Dual conjugate compounds for extrahepatic delivery

Abstract

The present disclosure provides double stranded ribonucleic acid (dsRNA) agents for inhibiting expression of a target gene, comprising an antisense strand which is complementary to the target gene; a sense strand which is complementary to the antisense strand and forms a double stranded region with the antisense strand; at least one alpha-v-beta-6 (αvβ6) integrin targeting ligand that mediates delivery to muscle tissue conjugated to at least one strand; and at least one in vivo delivery enhancing moiety conjugated to one or more internal positions on at least one strand. The present disclosure also provides compositions comprising such dsRNA agents, and methods of use thereof for treating a subject having a disorder that would benefit from reduction in expression of the target gene.

Description

[0001]Atty. Docket No.121301-23820 / ALN-523-WO DUAL CONJUGATE COMPOUNDS FOR EXTRAHEPATIC DELIVERY RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No.63 / 659,097, filed on 5 June 12, 2024. The entire contents of the foregoing application are hereby incorporated herein by reference. SEQUENCE LISTING The application contains a Sequence Listing which has been submitted electronically in .XML 10 format and is hereby incorporated by reference in its entirety. Said .XML copy, created on June 5, 2025, is named “ALN-523_ST.xml” and is 608,848 bytes in size. The sequence listing contained in this .XML file is part of the specification and is hereby incorporated by reference herein in its entirety. BACKGROUND OF THE DISCLOSURE 15 Efficient delivery of an RNAi agent to cells in vivo requires specific targeting and substantial protection from the extracellular environment, particularly serum proteins. RNAi-based therapeutics show promising clinical data for treatment of liver-associated disorders. However, RNAi delivery into extra-hepatic tissues remains an obstacle, limiting the use of RNAi-based therapies. One of the limiting factors is the ability to deliver intact RNAi efficiently to extra-hepatic tissues, 20 such as muscle tissues, e.g., skeletal muscle tissues and / or cardiac muscle tissues. Previous work has used delivery reagents such as liposomes, cationic lipids, and nanoparticles forming complexes to aid the intracellular internalization of RNAi agents into extra-hepatic cells. However, only limited success in delivering RNAi agents to extra-hepatic tissues, like muscle tissue, after systemic administration has been reported. For example, although cholesterol-conjugated RNAi 25 agents are delivered to muscles after intravenous injection, a high dose (50 mg / kg) is required to achieve sustainable gene silencing. In addition, cholesterol conjugates are highly toxic at high concentrations, limiting their potential for clinical applications. Thus, systemic delivery of oligonucleotides to muscle tissue remains a challenge and, accordingly, there is a continuing need for new and improved compositions and methods for delivering 30 RNAi agents in vivo. SUMMARY OF THE DISCLOSURE The present disclosure is based, at least in part, on the surprising discovery that conjugating at least one alpha-v-beta-6 (αvβ6) integrin targeting ligand and at least one in vivo delivery enhancing 35 moiety, e.g., a moiety comprising at least one C10-C26 hydrocarbon chain conjugated to at least one strand of a dsRNA agent, e.g., the sense strand, provides surprisingly efficient in vivo delivery to extrahepatic tissue, i.e., muscle tissue, resulting in efficient entry and internalization of the dsRNA agent into muscle tissue ( e.g., skeletal muscle tissue and / or cardiac muscle tissue), and surpringly good 1 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO inhibition of target gene expression in muscle tissue (e.g., skeletal muscle tissue and / or cardiac muscle tissue). Accordingly, in one aspect, the present disclosure provides a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of a target gene, comprising: an antisense strand which is 5 complementary to the target gene; a sense strand which is complementary to the antisense strand and forms a double stranded region with the