639 cPrpusAfsusCfaAfuagugCfaAfuCfaUfuusc 364 AC909844 LP183-(NH- C6)s(invAb)scugaagaaAfCfUfugguaaucuas(invAb) 640 cPrpusAfsgsAfuUfaccaaGfuUfuCfuUfcasg 365 AC909845 LP183-(NH- C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 632 cPrpusGfsusCfaAfaagugAfaCfuGfaUfgcsa 332 AC909894 LP183-(NH- C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 632 usGfsusCfaAfaagugAfaCfuGfaUfgcsa 325 WO 2025 / 160224                                   PCT / US2025 / 012678 AC ID Number Sense Strand (Fully Modified with Conjugated Targeting Ligand) (5’ -> 3’) SEQ ID NO. Antisense Strand (5’ -> 3’) SEQ ID NO. AC909895 LP183-(NH- C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 632 cPrpusGfsusCfaaaagugAfaCfuGfaugcsa 366 AC909896 LP183-(NH- C6)s(invAb)scgcaucagUfUfCfacuuuugacas(invAb) 641 cPrpusGfsusCfaaaagugAfaCfuGfaugcsg 329 AC909897 LP183-(NH- C6)s(invAb)sggcaucagUfUfCfacuuuugacas(invAb) 642 cPrpusGfsusCfaaaagugAfaCfuGfaugcsc 367 AC909898 LP183-(NH- C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 632 cPrpusGfsuCfaaaagugAfaCfuGfaugcsa 368 AC909899 LP183-(NH- C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 632 cPrpusGfsuCfaaaagugAfaCfuGfaugcssa 369 AC909900 LP183-(NH- C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 632 cPrpusGfsuCfaaaagugAfaCfuGfaugscsa 370 AC909901 LP183-(NH- C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 632 cPrpuGfuC faaaagugAfaCfuGfaugscsa 371 AC909902 LP183-(NH- C 6)s (inv Ab)sugcaucagUfuC faC fuuuugacas(inv Ab) 643 cPrpusGfsusCfaaaagugAfaCfuGfaugcsa 366 AC909903 LP183-(NH- C6)s(invAb)sugcaucAfgUfuCfacuuuugacas(invAb) 644 cPrpusGfsusCfaaaagugAfaCfuGfaugcsa 366 AC909904 LP183-(NH- C6)s(invAb)sugcaucagUfUfCfAfcuuuugacas(invAb) 645 cPrpusGfsusCfaaaagugAfaCfuGfaugcsa 366 AC909905 LP183-(NH- C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 632 cPrpusGfsuscaaAfagugAfaCfuGfaugcsa 372 AC909906 LP183-(NH- C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 632 cPrpusGfsuscaaaaGfugAfaCfuGfaugcsa 373 AC909907 LP183-(NH- C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 632 cPrpusGfsuscaaaagugaaCfuGfaugcsa 374 AC909908 LP183-(NH- C6)s(invAb)sugcaucagUfuCfaCfuuuugacas(invAb) 643 cPrpusGfsuscaaaaGfugAfaCfuGfaugcsa 373 WO 2025 / 160224                                   PCT / US2025 / 012678 AC ID Number Sense Strand (Fully Modified with Conjugated Targeting Ligand) (5’ -> 3’) SEQ ID NO. Antisense Strand (5’ -> 3’) SEQ ID NO. AC909909 LP183-(NH- C6)s(invAb)sugcaucagUfuCfaCfuuuugacas(invAb) 643 cPrpusGfsuCfaaaagugAfaCfuGfaugscsa 370 AC909910 LP183-(NH- C6)s(invAb)sugcaucagUfuCfaCfuuuugacas(invAb) 643 cPrpuGfuC faaaagugAfaCfuGfaugscsa 371 AC909911 LP183-(NH- C6)s(invAb)sugcaucagUfUfCfacuuuugacas(invAb) 632 cPrpusGfsusCfaaAuNAagugAfaCfuGfaugcsa 375 AC909919 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 628 cPrpusGfsasAfaguuguaGfuAfgUfcgcgsa 351 AC909920 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 628 cPrpusGfsaAfaguuguaGfuAfgUfcgcgsa 352 AC909921 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 628 cPrpusGfsaAfaguuguaGfuAfgUfcgcgssa 353 AC909922 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 628 cPrpusGfsaAfaguuguaGfuAfgUfcgcsgsa 354 AC909923 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 628 cPrpuGfaAfaguuguaGfuAfgUfcgcsgsa 355 AC909924 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 628 cPrpusGfsaaagUfuguaGfuAfgUfcgcsgsa 356 AC909925 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 628 cPrpusGfsaaaguuGfuaGfuAfgUfcgcsgsa 357 AC909926 LP183-(NH- C6)s(invAb)sucgcgacuAfcUfaCfaacuuucas(invAb) 646 cPrpusGfsaAfaguuguaGfuAfgUfcgcsgsa 354 AC909927 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 628 cPrpusGfsaAfagUuNAUguaGfuAfgUfcgcsgsa 358 AC909928 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 628 cPrpusGfsaaaguuguaGfuAfgUfcgcsgsa 359 AC909929 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfacaacuuucas(invAb) 628 cPrpusGfsaaaguuguaguAfgUfcgcsgsa 360 WO 2025 / 160224                                   PCT / US2025 / 012678 AC ID Number Sense Strand (Fully Modified with Conjugated Targeting Ligand) (5’ -> 3’) SEQ ID NO. Antisense Strand (5’ -> 3’) SEQ ID NO. AC910162 LP183-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 633 cPrpusUfsgsAfuUfagcagGfuCfaAfaAfgusg 333 AC910163 LP183-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 633 usUfsgsAfuUfagcagGfuCfaAfaAfgusg 376 AC910164 LP183-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 633 cPrpusUfsgsAfuuagcagGfuCfaAfaagusg 377 AC910165 LP183-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 633 cPrpusUfsgAfuuagcagGfuCfaAfaagusg 378 AC910166 LP183-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 633 cPrpusUfsgAfuuagcagGfuCfaAfaagussg 379 AC910167 LP183-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 633 cPrpusUfsgAfuuagcagGfuCfaAfaagsusg 380 AC910168 LP183-(NH- C 6)s (inv Ab)s cacuuuugAfCfC fugcuaaucaas (inv Ab) 633 cPrpusUfsgsAfuuagcagGfuCfaAfaagsusg 381 AC910169 LP183-(NH- C6)s(invAb)scacuuuugAfcCfuGfcuaaucaas(invAb) 647 cPrpusUfsgAfuuagcagGfuCfaAfaagsusg 380 AC910170 LP183-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 633 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC910171 LP183-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 633 cPrpusUfsgauuagCfagGfuCfaAfaagsusg 382 AC910172 LP183-(NH- C6)s (inv Ab)s cacuuuugAfCfC fugcuaaucaas (inv Ab) 633 cPrpusUfsgauuagcagGfuCfaAfaagsusg 383 AC910173 LP183-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 633 cPrpusUfsgauuagcagguCfaAfaagsusg 384 AC910174 LP183-(NH- C6)s(invAb)scacuuuugAfcCfuGfcuaaucaas(invAb) 647 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 AC910175 LP183-(NH- C6)s (inv Ab)s cacuuuugAfCfC fugcuaaucaas (inv Ab) 633 cPrpusUfsgAfuUuNAagcagGfuCfaAfaagsusg 385 WO 2025 / 160224                                   PCT / US2025 / 012678 AC ID Number Sense Strand (Fully Modified with Conjugated Targeting Ligand) (5’ -> 3’) SEQ ID NO. Antisense Strand (5’ -> 3’) SEQ ID NO. AC910176 LP183-(NH- C6)s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb) 633 cPrpusUfsgAfuuAuNAgcagGfuCfaAfaagsusg 386 AC910274 LP183-(NH- C6)s(invAb)sucgcgaCfuAfcUfacaacuuucas(invAb) 648 cPrpusGfsaAfaguuguaGfuAfgUfcgcsgsa 354 AC910275 LP183-(NH- C6)s(invAb)sucgcgacuAfCfUfAfcaacuuucas(invAb) 649 cPrpusGfsaAfaguuguaGfuAfgUfcgcsgsa 354 AC910276 LP183-(NH- C6)s(invAb)sucgcgacuAfcUfAfcaacuuucas(invAb) 650 cPrpusGfsaAfaguuguaGfuAfgUfcgcsgsa 354 AC910277 LP183-(NH- C6)s(invAb)sccgcgacuAfCfUfacaacuuucas(invAb) 651 cPrpusGfsaAfaguuguaGfuAfgUfcgcsgsg 387 AC910278 LP183-(NH- C6)s(invAb)sucgcgacuAfcUfaCfaacuuucas(invAb) 646 cPrpusGfsaaagUfuguaGfuAfgUfcgcsgsa 356 AC910279 LP183-(NH- C6)s(invAb)sucgcgacuAfcUfaCfaacuuucas(invAb) 646 cPrpusGfsaaaguuGfuaGfuAfgUfcgcsgsa 357 AC910280 LP183-(NH- C6)s(invAb)sucgcgacuAfcUfaCfaacuuucas(invAb) 646 cPrpusGfsaaaguuguaGfuAfgUfcgcsgsa 359 AC910281 LP183-(NH- C6)s(invAb)sucgcgacuAfcUfaCfaacuuucas(invAb) 646 cPrpusGfsaaaguuguaguAfgUfcgcsgsa 360 AC910286 LP183-(NH- C6)s(invAb)scgcaucagUfUfCfacuuuugacas(invAb) 641 cPrpusGfsuCfaaaagugAfaCfuGfaugscsg 327 AC910287 LP183-(NH- C6)s(invAb)scgcaucagUfUfCfAfcuuuugacas(invAb) 652 cPrpusGfsusCfaaaagugAfaCfuGfaugcsg 329 AC910288 LP183-(NH- C6)s(invAb)scgcaucagUfUfCfAfcuuuugacas(invAb) 652 cPrpusGfsuCfaaaagugAfaCfuGfaugscsg 327 AC910289 LP183-(NH- C6)s(invAb)scgcaucagUfuCfAfcuuuugacas(invAb) 653 cPrpusGfsuCfaaaagugAfaCfuGfaugscsg 327 AC910290 LP183-(NH- C6)s(invAb)scgcaucagUfuCfacuuuugacas(invAb) 654 cPrpusGfsuCfaaaagugAfaCfuGfaugscsg 327 WO 2025 / 160224                                   PCT / US2025 / 012678 AC ID Sense Strand (Fully Modified with Conjugated Number Targeting Ligand) (5’ -> 3’) AC910291 LP183-(NH- C6)s(invAb)scgcaucagUfuCfaCfuuuugacas(invAb) AC910292 LP183-(NH- C6)s(invAb)scgcaucagUfuCfacuuuugacas(invAb) AC911150 LP293-(NH- C6)s(invAb)scgcaucagUfuCfaCfuuuugacas(invAb) AC911151 LP293-(NH- C6)s(invAb)scacuuuugAfcCfuGfcuaaucaas(invAb) 00 00 SEQ ID NO. Antisense Strand (5’ -> 3’) SEQ ID NO. 655 cPrpusGfsuCfaaaagugAfaCfuGfaugscsg 327 654 cPrpusGfsucaaAfagugAfaCfuGfaugscsg 388 656 cPrpusGfsuCfaaaagugAfaCfuGfaugscsg 327 657 cPrpusUfsgauuAfgcagGfuCfaAfaagsusg 328 WO 2025 / 160224                                   PCT / US2025 / 012678

[0133] In some embodiments, an AR RNAi agent is prepared or provided as a salt, mixed salt, or a free-acid. In some embodiments, an AR RNAi agent is prepared or provided as a pharmaceutically acceptable salt. In some embodiments, an AR RNAi agent is prepared or provided as a pharmaceutically acceptable sodium or potassium salt The RNAi agents described herein, upon delivery to a cell expressing an AR gene, inhibit or knockdown expression of one or more AR genes in vivo and / or in vitro. Targeting Groups, Linking Groups, Lipid moieties, and Delivery Vehicles

[0134] In some embodiments, an AR RNAi agent contains or is conjugated to one or more non-nucleotide groups including, but not limited to, a targeting group, a linking group, a pharmacokinetic / pharmacodynamic (PK / PD) modulator, a delivery polymer, or a delivery' vehicle. The non-nucleotide group can enhance targeting, delivery', or attachment of the RNAi agent. The non-nucleotide group can be covalently linked to the 3' and / or 5' end of either the sense strand and / or the antisense strand. In some embodiments, an AR RNAi agent contains a non-nucleotide group linked to the 3' and / or 5' end of the sense strand. In some embodiments, a non-nucleotide group is linked to the 5' end of an AR RNAi agent sense strand. A nonnucleotide group can be linked directly7 or indirectly7 to the RNAi agent via a linker / linking group. In some embodiments, a non-nucleotide group is linked to the RNAi agent via a labile, cleavable, or reversible bond or linker.

[0135] In some embodiments, a non-nucleotide group enhances the pharmacokinetic or biodistribution properties of an RNAi agent or conjugate to which it is attached to improve cell- or tissue-specific distribution and cell-specific uptake of the conjugate. In some embodiments, a non-nucleotide group enhances endocytosis of the RNAi agent.

[0136] Targeting groups or targeting moieties enhance the pharmacokinetic or biodistribution properties of a conjugate or RNAi agent to which they are attached to improve cell-specific (including, in some cases, organ specific) distribution and cell-specific (or organ specific) uptake of the conjugate or RNAi agent. A targeting group can be monovalent, divalent, trivalent, tetravalent, or have higher valency for the target to which it is directed. Representative targeting groups include, without limitation, compounds with affinity to cell surface molecule, cell receptor ligands, hapten, antibodies, monoclonal antibodies, antibody fragments, and antibody mimics w'ith affinity7 to cell surface molecules. In some embodiments, a targeting group is linked to an RNAi agent using a linker, such as a PEG linker or one, tw o, or three abasic and / or ribitol (abasic ribose) residues, which in some instances can serve as linkers.

[0137] A targeting group, with or without a linker, can be attached to the 5' or 3' end of any of the sense and / or antisense strands disclosed in Tables 2, 3. 4, 5, 6, and 10. A linker, with or without a targeting group, can be attached to the 5' or 3' end of any of the sense and / or antisense strands disclosed in Tables 2, 3, 4, 5. 6, and 10.

[0138] The AR RNAi agents described herein can be synthesized having a reactive group, such as an amino group (also referred to herein as an amine), at the 5'-terminus and / or the 3'-terminus. The reactive group can be used subsequently to attach a targeting moiety using methods typical in the art.

[0139] For example, in some embodiments, the AR RNAi agents disclosed herein are synthesized having an NH2-C6 group at the 5'-terminus of the sense strand of the RNAi agent. The terminal amino group subsequently can be reacted to form a conjugate with, for example, a group that includes a lipid moiety or antigen binding protein. In some embodiments, the AR RNAi agents disclosed herein are synthesized having one or more alky ne groups at the 5'-terminus of the sense strand of the RNAi agent.

[0140] In some embodiments, targeting groups are linked to the AR RN Ai agents without the use of an additional linker. In some embodiments, the targeting group is designed having a linker readily present to facilitate the linkage to an AR RNAi agent. In some embodiments, when two or more RNAi agents are included in a composition, the two or more RNAi agents can be linked to their respective targeting groups using the same linkers. In some embodiments, when two or more RNAi agents are included in a composition, the two or more RNAi agents are linked to their respective targeting groups using different linkers.

[0141] In some embodiments, a linking group is conjugated to the RNAi agent. The linking group facilitates covalent linkage of the agent to a targeting group, pharmacokinetic modulator, delivery polymer, or delivery vehicle. The linking group can be linked to the 3' and / or the 5' end of the RNAi agent sense strand or antisense strand. In some embodiments, the linking group is linked to the RNAi agent sense strand. In some embodiments, the linking group is conjugated to the 5' or 3' end of an RNAi agent sense strand. In some embodiments, a linking group is conjugated to the 5' end of an RNAi agent sense strand. Examples of linking groups, include but are not limited to: C6-SS-C6, 6-SS-6, reactive groups such a primary amines (e.g.. NH2-C6) and alkynes, alkyl groups, abasic residues / nucleotides, ammo acids, tri-alkyne functionalized groups, ribitol, and / or PEG groups. Examples of certain linking groups are provided in Table 11.

[0142] A linker or linking group is a connection between two atoms that links one chemical group (such as an RNAi agent) or segment of interest to another chemical group (such as a targeting group, pharmacokinetic modulator, or delivery' polymer) or segment of interest via one or more covalent bonds. A labile linkage contains a labile bond. A linkage can optionally include a spacer that increases the distance between the two joined atoms. A spacer may further add flexibility and / or length to the linkage. Spacers include, but are not be limited to, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, aralkyl groups, aralkenyl groups, and aralkynyl groups; each of which can contain one or more heteroatoms, heterocycles, amino acids, nucleotides, and saccharides. Spacer groups are well known in the art and the preceding list is not meant to limit the scope of the description. In some embodiments, an AR RNAi agent is conjugated to a polyethylene glycol (PEG) moiety, or to a hydrophobic group having 12 or more carbon atoms, such as a cholesterol or palmitoyl group.

[0143] In some embodiments, an AR RNAi agent is linked to one or more antigen binding proteins. Antigen binding proteins may enhance the bioavailability of the RNAi agent, the delivery of the RNAi agent to a cell of interest, or the facilitation of shuttling the RNAi agent across the blood brain barrier. In some embodiments, the antigen binding protein may be conjugated to a linker at the 3' or 5' end of a sense strand or an antisense strand of an RNAi agent described herein. In some embodiments, an antigen binding protein may be linked at both the 3' or 5' end of either the sense strand or the antisense strand of an RNAi agent described herein.

[0144] In some embodiments, an antigen binding protein may be conjugated to an AR RNAi agent by reacting an AR RNAi agent comprising an amine-comprising linker, for example, (NH2-C6) (see Table 10). In some embodiments, the amine-comprising linker may be located on the 5' end of the sense strand or the antisense strand of an AR RNAi agent. In some embodiments, the amine-comprising linker may be located on the 3' end of the sense strand or the antisense strand of an RNAi agent.

[0145] Any of the AR RNAi agent nucleotide sequences listed in Tables 2, 3, 4, 5, 6, and 9, whether modified or unmodified, can contain 3' and / or 5' targeting group(s), linking group(s), and / or antigen binding fragments. Any of the AR RNAi agent duplexes listed in Tables 7, 8, and 9, whether modified or unmodified, can further compnse a targeting group or linking group, but not limited to, those depicted in Table 10, and the targeting group or linking group can be attached to the 3' or 5' terminus of either the sense strand or the antisense strand of the AR RNAi agent duplex.

[0146] In some embodiments, an AR RNAi agent is linked to one or more lipid moieties. Lipid moieties may enhance the pharmacodynamic or pharmacokinetic properties of the RNAi agent. In some embodiments, the lipid moiety or antigen binding protein may be conjugated to a linker at the 3' or 5' end of a sense strand or an antisense strand of an RNAi agent described herein. In some embodiments, a lipid moiety or antigen binding protein may be linked at both the 3' or 5' end of either the sense strand or the antisense strand of an RNAi agent described herein.

[0147] In some embodiments, a lipid moiety or antigen binding protein may be conjugated to an AR RNAi agent by reacting an AR RNAi agent comprising an amine-comprising linker, for example, (NH2-C6) (see table 11). In some embodiments, the amine-comprising linker may be located on the 5' end of the sense strand or the antisense strand of an AR RNAi agent. In some embodiments, the amine-comprising linker may be located on the 3' end of the sense strand or the antisense strand of an RNAi agent.