antisense strand; at least one αvβ6 integrin targeting ligand that mediates delivery to muscle tissue conjugated to at least one strand; and at least one in vivo delivery enhancing moiety conjugated to one or more internal positions on at least one strand. The dsRNA agent of claim 1, wherein the in vivo delivery enhancing moiety comprises at least 10 one C10-C26 hydrocarbon chain. In some embodiments, the in vivo delivery enhancing moiety comprises at least one C22 hydrocarbon chain, at least one C17 hydrocarbon chain or at least one C11 hydrocarbon chain. In some embodiments, the at least one C10-C26 hydrocarbon chain is unsubstituted or substituted with at least one functional group selected from the group consisting of hydroxyl, amine, 15 carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne, e.g., a carboxylic acid group. In some embodiments, the at least one C10-C26 hydrocarbon chain is covalently attached to the following moiety: wherein is a bond connecting the moiety to the at least one C10-C26 hydrocarbon. 20 In some embodiments, the in vivo delivery enhancing moiety is attached to the dsRNA agent via a linker or via a carrier or via an internucleotide phosphate linkage. In some embodiments, the in vivo delivery enhancing moiety is attached to the dsRNA agent via a linker, e.g., a linker comprising an ether, a thioether, a urea, a carbonate, an amine, an amide, a maleimide-thioether, a disulfide, a phosphodiester, a sulfonamide linkage, a product of a click reaction,25 or carbamate. In some embodiments, the linker is selected from the group consisting of -(CH2)nNH-; - C(O)(CH2)nNH-; -NR’’’’(CH2)nNH-, -C(O)-(CH2)n-C(O)-; -C(O)-(CH2)n-C(O)O-; -C(O)-O-; -C(O)- (CH2)n-NH-C(O)-; -C(O)-(CH2)n-; -C(O)-NH-; -C(O)-; -(CH2)n-C(O)-; -(CH2)n-C(O)O-; -(CH2)n-; and - (CH2)n-NH-C(O)-; wherein n is a number from 1 to 20; and R’’’’ is C1-C6alkyl. In some embodiments, the linker comprises –(CH2)n-NH-C(O)- or –(CH2)n-NH-C(O)-(CH2)2-C(COOH)-NH-C(O)-, wherein n is30 a number from 1 to 20. In some embodiments, the linker comprises –(CH)2-O-(CH2CH2)-(O)-(CH2CH2)- NH-C(O)-. In some embodiments, the in vivo delivery enhancing moiety comprises the following structure: 2 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO , , 3 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO wherein the broken bond represents the bond to the remainder of the dsRNA agent. In one embodiment, the αvβ6 integrin targeting ligand comprises the structure: 5 the broken bond represents the bond to the remainder of the dsRNA agent. In one embodiment, the αvβ6 integrin targeting ligand comprises the structure: wherein RLigis 4 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO broken bond represents the bond to the remainder of the dsRNA agent. In one embodiment, the αvβ6 integrin targeting ligand comprises the structure: 5 In one embodiment, the αvβ6 integrin targeting ligand comprises the structure: 10 5 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO the broken bond represents the bond to the remainder of the dsRNA agent. In one embodiment, the αvβ6 integrin targeting ligand comprises the structure: 5 broken bond represents the bond to the remainder of the dsRNA agent. In some embodiments, the αvβ6 integrin targeting ligand or the αvβ6 integrin targeting ligand together with a linker useful in the present disclosure comprises a structure selected from the table below: 6 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO 7 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO wherein Z1 is a linker linking the the αvβ6 integrin targeting ligand to the remainder of the dsRNA agent and wherein * represents the bond to the remainder of the dsRNA agent. 8 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments, the at least one αvβ6 integrin targeting ligand is conjugated to the sense strand, e.g., to the 3’-end of the sense strand or the 5’-end of the sense strand. In some embodiments, the at least one αvβ6 integrin targeting ligand is conjugated to both the 5’-end and the 3’-end of the sense 5 strand. In some embodiments, the at least one αvβ6 integrin targeting ligand is conjugated to an internal position of the sense strand. In some embodiments, the at least one αvβ6 integrin targeting ligand is conjugated to the antisense strand, e.g., to the 3’ end antisense strand or the 5’ end of the antisense strand. In some embodiments, the at least one αvβ6 integrin targeting ligand is conjugated to both the 5’-end and the 3’- 10 end of the antisense strand. In some embodiments, the at least one αvβ6 integrin targeting ligand is conjugated to an internal position of the antisense strand. In some embodiments, the at least one in vivo delivery enhancing moiety is conjugated to an internal position of the sense strand. In some embodiments, the at least one in vivo delivery enhancing moiety is conjugated to an internal position or an external position of the sense strand. In some 15 embodiments, the at least one in vivo delivery enhancing moiety is conjugated to an external position of the sense strand. In other embodiments, the at least one in vivo delivery enhancing moiety is not conjugated to an internal position of the sense strand. In some embodiments, the at least one in vivo delivery enhancing moiety is conjugated to one or more of the following internal positions: positions 4-8 and 13-18 on the sense strand, counting from the 20 5’ end. In some embodiments, the at least one in vivo delivery enhancing moiety is conjugated to one or more of the following internal positions: positions 5, 6, 7, 15, 16 and 17 on the sense strand, counting from the 5’-end. In one embodiment, the at least one in vivo delivery enhancing moiety is conjugated to position 6 on the sense strand, counting from the 5’-end. In some embodiments, the at least one in vivo delivery enhancing moiety is conjugated to an 25 internal position of the antisense strand. In some embodiments, the at least one in vivo delivery enhancing moiety is conjugated to an internal position or an external position of the antisense strand. In some embodiments, the at least one in vivo delivery enhancing moiety is conjugated to an external position of the antisense strand. In other embodiments, the at least one in vivo delivery enhancing moiety is not conjugated to an internal position of the antisense strand. 30 In some embodiments, the at least one in vivo delivery enhancing moiety is conjugated to one or more of the following internal positions: positions 6-10 and 15-18 on the antisense strand, counting from the 5’-end. In some embodiments, the at least one in vivo delivery enhancing moiety is conjugated to one or more of the following internal positions: positions 15, 16 and 17 on the antisense strand, counting from the 5’-end. 35 In some embodiments, the at least one αvβ6 integrin targeting ligand and the at least one in vivo delivery enhancing moiety are both conjugated to the sense strand. In some embodiments, 9 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO the at least one αvβ6 integrin targeting ligand and the at least one in vivo delivery enhancing moiety are both conjugated to the antisense strand. In some embodiments, the at least one αvβ6 integrin targeting ligand is conjugated to the sense strand and the at least one in vivo delivery enhancing moiety is conjugated to the antisense strand. In 5 some embodiments, the at least one αvβ6 integrin targeting ligand is conjugated to the antisense strand and the at least one in vivo delivery enhancing moiety is conjugated to the sense strand. In some embodiments, the sense strand and the antisense strand are each independently 15-30 nucleotides in length; 19 to 25 nucleotides in length; or 21 to 23 nucleotides in length. In some embodiments, the target gene is selected from the group consisting of myostatin 10 (MSTN); Cholinergic Receptor Nicotinic Alpha 1 Subunit (CHRNA1); Cholinergic Receptor Nicotinic Beta 1 Subunit (CHRNB1); Cholinergic Receptor Nicotinic Delta Subunit (CHRND); Cholinergic Receptor Nicotinic Epsilon Subunit (CHRNE); Cholinergic Receptor Nicotinic Gamma Subunit (CHRNG); Collagen Type XIII Alpha 1 Chain (COL13A1); Docking Protein 7 (DOK7); LDL Receptor Related Protein 4 (LRP4); Muscle Associated Receptor Tyrosine Kinase (MUSK); Receptor Associated 15 Protein Of The Synapse (RAPSN); Sodium Voltage-Gated Channel Alpha Subunit 4 (SCN4A); and Double Homeobox 4 (DUX4), dystrophy myotonic protein kinase (DMPK), glycogen synthase 1 (GYS1), survival of motor neuron 1 (SMN1), alpha-glucosidase (GAA); adrenoceptor beta 1 (ADRB1); calcium voltage-gated channel subunit alpha1 C (CACNA1C); calcium voltage-gated channel subunit alpha1 G (CACNA1G) (T type calcium cchannel); angiotensin II receptor type 1(AGTR1); Sodium 20 Voltage-Gated Channel Alpha Subunit 2 (SCN2A); Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 1 (HCN1); Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4 (HCN4); Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 3 (HCN3); Potassium Voltage-Gated Channel Subfamily A Member 5 (KCNA5); Potassium Inwardly Rectifying Channel Subfamily J Member 3 (KCNJ3); Potassium Inwardly Rectifying Channel Subfamily J Member 25 4 (KCNJ4); phospholamban (PLN); calcium / calmodulin dependent protein kinase II delta (CAMK2D); or Phosphodiesterase 1 (PDE1). In one aspect, the present disclosure provides cells containing any of the dsRNA agents of the disclosure. In another aspect, the present disclosure provides a pharmaceutical composition for inhibiting 30 expression of the target gene, comprising any of the dsRNA agents of the disclosure. In one embodiment, the dsRNA agent is present in a buffer solution, e.g., a buffer solution comprising acetate, citrate, prolamine, carbonate, or phosphate, or any combination thereof. In one embodiment, the buffer solution is phosphate buffered saline (PBS). In other embodiments, the dsRNA agent is present in an unbuffered solution, e.g., in water or normal saline. 35 In one aspect, the present disclosure provides a method of inhibiting expression of a target gene in a skeletal muscle cell and / or a cardiac muscle cell. The method includes contacting the cell with any of the dsRNA agents of the disclosure or any of the pharmaceutical compositions of the disclosure, e.g., 10 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO and maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of the target gene in the skeletal muscle cell and / or cardiac muscle cell, thereby inhibiting expression of the target gene in the skeletal muscle cell and / or cardiac muscle cell. In one embodiment, the cell is within a subject, e.g., human subject. 5 In certain embodiments, contacting the cell with the dsRNA agent or pharmaceutical composition inhibits the expression of the target gene by at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In one embodiment, inhibiting expression of the target gene decreases the target gene protein level in serum of the subject by at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. 10 In one aspect, the present disclosure provides a method of treating a subject having a muscle disorder, e.g., a skeletal muscle disorder and / or a cardiac muscle disorder. The method includes administering to the subject a therapeutically effective amount of any of the dsRNA agents of the disclosure or any of the pharmaceutical compositions of the disclosure, thereby treating the subject. In one embodiment, the muscle disorder is selected from the group consisting of Myostatin- 15 related muscle hypertrophy, congenital myasthenic syndrome, facioscapulohumeral muscular dystrophy (FSHD), Spinal Muscular Atrophy (SMA), Myotonic Dystrophy Type 1 (DM1), Pompe disease, PLN cardiomyopathy, spasticity, obstructive hypertrophic cardiomyopathy (HOCM); familial hypertrophic cardiomyopathy (FHC); Heart failure with preserved ejection fraction (HFPEF); atrial fibrillation (AFIB); ventricular fibrillation (VFIB); angina; myocardial infarction (MI); heart failure or heart failure 20 with reduced ejection fraction (HFREF); supraventricular tachycardia (SVT); hypertrophic cardiomyopathy (HCM); and PLN cardiomyopathy. In one embodiment, the skeletal muscle disorder is selected from the group consisting of Myostatin-related muscle hypertrophy, congenital myasthenic syndrome, facioscapulohumeral muscular dystrophy (FSHD), Spinal Muscular Atrophy (SMA), Myotonic Dystrophy Type 1 (DM1), Pompe 25 disease, PLN cardiomyopathy, and spasticity. In one embodiment, the cardiac muscle disorder is selected from the group consisting of