[0148] In some embodiments, an RNAi agent comprising an amine-comprising linker, such as (NH2-C6) or (NH2-C6)s, may be reacted with a lipid comprising an activated ester moiety. Example lipids with activated ester moieties include LP183-p, LP 283-p, LP293-p, LP294-p, LP304-p, LP310-p, LP383-p, LP395-p, and LP396-p as shown in Table 11 below.

[0149] For example, in some embodiments, the AR RNAi agents disclosed herein are synthesized having an NH2-C6 group at the 5'-terminus of the sense strand of the RNAi agent. The terminal amino group subsequently can be reacted to form a conjugate with, for example, a group that includes an antigen binding protein. In some embodiments, the AR RNAi agents disclosed herein are synthesized having one or more alky ne groups at the 5'-terminus of the sense strand of the RNAi agent.

[0150] In some embodiments, an AR RNAi agent may be conjugated to a lipid moiety or antigen binding protein using phosphoramidite synthesis. Synthesizing oligonucleotides using phosphorami dites is well-known in the art. In some embodiments, a lipid moiety or antigen binding protein may be conjugated to the 5' end of the sense strand or the antisense strand of an AR RNAi agent using a phosphoramidite. In some embodiments, a lipid moiety or antigen binding protein may be conjugated to the 3' end of the sense strand or the antisense strand of an AR RNAi agent using a phosphoramidite. In some embodiments, a phosphoramidite selected from (2C8C12)-p, (2C6C10)-p, LP429 phosphoramidite, HO-C16-p, C16-p, or C22-p, all as shown in Table 11 below', may be used to conjugate a lipid moiety or antigen binding protein to an AR RNAi agent.

[0151] In some embodiments, AR RNAi agents may comprise a lipid moiety or antigen binding protein on an internal nucleotide (i.e., not on the 3' or 5' terminal nucleotides.) In some embodiments, an internal nucleotide may be linked to the 2' position of nbose. In some embodiments AR RNAi agents may comprise aC16, uC16. cC16, or gC16 as shown in Table 11 below'.

[0152] Any of the AR RNAi agent nucleotide sequences listed in Tables 2, 3, 4, 5, 6, and 10, whether modified or unmodified, can contain 3' and / or 5' targeting group(s), linking group(s), and / or lipid moieties. Any of the AR RNAi agent sequences listed in Tables 3, 4, 5, 6, and 10, or are otherwise described herein, which contain a 3' or 5' targeting group, linking group, and / or lipid moiety or antigen binding protein can alternatively contain no 3' or 5' targeting group, linking group, or lipid moiety or antigen binding protein, or can contain a different 3' or 5' targeting group, linking group, or lipid moiety or antigen binding protein including, but not limited to, those depicted in Table 11. Any of the AR RNAi agent duplexes listed in Tables 7, 8, 9 and 10, whether modified or unmodified, can further comprise a targeting group or linking group, including, but not limited to, those depicted m Table 11, and the targeting group or linking group can be attached to the 3' or 5' terminus of either the sense strand or the antisense strand of the AR RNAi agent duplex.

[0153] Examples of certain modified nucleotides, capping moieties, lipid moieties, and linking groups are provided in Table 11. Table 11. Structures Representing Various Modified Nucleotides, Capping Moieties. lipid moieties and Linking Groups (wherein ? indicates the point of connection) used throughout the present disclosure cPrpu cPrpus o o gC16 gC16s When positioned internally: linkage towards 5' end linkage towards 5' end O" v°'?-o 0 linkage towards 3' end S" 0 linkage towards 3' end (invAb) When positioned at the 3' terminal end: (invAb)s linkage towards 5' end HO (invAb) O ii „P^ ■° 6_o- o II ■° I _o- (NHC6) O (NHC6)s O~ ii (C6) (C6)s When position at the 3' terminal end: linkage towards 5' end OH (C6-SS-C6) When positioned internally: linkage towards 5' end linkage towards 3' end (C6-SS-C6) When position at the 3' terminal end: linkage towards 5' end (6-SS-6) When positioned internally: linkage towards 5' end             linkage towards 3' end (6-SS-6) L-1026 O LP183 LP183s LP183r 2          n / ° ''p^ H          ©s' ° s LP183r- o 1                   ^N N                            p "                                      1 N p LP283 0 LP283- F ?fyS F F P OH LP293 0 OH LP293- F jCxbi F P LP294 OH 0 LP294- F OH 0 F^|*l F P LP304 1                 0 JL 0 O LP396 LP396-p (2C8C12)s (2C8C12)-p ii O (2C6C10)s (2C6C10)-p L-1045 Linkage to Fab Linkage toward RNAi agent L-1063 Linkage to Fab L-1064 L-1100 L-1176 Linkage to Fab L20-L-1306 L-1026-L-1306 L-1288 L-1289 L-1307 Linkage toward RNAi agent

[0154] Alternatively, other linking groups known in the art may be used. In many instances, linking groups can be commercially acquired or alternatively, are incorporated into commercially available nucleotide phosphoramidites. (See, e.g., International Patent Application Publication No. WO 2019 / 161213. which is incorporated herein by reference in its entirety).

[0155] In some embodiments, an AR RNAi agent is delivered without being conjugated to a targeting ligand or pharmacokinetic / pharmacodynamic (PK / PD) modulator (referred to as being “naked” or a “naked RN Ai agent”).

[0156] In some embodiments, an AR RNAi agent is conjugated to a targeting group, a linking group, a PK modulator, and / or another non-nucleotide group to facilitate delivery of the AR RNAi agent to the cell or tissue of choice, for example, to a CNS and / or skeletal muscle cell in vivo. In some embodiments, an AR RNAi agent is conjugated to a lipid moiety or antigen binding protein.

[0157] In some embodiments, an AR RNAi agent is delivered without being conjugated to an antigen binding protein or other targeting group (referred to as being “naked” or a “naked RNAi agent”).

[0158] In some embodiments, an AR RNAi agent is conjugated to a targeting group, a linking group, a PK modulator, and / or another non-nucleotide group to facilitate delivery of the AR RNAi agent to the cell or tissue of choice, for example, to a CNS cell in vivo. In some embodiments, an AR RNAi agent is conjugated to an antigen binding protein.

[0159] In some embodiments, a delivery vehicle may be used to deliver an RNAi agent to a cell or tissue. A delivery vehicle is a compound that improves delivery of the RNAi agent to a cell or tissue. A delivery vehicle can include, or consist of, but is not limited to: a polymer, such as an amphipathic polymer, a membrane active polymer, a peptide, a melittin peptide, a melittin-like peptide (MLP), a lipid, a reversibly modified polymer or peptide, or a reversibly modified membrane active polyamine.

[0160] In some embodiments, the RNAi agents can be combined with lipids, nanoparticles, polymers, liposomes, micelles, DPCs or other delivery systems available in the art for nucleic acid delivery. The RNAi agents can also be chemically conjugated to targeting groups, lipids (including, but not limited to cholesteryl and cholesteryl derivatives), encapsulating m nanoparticles, liposomes, micelles, conjugating to polymers or DPCs (see, for example WO 2000 / 053722, WO 2008 / 022309, WO 2011 / 104169, and WO 2012 / 083185, WO 2013 / 032829, WO 2013 / 158141, each of which is incorporated herein by reference), by iontophoresis, or by incorporation into other delivery vehicles or systems available in the art such as hydrogels, cyclodextrins, biodegradable nanocapsules, bioadhesive microspheres, or proteinaceous vectors. In some embodiments the RNAi agents can be conjugated to antibodies having affinity for CNS and / or skeletal muscle cells. In some embodiments, the RNAi agents can be linked to targeting ligands that have affinity for CNS and / or skeletal muscle cells or receptors present on CNS and / or skeletal muscle cells. Antigen Binding Proteins

[0001] In one aspect, AR RNAi agents are conjugates to antigen binding proteins. In some embodiments, the antigen binding protein may be selected from the group consisting of: an antibody, an antibody fragment (e.g., an antigen binding fragment, or Fab), scFv, or other functional component or derivative of an antibody encompassing a Fab and / or complementary -determining regions (CDRs) disclosed herein.

[0002] In some embodiments, the antigen binding protein may act as a shuttle to facilitate the crossing of the blood brain barrier (BBB) of the RNAi agent, such that the RNAi agent may be administered subcutaneously and reach CNS tissue. In some embodiments, the antigen binding protein is an anti-Transferrin 1 (TfRl) antibody or Fab.

[0003] In some embodiments, the antigen binding protein is a Fab. In some embodiments, the Fab comprises (i) 6 complementary determining regions (CDRs), (ii) 3 CDRs on the variable light chain (VL), or (iii) 3 CDRs on the variable heavy chain (VH). In some embodiments, the Fab comprises a light constant chain 1 (CL). In some embodiments, the light constant chain 1 (CL)                                     sequence                                     is: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:    717). In some embodiments. the light chain sequence is: DIQLTQSPSSLSASVGDRVTITCRASDKLYSNLAWYQQKPGKAPKLLIYDATLLASGV PSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWGTPLTFGQGTKVEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 718).

[0004] In some embodiments, the Fab comprises a heavy constant chain 1 (CH). In some embodiments, the heavy constant chain 1 (CH) is: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH (SEQ ID NO: 719). In some embodiments the heavy chain sequence is : EVQLVESGGGLVQPGGSLRLSCATSGFTFTSYWMHWVRQAPGKGLEWVAEINPTNG RTNYIEKFKSRITLSVDKSKSTVYLQMNSLRAEDTAVYYCARGTRAYHYWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH (SEQ ID NO: 720).

[0005] In some embodiments, the antigen binding protein may have a VL CDR1 sequence selected from the group consisting of: RASDGLYSNLA (SEQ ID NO: 721), RASDNLYRNLA (SEQ ID NO: 722), and RASDKLYSNLA (SEQ ID NO: 723).

[0006] In some embodiments, the antigen binding protein may have a VL CDR2 sequence selected from the group consisting of: DATLLAS (SEQ ID NO: 724), DARNLAS (SEQ ID NO: 725), DAFNLAS (SEQ ID NO: 726), DATRLAS (SEQ ID NO: 727), DATKLAS (SEQ ID NO: 728), and DAKNLAS (SEQ ID NO: 729).

[0007] In some embodiments, the antigen binding protein may have a VL CDR 3 sequence of QHFWGTPLT (SEQ ID NO: 730).

[0008] In some embodiments, the antigen binding protein may have a VH CDR1 sequence selected from the group consisting of: GYTFNSYWMH (SEQ ID NO: 731), GYTFKSYWMH (SEQ ID NO: 732), GFTFTSYWMH (SEQ ID NO: 733), GYTFTSYWVH (SEQ ID NO: 734), and GYTFTSYWMH (SEQ ID NO: 735).

[0009] In some embodiments, the antigen binding protein may have a VH CDR2 sequence selected from the group consisting of: EINPTNGRVNYIEKFKS (SEQ ID NO: 736), EINPTNGRFNYIEKFKS (SEQ ID NO: 737), EINPTNGRTNYIEKFKS (SEQ ID NO: 738). and EINPTNGRSNYIEKFKS (SEQ ID NO: 739).

[0010] In some embodiments, the antigen binding protein may have a VH CDR3 sequence of: GTRAYHY (SEQ ID NO: 740).

[0011] In some embodiments, the antigen binding protein comprises a VL sequence of any one of the sequences listed in Table A below. Each of the Fabs described in Table A has a light chain                      constant                     sequence                      of: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 717)

[0012] Table A. VL chains with CDR mutation combinations. SEQ ID NO. Fab VL SEQUENCE 741 FabOOOl DIQMTQSPSSLSASVGDRVTITCRASDNLYSNLAWYQQKP GKSPKLLVYDATNLADGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQHFWGTPLTFGQGTKVEIK 741 Fab0002 DIQMTQSPSSLSASVGDRVTITCRASDNLYSNLAWYQQKP GKSPKLLVYDATNLADGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQHFWGTPLTFGQGTKVEIK SEQID NO. Fab VL SEQUENCE 741 Fab0044 D1QMTQSPSSLSASVGDRVT1TCRASDNLYSNLAWYQQKP GKSPKLLVYDATNLADGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQHFWGTPLTFGQGTKVEIK 741 Fab0046 DIQMTQSPSSLSASVGDRVTITCRASDNLYSNLAWYQQKP GKSPKLLVYDATNLADGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQHFWGTPLTFGQGTKVEIK 741 Fab0056 DIQMTQSPSSLSASVGDRVTITCRASDNLYSNLAWYQQKP GKSPKLLVYDATNLADGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQHFWGTPLTFGQGTKVEIK 741 FabOO58 DIQMTQSPSSLSASVGDRVTITCRASDNLYSNLAWYQQKP GKSPKLLVYDATNLADGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQHFWGTPLTFGQGTKVEIK 742 Fab0060 DIQLTQSPSSLSASVGDRVTITCRASDGLYSNLAWYQQKPG KAPKLLIYDATKLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQHFWGTPLTFGQGTKVEIK 742 Fab0061 DIQLTQSPSSLSASVGDRVTITCRASDGLYSNLAWYQQKPG KAPKLLIYDATKLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQHFWGTPLTFGQGTKVEIK 743 Fab0062 DIQLTQSPSSLSASVGDRVTITCRASDGLYSNLAWYQQKPG KAPKLLIYDAFNLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYC QHFWGTPLTFGQGTKVEIK 744 Fab0063 DIQLTQSPSSLSASVGDRVTITCRASDGLYSNLAWYQQKPG KAPKLLIYDATRLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQHFWGTPLTFGQGTKVEIK 745 Fab0064 DIQLTQSPSSLSASVGDRVTITCRASDGLYSNLAWYQQKPG KAPKLLIYDAKNLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYC QHFWGTPLTFGQGTKVEIK 746 Fab0065 DIQLTQSPSSLSASVGDRVTITCRASDNLYRNLAWYQQKPG KAPKLLIYDATKLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQHFWGTPLTFGQGTKVEIK 743 Fab0066 DIQLTQSPSSLSASVGDRVTITCRASDGLYSNLAWYQQKPG KAPKLLIYDAFNLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQHFWGTPLTFGQGTKVEIK 746 Fab0067 DIQLTQSPSSLSASVGDRVTITCRASDNLYRNLAWYQQKPG KAPKLLIYDATKLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQHFWGTPLTFGQGTKVEIK 742 Fab0068 DIQLTQSPSSLSASVGDRVTITCRASDGLYSNLAWYQQKPG KAPKLLIYDATKLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQHFWGTPLTFGQGTKVEIK 742 Fab0069 DIQLTQSPSSLSASVGDRVTITCRASDGLYSNLAWYQQKPG KAPKLLIYDATKLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQHFWGTPLTFGQGTKVEIK 747 Fab0070 DIQLTQSPSSLSASVGDRVTITCRASDKLYSNLAWYQQKPG KAPKLLIYDATLLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQHFWGTPLTFGQGTKVEIK SEQ ID NO. Fab VL SEQUENCE 748 Fab0071 DIQLTQSPSSLSASVGDRVTITCRASDGLYSNLAWYQQKPG KAPKLLIYDARNLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQHFWGTPLTFGQGTKVEIK 749 Fab0072 DIQLTQSPSSLSASVGDRVTITCRASDNLYRNLAWYQQKPG KAPKLLIYDARNLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYC QHFWGTPLTFGQGTKVEIK 746 Fab0073 DIQLTQSPSSLSASVGDRVTITCRASDNLYRNLAWYQQKPG KAPKLLIYDATKLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQHFWGTPLTFGQGTKVEIK 745 Fab0074 DIQLTQSPSSLSASVGDRVTITCRASDGLYSNLAWYQQKPG KAPKLLIYDAKNLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYC QHFWGTPLTFGQGTKVEIK 747 Fab0165 DIQLTQSPSSLSASVGDRVTITCRASDKLYSNLAWYQQKPG KAPKLLIYDATLLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQHFWGTPLTFGQGTKVEIK 747 Fab0166 DIQLTQSPSSLSASVGDRVTITCRASDKLYSNLAWYQQKPG KAPKLLIYDATLLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYC QHFWGTPLTFGQGTKVEIK 747 Fab0167 D1QLTQSPSSLSASVGDRVTITCRASDKLYSNLAWYQQKPG KAPKLLIYDATLLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQHFWGTPLTFGQGTKVEIK 747 Fab0168 DIQLTQSPSSLSASVGDRVTITCRASDKLYSNLAWYQQKPG KAPKLLIYDATLLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYC QHFWGTPLTFGQGTKVEIK 747 xAb000293 D1QLTQSPSSLSASVGDRVTITCRASDKLYSNLAWYQQKPG KAPKLLIYDATLLASGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQHFWGTPLTFGQGTKVEIK

[0013] In some embodiments, the antigen binding protein comprises a VL sequence of any one of the sequences listed in Table B below. Each of the Fabs described in Table B has a heavy chain                      constant                     sequence                      of: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH (SEQ ID NO: 719). Table B. VH chains with CDR mutation combinations. SEQ ID NO. Fab VH SEQUENCE 750 FabOOOl EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVR QAPGQRLEWIGEINPTNGRTNYIEKFKSRATLTVDKSASTA YMELS SLRSEDTAVYYC ARGTRAYHYWGQGTMVTVS S 750 Fab0002 EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVR QAPGQRLEWIGEINPTNGRTNYIEKFKSRATLTVDKSASTA SEQ ID NO. Fab VH SEQUENCE YMELS SLRSEDTAVYYC ARGTRAYHYWGQGTMVTVS S 750 Fab0044 EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVR QAPGQRLEWIGEINPTNGRTNYIEKFKSRATLTVDKSASTA YMELS SLRSEDTAVYYC ARGTRAYHYWGQGTMVTVS S 750 Fab0046 EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVR QAPGQRLEWIGEINPTNGRTNYIEKFKSRATLTVDKSASTA YMELS SLRSEDTAVYYC ARGTRAYHYWGQGTMVTVS S 750 Fab0056 EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVR QAPGQRLEWIGEINPTNGRTNYIEKFKSRATLTVDKSASTA YMELS SLRSEDTAVYYC ARGTRAYHYWGQGTMVTVS S 750 FabOO58 EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVR QAPGQRLEWIGEINPTNGRTNYIEKFKSRATLTVDKSASTA YMELS SLRSEDTAVYYC ARGTRAYHYWGQGTMVTVS S 751 Fab0060 EVQLVESGGGLVQPGGSLRLSCATSGYTFTSYWVHWVRQ APGKGLEWVAEINPTNGRTNYIEKFKSRITLSVDKSKSTVY LQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 752 Fab0061 EVQLVESGGGLVQPGGSLRLSCATSGYTFTSYWMHWVR QAPGKGLEWVAEINPTNGRVNYIEKFKSRITLSVDKSKST VYLQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 752 Fab0062 EVQLVESGGGLVQPGGSLRLSCATSGYTFTSYWMHWVR QAPGKGLEWVAEINPTNGRVNYIEKFKSRITLSVDKSKST VYLQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 752 Fab0063 EVQLVESGGGLVQPGGSLRLSCATSGYTFTSYWMHWVR QAPGKGLEWVAEINPTNGRVNYIEKFKSRITLSVDKSKST VYLQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 752 Fab0064 EVQLVESGGGLVQPGGSLRLSCATSGYTFTSYWMHWVR QAPGKGLEWVAEINPTNGRVNYIEKFKSRITLSVDKSKST VYLQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 753 Fab0065 EVQLVESGGGLVQPGGSLRLSCATSGYTFTSYWVHWVRQ APGKGLEWVAEINPTNGRSNYIEKFKSRITLSVDKSKSTVY LQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 754 Fab0066 EVQLVESGGGLVQPGGSLRLSCATSGYTFTSYWVHWVRQ APGKGLEWVAEINPTNGRVNYIEKFKSRITLSVDKSKSTV YLQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 751 Fab0067 EVQLVESGGGLVQPGGSLRLSCATSGYTFTSYWVHWVRQ APGKGLEWVAEINPTNGRTNYIEKFKSRITLSVDKSKSTVY LQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 754 Fab0068 EVQLVESGGGLVQPGGSLRLSCATSGYTFTSYWVHWVRQ APGKGLEWVAEINPTNGRVNYIEKFKSRITLSVDKSKSTV YLQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 753 Fab0069 EVQLVESGGGLVQPGGSLRLSCATSGYTFTSYWVHWVRQ APGKGLEWVAEINPTNGRSNYIEKFKSRITLSVDKSKSTVY LQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 755 FabOO7O EVQLVESGGGLVQPGGSLRLSCATSGFTFTSYWMHWVRQ APGKGLEWVAEINPTNGRTNYIEKFKSRITLSVDKSKSTVY LQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 756 Fab0071 EVQLVESGGGLVQPGGSLRLSCATSGYTFNSYWMHWVR SEQ ID NO. Fab VH SEQUENCE QAPGKGLEWVAEINPTNGRTNYIEKFKSRITLSVDKSKSTV YLQMNSLRAEDTAVYYC ARGTRAYHYWGQGTL VTV S S 757 Fab0072 EVQLVESGGGLVQPGGSLRLSCATSGYTFNSYWMHWVR QAPGKGLEWVAEINPTNGRFNYIEKFKSRITLSVDKSKSTV YLQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 758 FabOO73 EVQLVESGGGLVQPGGSLRLSCATSGYTFKSYWMHWVR QAPGKGLEWVAEINPTNGRTNYIEKFKSRITLSVDKSKSTV YLQMNSLRAEDTAVYYC ARGTRAYHYWGQGTL VTV S S 758 Fab0074 EVQLVESGGGLVQPGGSLRLSCATSGYTFKSYWMHWVR QAPGKGLEWVAEINPTNGRTNYIEKFKSRITLSVDKSKSTV YLQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 755 Fab0165 EVQLVESGGGLVQPGGSLRLSCATSGFTFTSYWMHWVRQ APGKGLEWVAEINPTNGRTNYIEKFKSRITLSVDKSKSTVY LQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 755 Fab0166 EVQLVESGGGLVQPGGSLRLSCATSGFTFTSYWMHWVRQ APGKGLEWVAEINPTNGRTNYIEKFKSRITLSVDKSKSTVY LQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 755 Fab0167 EVQLVESGGGLVQPGGSLRLSCATSGFTFTSYWMHWVRQ APGKGLEWVAEINPTNGRTNYIEKFKSRITLSVDKSKSTVY LQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 755 Fab0168 EVQLVESGGGLVQPGGSLRLSCATSGFTFTSYWMHWVRQ APGKGLEWVAEINPTNGRTNYIEKFKSRITLSVDKSKSTVY LQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS 755 xAb000293 EVQLVESGGGLVQPGGSLRLSCATSGFTFTSYWMHWVRQ APGKGLEWVAEINPTNGRTNYIEKFKSRITLSVDKSKSTVY LQMNSLRAEDTAVYYCARGTRAYHYWGQGTLVTVSS

[0014] Tables C-H show the CDR1 and CDR2 variants from VL and VH with the combined beneficial mutations. Table C. VL CDR1 variant SEQ ID NO: Fab CDR1 759 FabOOOl RASDNLYSNLA 759 Fab0002 RASDNLYSNLA 759 Fab0044 RASDNLYSNLA 759 Fab0046 RASDNLYSNLA 759 Fab0056 RASDNLYSNLA 759 Fab0058 RASDNLYSNLA 721 Fab0060 RASDGLYSNLA 721 Fab0061 RASDGLYSNLA 721 Fab0062 RASDGLYSNLA 721 Fab0063 RASDGLYSNLA 721 Fab0064 RASDGLYSNLA 722 Fab0065 RASDNLYRNLA 721 Fab0066 RASDGLYSNLA 722 Fab0067 RASDNLYRNLA 721 Fab0068 RASDGLYSNLA 721 Fab0069 RASDGLYSNLA 723 Fab0070 RASDKLYSNLA 721 Fab0071 RASDGLYSNLA 722 Fab0072 RASDNLYRNLA 722 Fab0073 RASDNLYRNLA 721 Fab0074 RASDGLYSNLA 723 Fab0165 RASDKLYSNLA 723 Fab0166 RASDKLYSNLA 723 Fab0167 RASDKLYSNLA 723 Fab0168 RASDKLYSNLA 723 xAb000293 RASDKLYSNLA Table D. VL CDR2 variants SEQ ID NO: Fab CDR2 760 FabOOOl DATNLAD 760 Fab0002 DATNLAD 760 Fab0044 DATNLAD 760 Fab0046 DATNLAD 760 Fab0056 DATNLAD 760 FabOO58 DATNLAD 728 Fab0060 DATKLAS 728 Fab0061 DATKLAS 726 Fab0062 DAFNLAS 727 Fab0063 DATRLAS 729 Fab0064 DAKNLAS 728 Fab0065 DATKLAS 726 Fab0066 DAFNLAS 728 Fab0067 DATKLAS 728 Fab0068 DATKLAS 728 Fab0069 DATKLAS 724 FabOO7O DATLLAS 725 Fab0071 DARNLAS 725 Fab0072 DARNLAS 728 Fab0073 DATKLAS 729 Fab0074 DAKNLAS 724 Fab0165 DATLLAS 724 Fab0166 DATLLAS 724 Fab0167 DATLLAS 724 Fab0168 DATLLAS 724 xAb000293 DATLLAS Table E. VL CDR3 variant SEQ ID NO: Fab CDR3 730 FabOOOl QHFWGTPLT 730 Fab0002 QHFWGTPLT 730 Fab0044 QHFWGTPLT 730 Fab0046 QHFWGTPLT 730 Fab0056 QHFWGTPLT 730 Fab0058 QHFWGTPLT 730 Fab0060 QHFWGTPLT 730 Fab0061 QHFWGTPLT 730 Fab0062 QHFWGTPLT 730 Fab0063 QHFWGTPLT 730 Fab0064 QHFWGTPLT 730 Fab0065 QHFWGTPLT 730 Fab0066 QHFWGTPLT 730 Fab0067 QHFWGTPLT 730 Fab0068 QHFWGTPLT 730 Fab0069 QHFWGTPLT 730 Fab0070 QHFWGTPLT 730 Fab0071 QHFWGTPLT 730 Fab0072 QHFWGTPLT 730 Fab0073 QHFWGTPLT 730 Fab0074 QHFWGTPLT 730 Fab0165 QHFWGTPLT 730 Fab0166 QHFWGTPLT 730 Fab0167 QHFWGTPLT 730 Fab0168 QHFWGTPLT 730 xAb000293 QHFWGTPLT Table F. VH CDR1 variants SEQ ID NO: Fab CDR1 735 FabOOOl GYTFTSYWMH 735 Fab0002 GYTFTSYWMH 735 Fab0044 GYTFTSYWMH 735 Fab0046 GYTFTSYWMH 735 Fab0056 GYTFTSYWMH 735 Fab0058 GYTFTSYWMH 734 Fab0060 GYTFTSYWVH 735 Fab0061 GYTFTSYWMH 735 Fab0062 GYTFTSYWMH 735 Fab0063 GYTFTSYWMH 735 Fab0064 GYTFTSYWMH 734 Fab0065 GYTFTSYWVH 734 Fab0066 GYTFTSYWVH 734 Fab0067 GYTFTSYWVH 734 Fab0068 GYTFTSYWVH 734 Fab0069 GYTFTSYWVH 733 Fab0070 GFTFTSYWMH 731 Fab0071 GYTFNSYWMH 731 Fab0072 GYTFNSYWMH 732 Fab0073 GYTFKSYWMH 732 Fab0074 GYTFKSYWMH 733 Fab0165 GFTFTSYWMH 733 Fab0166 GFTFTSYWMH 733 Fab0167 GFTFTSYWMH 733 Fab0168 GFTFTSYWMH 733 xAb000293 GFTFTSYWMH Table G. VH CDR2 variants SEQ ID NO: Fab CDR2 738 FabOOOl EINPTNGRTNYIEKFKS 738 Fab0002 EINPTNGRTNYIEKFKS 738 Fab0044 EINPTNGRTNYIEKFKS 738 Fab0046 EINPTNGRTNYIEKFKS 738 Fab0056 EINPTNGRTNYIEKFKS 738 FabOO58 EINPTNGRTNYIEKFKS 738 Fab0060 EINPTNGRTNYIEKFKS 736 Fab0061 EINPTNGRVNYIEKFKS 736 Fab0062 EINPTNGRVNYIEKFKS 736 Fab0063 EINPTNGRVNYIEKFKS 736 Fab0064 EINPTNGRVNYIEKFKS 739 Fab0065 EINPTNGRSNYIEKFKS 736 Fab0066 EINPTNGRVNYIEKFKS 738 Fab0067 EINPTNGRTNYIEKFKS 736 Fab0068 EINPTNGRVNYIEKFKS 739 Fab0069 EINPTNGRSNYIEKFKS 738 FabOO7O EINPTNGRTNYIEKFKS 738 FabOO71 EINPTNGRTNYIEKFKS 737 Fab0072 EINPTNGRFNYIEKFKS 738 FabOO73 EINPTNGRTNYIEKFKS 738 Fab0074 EINPTNGRTNYIEKFKS 738 Fab0165 EINPTNGRTNYIEKFKS 738 Fab0166 EINPTNGRTNYIEKFKS 738 Fab0167 EINPTNGRTNYIEKFKS 738 Fab0168 EINPTNGRTNYIEKFKS 738 xAb000293 EINPTNGRTNYIEKFKS Table H. VH CDR3 variants SEQ ID NO: Fab CDR3 740 FabOOOl GTRAYHY 740 Fab0002 GTRAYHY 740 Fab0044 GTRAYHY 740 Fab0046 GTRAYHY 740 Fab0056 GTRAYHY 740 Fab0058 GTRAYHY 740 Fab0060 GTRAYHY 740 Fab0061 GTRAYHY 740 Fab0062 GTRAYHY 740 Fab0063 GTRAYHY 740 Fab0064 GTRAYHY 740 Fab0065 GTRAYHY 740 Fab0066 GTRAYHY 740 Fab0067 GTRAYHY 740 Fab0068 GTRAYHY 740 Fab0069 GTRAYHY 740 Fab0070 GTRAYHY 740 Fab0071 GTRAYHY 740 Fab0072 GTRAYHY 740 Fab0073 GTRAYHY 740 Fab0074 GTRAYHY 740 Fab0165 GTRAYHY 740 Fab0166 GTRAYHY 740 Fab0167 GTRAYHY 740 Fab0168 GTRAYHY 740 xAb000293 GTRAYHY Table I. Fab-Fc chain sequences SEQ ID NO: Fab Amino Acid Sequence 763 xAb000293 DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITR EPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVCTLPPS REEMTKNQVSLSCAVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK

[0015] In some embodiments. RNAi agents may be conjugated to an antigen binding protein specific to a non-human mammal to carry out studies. RNAi agents may be conjugated to a mouse-specific anti-transferrin antibody such as Fab0016. Fab0016 as used herein refers to an antibody fragment having a light chain sequence of: DIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLLIYGATSLADGV PSRFSGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELKRADAAPTVS IFPPSTEQLATGGASVVCLMNNFYPRDISVKWKIDGTERRDGVLDSVTDQDSKDSTY SMSSTLSLTKADYESHNLYTCEVVHKTSSSPVVKSFNRNEC (SEQ ID NO: 761), and a heavy                     chain                     sequence                     of: EVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSS KMNYADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQG VSVTVSSAETTAPSVYPLAPGTALKSNSMVTLGCLVKGYFPEPVTVTWNSGALSSGV HTFPAVLQSGLYTLTSSVTVPSSTWSSQAVTCNVAHPASSTKVDKKIVPREC (SEQ ID NO: 762) Pharmaceutical Compositions and Formulations

[0161] The AR RNAi agents disclosed herein can be prepared as pharmaceutical compositions or formulations (also referred to herein as "‘medicaments’’). In some embodiments, pharmaceutical compositions include at least one AR RNAi agent. These pharmaceutical compositions are particularly useful in the inhibition of the expression of AR mRNA in a target cell, a group of cells, a tissue, or an organism. The pharmaceutical compositions can be used to treat a subject having a disease, disorder, or condition that would benefit from reduction in the level of the target mRNA, or inhibition in expression of the target gene. The pharmaceutical compositions can be used to treat a subject at risk of developing a disease or disorder that would benefit from reduction of the level of the target mRNA or an inhibition in expression the target gene. In one embodiment, the method includes administering an AR RNAi agent linked to a targeting ligand or an antigen binding protein as described herein, to a subject to be treated. In some embodiments, one or more pharmaceutically acceptable excipients (including vehicles, carriers, diluents, and / or delivery' polymers) are added to the pharmaceutical compositions that include an AR RNAi agent, thereby forming a pharmaceutical formulation or medicament suitable for in vivo delivery' to a subject, including a human.

[0162] The pharmaceutical compositions that include an AR RNAi agent and methods disclosed herein decrease the level of the target mRNA in a cell, group of cells, group of cells, tissue, organ, or subject, including by administering to the subject a therapeutically effective amount of a herein described AR RNAi agent, thereby inhibiting the expression of AR mRNA in the subject. In some embodiments, the subject has been previously identified or diagnosed as having a disease or disorder that can be mediated at least in part by a reduction in AR expression. In some embodiments, the subject has been previously diagnosed with having one or more neurodegenerative diseases such as SBMA. In some embodiments the neurodegenerative disease is SBMA.

[0163] In some embodiments the subject has been previously diagnosed with having neurodegenerative disease.

[0164] Embodiments of the present disclosure include pharmaceutical compositions for delivering an AR RNAi agent to a CNS and / or skeletal muscle cell in vivo. Such pharmaceutical compositions can include, for example, an AR RNAi agent conjugated to a lipid moiety or antigen binding moiety.

[0165] In some embodiments, the described pharmaceutical compositions including an AR RNAi agent are used for treating or managing clinical presentations in a subject that would benefit from the inhibition of expression of AR. In some embodiments, a therapeutically or prophylactically effective amount of one or more of pharmaceutical compositions is administered to a subject in need of such treatment. In some embodiments, administration of any of the disclosed AR RNAi agents can be used to decrease the number, severity, and / or frequency of symptoms of a disease in a subject.

[0166] In some embodiments, the described AR RNAi agents are optionally combined with one or more additional (i.e., second, third, etc.) therapeutics. A second therapeutic can be another AR RNAi agent (e.g., an AR RNAi agent that targets a different sequence within an AR gene). In some embodiments, a second therapeutic can be an RNAi agent that targets the AR gene. An additional therapeutic can also be a small molecule drug, antibody, antibodyfragment, and / or aptamer. The AR RNAi agents, with or without the one or more additional therapeutics, can be combined with one or more excipients to form pharmaceutical compositions.

[0167] The descri bed pharmaceutical compositions that include an AR RNAi agent can be used to treat at least one symptom in a subject having a disease or disorder that would benefit from reduction or inhibition in expression of AR mRNA. In some embodiments, the subject is administered a therapeutically effective amount of one or more pharmaceutical compositions that include an AR RNAi agent thereby treating the symptom. In other embodiments, the subject is administered a prophylactically effective amount of one or more AR RNAi agents, thereby preventing or inhibiting the at least one symptom.

[0168] In some embodiments, one or more of the described AR RNAi agents are administered to a mammal in a pharmaceutically acceptable carrier or diluent. In some embodiments, the mammal is a human.

[0169] The route of administration is the path by which an AR RNAi agent is brought into contact with the body. In general, methods of administering drugs, oligonucleotides, and nucleic acids, for treatment of a mammal are well known in the art and can be applied to administration of the compositions described herein. The AR RNAi agents disclosed herein can be administered via any suitable route in a preparation appropriately tailored to the particular route. Thus, in some embodiments, the herein described pharmaceutical compositions are administered via inhalation, intranasal administration, intratracheal administration, or oropharyngeal aspiration administration. In some embodiments, the pharmaceutical compositions can be administered by injection, for example, intravenously, intramuscularly, intracutaneously, subcutaneously, intracerebroventricularly. intraarticularly, intraocularly, or intraperitoneally, or topically.

[0170] The pharmaceutical compositions including an AR RNAi agent described herein can be delivered to a cell, group of cells, tissue, or subject using oligonucleotide delivery technologies known in the art. In general, any suitable method recognized in the art for delivering a nucleic acid molecule (in vitro or in vivo) can be adapted for use with the compositions described herein. For example, delivery can be by local administration, (e.g., direct injection, implantation, or topical administering), systemic administration, or subcutaneous, intravenous, intraperitoneal, or parenteral routes, including intracranial (e.g., intraventricular, intraparenchymal and intrathecal), mtracerebroventricular, intramuscular, transdermal, airway (aerosol), nasal, oral, rectal, or topical (including buccal and sublingual) administration. In some embodiments, the compositions are administered via inhalation, intranasal administration, oropharyngeal aspiration administration, or intratracheal administration. For example, in some embodiments, it is desired that the AR RNAi agents described herein inhibit the expression of an AR gene in the CNS or skeletal muscle tissue.

[0171] In some embodiments, the pharmaceutical compositions described herein comprise one or more pharmaceutically acceptable excipients. The pharmaceutical compositions described herein are formulated for administration to a subject.

[0172] As used herein, a pharmaceutical composition or medicament includes a pharmacologically effective amount of at least one of the described therapeutic compounds and one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients (excipients) are substances other than the Active Pharmaceutical Ingredient (API, therapeutic product, e.g., AR RNAi agent) that are intentionally included in the drug delivery' system. Excipients do not exert or are not intended to exert a therapeutic effect at the intended dosage. Excipients can act to a) aid in processing of the drug delivery' system during manufacture, b) protect, support or enhance stability, bioavailability or patient acceptability of the API, c) assist in product identification, and / or d) enhance any' other attribute of the overall safety, effectiveness, of delivery of the API during storage or use. A pharmaceutically acceptable excipient may or may not be an inert substance.

[0173] Excipients include, but are not limited to: absorption enhancers, anti-adherents, antifoaming agents, anti-oxidants, binders, buffering agents, carriers, coating agents, colors, delivery enhancers, delivery polymers, detergents, dextran, dextrose, diluents, disintegrants, emulsifiers, extenders, fillers, flavors, glidants, humectants, lubricants, oils, polymers, preservatives, saline, salts, solvents, sugars, surfactants, suspending agents, sustained release matrices, sweeteners, thickening agents, tonicity agents, vehicles, water-repelling agents, and wetting agents.

[0174] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water-soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor® ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof The proper fluidity' can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, poly alcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0175] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic di spersion medium and the required other ingredi ents from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0176] Formulations suitable for intra-articular administration can be in the form of a sterile aqueous preparation of the drug that can be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems can also be used to present the drug for both intra-articular and ophthalmic administration.

[0177] The active compounds can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated deliver}' systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled m the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0178] The AR RNAi agents can be formulated in compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

[0179] A pharmaceutical composition can contain other additional components commonly found in pharmaceutical compositions. Such additional components include, but are not limited to: anti-pruritics, astringents, local anesthetics, or anti-inflammatory agents (e.g., antihistamine, diphenhydramine, etc.). It is also envisioned that cells, tissues, or isolated organs that express or comprise the herein defined RNAi agents may be used as “pharmaceutical compositions.” As used herein, “pharmacologically effective amount,” “therapeutically effective amount,” or simply “effective amount” refers to that amount of an RNAi agent to produce a pharmacological, therapeutic, or preventive result.