obstructive hypertrophic cardiomyopathy (HOCM); familial hypertrophic cardiomyopathy (FHC); Heart failure with preserved ejection fraction (HFPEF); atrial fibrillation (AFIB); ventricular fibrillation (VFIB); angina; myocardial infarction (MI); heart failure or heart failure with reduced ejection fraction 30 (HFREF); supraventricular tachycardia (SVT); hypertrophic cardiomyopathy (HCM); and PLN cardiomyopathy. The dsRNA agent or pharmaceutical composition may be administered to the subject subcutaneously, intramusclularly, intravenously, or via inhalation. In one embodiment, the therapeutic methods of the disclosure further include administering to 35 the subject an additional agent or a therapy suitable for treatment or prevention of an extrahepatic disorder. 11 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 is a bar graph showing AD-1812376 mediated SOD1 knockdown in quadriceps and gastrocnemius of a mouse model at Day 21 following a single IV dose of 2 mg / kg. PBS as used for the control group. 5 FIG.2: is a bar graph showing AD-1812376 mediated SOD1 knockdown in quadriceps, gastrocnemius and liver of non-human primates at Days 29 and 57 following a single IV dose of 1 mg / kg, 3 mg / kg or 9 mg / kg. PBS was used for the control group. FIG.3: is a bar graph showing AD-2032892 mediated SOD1 knockdown in liver, quadriceps and gastrocnemius of a mouse model at Day 21 following administration of a single IV dose of 1 mg / kg, 10 3 mg / kg or 9 mg / kg. PBS was used for the control group. FIG.4: is a bar graph showing AD-2032892 mediated NHP SOD1 knockdown in gastrocnemius, quadriceps and liver of non-human primates following administration of a single IV dose of 10 mg / kg. PBS was used for the control group. FIG.5: is a bar graph showing NHP SOD1 knockdown mediated by AD-2432777, AD-2241090, 15 AD-2315832, AD-2315873 and AD-2315833 in biceps, gastrocnemius and quadriceps of non-human primates at Day 29 following administration of a single IV dose of 10 mg / kg. PBS was used for the control group. FIG.6: is a bar graph showing NHP SOD1 knockdown mediated by AD-2432777 and AD- 2640041 in biceps, gastrocnemius and soleus of non-human primates at Day 28 following administration 20 of a single SC 10 mg / kg dose. PBS was used for the control group. FIG.7: is a bar graph showing AD-2432777, AD-2902547, AD-2889354, AD-2889355, AD- 2889356, and AD-2889357 mediated SOD1 knockdown in quadriceps of a mouse model at Day 7 following administration of a single subcutaneous dose of 1 mg / kg. PBS was used for the control group. FIG.8: is a bar graph showing AD-2432777, AD-2902547, AD-2889354, AD-2889355 and AD- 25 2889356, and AD-2889357 mediated SOD1 knockdown in heart of a mouse model at Day 7 following administration of a single subcutaneous dose of 1 mg / kg. PBS was used for the control group. FIG.9: is a bar graph showing AD-2640041, AD-2700084, AD-2700085, AD-2700086, AD- 2700087, AD-2700088, AD-2700089, AD-2700090, AD-2700091, AD-2700092, AD-2700093, AD- 2700094, AD-2700095, AD-2700096, AD-2700097, and AD-2700099 mediated SOD1 knockdown in 30 quadricep of a mouse model at Day 7 following administration of a single IV dose of 0.3 mg / kg. PBS was used for the control group. FIG.10: is a bar graph showing AD-2640041, AD-2700084, AD-2700085, AD-2700086, AD- 2700087, AD-2700088, AD-2700089, AD-2700090, AD-2700091, AD-2700092, AD-2700093, AD- 2700094, AD-2700095, AD-2700096, AD-2700097, and AD-2700099 mediated SOD1 knockdown in 35 gastrocnemius of a mouse model at Day 7 following administration of a single IV dose of 0.3 mg / kg. PBS was used for the control group. 