[0180] In some embodiments, the methods disclosed herein further comprise the step of administering a second therapeutic or treatment in addition to administering an RNAi agent disclosed herein. In some embodiments, the second therapeutic is another AR RNAi agent (e.g., an AR RNAi agent that targets a different sequence within the AR target). In other embodiments, the second therapeutic can be a small molecule drug, an antibody , an antibody fragment, and / or an aptamer.

[0181] In some embodiments, described herein are compositions that include a combination or cocktail of at least two AR RNAi agents having different sequences. In some embodiments, the two or more AR RNAi agents are each separately and independently linked to lipids.

[0182] Described herein are compositions for delivery' of AR RNAi agents to central nervous system cells. Furthermore, compositions for delivery of AR RNAi agents to cells, including neurons, astrocytes, microglia and endothelial cells, in vivo, are generally described herein.

[0183] Generally, an effective amount of an AR RNAi agent disclosed herein will be in the range of from about 0.0001 to about 20 mg / kg of body weight / deposited dose, e.g., from about 0.001 to about 5 mg / kg of body weight / deposited dose. In some embodiments, an effective amount of an AR RNAi agent will be in the range of from about 0.01 mg / kg to about 3.0 mg / kg of body weight per deposited dose. In some embodiments, an effective amount of an AR RNAi agent will be in the range of from about 0.03 mg / kg to about 2.0 mg / kg of body weight per deposited dose. In some embodiments, an effective amount of an AR RNAi agent will be in the range of from about 0.01 to about 1.0 mg / kg of deposited dose per body weight. In some embodiments, an effective amount of an AR RNAi agent will be in the range of from about 0.50 to about 1.0 mg / kg of deposited dose per body weight. The amount administered will also likely depend on such variables as the overall health status of the patient, the relative biological efficacy of the compound delivered, the formulation of the drug, the presence and types of excipients in the formulation, and the route of administration. Also, it is to be understood that the initial dosage administered can be increased beyond the above upper level to rapidly achieve the desired blood-level or tissue level, or the initial dosage can be smaller than the optimum. In some embodiments, a dose is administered daily. In some embodiments, a dose is administered weekly. In further embodiments, a dose is administered bi-weekly, tri-weekly, once monthly, or once quarterly (i.e., once even7 three months).

[0184] For treatment of disease or for formation of a medicament or composition for treatment of a disease, the pharmaceutical compositions described herein including an AR RNAi agent can be combined with an excipient or with a second therapeutic agent or treatment including, but not limited to: a second or other RNAi agent, a small molecule drug, an antibody, an antibody fragment, peptide, and / or an aptamer.

[0185] The described AR RNAi agents, when added to pharmaceutically acceptable excipients or adjuvants, can be packaged into kits, containers, packs, or dispensers. Methods of Treatment and Inhibition of AR Expression

[0186] The AR RNAi agents disclosed herein can be used to treat a subject (e.g., a human or other mammal) having a disease or disorder that would benefit from administration of the RNAi agent. In some embodiments, the RNAi agents disclosed herein can be used to treat a subject (e.g., a human) that would benefit from a reduction and / or inhibition in expression of AR mRNA and / or a reduction in AR receptor levels.

[0187] In some embodiments, the RNAi agents disclosed herein can be used to treat a subject (e.g., a human) having a disease or disorder for which the subject would benefit from reduction in androgen receptor, including but not limited to, SBMA. Treatment of a subject can include therapeutic and / or prophylactic treatment. The subject is administered a therapeutically effective amount of any one or more AR RNAi agents described herein. The subject can be a human, patient, or human patient. The subject may be an adult, adolescent, child, or infant. Administration of a pharmaceutical composition described herein can be to a human being or animal.

[0188] Mutant AR activity is known to promote neurodegenerative disorders. In some embodiments, the described AR RNAi agents are used to treat at least one symptom mediated at least in part by a reduction in mutant AR levels, in a subject. The subject is administered a therapeutically effective amount of any one or more of the described AR RNAi agents. In some embodiments, the subject is administered a prophylactically effective amount of any one or more of the described RNAi agents, thereby treating the subject by preventing or inhibiting the at least one symptom.

[0189] In certain embodiments, the present disclosure provides methods for treatment of diseases, disorders, conditions, or pathological states mediated at least in part by AR gene expression, in a patient in need thereof, wherein the methods include administering to the patient any of the AR RNAi agents described herein.

[0190] In some embodiments, the AR RNAi agents are used to treat or manage a clinical presentation or pathological stale in a subject, wherein the clinical presentation or pathological state is mediated at least in part by a reduction in AR expression. The subject is administered a therapeutically effective amount of one or more of the AR RNAi agents or AR RNAi agentcontaining compositions described herein. In some embodiments, the method comprises administering a composition comprising an AR RNAi agent described herein to a subject to be treated.

[0191] In a further aspect, the disclosure features methods of treatment (including prophylactic or preventative treatment) of diseases or symptoms that may be addressed by a reduction in AR receptor levels, the methods comprising administering to a subject in need thereof an AR RNAi agent that includes an antisense strand comprising the sequence of any of the sequences in Table 2, Table 3, or Table 10. Also described herein are compositions for use in such methods.

[0192] The described AR RNAi agents and / or compositions that include AR RNAi agents can be used in methods for therapeutic treatment of disease or conditions caused by enhanced or elevated AR receptor activity levels. Such methods include administration of an AR RNAi agent as described herein to a subject, e.g., a human or animal subject.

[0193] In another aspect, the disclosure provides methods for the treatment (including prophylactic treatment) of a pathological state (such as a condition or disease) mediated at least in part by AR expression, wherein the methods include administering to a subject a therapeutically effective amount of an RNAi agent that includes an antisense strand comprising the sequence of any of the sequences in Table 2, Table 3, or Table 10.

[0194] In some embodiments, methods for inhibiting expression of an AR gene are disclosed herein, wherein the methods include administering to a cell an RNAi agent that includes an antisense strand comprising the sequence of any of the sequences in Table 2, Table 3, or Table 10.

[0195] In some embodiments, methods for the treatment (including prophylactic treatment) of a pathological state mediated at least in part by AR expression are disclosed herein, wherein the methods include administering to a subject a therapeutically effective amount of an RNAi agent that includes a sense strand comprising the sequence of any of the sequences in Table 2, Table 4, Table 5, Table 6, or Table 10.

[0196] In some embodiments, methods for inhibiting expression of an AR gene are disclosed herein, wherein the methods comprise administering to a cell an RNAi agent that includes a sense strand comprising the sequence of any of the sequences in Table 2, Table 4, Table 5, Table 6, or Table 10.

[0197] In some embodiments, methods for the treatment (including prophylactic treatment) of a pathological state mediated at least in part by AR expression are disclosed herein, wherein the methods include administering to a subject a therapeutically effective amount of an RNAi agent that includes a sense strand comprising the sequence of any of the sequences in Table 4, Table 5, Table 6, or Table 10, and an antisense strand comprising the sequence of any of the sequences in Table 3 or Table 10.

[0198] In some embodiments, methods for inhibiting expression of an AR gene are disclosed herein, wherein the methods include administering to a cell an RNAi agent that includes a sense strand comprising the sequence of any of the sequences in Table 4, Table 5, Table 6, or Table 10, and an antisense strand comprising the sequence of any of the sequences in Table 3 or Table 10.

[0199] In some embodiments, methods of inhibiting expression of an AR gene are disclosed herein, wherein the methods include administering to a subject an AR RNAi agent that includes a sense strand consisting of the nucleobase sequence of any of the sequences in Table 4, Table 5, Table 6, or Table 10, and the antisense strand consisting of the nucleobase sequence of any of the sequences in Table 3 or Table 10. In other embodiments, disclosed herein are methods of inhibiting expression of an AR gene, wherein the methods include administering to a subject an AR RNAi agent that includes a sense strand consisting of the modified sequence of any of the modified sequences in Table 4, Table 5, Table 6, or Table 10, and the antisense strand consisting of the modified sequence of any of the modified sequences in Table 3 or Table 10.

[0200] In some embodiments, methods for inhibiting expression of an AR gene in a cell are disclosed herein, wherein the methods include administering one or more AR RNAi agents comprising a duplex structure of one of the duplexes set forth in Tables 7, 8, 9. and 10.

[0201] In some embodiments, the gene expression level and / or mRNA level of an AR gene in certain CNS cells and / or skeletal muscle cells of subject to whom a described AR RNAi agent is administered is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%. 55%. 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%. 97%. 98%, 99%, or greater than 99%, relative to the subject prior to being administered the AR RNAi agent or to a subject not receiving the AR RNAi agent. In some embodiments, the AR receptor or AR protein levels in certain CNS and / or skeletal muscle cells of a subject to whom a described AR RNAi agent is administered is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%. 55%. 60%. 65%, 70%, 75%. 80%, 85%. 90%. 95%. 96%. 97%. 98%, 99%, or greater than 99%, relative to the subject prior to being administered the AR RNAi agent or to a subject not receiving the AR RNAi agent. Hie gene expression level, protein level, and / or mRNA level in the subject may be reduced in a cell, group of cells, and / or tissue of the subject. In some embodiments, the AR mRNA levels in certain CNS and / or skeletal muscle cells subject to whom a described AR RNAi agent has been administered is reduced by at least about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%. 85%, 90%, 95%. or 98% relative to the subject prior to being administered the AR RNAi agent or to a subject not receiving the AR RNAi agent.

[0202] A reduction in gene expression, mRNA, and protein levels can be assessed by any methods known in the art. Reduction or decrease in AR receptor activity level and / or AR protein levels are collectively referred to herein as a decrease in, reduction of, or inhibition of AR expression. The Examples set forth herein illustrate known methods for assessing inhibition of AR expression and AR gene expression. Cells, Tissues, Organs, and Non-Human Organisms

[0203] Cells, tissues, organs, and non-human organisms that include at least one of the AR RNAi agents described herein are contemplated. The cell, tissue, organ, or non-human organism is made by delivering the RNAi agent to the cell, tissue, organ, or non-human organism. Additional Illustrative Embodiments

[0204] Provided here are certain additional illustrative embodiments of the disclosed technology. These embodiments are illustrative only and do not limit the scope of the present disclosure or of the claims attached hereto. 1. An RNAi agent for inhibiting expression of an Androgen Receptor (AR) gene, comprising: an antisense strand comprising at least 17 contiguous nucleotides differing by 0 or 1 nucleotides from any one of the sequences provided in Table 2 or Table 3; and a sense strand comprising a nucleotide sequence that is at least partially complementary to the antisense strand. 2. The RNAi agent of embodiment 1. wherein the antisense strand comprises nucleotides 2-18 of any one of the sequences provided in Table 2 or Table 3. 3. The RNAi agent of embodiment 1 or embodiment 2, wherein the sense strand comprises a nucleotide sequence of at least 17 contiguous nucleotides differing by 0 or 1 nucleotides from any one of the sequences provided in Table 2 or Table 4, and wherein the sense strand has a region of at least 85% complementarity over the 17 contiguous nucleotides to the antisense strand. 4. The RNAi agent of any one of embodiments 1-3, wherein at least one nucleotide of the AR RNAi agent is a modified nucleotide or includes a modified intemucleoside linkage. 5. The RNAi agent of any one of embodiments 1-4, wherein all or substantially all of the nucleotides are modified nucleotides. 6. The RNAi agent of any one of embodiments 4-5, wherein the modified nucleotide is selected from the group consisting of: 2'-O-methyl nucleotide, 2'-fluoro nucleotide, 2'-deoxy nucleotide, 2’,3'-seco nucleotide mimic, locked nucleotide, 2'-F-arabino nucleotide, 2'- methoxy ethyl nucleotide, abasic nucleotide, ribitol, inverted nucleotide, inverted 2'-O-methyl nucleotide, inverted 2'-deoxy nucleotide, 2'-amino-modified nucleotide, 2'-alkyl-modified nucleotide, morpholino nucleotide, vinyl phosphonate-containing nucleotide, cyclopropyl phosphonate-containing nucleotide, and 3'-O-methyl nucleotide. 7. The RNAi agent of embodiment 5. wherein all or substantially all of the nucleotides are modified with 2'-O-methyl nucleotides, 2'-fluoro nucleotides, or combinations thereof. 8. The RNAi agent of any one of embodiments 1-7, wherein the antisense strand comprises the nucleotide sequence of any one of the modified sequences provided in Table 3. 9. The RNAi agent of any one of embodiments 1-8, wherein the sense strand comprises the nucleotide sequence of any one of the modified sequences provided in Table 4. 10. The RNAi agent of embodiment 1. wherein the antisense strand comprises the nucleotide sequence of any one of the modified sequences provided in Table 3 and the sense strand comprises the nucleotide sequence of any one of the modified sequences provided in Table 4. 11. The RNAi agent of any one of embodiments 1-10. wherein the sense strand is between 18 and 30 nucleotides in length, and the antisense strand is between 18 and 30 nucleotides in length. 12. The RNAi agent of embodiment 11, wherein the sense strand and the antisense strand are each between 18 and 27 nucleotides in length. 13. The RNAi agent of embodiment 12, wherein the sense strand and the antisense strand are each between 18 and 24 nucleotides in length. 14. The RNAi agent of embodiment 13, wherein the sense strand and the antisense strand are each 21 nucleotides in length. 15. The RNAi agent of embodiment 14, wherein the RNAi agent has two blunt ends. 16. The RNAi agent of any one of embodiments 1-15. wherein the sense strand comprises one or two terminal caps. 17. The RNAi agent of any one of embodiments 1-16, wherein the sense strand comprises one or two inverted abasic residues. 18. The RNAi agent of embodiment 1. wherein the RNAi agent comprises of a sense strand and an antisense strand that form a duplex having the structure of any one of the duplexes in Table 7, Table 8, Table 9, or Table 10. 19. The RNAi agent of embodiment 18, wherein all or substantially all of the nucleotides are modified nucleotides. 20. The RNAi agent of embodiment 19, wherein all or substantially all of the nucleotides are modified nucleotides. 21. The RNAi agent of any one of embodiments 19-20, wherein the sense strand further includes inverted abasic residues at the 3’ terminal end of the nucleotide sequence, at the 5’ end of the nucleotide sequence, or at both. 22. The RNAi agent of any one of embodiments 1 -21, wherein the RNAi agent is linked to a lipid moiety or linked to an antigen binding protein. 23. The RNAi agent of any one of embodiments 1-22. wherein the RNAi agent is linked to a lipid moiety. 24. The RNAi agent of embodiment 23, wherein the lipid moiety is selected from the group consisting of: O LP183 wherein ? indicates the point of connection to the RNAi agent. 25. The RNAi agent of embodiment 23 or embodiment 24, wherein the lipid moiety is conjugated to the sense strand. 26. The RNAi agent of embodiment 25, wherein the lipid moiety is conjugated to the 5’ terminal end of the sense strand. 27. The RNAi agent of any of embodiments 1-22, wherein the RNAi agent is linked to an antigen binding protein. 28. The RNAi agent of any one of embodiments 1-27. wherein the antigen binding protein is an antibody fragment (Fab) that specifically binds to one or more epitopes on a transferrin receptor (TfRl). 29. The RNAi agent of embodiment 28, wherein the Fab comprises (i) 6 complementary determining regions (CDRs), (ii) 3 CDRs on the variable light chain (VL), and / or (iii) 3 CDRs on the variable heavy chain (VH). 30. The RNAi agent of embodiment 29, wherein the variable light chain has a VL CDR1 sequence selected from the group consisting of: RASDGLYSNLA (SEQ ID NO: 721), RASDNLYRNLA (SEQ ID NO: 722), and RASDKLYSNLA (SEQ ID NO: 723); a VL CDR2 sequence selected from the group consisting of: DATLLAS (SEQ ID NO: 724), DARNLAS (SEQ ID NO: 725), DAFNLAS (SEQ ID NO: 726), DATRLAS (SEQ ID NO: 727). DATKLAS (SEQ ID NO: 728), and DAKNLAS (SEQ ID NO: 729); and / or a VL CDR 3 sequence of QHFWGTPLT (SEQ ID NO: 730). 31. The RNAi agent of embodiment 29 or 30, wherein the variable light chain comprises the sequence: DIQLTQSPSSLSASVGDRVTITCRASDKLYSNLAWYQQKPGKAPKLLIYDATLLASGV PSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWGTPLTFGQGTKVEIK (SEQ ID NO: 747). 32.   The RNAi agent of any one of embodiments 29-31, wherein the variable heavy chain has a VH CDR1 sequence selected from the group consisting of GYTFNSYWMH (SEQ ID NO: 731), GYTFKSYWMH (SEQ ID NO: 732), GFTFTSYWMH (SEQ ID NO: 733), GYTFTSYWVH (SEQ ID NO: 734), and GYTFTSYWMH (SEQ ID NO: 735), a VH CDR2 sequence selected from the group consisting of: EINPTNGRVNYIEKFKS (SEQ ID NO: 736). EINPTNGRFNYIEKFKS (SEQ ID NO: 737), EINPTNGRTNYIEKFKS (SEQ ID NO: 738), and EINPTNGRSNYIEKFKS (SEQ ID NO: 739); and / or a VH CDR3 sequence of: GTRAYHY (SEQ ID NO: 740). 33.   The RNAi agent of any one of embodiments 29-32, wherein the variable heavy chain comprises the sequence: EVQLVESGGGLVQPGGSLRLSCATSGFTFTSYWMHWVRQAPGKGLEWVAEINPTNG RTNYIEKFKSRITLSVDKSKSTVYLQMNSLRAEDTAVYYCARGTRAYHYWGQGTLV TVSS (SEQ ID NO: 755). 34.   The RNAi agent of any one of embodiments 28-33, wherein the Fab further comprises a light constant chain 1 (CL). 35.    The RNAi agent of embodiment 34 wherein the light constant chain 1 (CL) sequence is: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 717). 36.   The RNAi agent of any one of embodiments 28-35, wherein the Fab further comprises a heavy constant chain 1 (CH). 37. The RNAi agent of embodiment 36 wherein the heavy constant chain 1 (CH) sequence is: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH (SEQ ID NO: 719). 38. The RNAi agent of any one of embodiments 28-37, wherein the antibody fragment (Fab) binds TfRl with an affinity of at least 1 nM KD. 39. A conjugate comprising the RNAi agent of any one of embodiments 1-21 conjugated to an antibody fragment (Fab) that specifically binds to one or more epitopes on a transferrin receptor (TfRl). 40. The conjugate of embodiment 39, wherein the Fab comprises (i) 6 complementary determining regions (CDRs), (ii) 3 CDRs on the variable light chain (VL), or (iii) 3 CDRs on the variable heavy chain (VH). 41. The conjugate of embodiment 40, wherein the variable light chain has a VL CDR1 sequence selected from the group consisting of: RASDGLYSNLA (SEQ ID NO: 721), RASDNLYRNLA (SEQ ID NO: 722). and RASDKLYSNLA (SEQ ID NO: 723); a VL CDR2 sequence selected from the group consisting of: DATLLAS (SEQ ID NO: 724), DARNLAS (SEQ ID NO: 725), DAFNLAS (SEQ ID NO: 726), DATRLAS (SEQ ID NO: 727), DATKLAS (SEQ ID NO: 728), and DAKNLAS (SEQ ID NO: 729); and / or a VL CDR 3 sequence of QHFWGTPLT (SEQ ID NO: 730). 42.    The conjugate of embodiment 40 or 41, wherein the variable light chain comprises the sequence: DIQLTQSPSSLSASVGDRVTITCRASDKLYSNLAWYQQKPGKAPKLLIYDATLLASGV PSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWGTPLTFGQGTKVEIK (SEQ ID NO: 747). 43. The conjugate of any one of embodiments 40-42, wherein the variable heavy chain has a VH CDR1 sequence selected from the group consisting of: GYTFNSYWMH (SEQ ID NO: 731), GYTFKSYWMH (SEQ ID NO: 732). GFTFTSYWMH (SEQ ID NO: 733), GYTFTSYWVH (SEQ ID NO: 734), and GYTFTSYWMH (SEQ ID NO: 735). a VH CDR2 sequence selected from the group consisting of: EINPTNGRVNYIEKFKS (SEQ ID NO: 736), EINPTNGRFNYIEKFKS (SEQ ID NO: 737), EINPTNGRTNYIEKFKS (SEQ ID NO: 738), and EINPTNGRSNYIEKFKS (SEQ ID NO: 739); and / or a VH CDR3 sequence of: GTRAYHY (SEQ ID NO: 740). 44. The conjugate of any one of embodiments 40-43, wherein the variable heavy chain comprises                                  the                                  sequence: EVQLVESGGGLVQPGGSLRLSCATSGFTFTSYWMHWVRQAPGKGLEWVAEINPTNG RTNYIEKFKSRITLSVDKSKSTVYLQMNSLRAEDTAVYYCARGTRAYHYWGQGTLV TVSS (SEQ ID NO: 755) 45. The conjugate of any one of embodiments 39-44 wherein the Fab further comprises a light constant chain 1 (CL). 46. The conjugate of embodiment 45 wherein the light constant chain 1 (CL) sequence is: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 717). 47. The conjugate of any one of embodiments 39-46, wherein the Fab further comprises a heavy constant chain 1 (CH). 48. The conjugate of embodiment 47 wherein the heavy constant chain 1 (CH) sequence is: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH (SEQ ID NO: 719). 49.    The conjugate of any one of embodiments 39-48, wherein the antibody fragment (Fab) binds TfRl with an affinity of at least 1 nM KD. 50. The conjugate of embodiment any one of embodiments 39-49, wherein the RNAi agent is conjugated to the Fab using a covalent or non-covalent bond, ionic bond, hydrogen bond, hydrophobic interaction, peptide, polymer, or a nucleic acid binding protein. 51.    The conjugate of any one of embodiments 39-50. wherein the RNAi agent is conjugated to the Fab through a linker comprising a structure selected from the group consisting of: o wherein 5 a represents a point of attachment to the Fab, and *r represents a point of attachment to the RNAi agent portion of the conjugate. 52. The RNAi agent of any one of embodiments 1 -21, wherein the RNAi agent is linked to a targeting ligand. 53. The RNAi agent of embodiment 52, wherein the targeting ligand is linked to the sense strand. 54. The RNAi agent of embodiment 53, wherein the targeting ligand is linked to the 5’ terminal end of the sense strand. 55. The RNAi agent of any of embodiments 52-54, wherein the targeting ligand has affinity for a skeletal muscle cell and / or a cell receptor expressed on a skeletal muscle cell. 56. The RNAi agent of any of embodiments 52-55, wherein the targeting ligand has affinity for an integrin alpha-v-beta 6 (av06) receptor. 57. The RNAi agent of any of embodiments 52-56, wherein the targeting ligand is: or a pharmaceutically acceptable salt thereof, wherein ? indicates the point of connection to the RNAi agent. 58. The RNAi agent of any one of embodiments 1-21 or 52-57, wherein the RNAi agent is further linked to a pharmacokinetic / pharmacodynamic (PK / PD) modulator. 59.   The RNAi agent of embodiment 58, wherein the PK / PD modulator is linked to the sense strand. 60. The RNAi agent of embodiment 59. wherein the PK / PD modulator is linked to the 3’ terminal end of the sense strand. 61. The RNAi agent of any one of embodiments 58-60, wherein the PK / PD modulator is selected from the group consisting of: wherein Rz comprises the RNAi agent. 62. A composition comprising the RNAi agent of any one of embodiments 1-38 or 52-61, or the conjugate of any one of embodiments 39-51, wherein the composition further comprises a pharmaceutically acceptable excipient. 63. The composition of embodiment 62, further comprising a second RNAi agent capable of inhibiting the expression of Androgen Receptor gene expression. 64. The composition of any one of embodiments 62-63, further comprising one or more additional therapeutics. 65. The composition of any of embodiments 62-64, wherein the RNAi agent is a sodium salt. 66. The composition of any of embodiments 62-65, wherein the pharmaceutically acceptable excipient is water for injection. 67. The composition of any of embodiments 62-65, wherein the pharmaceutically acceptable excipient is a buffered saline solution. 68. A method for inhibiting expression of an AR gene in a cell, the method comprising introducing into a cell an effective amount of the RNAi agent of any one of embodiments 138 or 52-61, the conjugate of any one of embodiments 39-51, or the composition of any one of embodiments 62-67. 69.    The method of embodiment 68, wherein the cell is within a subject. 70.    The method of embodiment 69, wherein the subject is a human subject. 71. The method of any one of embodiments 68-70, wherein following the administration of the RNAi agent the Androgen Receptor (AR) gene expression is inhibited by at least about 30%. 72. A method of treating one or more symptoms or diseases associated with enhanced or elevated membrane AR activity' levels, the method comprising administering to a human subject in need thereof a therapeutically effective amount of the composition of any one of embodiments 62-67. 73.    The method of embodiment 72, wherein the disease is a neurodegenerative disease. 74.    The method of embodiment 73, wherein the neurodegenerative disease is spinal and bulbar muscular atrophy (SBMA). 75. The method of any one of embodiments 68-74, wherein the RNAi agent is administered at a deposited dose of about 0.01 mg / kg to about 5.0 mg / kg of body7 weight of the subj ect. 76. The method of any one of embodiments 68-75, wherein the RNAi agent is administered at a deposited dose of about 0.03 mg / kg to about 2.0 mg / kg of body weight of the subj ect. 77. The method of any of embodiments 68-76, wherein the RNAi agent is administered in two or more doses. 78. Use of the RNAi agent of any one of embodiments 1-38 or 52-61. or the conjugate of any one of embodiments 39-51, for the treatment of a disease, disorder, or symptom that is mediated at least in part by mutant AR activity and / or AR gene expression. 79. Use of the composition according to any one of embodiments 62-67, for the treatment of a disease, disorder, or symptom that is mediated at least in part by Androgen Receptor (AR) activity and / or Androgen Receptor (AR) gene expression. 80. Use of the composition according to any one of embodiments 62-67, for the manufacture of a medicament for treatment of a disease, disorder, or symptom that is mediated at least in part by Androgen Receptor (AR) and / or Androgen Receptor (AR) gene expression. 81. The use of any one of embodiments 78-80, wherein the disease is a neurodegenerative disease. 82. A method of making an RNAi agent of any one of embodiments 1-38 or 52-61, comprising annealing a sense strand and an antisense strand to form a double-stranded ribonucleic acid molecule. 83.    The method of embodiment 82, wherein the sense strand comprises a lipid moiety. 84.    The method of embodiment 82, wherein the sense strand comprises an antigen binding moiety. 85.    The method of embodiment 82, wherein the sense strand comprises a targeting ligand. 86.    The method of embodiment 85, wherein the sense strand further comprises a PK / PD modulator. 87. The method of embodiment 83, comprising conjugating a lipid moiety to the sense strand. 88. The method of embodiment 84, comprising conjugating an antigen binding moiety to the sense strand. 89. The method of embodiment 85, comprising conjugating a targeting ligand to the sense strand. 90. The method of embodiment 86, comprising conjugating a PK / PD modulator to the sense strand. Examples Example 1. Synthesis of AR RNAi Agents.

[0205] AR RNAi agent duplexes disclosed herein were synthesized in accordance with the following:

[0206] A. Synthesis. The sense and antisense strands of the AR RNAi agents were synthesized according to phosphoramidite technology on solid phase used in oligonucleotide synthesis. Depending on the scale, a MerMade96E® (Bioautomation), a MerMadel2® (Bioautomation), or an OP Pilot 100 (GE Healthcare) was used. Syntheses were performed on a solid support made of controlled pore glass (CPG, 500 A or 600A, obtained from Prime Synthesis, Aston, PA, USA). All RNA and 2'-modified RNA phosphoramidites were purchased from Thermo Fisher Scientific (Milwaukee. WI, USA). Specifically, the 2'-O-methyl phosphoramidites that were used included the following: (5'-O-dimethoxytntyl-N6-(benzoyl)-2'-O-methyl-adenosine-3'-O-(2-cyanoethyl-N,N-diisopropylamino) phosphoramidite, 5'-O-dimethoxy-trityl-N4-(acetyl)-2'-O-methyl-cytidine-3'-O-(2-cyanoethyl-N,N-diisopropyl-amino) phosphoramidite, (5'-O-dimethoxytrityl-N2-(isobutyryl)-2'-O-methyl-guanosine-3'-O-(2-cyanoethyl-N,N-diisopropylamino) phosphoramidite, and 5'-O-dimethoxytrityl-2'-O-methyl-uridine-3'-O-(2-cyanoethyl-N,N-diisopropylamino) phosphoramidite. The 2'-deoxy-2'-fluoro-phosphoramidites carried the same protecting groups as the 2'-O-methyl RNA amidites. 5'-dimelhoxytrityl-2'-O-methyl-inosine-3'-O-(2-cyanoethyl-N,N-diisopropylamino) phosphoramidites were purchased from Glen Research (Virginia). The inverted abasic (3'-O-dimethoxytrityl-2'-deoxyribose-5'-O-(2-cyanoethyl-N,N-diisopropylamino) phosphoramidites were purchased from ChemGenes (Wilmington, MA, USA). Hie following UNA phosphoramidites were used: 5'-(4,4'-Dimethoxytrityl)-N6-(benzoyl)-2’,3'-seco-adenosine, 2'-benzoyl-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-(4,4'-Dimethoxytrityl)-N-acetyl-2',3'-seco-cytosine,                 2'-benzoyl-3'-[(2-cyanoethyl)-(N,N-diiso-propyl)]- phosphoramidite, 5'-(4,4'-Dimethoxytrityl)-N-isobutyryl-2',3'-seco-guanosine, 2'-benzoyl-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, and 5'-(4,4'-Dimethoxy-trityl)-2',3'-seco-undine, 2’-benzoyl-3'-[(2-cyanoethyl)-(N,N- diiso-propyl)]-phosphoramidite. TFA aminolink phosphoramidites were also commercially purchased (ThermoFisher). Linker L6 was purchased as propargyl-PEG5-NHS from BroadPharm (catalog # BP-20907) and coupled to the NH2-C6 group from an aminolink phosphoramidite to form -L6-C6-, using standard coupling conditions. The linker Alk-cyHex was similarly commercially purchased from Lumiprobe (alkyne phosphoramidite, 5?-terminal) as a propargyl-containing compound phosphoramidite compound to form the linker -Alk-cyHex-. In each case, phosphorothioate linkages were introduced as specified using the conditions set forth herein. The cyclopropyl phosphonate phosphoramidites were synthesized in accordance with International Patent Application Publication No. WO 2017 / 214112 (see also Altenhofer et. al., Chem. Communications (Royal Soc. Chem.), 57(55):6808-6811 (July 2021)).

[0207] Tri-alkyne-containing phosphoramidites were dissolved in anhydrous dichloromethane or anhydrous acetonitrile (50 mM), while all other amidites were dissolved in anhydrous acetonitrile (50 mM) and molecular sieves (3A) were added. 5-Benzylthio-lH-tetrazole (BTT. 250 mM in acetonitrile) or 5-Ethylthio-lH-tetrazole (ETT, 250 mM in acetonitrile) w7as used as activator solution. Coupling times were 10 minutes (RNA), 90 seconds (2' O-Me), and 60 seconds (2' F). In order to introduce phosphorothioate linkages, a 100 mM solution of 3-phenyl l,2,4-dithiazoline-5-one (POS, obtained from PolyOrg, Inc., Leominster, MA, USA) in anhydrous acetonitrile was employed.

[0208] Alternatively, tri-alkyne moieties were introduced post-synthetically (see section E, below). For this route, the sense strand was functionalized with a 5' and / or 3' terminal nucleotide containing a primary amine. TFA aminolink phosphoramidite was dissolved in anhydrous acetonitrile (50 mM) and molecular sieves (3A) were added. 5-Benzylthio-lH-tetrazole (BTT, 250 mM in acetonitrile) or 5-Ethylthio-lH-tetrazole (ETT, 250 mM in acetonitrile) was used as activator solution. Coupling times were 10 minutes (RNA), 90 seconds (2' O-Me), and 60 seconds (2' F). In order to introduce phosphorothioate linkages, a 100 mM solution of 3-phenyl l,2,4-dithiazoline-5-one (POS, obtained from PolyOrg. Inc., Leominster. MA, USA) in anhydrous acetonitrile was employed.

[0209] B. Cleavage and deprotection of support bound oligomer. After finalization of the solid phase synthesis, the dried solid support was treated with a 1:1 volume solution of 40 wt. % methylamine in w7ater and 28% to 31% ammonium hydroxide solution (Aldrich) for 1.5 hours at 30°C. The solution was evaporated and the solid residue was reconstituted in water (see below7).

[0210] C. Purification. Crude oligomers were purified by anionic exchange HPLC using aTSKgel SuperQ-5PW 13pm column and Shimadzu LC-8 system. Buffer A was 20 mM Tris, 5 mM EDTA, pH 9.0 and contained 20% Acetonitrile and buffer B was the same as buffer A with the addition of 1.5 M sodium chloride. UV traces at 260 nm were recorded. Appropriate fractions were pooled then run on size exclusion HPLC using a GE Healthcare XK 16 / 40 column packed with Sephadex G-25 fine with a running buffer of lOOmM ammonium bicarbonate, pH 6.7 and 20% Acetonitrile or filtered water. Alternatively, pooled fractions were desalted and exchanged into an appropriate buffer or solvent system via tangential flow filtration.

[0211] D. Annealing. Complementary' strands were mixed by combining equimolar RNA solutions (sense and antisense) in lx PBS (Phosphate-Buffered Saline, lx, Coming, Cellgro) to form the RNAi agents. Some RNAi agents were lyophilized and stored at -15 to -25°C. Duplex concentration was determined by measuring the solution absorbance on a UV-Vis spectrometer in lx PBS. The solution absorbance at 260 nm was then multiplied by a conversion factor (0.050 mg / (mL-cm)) and the dilution factor to determine the duplex concentration.

[0212] E Synthesis of Lipids

[0213] If lipids described herein are not included in Example IE, it is to be assumed that the compounds are commercially available. For example, LP395p and LP396p were purchased.

[0214] Synthesis of LP183 phosphoramidite TEA DCM

[0215] To a solution of compound 2 (2.00 g) in DCM w as added TEA (2.27 mL) follow ed by compound 1 (4.931 g) dropwdse at room temperature. Then the mixture was stirred at room temperature for 2h. The mixture w as then filtered. The white solid was dried overnight. Product is as white solid, yield. 4.267g, 74%. LC-MS: calculated [M+H] 356.35, found 356.63.

[0216] To a mixture of compound 1 (2.54 g) in 120 mL DCM w as added compound 3 (0.61 g) followed by compound 2 (5.37 g) drop wise at room temperature. Then the mixture was stirred at room temperature overnight. 5 mL TEA was added followed by Celite. After removing solvent in vacuo, the residue was loaded on a 40g column by dry method. Hexanes (2% TEA) to 50% EtOAc (2% TEA) in Hexanes (2% TEA) as gradient was used to purify the product. Product is a white waxy solid, yield 3.462 g, 87%. LC-MS: calculated [M+H] 556.46, found 556.64.

[0217] Synthesis of LP2 83-p

[0218] To a solution of compound 1 (49 mg), NEts (0.068 mL), and COMU (76.8 mg) in DMF was added compound 2 (29.8 mg) under ambient conditions. The reaction was stirred until full conversion was observed by LC-MS. Conversion was not able to be clearly observed by LC-MS, and instead, reaction was allowed to stir for 30 min. until bright yellow^ color (before the addition of compound 2) transitioned to a honey orange color and all material was observed to be mainly dissolved. The reaction mixture was washed with water, extracted with DCM, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by CombiFlash® via DCM liquid-load onto a 12-g column with a gradient hexanes to 100% EtOAc in which product eluted at 31% B. The product was concentrated under vacuum to provide a white solid residue and confirmed by 1H NMR in CDCb.

[0219] Synthesis of LP293-p

[0220] To a solution of compound 1 (73 mg), NEts (0.112 mL). and COMU (126 mg) in DMF was added compound 2 (48.9 mg) under ambient conditions. The reaction was stirred until full conversion was observed by LC-MS. Conversion was not able to be clearly observed by LC-MS, and instead, reaction was allowed to stir for 30 min. until bright yellow color (before the addition of compound 2) transitioned to a honey orange color and all material was observed to be mainly dissolved. The reaction mixture was then washed with water, extracted with DCM, dried over NasSCh, filtered, and concentrated under vacuum. The residue was purified by CombiFlash® via DCM liquid-load onto a 12-g column with a gradient hexanes to 100% EtOAc in which product eluted at 30% B. The product was concentrated under vacuum to provide a white solid residue and confirmed by 1H NMR in CDCls.

[0221] Synthesis of LP294-p

[0222] To a solution of compound 1 (40.3 mg), NEt? (0.062 mb), and COMU (69.7 mg) in DCM was added compound 2 (27.0 mg) under ambient conditions. The reaction was stirred until full conversion was observed by LC-MS. Conversion was not able to be clearly observed by LC-MS. and instead, reaction was allowed to stir for 30 min. until bright yellow' color (before the addition of compound 2) transitioned to a honey orange color and all material w'as observed to be mainly dissolved. The reaction mixture w as directly concentrated for isolation. The residue was purified by CombiFlash® via DCM liquid-load onto a 12-g column with a gradient hexanes to 100% EtOAc in which product eluted at 32% B. The product was concentrated under vacuum to provide a white solid residue and confirmed by 1H NMR in CDCh.

[0224] 1 (200 mg, 0.377 mmol, 1.0 eqv.) was hydrolyzed with LiOH (151 mg, 3.77 mmol, 10.0 eqv.) in MeOH / TFH / H2O(l: 1:1,90 mL). After removing all organic solvent, the aqueous phase was acidified to pH=3 with IN HC1. The reaction mixture extracted with ethyl acetate (100 mL x3). The organic phases were combined, dried with Na2SO4 and concentrated to get crude acid.

[0225] To a solution of above crude acid and tetrafluorophenol 4 (68.9 mg, 0.415 mmol, 1.10 eqv.) in 30 mL DCM was added COMU (194 mg, 0.453 mmol, 1.20 eqv.) and then TEA (0.158 mL, 1.13 mmol, 3.0 eqv.) under ambient conditions. The reaction was stirred until full conversion was observed by LC-MS. The reaction mixture was washed with IN HC1, then brine. Dry with NazSOr and concentrated. The reaction mixture was purified by CombiFlash® using silica gel as the stationary phase with a gradient of EA to Hex 0-100%. 170 mg product was obtained (85% yield).

[0226] Synthesis of LP-310p

[0227] To the solution of 1 in DCM was added DIPEA (0.057 mL), COMU (0.077 g) and 2 (0.0300 g) at room temperature. After stirring at room temperature for 2h, the reaction was quenched with 0. IN HC1. The organic layer was washed with brine. After removing the solvent, the residue was loaded on a 4g column. Hexanes to 50% Hexanes in EtOAc as gradient was used to purify. Product was a white solid, 46mg, 44%. LC-MS: calculated [M+H] 422.36, found 422.61.

[0228] The solution of 1 (0.046 g) in 4N HCl / Dioxane (2 mL) was stirred at room temperature overnight. After removing the solvent in vacuo, the residue was placed under high vacuum for 3h. Then the residue was dissolved in DCM at room temperature, then COMU (0.0700 g), DIPEA (0.038 mL) and 2 (0.036 g) were added at room temperature. After stirring at room temperature for 2h, the solvent was removed in vacuo. The residue was loaded on a 4g column. Hexanes to 50% Hexanes in EtOAc as gradient was used to purify. Product was a white solid, 21mg, 38%. LC-MS: calculated [M+H] 514.29, found 514.61.

[0229] Synthesis of LP383-p O

[0230] To the solution of compound 1 (0.050 g) in 5 mL DCM was added compound 2 (0.023 g) and EDC (0.039 g) at room temperature. The mixture was stirred at room temperature for Ih. After removing the solvent in vacuo, the residue was loaded on a 4g column by dry method. Hexanes to 50%EtOAc in Hexanes was used to purify the product. Pdt is a white solid, yield, 29mg. LC-MS: calculated [M+H+H20] 388.27, found 388.03.

[0231] Synthesis of LP409 phosphoramidite O

[0232] Compounds 1 (1.40 g) and 2 (0.613 g) were dissolved in 100 mL THF, then TEA (2.01 mL) was added. The reaction was stirred at 60°C until full conversion was confirmed via LC-MS (2-3 hours). The reaction was cooled down to room temperature. Product obtained as whilte precipitate, which was filtered and washed with Acetone (20mL). Compound structure was verified using ’H and ,3P NMR.

[0233] Compounds 1 (1.9 g), 2 (0.846 g) and 3 (2.98 g) were dissolved in 100 mL DCM then heated to 40°C. The reaction was stirred until the solution became clear. The reaction was cooled down to room temperature and stirred overnight. After removing all DCM, the product was dry loaded onto a 24g column. Product was obtained as a white solid using 0-50% (EA / Hex, 1% TEA added) as mobile phase.

[0234] Synthesis of (2C8C12) phosphoramidite

[0235] 2-ocytyl-l-decanol (1.00 grams, 3.35 mmol) and diisopropylamonium tetrazolide (0.2868 grams, 1.68 mmol) were placed in a flask and the flask was purged with nitrogen. DCM (50 mL) was added to the mixture and 2-Cyanoethyl A,A,MA"-tetraisopropylphosphorodiamidite (2.66 mL, 8.37 mmol) w'as added dropwise. Upon completion of the reaction. 3 mL of triethylamine was added to the reaction and the reaction was concentrated directly onto celite for purification. The crude product w as purified buy silica gel chromatography (0:100 EtOAc:hexanes + 2% triethylamine to 100:0 EtOAc:Hexanes + 2% tri ethylamine) The product eluted w'ith 100% Hexanes. Fractions containing product were concentrated to 1.268 g (76% yield) of a clear liquid.

[0236] Synthesis of (2C6C10) phosphoramidite

[0237] 2-hexy 1-1 -decanol (1.00 g, 4.13 mmol) and diisopropylamonium tetrazolide (0.353 g, 2.06 mmol) were placed in a flask and the flask was purged with nitrogen. DCM (50 mL) was added to the mixture and 2-Cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite (3.27 mL, 10.3 mmol) was added dropwise. . Upon completion of the reaction, 3 mL of triethyl amine was added to the reaction and the reaction was concentrated directly onto celite for purification. The crude product was purified buy silica gel chromatography (0:100 EtOAc:hexanes + 2% triethylamine to 100:0 EtOAc:Hexanes + 2% triethylamine) The product eluted with 100% Hexanes. Fractions containing product were concentrated to 1.32 g (72% yield) of a clear liquid.

[0238] Synthesis of HO-C16 phosphorami dite 'OH DIPEA

[0239] 1,16-hexadecanediol, N,N-diisopropylethylamine (0.100 g) was dissolved in 2 mL THF. 4,4“-Dimethoxy trityl chloride (2.2 g, 6.6 mmol) was added slowly as a solid. After 2 h, the reaction was concentrated by rotary' evaporation, and the product was purified by column chromatography (25% ethyl acetate / 75% hexane).

[0240] DMT-O-Cis-OH (0.200 g), Bis(diisopropylamino)(2-cyanoethoxy)phosphine (0.227 mL) and BisDiisopropylammonium tetrazolide (0.0611 g) were dissolved in anhydrous DCM at room temperature. The reaction was capped and stirred overnight. Conversion was determined via LC-MS (0.25M NH4 HCOuFLO buffer system). Celite® was added to the reaction mixture and it was concentrated under vacuum until a white powder remained. The mixture was loaded dry onto a silica column (12 gram) using a EtOAc / Hexanes (1% Triethylamine) solvent system to prevent hydrolysis from the silica gel.[1] The product w?as characterized by 31PNMR, ^NMR, and LC-MS.

[0241] Synthesis of C16 phosporamidite

[0242] Cetyl alcohol (1.10 g), Bis(diisopropylamino)(2-cyanoethoxy)phosphine (2.88 mL) and BisDiisopropylarnmonium tetrazolide (0.778 g) were dissolved in a solution of DCM at room temperature. The reaction was capped and stirred overnight. Conversion was determined via LC-MS (0.25M NH4 HCO3H2O buffer system). Celite® was added to the reaction mixture and it was concentrated under vacuum until a white powder remained. The mixture was loaded dry onto a silica column (12 gram) using a s EtOAc / Hexanes (1% Triethylamine) solvent system to prevent hydrolysis from the silica gel. The desired product was not retained on the column and came out shortly after being loaded. The isolated product was then charaterized by LC-MS, ‘HNMR and 31PNMR. Final yield: 856.5 mg (93.8%).

[0243] Synthesis of C22 phosporamidite

[0244] Docosanol (1.10 g), Bis(diisopropylamino)(2-cyanoethoxy)phosphine (2.1 mL) and BisDiisopropylarnmonium tetrazolide (0.577 g) were dissolved in a solution of DCM at room temperature. The reaction was capped and stirred overnight. Conversion was determined via LC-MS (0.25M NH4 HCO3:H2O buffer system). Celite® was added to the reaction mixture and it was concentrated under vacuum until a white powder remained. The mixture was loaded dry onto a silica column (12 gram) pretreated with 3 mL of triethylamine using a EtOAc / Hexanes (1% Triethylamine) solvent system to prevent hydrolysis from the silica gel. The isolated product was then charaterized by LC-MS, ’HNMR and 3lPNMR. Final yield: 2.1085 g (118.8%).

[0245] Synthesis of phosphoramidite for aC16 internal nucleotide NaH, Br-(CH2)15CH3 DMF TMS-CI, PhCOCI Py DMT-CI, DMAP

[0246] Compound 2: Sodium hydride (60% dispersion in mineral oil, 4.17g, 104 mmol) was added in 2 portions (15 min apart) into a cold solution of adenosine 1 (12.5 g, 46.77 mmol) in anhydrous DMF (250 mL). The cooling bath was removed, the reaction mixture was stirred for 1.5h at RT and 1-bromohexadecane (18 g, 59 mmol) was added. Following 16 h of stirring at RT ethanol (5 mL) was added, stirred for 15 min, DMF was removed on a rotavapor, and toluene w?as evaporated twice to get nd of residual DMF. The product was isolated on CombiFlash following solid load with 40g of silica gel using 220g SiO2 column. Eluent: DCM (A) - 20% MeOH in DCM (B), B = 0 - 20%, 15 min, then 20% for 5 min. Product was dried in vacuo ON. Yield 2.726 g. Calculated: MW 491.68. Found: MS (ES, positive): 492.46 [M+H]+.

[0247] Compound 3: A solution of compound 2 (2.7 g, 5.49 mmol) in anhydrous pyridine (40 mL) was cooled on an ice bath and TMS-C1 (2.25 mL, 17.73 mmol) was added. The reaction mixture was stirred for 30 min on ice bath, benzoyl chloride (1.5 mL, 12.9 mmol) was added, the cooling bath w as removed in 30 min, stirring was continued overnight. In 16 h the reaction mixture was cooled on ice bath, water (7.5 mL) was added, stirred for additional 30 min. Concentrated NILOH (7.5 mL) was added and all volatiles were removed on a rotavapor. To get rid of side bis-acylated adduct, the crude material was dissolved in MeOH (125 mL) and treated with NH4OH (13 mL) for 25 min. The solvent was removed on a rotavapor and toluene was evaporated once. CombiFlash® purification was performed using solid load with silica gel (18 g) on 80 g column using eluent: DCM - 20% MeOH in DCM, 0 - 20%, 50 min. Yield 2.66g. Calculated: MW 595.79 Found: MS (ES, positive): 596.53 [M+H]+.

[0248] Compound 4: Compound 3 (1.55g, 2.60 mmol) was dried by successive evaporations of toluene and anhydrous pyridine using dry' rotavapor. It was dissolved in anhydrous pyridine (10 mL), and DMAP (12 mg, 0.1 mmol) was added followed by dimethoxy trityl chloride (965 mg, 2.9 mmol). The reaction was stirred for 16 h at RT. All volatiles were removed on a rotavapor, the residual pyridine was removed by evaporation of toluene. The residue was partitioned between DCM and aqueous NaHCOs. The organic phase was separated, the aqueous was extracted with DCM, combined organic phases yvere dried (Na2SO4) and concentrated. The product was isolated on CombiFlash® using 40 g column, eluent: hexane (A) - ethyl acetate (B) + 1% of Et3N, B= 20-60%, 40 min. Yield 1.845 g. Calculated: MW 898.16. Found: MS (ES, positive): 899.65 [M+H]+.

[0249] Compound 5: Compound 4 (1.845 g. 2.052 mmol) yvas dried by 2 evaporations of toluene. It was dissolved in anhydrous DCM (30 mL), diisopropylammonium tetrazolide (176 mg, 1.03 mmol) and dry molecular sieves (100 mg) yvere added and stirred for 30 min. 2-Cyanoethyl N,N,N’,N'-tetraisopropylphosphorodiamidite (804 mg, 2.67 mmol) was added and stirring w as continued for 16 h. The reaction mixture was diluted 3 times w ith anhy drous DCM, filtered, and stirred with 150 mL of cold NaHCOs solution for 5 min. Organic phase w as separated, aqueous yvas extracted with DCM, combined organic phases were washed with NaHCCE, and dried (Na2SO4). The product was isolated on CombiFlash® using 40 g column, eluent: hexane (A) - ethyl acetate (B) + 1% of Et3N. B= 15-60%. 30 min. Yield 1.386 g. Calculated: MW 1098.38. Found: MS (ES, positive): 1099.17 [M+H]+.

[0250] Synthesis of phosphoramidite for gC 16 internal nucleotide 4

[0251] Compound 2: A solution of N2-lsobutyrylguanosine 1 (5g, 14.15 mmol) in anhydrous DMF (120 mL) was added into a cold flask with sodium hydride (60% dispersion in mineral oil, 1.3g, 32.55 mmol). The cooling bath was removed, the reaction mixture was stirred for 3h at RT and 1-bromohexadecane (5.61 g, 18.4 mmol) was added. The reaction mixture was stirred at 50°C for 72 h and EtOH (2 mL) was added. DMF was removed on a rotavapor, and toluene was evaporated twice to get rid of residual DMF. The product was isolated on CombiFlash® following solid load with 30g of silica gel using 120g column. System for separation: A= DCM : EtOAc (1:1); B = DCM:EtOAc:MeOH (9:9:2). B=0 - 100%, 50 min. Kept fraction B = 32-70%. Yield 2.45 g.Calculated: MW 577.77. Found: MS (ES, positive): 579.39 [M+H]+.

[0252] Compound 3: Compound 2 (2.129 g, 3.69 mmol) was dried by 2 evaporations of toluene followed by one evaporation of anhydrous pyridine. It was dissolved in anhydrous pyridine (40 mL), dimethoxytrityl chloride (1.375 g, 4.06 mmol) and DMAP (18 mg, 0.148 mmol) were added and stirred overnight. All volatiles were removed on a rotavapor followed by 2 evaporations of toluene. The residue was taken m DCM (150 mL) and stirred with NaHCOs (50 mL) for 3 min. The organic phase was separated, the aqueous phase was extracted with DCM, combined organic phases were washed with NaHCOv and dried (Na2SO4). The product was isolated on CombiFlash® using 40 g column, eluent: hexane (A) - ethyl acetate (B) + 1% of Et3N. B= 20-90%. 40 min. Kept fraction B= 58-70%. Yield 1.606 g. Calculated: MW 880.14. Found: MS (ES. positive): 881.34 [M+H]+.

[0253] Compound 4: Compound 3 (1.4 g, 1.59 mmol) was dried by 2 evaporations of toluene. It was dissolved in anhydrous DCM (30 mL), diisopropylammonium tetrazolide (136 mg, 0.8 mmol) and dry molecular sieves (100 mg) were added and stirred for 30 min. 2-Cyanoethyl N,N.N',N'-tetraisopropylphosphorodiamidite (767 mg, 2.54 mmol) was added and stirring was continued for 16 h. Et?N (0.3 mL) w?as added followed by silica gel (6g). The mixture was concentrated in vacuo and solid loaded on CombiFlash®. Product was isolated using 40 g column, eluent: hexane(A) - ethyl acetale(B) + 1% of EhN, B= 20-90%, 35 min. Yield 836 mg. Calculated: MW 1080.36. Found: MS (ES, positive): 1081.38 [M+H]+.

[0254] Synthesis of phosphoramidite for uC16 internal nucleotide DMAP, Py OH , AIMe Diglyme (C2H5)3N • 3 HF THF DMT-CI, DMAP Et3N, Py

[0255] Compound 2: Dry 2.2'-Cyclouridine 1 (18 g, 79.6 mmol) and DMAP (486 mg. 3.98 mmol) were suspended in anhydrous pyridine (120 mL) and treated with tert-butyl(chloro)diphenylsilane (25.6 g, 93.14 mmol). The reaction mixture was stirred at RT for 48 h. Pyridine was removed on a rotavapor, The residual pyridine was co-evaporated with toluene. The residue was dissolved in ethyl acetate (200 mL), washed with 10% H3PO4 (75 mL), 5% NaCl, and brine, then dried with Na2SO4. Compound 2 was isolated following CombiFlash® purification using two 120 g SiO2 columns, eluent DCM (A) - 20% MeOH (B) in DCM, B= 0-60%. Yield 14 g. Calculated: MW 464.59. Found: MS (ES, positive): 465.71 [M+H]+.

[0256] Compound 3: Hexadecanol (49.6 g, 204.4 mmol) was dried in vacuo overnight. It was dissolved in dry diglyme (38 mL) with heating and cooled to RT. AlMes (2M solution in heptane, 31.25 mL, 62.5 mmol) was slowly added under flow of N2 and the reaction mixture was heated at 110°C until methane evolution ceased (30 min). It was cooled to RT, and dry uridine derivative 2 (13.2 g, 28.39 mmol) was added as a solid, dry diglyme was added (30 mL). The reaction was heated at 140°C for 18 h. It was partitioned between 10% H3PO4 (300 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc; combined organic phases were washed twice with 5% NaCl, brine, and dried with Na2SO4. Following filtration and concentration the crude solid was dried by evaporation of toluene and kept in vacuo overnight. Crude product 3 (115.8 g) was directly used in the following step.

[0257] Compound 4: Crude compound 3 was dissolved in THF (130 mL), triethylamine trishy drofluoride (18 mL, 114 mmol) was added, and the reaction mixture was stirred for 3 days. The product was partitioned between EtOAc (300 mL) and 5% aqueous NaCl (250 mL). Organic phase was separated, the aqueous phase was extracted with EtOAc, combined organic phases were washed with brine, dried (Na2.SO4), and concentrated to dryness. Product 4 was isolated following CombiFlash® purification on two 220 g SiO2 columns applying solid load with 60 g of silica gel. Eluent: DCM (A), 10% MeOH in DCM (B), B= 0-60% in 60 min. Product was dried by 2 evaporations of toluene. Yield 5.63 g. Calculated: MW 468.64. Found: MS (ES, positive): 469.52 [M+H]+; 491.52 [M+Na]+.

[0258] Compound 5: Compound 4 (5.63 g, 12 mmol), 4,4’-dimethoxytrytyl chloride (5.2 g, 15.36 mmol), and DMAP (293 mg, 2.4 mmol) were dissolved in anhydrous pyridine (40 mL), EtsN (2.17 mL, 15.36 mmol) was added and stirred for 16 h. The reaction was quenched with MeOH (0.6 mL), stirred for 15 min, pyridine was removed in vacuo, the residue was partitioned between EtOAc (230 mL) and 5% aqueous NaCl (230 mL). The organic phase was separated, aqueous phase was extracted with EtOAc, combined organic phases were washed with brine and dried overNa2SO4. CombiFlash® purification using 120g SiO2 column, eluent: Hexane(A) -EtOAc (B), B= 10-50% 60 min. Yield 8.271 g. Calculated: MW 771.01. Found: MS (ES, positive): 772. 35 [M+H]+.

[0259] Compound 6: Compound 5 (2.33 g, 3.024 mmol) was dried by 2 evaporations of anhydrous ACN and placed in high vacuo for 2h. The dry compound 5 was dissolved in anhydrous DCM (40 mL) and stirred with diisopropylammonium tetrazolide (704 mg. 4.11 mmol) and molecular sieves for 20 min. 2-Cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite (1.404 g, 4.66 mmol) was added, the reaction mixture was stirred for 16 h at RT, diluted to 100 ml with anhydrous DCM, the solid was filtered, and shaken with cold NaHCOs (100 mL) for 5 min. The organic layer wfas separated, washed with NaHCOs, dried (Na2.SO4) and product was purified on CombiFlash® using 40 g SiO2 column. Eluent: hexane (A)-EtOAc (B) with 1% EtsN, B= 15-50?4 Yield 2g. Calculated: MW 971.23. Found: MS (ES, positive): 972.17 [M+H]+.

[0260] Synthesis of phosphoramidite for cC16 internal nucleotide

[0261] Compound 2: 5'-O-DMT-protected Uracil-derivative 1, described in preparation of cC16 (11.687g, 15.15 mmol) was dissolved in anhydrous pyridine (100 mL) and cooled on ice bath. TMS-C1 (7.8 mL, 61 mmol) was added, the cooling bath was removed, reaction was stirred for 30 min at RT and cooled on an ice bath again.

[0262] In a separate flask 1.2,4-triazole (35 g. 50.7 mmol) was suspended in anhydrous CAN (200 mL), cooled on ice bath, POCh (11.2 mL, 120 mmol) was slowly added over 10 min, and stirred for 5 min at 0°C. EtsN (84 mL, 595 mmol) was added slowly over 30 min and stirred at 0°C for 30 min.

[0263] The cooled content with silylated Uracil derivative from the fist flask was quickly added in one portion to the mixture with 1,2,4-triazole, stirred for lOmin and cooling bath was removed. The stirring was continued for 5h at RT. The reaction mixture was concentrated to 1 / 3 of its volume on a rotavapor, diluted with EtOAc (600 mL), and washed with 5% NaCl (2 x 400 mL). An aqueous phase was back-extracted with EtOAc (200 mL). Combined EtOAc layers were washed with brine and dried (NajSOr). The EtOAc solution was filtered and concentrated and dried in vacuo to obtain crude derivative 2 (17.46 g).

[0264] Compound 3: Cmde compound 4 was dissolved in dry dioxane (220 mL) in thick wall IL RB flask, concentrated ammonium hydroxide solution (50 mL) was added, the flask was sealed with rubber septa, and the reaction mixture was stirred for 40 h at RT. All volatiles were removed on a rotavapor. Toluene was evaporated twice to dry the residue. Product was isolated on a CombiFlash following solid load with 35g of silica gel using 220g SiO2 column. Eluent: DCM (A) - 10%MeOH in DCM (B), B= 0 - 45%, 60 min. Yield 7.81. Calculated: MW 770.02. Found: MS (ES, positive): 770.31 [M+H]+, 1541.24 [2M+H]+.

[0265] Compound 4: Compound 3 (6.94 g, 9 mmol) was dried by evaporation of anhydrous DMF and was dissolved in anhydrous DMF (60 mL). Acetic anhydride (1.75 mL, 18 mmol) was added and stirred at RT for 16 h. NaHCOs solution (250 mL) was added and product w as extracted with DCM (2 x 200 mL). It w?as washed with brine (50 mL), dried (Na2SO4), concentrated and dried by 2 successive evaporations of toluene. CombiFlash® purification w?as performed using 120 g SiO2 column, eluent: DCM (A), 5%MeOH in DCM (B), B= 0-40% 60 min. Yield 6.55 g. Calculated: MW 812.06. Found: MS (ES, positive): 813.36 [M+H]+.

[0266] Compound 5: Compound 4 (6.55 g, 8.07 mmol) was dried by 2 evaporations of toluene. It was dissolved in anhydrous DCM (166 mL) and stirred with diisopropylammonium tetrazolide (2.188 g, 12.78 mmol) and molecular sieves (500 mg) for 20 min. 2-Cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite (4.376 g, 14.52 mmol) was added, the reaction mixture was stirred for 16 h at RT. diluted to 300 ml with anhydrous DCM, the solid w^as filtered, and shaken with cold NaHCCb (150 mL) for 5 min. Organic layer was separated, washed with NaHCOs, dried (Na2SO4) and product was purified on CombiFlash® using 120 g SiO2 column. Eluent: hexane (A) - EtOAc (B), B= 10-50%, 60 min. Yield 6.29 g. Calculated: MW 1012.28. Found: MS (ES. positive): 1013.89 [M+H]+. Synthesis of RNAi Agents and TfRl-Specific Conjugates F Conjugation of RNAi agents to Fabs and Capping with CP-1113.

[0267] RNAi agents described herein comprising a free amine were conjugated to L20-p F L20'p                using standard amide reaction chemistry following cleavage from the solid phase. To a solution ofFab in PBS (0.2umol, 1.0-10.0 mg / mL in PBS) was added a freshly prepared solution of (tris(2-carboxyethyl)phosphine) hydrochloride (TCEP-HC1) in PBS (5-20 eq, 70 mM). The reaction was held overnight at room temperature and covered from light. The next day. TCEP was removed by loading the reaction mixture on a PD-10 desalting column equilibrated with PBS and eluted with PBS. The concentration of Fab in the eluate was determined using the theoretical absorptivity factor at 280 nm. A solution of L20-modified sense strand in sodium phosphate buffer was prepared, and the concentration was determined using the theoretical absorptivity’ factor at 260 nm. To the desalted Fab solution was added L20-modified sense strand (1-1.3 eq, 0.5-2.5 mM), and the reaction was mixed endover-end. Analysis by SEC Method 1 and AIEX Method 1 show a mixture of starting Fab, DARI, and DAR2. After 1 hour, a solution of CP-1113-p:     CP-1113-p            in DMSO and added to the reaction mixture (3 eq, 36 mM). After 1 hour, a solution of L-cysteine in PBS was added to the reaction mixture (6-10 eq, 165 mM). Finally, the conjugate was annealed by addition of antisense strand (1.2-1.5 eq, 0.5-2.5 mM). Tire conjugate was purified by an AKTA Pure FPLC system equipped with 20 mM tris pH 8 (Buffer A), 20 mM tris 1500 mM NaCl (Buffer B), and a 5 x 200 mm column packed with Tosoh SuperQ 5PW (20 micron). The crude reaction mixture was pump loaded onto the column and eluted with a gradient of 1040% Buffer B. DARI and DAR2 fractions were differentiated by SEC Method 1, AEX Method 1, and Nanodrop 260 / 280 readings. DARI fractions were pooled and buffer exchanged to PBS using a PD-10 desalting column. The purified conjugate was analyzed by SEC Method 1 and eluted as a monomeric peak with a retention time of 13.2 minutes. G. Conjugation ofRNAi agents to Fabs and Capping with NEM.

[0268] RNAi agents described herein comprising a free amine were conjugated to L20-p F L20'P                using standard amide reaction chemistry following cleavage from the solid phase. To a solution of Fab in PBS (10 mg, 0.2 umol, 1.0-10.0 mg / mL in PBS) was added a freshly prepared solution of TCEP-HC1 in PBS (5-20 eq, 70 mM). The reaction was held overnight at room temperature and covered from light. The next day, TCEP was removed by loading the reaction mixture on to a PD-10 desalting column equilibrated with 20 mM tris pH 8 and eluted with 20 mM tris pH 8. The concentration of Fab in the eluate was determined using the theoretical absorptivity factor at 280 nm. A solution of L20-modified sense strand in sodium phosphate buffer was prepared, and the concentration was determined using the theoretical absorptivity factor at 260 nm. To the desalted Fab solution was added L20-modified sense strand (1-1.3 eq, 0.5-2.5 mM), and the reaction was mixed end-over-end. Analysis by SEC Method 1 and AIEX Method 1 show a mixture of starting Fab, DARI, and DAR2. After 1 hour, a solution of N-ethyl maleimide (NEM) in 20 mM tris pH 8 was added to the reaction mixture (12 eq, 160 mM). After 1 h, the conjugate was annealed by addition of antisense strand (1.2-1.5 eq, 0.5-2.5 mM). The conjugate was purified by an AKTA Pure FPLC system equipped with 20 mM tris pH 8 (Buffer A), 20 mM tris 1500 mM NaCl (Buffer B), and a 5 x 200 mm column packed with Tosoh SuperQ 5PW (20 micron). The crude reaction mixture was loaded onto the column and eluted with a gradient of 10-40% Buffer B. DARI and DAR2 fractions were differentiated by SEC Method 1, AEX Method 1, and UV-Vis 260 / 280 measurements. DARI fractions were pooled and buffer exchanged to PBS using a PD-10 column. The purified conjugate was analyzed by SEC Method 1 and eluted as a monomeric peak with a retention time of 13.2 minutes. SEC Method 1 Mobile phases Phosphate Buffered Saline pH 7.4 Column Superdex 200 Increase 10 / 300 GL Cytiva PN 29219757 Column temperature 25°C Autosampler ambient Injection volume 40 uL of 1 mg / mL protein (variable) Flow rate 1.0 mL / min isocratic Wavelength PDA 190-450 nm; monitor 230 nm, 260 nm, 280 nm Run time 30 minutes AIEX Method 1 Mobile phases C: 20 mM tris pH 8.0, D: 20 mM tris 1500 mM NaCl pH 8.0 Column ProPac SAX-10 4 mm x 250 mm, 10 um Thermo Fisher Scientific PN 054997 Column temperature 30°C Autosampler 5°C Injection volume 20 pl of 0.2 mg / mL oligo (variable) Flow rate 1.0 mL / min (variable) Wavelength PDA 190-450 nm; monitor 230 nm, 260 nm, 280 nm Run time 12.5 minutes Gradient Time(min) Event Value 0 D. Cone 0 0.10 D.Conc 0 0.11 D.Conc 25 10.11 D.Conc 75 10.11 T.Flow 1 10.12 D.Conc 0 10.12 T.Flow 1.5 12.50 Controller Stop

[0269] RNAi agents described herein comprising a free amine were conjugated to L1026-p: following cleavage from the solid phase according to the following procedure:

[0270] To a solution ofFab0070 (28 mg, 0.59 umol, 5.55 mg / mL in PBS) was added a freshly prepared solution of TCEP-HC1 in PBS (5 eq, 70 mM, 42 uL). The reduction was mixed endover-end at ambient temperature for 15 minutes then held at 5°C overnight without agitation. The next day, TCEP was removed by loading the reaction mixture on two PD-10 desalting columns (Cytiva) equilibrated with 20 mM tris 50 mM NaCl pH 7.6 (alternatively, 20 mM tris pH 8 or PBS buffer can be used) and eluted with the same buffer. The concentration of the Fab in the eluate was determined using the theoretical absorptivity factor at 280 nm. A solution of L-1026-modified sense strand (CS915332) in 10 mM sodium phosphate buffer pH 6.0-6.5 was prepared, and the concentration was determined using the theoretical absorptivity factor at 260 nm. To the desalted Fab solution was added L-1026-modified CS915332 (1.15 eq, 2.75 mM, 240 uL), and the reaction was mixed end-over-end at ambient temperature. Analysis by SEC Method 1 and AIEX Method 1 show a mixture of starting Fab0070, DARI product, and DAR2 product. After 30 m, a solution of L-cysteine in 20 mM tris 50 mM NaCl pH 7.6 (alternatively, some L-1026 conjugates have been prepared in 20 mM tns pH 8 or PBS buffer solutions) was added to the reaction mixture (10 eq. 165 mM. 36 uL). After 30 m, the conjugate was annealed by addition of antisense strand (CA003820) (1.3 eq, 1.45 mM in water, 529 uL). The conjugate was purified by an AKTA Pure FPLC system equipped with 20 mM tris pH 8 (Buffer A), 20 mM tris 1500 mM NaCl (Buffer B), and a 5 x 200 mm column packed with Tosoh SuperQ 5PW (20 micron). The crude reaction mixture was loaded onto the column and eluted with a gradient of 10-40% Buffer B. DARI and DAR2 fractions were differentiated by SEC Method 1, AIEX Method 1, and UV-Vis 260 / 280 measurements. DARI fractions were pooled and buffer exchanged to PBS using two PD-10 columns. The purified conjugate was analyzed by SEC Method 1 and eluted as a monomeric peak with a retention time of 7.2 minutes. SEC Method 1 Mobile phases 2x Phosphate Buffered Saline pH 7.4 Column ACQUITY UPLC Protein BEH SEC Column, 200 A, 1.7 pm, 4.6 mm X 300 mm Waters PN 186005226 Column temperature 30°C Autosampler ambient Injection volume 2-5 uL Flow rate 0.3 mL / min Wavelength PDA 190-450 nm Run time 20 minutes AIEX Method 1 Mobile phases C: 20 mM tris pH 8.0, D: 20 mM tris 1500 mM NaCl pH 8.0 Column ProPac SAX-10 4 mm x 250 mm, 10 um Thermo Fisher Scientific PN 054997 Column temperature 30°C Autosampler 5°C Injection volume 5-20 pl Flow rate 1.0 mL / min (variable) Wavelength PDA 190-450 nm Run time 12.5 minutes Gradient Time(min) Event Value 0 D. Cone 10 0.10 D.Conc 10 0.11 D.Conc 25 10.11 D.Conc 75 10.11 T.Flow 1 10.12 D.Conc 10 10.12 T.Flow 1.5 12.50 Controller Stop H. Conjugation of RNAi agents to Fabs. Synthesis of Fab0070-L-1288

[0271] To a solution of Fab0070 in PBS (82 mg, 8.2 mg / mL) was added a freshly prepared solution of TCEP-HC1 in PBS (5 eq). The reaction mixture was held overnight at 5°C. The next day, the reaction mixture was buffer exchanged to 20 mM tris 50 mM NaCl pH 7.6 using four PD-10 columns equilibrated with the same buffer. The concentration was determined by Nanodrop, and the solution was diluted to 2 mg / mL with 20 mM tris 50 mM NaCl pH 7.6. The solution was diluted with DMSO (1.95 mL). A solution of L-1288 was prepared (2 mg / mL in DMSO) and charged (1.6 mL, 3.19 mg, 3 eq) over 15 m. After 10 m, the reaction was quenched with cysteine (10 eq). Insoluble material was removed by centrifugation. The supernatant removed, filtered, diluted 1:1 with PBS, and concentrated / desalted using Pierce 10K MWCO spin columns to a volume of 8 mL. Finally, the solution was buffer exchanged by loading onto a HiPrep 26 / 10 desalting column and eluting with PBS. The final yield was approximately 80 mg.

[0272] Bioconjugation of L-1289

[0273] Lyophilized CS915332 (86 mg, 11.6 umol) was brought up in DMF (1.58 mL) and water (215 uL) and sonicated. To the solution was added triethylamine (9.7 uL, 6 eq) and a solution of L-1289 in DMF (50 mg / mL, 344 uL, 3 eq). The progress of the reaction w as monitored by LCMS. After 1 h, added additional triethylamine (4 eq) and L-1289 solution (2 eq). After 20 m, LCMS showed complete conversion. The reaction mixture was acidified with phosphoric acid (200 mg / mL in water, 5 eq). The crude solution was added dropwise to a mixture of acetonitrile (43 mL) and PBS (1.7 mL). The precipitate was collected by centrifugation and the supernatant was discarded. The pellet was dissolved in water (1.5 mL) and added to acetonitrile (43 mL). The precipitate was collected by centrifugation and dissolved in PBS (5 mL). The yield was 88 mg (98%).

[0274] Conjugation of Fab0070-L-1288 with L-1307 modified sense strand

[0275] To a solution of Fab0070-L-1288 in PBS (12.5 mg, 6.97 mg / mL, 1.79 mL, 1 eq) was added a solution of L1307-modified sense strand: L-1307s(invAb)scacuuuugAfCfCfugcuaaucaas(invAb), (i.e., CS009529, SEQ ID NO.: 771) in PBS (6.18 mg, 17.9 mg / mL, 345 uL, 3 eq). The combined solution was mixed end-over-end for 10 m then stored at 5°C without agitation. The next day, the reaction was warmed to room temperature and annealed with antisense strand CA003820, 6.23 mg, 10.4 mg / mL, 599 uL, 3.3 eq. The conjugate w as purified by an AKTA Pure FPLC system equipped with 20 mM tris pH 8 (Buffer A), 20 mM tris 1500 mM NaCl (Buffer B), and a 5 x 200 mm column packed with Tosoh SuperQ 5PW (20 micron). The crude reaction mixture was diluted to 40 mL with MPA. loaded onto the column, and eluted with a gradient of 10-40% Buffer B. DARI-containing fractions were pooled and buffer exchanged to PBS using two PD-10 columns. The conjugate was analyzed by SEC Method 1 and found to be 99% pure with a retention time of 7.2 m. This procedure was also followed to generate the Fab-L-1288-L-1289-RNAi conjugates disclosed herein. SEC Method 1 Mobile phases 2x Phosphate Buffered Saline pH 7.4 Column ACQUITY UPLC Protein BEH SEC Column. 200 A, 1.7 pm, 4.6 mm X 300 mm Waters PN 186005226 Column temperature 30°C Autosampler ambient Injection volume 2-5 uL Flow rate 0.3 mL / min Wavelength PDA 190-450 nm Run time 20 minutes I.      Synthesis of antibody-siRNA linkers

[0276] The synthesis of various Fab linkers used throughout the present application are provided below. Synthesis of 2,3,5,6-tetrafluorophenyl 16-((3,5-bis(5-(methylsulfonyl)-l,3,4-oxadiazol-2- yl)phenyl)amino)-16-oxo-4,7,10,13-tetraoxahexadecanoate (i.e., L-1026-p)

[0277] Compound 6 (2.35 g, 7.31 mmol; prepared according to Sarbisheh et al. Bioconjugate Chemistry 2020 31 (12). 2789-2806), EDC-HC1 (2.38 g, 12.43 mmol), and K-Oxyma (2.50 g, 13.9 mmol) were combined as solids and slurried in DMF (190 mL) under N2 at ambient temperature. Compound 7 (1.1.92 g, 5.48 mmol) was added as a solution in DMF (10 mL). After 5 m, tri ethylamine (4.5 mL, 32.2 mmol) was added dropwise at ambient temperature. The reaction mixture was heated at 50°C for 2 days. The reaction mixture was concentrated under reduced pressure to a red oil which was slurried in DCM (250 mL) and washed with sat. aq. sodium bicarbonate (200 mL). The layers were separated, and the aqueous layer w?as further extracted with DCM (100 mL). The combined organic phase was washed with water (200 mL) and brine (200 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was purified by normal phase SiCh chromatography with a gradient of ethyl acetate in DCM (0-100%). Yield of compound 8: 1.77 g (49%), partially contaminated with compound 6. Calculated mw for compound 8: 653.77 g / mol, found m / z (ESI, positive mode): 654.83.

[0278] Compound 8 (1.77 g, 2.71 mmol) w as dissolved in TFA:DCM [1:1 ] (18 mL) and stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure then coevaporated with toluene (3x30 mL). The residue was purified by normal phase SiO2 chromatography with a gradient of DCM containing 0.1% formic acid and methanol (07%). Yield of compound 9: 1.30 g (80%). Calculated mw for compound 9: 597.66 g / mol, found m / z (ESI, positive mode): 598.79. p 0

[0279] Compound 9 (1.30 g, 2.18 mmol) was dissolved in DCM (50 mL) and cooled to 0°C. A 100 mg / mL solution of m-CPBA solution was prepared by dissolving 10.38 g w-CPBA (77 wt%) in 80 mL DCM and drying with sodium sulfate until clear. To the solution of compound 9 was added 58 mL m-CPBA (5.85 g, 26.1 mmol) dropwise at 0°C. The reaction mixture was warmed to ambient temperature and allowed to proceed overnight. The reaction mixture was concentrated, slurried in DCM 0.1% formic acid (50 mL), and filtered. The filtrate was purified by normal phase SiO2 chromatography with a gradient of DCM containing 0.1% formic acid and methanol (0-10%). Yield of compound 10: 1.03 g (72%). Calculated mw for compound 10: 661.65 g / mol, found m / z (ESI, positive mode): 662.65. L-1026

[0280] To a solution of compound 10 (1.03 g, 1.56 mmol) in DCM:ACN [4:11 (15 mL) at 0°C was added EDC (0.448 g, 2.34 mmol) followed by a solution of TFP (0.310 g, 1.87 mmol) in DCM:ACN [4:1] (5 mL). After 5 m, the reaction mixture was warmed to ambient temperature. After 1.5 h, the reaction mixture was concentrated to dryness. The crude was purified by preparative reverse phase HPLC (Phenomenex Gemini Cl 8 50 mm x 250 mm, 10 urn) using a gradient of water / acetonitrile containing 0.1% TFA. Product-containing fractions were concentrated under reduced pressure. Yield of L-1026-p: 1.10 g (87%). Calculated mw for compound L-1026-p: 809.71 g / mol. found m / z (ESI, positive mode): 810.62. NMR (400 MHz,[De]DMSO, 25°C): 5 = 2.64 (t, 2H), 3.00 (t, 2H), 3.49 (m, I2H), 3.74 (m, 10H), 7.92 (m, 1H), 8.34 (t, 1H), 8.68 (d, 2H), 10.67 (s, 1H).

[0281] To a suspension of compound 1 (5.00 g, 22.50 mmol) and CS2CO3 (25.66 g, 78.75 mmol) in anhydrous DMF (80 mL) was added methyl iodide (4.20 mL, 67.50 mmol) at room temperature. The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was quenched with water (200 mL) and the mixture was extracted with EtOAc (3 x 100 mL). The organic phase was combined and washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. Compound 2 was obtained as a light yellow solid. 5.41 g. 96%. Compound 2 was used directly without further purification. LC-MS: [M+H] calculated 251.05, found 251.18.

[0282] To a solution of compound 2 (5.41 g, 21.62 mmol) in THF / H2O (50 mL / 50 mL) was added LiOH (2.59 g, 108.08 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After removing THF under vacuum, the pH was adjusted to ~2 by [C] HC1. Then EtOAc (3 x 60 mL) was used to extract. The organic lay ers were combined, washed with brine, then dried over anhydrous Na?.SO4, and concentrated. Compound 3 w7as obtained as an off-white solid, 5 g, 98%. Compound 3 was used directly without further purification. LC-MS: calculated [M+H] 237.03, found 237.26. N-N 0 F

[0283] To a solution of compound 3 (5.81 g, 24.60 mmol) in THF / DMF (80 mL / 20 mL) was added EDC (7.07 g, 36.90 mmol), DMAP (0.30 g, 2.46 mmol) and compound 4 (6.13 g, 36.90 mmol) at room temperatwe. The reaction mixture was stirred at room temperature overnight. After removing solvent under vacuum, the residue was loaded on a 120 g column and compound 5 was eluted with 0-50% EtOAc in hexanes. Compound 5 was obtained as a white solid, 9.36 g, 99%. LC-MS: calculated [M+H] 385.03, found 385.46. \ n~n -s—C 0 Vo 6

[0284] To a solution of compound 5 (2.29 g, 5.96 mmol) in DCM (110 mL) was added 70% m-CPBA (5.14 g, 27.79 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 6 hows. Another 1.8 g m-CPBA was added at room temperature. The reaction mixture was stirred at room temperature overnight. After filtration, the solvent was removed under vacuum. The residue was recrystallized from DCM / EtOAc (50 mL / 50 mL) twice. Compound L20-p was obtained as white needle cry stals, 1.93 g, 78%. LC-MS: calculated [M+H] 417, found 417. Example 2. In Vivo Knockdown of AR in Mice

[0285] AR RNAi agents were evaluated in vivo in mouse. On Day 1, four (n=4) female C57bl / 6 mice were administered, via subcutaneous (SC) injection, either saline or AR RNAi agents (formulated in saline, at 3.0 mg / kg animal body weight), at an injection volume of 10 mL / kg of animal weight. Dosing was in accordance with Table 12 below.

[0286] Table 12. Dosing groups for the mice of Example 2. Group ID Dosing Route # Animals (n = ) 1. Saline Day 1 SC Injection n~4 2. 3.0 mg / kg AC908464 Day 1 SC Injection n = 4 3.3.0 mg / kg AC908468 Day 1 SC Injection n = 4 4. 3.0 mg / kg AC908469 Day 1 SC Injection n = 4 5.3.0 mg / kg AC908476 Day 1 SC Injection n = 4 6. 3.0 mg / kg AC908478 Day 1 SC Injection n = 4 7. 3.0 mg / kg AC908480 Day 1 SC Injection n = 4 8. 3.0 mg / kg AC908481 Day 1 SC Injection n = 4 9. 3.0 mg / kg AC908482 Day 1 SC Injection n = 4

[0287] Each of the AR RNAi agents included modified nucleotides that were conjugated at the 5’ terminal end of the sense strand to a targeting ligand that included three N-acetyl-galactosamine groups (tridentate ligand) having the modified sequences as set forth in the duplex structures herein (see Tables 3, 4, 5, 6, and 7 for specific modifications and structure information related to the AR RNAi agents; see Table 11 for structure of (NAG37) and (NAG37)s ligand). The AR RNAi agents evaluated in this Example study were cross-reactive across mouse and human AR.

[0288] On Day 8, the mice were euthaniz...

Claims

1. An RNAi agent for inhibiting expression of an Androgen Receptor (AR) gene, comprising:an antisense strand comprising at least 17 contiguous nucleotides differing by 0 or 1 nucleotides from any one of the sequences provided in Table 2 or Table 3; anda sense strand comprising a nucleotide sequence that is at least partially complementary to the antisense strand.

2. The RNAi agent of claim 1, wherein the antisense strand comprises nucleotides 2-18 of any one of the sequences provided in Table 2 or Table 3.

3. The RNAi agent of claim 1 or claim 2, wherein the sense strand comprises a nucleotide sequence of at least 17 contiguous nucleotides differing by 0 or 1 nucleotides from any one of the sequences provided in Table 2 or Table 4, and wherein the sense strand has a region of at least 85% complementarity over the 17 contiguous nucleotides to the antisense strand.

4. The RNAi agent of any one of claims 1-3. wherein at least one nucleotide of the AR RNAi agent is a modified nucleotide or includes a modified intemucleoside linkage.

5. The RNAi agent of any one of claims 1-4, wherein all or substantially all of the nucleotides are modified nucleotides.

6. The RNAi agent of any one of claims 4-5, wherein the modified nucleotide is selected from the group consisting of: 2'-O-methyl nucleotide, 2’-fluoro nucleotide, 2'-deoxy nucleotide, 2’,3'-seco nucleotide mimic, locked nucleotide, 2'-F-arabino nucleotide, 2'-methoxyethyl nucleotide, abasic nucleotide, ribitol, inverted nucleotide, inverted 2'-O-methyl nucleotide, inverted 2'-deoxy nucleotide, 2'-amino-modified nucleotide, 2'-alkyl-modified nucleotide, morpholino nucleotide, vinyl phosphonate-containing nucleotide, cyclopropyl phosphonate-containing nucleotide, and 3'-O-methyl nucleotide.

7. The RNAi agent of claim 5, wherein all or substantially all of the nucleotides are modified with 2'-O-methyl nucleotides, 2'-fluoro nucleotides, or combinations thereof.

8. The RNAi agent of any one of claims 1-7, wherein the antisense strand comprises the nucleotide sequence of any one of the modified sequences provided in Table 3.

9. The RNAi agent of any one of claims 1-8, wherein the sense strand comprises the nucleotide sequence of any one of the modified sequences provided in Table 4.

10. The RNAi agent of claim 1, wherein the antisense strand comprises the nucleotide sequence of any one of the modified sequences provided in Table 3 and the sense strand comprises the nucleotide sequence of any one of the modified sequences provided in Table 4.

11. The RNAi agent of any one of claims 1-10, wherein the sense strand is between 18 and 30 nucleotides in length, and the antisense strand is between 18 and 30 nucleotides in length.

12. The RNAi agent of claim 11, wherein the sense strand and the antisense strand are each between 18 and 27 nucleotides in length.

13. The RNAi agent of claim 12, wherein the sense strand and the antisense strand are each between 18 and 24 nucleotides in length.

14. The RNAi agent of claim 13, wherein the sense strand and the antisense strand are each 21 nucleotides in length.

15. The RNAi agent of claim 14, wherein the RNAi agent has two blunt ends.

16. The RNAi agent of any one of claims 1-15, wherein the sense strand comprises one ortwo terminal caps.

17. The RNAi agent of any one of claims 1-16, wherein the sense strand comprises one or two inverted abasic residues.

18. The RNAi agent of claim 1, wherein the RNAi agent comprises of a sense strand and an antisense strand that form a duplex having the structure of any one of the duplexes in Table 7, Table 8, Table 9, or Table 10.

19. The RNAi agent of claim 18, wherein all or substantially all of the nucleotides are modified nucleotides.

20. The RNAi agent of claim 19, wherein all or substantially all of the nucleotides are modified nucleotides.

21. The RNAi agent of any one of claims 19-20, wherein the sense strand further includes inverted abasic residues at the 3’ terminal end of the nucleotide sequence, at the 5’ end of the nucleotide sequence, or at both.

22. The RNAi agent of any one of claims 1-21, wherein the RNAi agent is linked to a lipid moiety or linked to an antigen binding protein.

23. The RNAi agent of any one of claims 1-22, wherein the RNAi agent is linked to a lipid moiety.

24. The RNAi agent of claim 23, wherein the lipid moiety is selected from the groupconsisting of:(2C8C12)sii(2C6C10)sLP409sH0-C16scl6sC22swherein ? indicates the point of connection to the RNAi agent.

25. The RNAi agent of claim 23 or claim 24, wherein the lipid moiety is conjugated to the sense strand.

26. The RNAi agent of claim 25, wherein the lipid moiety is conjugated to the 5’ terminal end of the sense strand.

27. The RNAi agent of any of claims 1-22, wherein the RNAi agent is linked to an antigen binding protein.

28. The RNAi agent of any one of claims 1-27, wherein the antigen binding protein is an antibody fragment (Fab) that specifically binds to one or more epitopes on a transferrin receptor (TfRl).

29. The RNAi agent of claim 28, wherein the Fab comprises (i) 6 complementary determining regions (CDRs), (ii) 3 CDRs on the variable light chain (VL), and / or (iii) 3 CDRs on the variable heavy chain (VH).

30. The RNAi agent of claim 29, wherein the variable light chain has a VL CDR1 sequence selected from the group consisting of: RASDGLYSNLA (SEQ ID NO: 721). RASDNLYRNLA (SEQ ID NO: 722), and RASDKLYSNLA (SEQ ID NO: 723); a VL CDR2 sequence selected from the group consisting of: DATLLAS (SEQ ID NO: 724), DARNLAS (SEQ ID NO: 725), DAFNLAS (SEQ ID NO: 726), DATRLAS (SEQ ID NO: 727). DATKLAS (SEQ ID NO: 728), and DAKNLAS (SEQ ID NO: 729); and / or a VL CDR 3 sequence of QHFWGTPLT (SEQ ID NO: 730).

31. The RNAi agent of claim 29 or 30, wherein the variable light chain comprises the sequence:DIQLTQSPSSLSASVGDRVTITCRASDKLYSNLAWYQQKPGKAPKLLIYDATLLASGV PSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWGTPLTFGQGTKVEIK (SEQ ID NO: 747).

32. The RNAi agent of any one of claims 29-31, wherein the variable heavy chain has a VH CDR1 sequence selected from the group consisting of: GYTFNSYWMH (SEQ ID NO: 731), GYTFKSYWMH (SEQ ID NO: 732), GFTFTSYWMH (SEQ ID NO: 733), GYTFTSYWVH (SEQ ID NO: 734), and GYTFTSYWMH (SEQ ID NO: 735), a VH CDR2 sequence selected from the group consisting of: EINPTNGRVNYIEKFKS (SEQ ID NO: 736), EINPTNGRFNYIEKFKS (SEQ ID NO: 737), EINPTNGRTNYIEKFKS (SEQ ID NO:738), and EINPTNGRSNYIEKFKS (SEQ ID NO: 739); and / or a VH CDR3 sequence of: GTRAYHY (SEQ ID NO: 740).

33. The RNAi agent of any one of claims 29-32, wherein the variable heavy chaincomprises the sequence:EVQLVESGGGLVQPGGSLRLSCATSGFTFTSYWMHWVRQAPGKGLEWVAEINPTNG RTNYIEKFKSRITLSVDKSKSTVYLQMNSLRAEDTAVYYCARGTRAYHYWGQGTLV TVSS (SEQ ID NO: 755).

34. The RNAi agent of any one of claims 28-33, wherein the Fab further comprises a light constant chain 1 (CL).

35. The RNAi agent of claim 34 wherein the light constant chain 1 (CL) sequence is: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 717).

36. The RNAi agent of any one of claims 28-35, wherein the Fab further comprises a heavy constant chain 1 (CH).

37. The RNAi agent of claim 36 wherein the heavy constant chain 1 (CH) sequence is: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH (SEQ ID NO: 719).

38. The RNAi agent of any one of claims 28-37, wherein the antibody fragment (Fab) bindsTfRl with an affinity of at least 1 nM KD.

39. A conjugate comprising the RNAi agent of any one of claims 1-21 conjugated to an antibody fragment (Fab) that specifically binds to one or more epitopes on a transferrin receptor (TfRl).

40. The conjugate of claim 39, wherein the Fab comprises (i) 6 complementary determining regions (CDRs), (ii) 3 CDRs on the variable light chain (VL), or (iii) 3 CDRs on the variable heavy chain (VH).

41. The conjugate of claim 40, wherein the variable light chain has a VL CDR1 sequence selected from the group consisting of: RASDGLYSNLA (SEQ ID NO: 721), RASDNLYRNLA (SEQ ID NO: 722). and RASDKLYSNLA (SEQ ID NO: 723); a VL CDR2 sequence selected from the group consisting of: DATLLAS (SEQ ID NO: 724), DARNLAS (SEQ ID NO: 725), DAFNLAS (SEQ ID NO: 726), DATRLAS (SEQ ID NO: 727), DATKLAS (SEQ ID NO: 728), and DAKNLAS (SEQ ID NO: 729); and / or a VL CDR 3 sequence of QHFWGTPLT (SEQ ID NO: 730).

42. The conjugate of claim 40 or 41, wherein the variable light chain comprises the sequence:DIQLTQSPSSLSASVGDRVTITCRASDKLYSNLAWYQQKPGKAPKLLIYDATLLASGV PSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWGTPLTFGQGTKVEIK (SEQ ID NO: 747).

43. The conjugate of any one of claims 40-42. wherein the variable heavy chain has a VH CDR1 sequence selected from the group consisting of: GYTFNSYWMH (SEQ ID NO: 731), GYTFKSYWMH (SEQ ID NO: 732), GFTFTSYWMH (SEQ ID NO: 733), GYTFTSYWVH (SEQ ID NO: 734), and GYTFTSYWMH (SEQ ID NO: 735), a VH CDR2 sequence selected from the group consisting of: EINPTNGRVNYIEKFKS (SEQ ID NO: 736), EINPTNGRFNYIEKFKS (SEQ ID NO: 737), EINPTNGRTNYIEKFKS (SEQ ID NO: 738), and EINPTNGRSNYIEKFKS (SEQ ID NO: 739); and / or a VH CDR3 sequence of: GTRAYHY (SEQ ID NO: 740).

44. The conjugate of any one of claims 40-43, wherein the variable heavy chain comprises the                                                                              sequence:EVQLVESGGGLVQPGGSLRLSCATSGFTFTSYWMHWVRQAPGKGLEWVAEINPTNG RTNYIEKFKSRITLSVDKSKSTVYLQMNSLRAEDTAVYYCARGTRAYHYWGQGTLV TVSS (SEQ ID NO: 755)45. The conjugate of any one of claims 39-44 wherein the Fab further comprises a light constant chain 1 (CL).

46. The conjugate of claim 45 wherein the light constant chain 1 (CL) sequence is: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 717).

47. The conjugate of any one of claims 39-46, wherein the Fab further comprises a heavy constant chain 1 (CH).

48. The conjugate of claim 47 wherein the heavy constant chain 1 (CH) sequence is: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH (SEQ ID NO: 719).

49. The conjugate of any one of claims 39-48, wherein the antibody fragment (Fab) binds TfRl with an affinity of at least 1 nM KD.

50. The conjugate of claim any one of claims 39-49. wherein the RNAi agent is conjugated to the Fab using a covalent or non-covalent bond, ionic bond, hydrogen bond, hydrophobic interaction, peptide, polymer, or a nucleic acid binding protein.

51. The conjugate of any one of claims 39-50, wherein the RNAi agent is conjugated to the Fab through a linker comprising a structure selected from the group consisting of:wherein represents a point of attachment to the Fab, and represents a point of attachment to the RNAi agent portion of the conjugate.

52. The RNAi agent of any one of claims 1-21, wherein the RNAi agent is linked to a targeting ligand.

53. The RNAi agent of claim 52, wherein the targeting ligand is linked to the sense strand.

54. The RNAi agent of claim 53, wherein the targeting ligand is linked to the 5? terminal end of the sense strand.

55. The RNAi agent of any of claims 52-54, wherein the targeting ligand has affinity for a skeletal muscle cell and / or a cell receptor expressed on a skeletal muscle cell.

56. The RNAi agent of any of claims 52-55, wherein the targeting ligand has affinity for an integrin alpha-v-beta 6 (avP6) receptor.

57. The RNAi agent of any of claims 52-56. wherein the targeting ligand is:or a pharmaceutically acceptable salt thereof, wherein ? indicates the point of connection to the RNAi agent.

58. The RNAi agent of any one of claims 1-21 or 52-57, wherein the RNAi agent is further linked to a pharmacokinetic / pharmacodynamic (PK / PD) modulator.

59. The RNAi agent of claim 58, wherein the PK / PD modulator is linked to the sense strand.

60. The RNAi agent of claim 59. wherein the PK / PD modulator is linked to the 3’ terminal end of the sense strand.

61. The RNAi agent of any one of claims 58-60, wherein the PK / PD modulator is selected from the group consisting of:wherein Rz comprises the RNAi agent.

62. A composition comprising the RNAi agent of any one of claims 1-38 or 52-61, or the conjugate of any one of claims 39-51, wherein the composition further comprises a pharmaceutically acceptable excipient.

63. The composition of claim 62, further comprising a second RNAi agent capable of inhibiting the expression of Androgen Receptor gene expression.

64. The composition of any one of claims 62-63, further comprising one or more additional therapeutics.

65. The composition of any of claims 62-64, wherein the RNAi agent is a sodium salt.

66. The composition of any of claims 62-65, wherein the pharmaceutically acceptableexcipient is water for injection.

67. The composition of any of claims 62-65, wherein the pharmaceutically acceptable excipient is a buffered saline solution.

68. A method for inhibiting expression of an AR gene in a cell, the method comprising introducing into a cell an effective amount of the RNAi agent of any one of claims 1-38 or 52-61, the conjugate of any one of claims 39-51, or the composition of any one of claims 6267.

69. The method of claim 68, wherein the cell is within a subject.

70. The method of claim 69, wherein the subject is a human subject.

71. The method of any one of claims 68-70, wherein following the administration of the RNAi agent the Androgen Receptor (AR) gene expression is inhibited by at least about 30%.

72. A method of treating one or more symptoms or diseases associated with enhanced or elevated membrane AR activity levels, the method comprising administering to a human subject in need thereof a therapeutically effective amount of the composition of any one of claims 62-67.

73. The method of claim 72. wherein the disease is a neurodegenerative disease.

74. The method of claim 73, wherein the neurodegenerative disease is spinal and bulbarmuscular atrophy (SBMA).

75. The method of any one of claims 68-74, wherein the RNAi agent is administered at a deposited dose of about 0.01 mg / kg to about 5.0 mg / kg of body weight of the subject.

76. The method of any one of claims 68-75, wherein the RNAi agent is administered at a deposited dose of about 0.03 mg / kg to about 2.0 mg / kg of body weight of the subject.

77. The method of any of claims 68-76, wherein the RNAi agent is administered in two or more doses.

78. Use of the RNAi agent of any one of claims 1-38 or 52-61, or the conjugate of any one of claims 39-51, for the treatment of a disease, disorder, or symptom that is mediated at least in part by mutant AR activity and / or AR gene expression.

79. Use of the composition according to any one of claims 62-67, for the treatment of a disease, disorder, or symptom that is mediated at least in part by Androgen Receptor (AR) activity and / or Androgen Receptor (AR) gene expression.

80. Use of the composition according to any one of claims 62-67, for the manufacture of a medicament for treatment of a disease, disorder, or symptom that is mediated at least in part by Androgen Receptor (AR) and / or Androgen Receptor (AR) gene expression.

81. The use of any one of claims 78-80, wherein the disease is a neurodegenerative disease.

82. A method of making an RNAi agent of any one of claims 1-38 or 52-61, comprising annealing a sense strand and an antisense strand to form a double-stranded ribonucleic acid molecule.

83. The method of claim 82. wherein the sense strand comprises a lipid moiety.

84. The method of claim 82, wherein the sense strand comprises an antigen bindingmoiety.

85. The method of claim 82, wherein the sense strand comprises a targeting ligand.

86. The method of claim 85, wherein the sense strand further comprises a PK / PD modulator.

87. The method of claim 83, comprising conjugating a lipid moiety to the sense strand.

88. The method of claim 84. comprising conjugating an antigen binding moiety to thesense strand.

89. The method of claim 85, comprising conjugating a targeting ligand to the sense strand.

90. The method of claim 86, comprising conjugating a PK / PD modulator to the sense strand.