12 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO FIG.11: is a bar graph showing AD-2640041, AD-2700084, AD-2700085, AD-2700086, AD- 2700087, AD-2700088, AD-2700089, AD-2700090, AD-2700091, AD-2700092, AD-2700093, AD- 2700094, AD-2700095, AD-2700096, AD-2700097, and AD-2700099 mediated SOD1 knockdown in heart of a mouse model at Day 7 following administration of a single IV dose of 0.3 mg / kg. PBS was 5 used for the control group. FIG.12: is a bar graph showing AD-3214512 mediated HPRT1 knockdown in quadricep and heart of a mouse model at Day 7 following administration of a single subcutaneous dose of 1 mg / kg. PBS was used for the control group. FIG.13 is a bar graph showing NHP DMPK knockdown mediaded by AD-3100656 in heart, 10 gastrocnemius, and quadriceps of non-human primates at Day 32 following a single subcutaneous dose of 3 mg / kg. The control group was the average of animals treated with non-DMPK targeting siRNAs. The DMPK mRNA % remaining is relative to two housekeeping genes (PPIB and ADD1). DETAILED DESCRIPTION 15 The present disclosure is based, at least in part, on the surprising discovery that conjugating at least one alpha-v-beta-6 (αvβ6) targeting ligand and at least one in vivo delivery enhancing moiety, e.g., a moiety comprising at least one C10-C26 hydrocarbon chain, to at least one strand of a dsRNA agent, e.g., the sense strand, provides surprisingly efficient in vivo delivery to extrahepatic tissue, i.e., muscle tissue, resulting in efficient entry and internalization of the dsRNA agent into extrahepatic tissue, e.g., muscle 20 tissue, e.g., skeletal muscle tissue and / or cardiac muscle tissue, and surprisingly good inhibition of target gene expression in extrahepatic tissue, e.g., muscle tissue, e.g., skeletal muscle tissue and / or cardiac muscle tissue. The following detailed description discloses dsRNA agents comprising at least one alpha-v-beta- 6 (αvβ6) targeting ligand and at least one in vivo delivery enhancing moiety that mediate delivery to 25 extrahepatic tissue, e.g., muscle tissue, e.g., skeletal muscle tissue and / or cardiac muscle tissue, to inhibit the expression of a target gene as well as compositions, ustes, and methods for treating subjects that would benefit from inhibition and / or reduction of the expression of the target gene. I. Definitions 30 In order that the present disclosure may be more readily understood, certain terms are first defined. In addition, it should be noted that whenever a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also intended to be part of this disclosure. In order that the present disclosure may be more readily understood, certain terms are first 35 defined. In addition, it should be noted that whenever a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also intended to be part of this disclosure. 13 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element, e.g., a plurality of elements. The term "including" is used herein to mean, and is used interchangeably with, the phrase 5 "including but not limited to". The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless context clearly indicates otherwise. For example, “sense strand or antisense strand” is understood as “sense strand or antisense strand or sense strand and antisense strand.” The term “about” is used herein to mean within the typical ranges of tolerances in the art. For 10 example, “about” can be understood as about 2 standard deviations from the mean. In certain embodiments, about means +10%. In certain embodiments, about means +5%. When about is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range. The term “at least”, “no less than”, or “or more” prior to a number or series of numbers is 15 understood to include the number adjacent to the term “at least”, and all subsequent numbers or integers that could logically be included, as clear from context. For example, the number of nucleotides in a nucleic acid molecule must be an integer. For example, “at least 19 nucleotides of a 21 nucleotide nucleic acid molecule” means that 19, 20, or 21 nucleotides have the indicated property. When at least is present before a series of numbers or a range, it is understood that “at least” can modify each of the 20 numbers in the series or range. As used herein, “no more than” or “or less” is understood as the value adjacent to the phrase and logical lower values or integers, as logical from context, to zero. For example, a duplex with an overhang of “no more than 2 nucleotides” has a 2, 1, or 0 nucleotide overhang. When “no more than” is present before a series of numbers or a range, it is understood that “no more than” can modify each of the 25 numbers in the series or range. As used herein, ranges include both the upper and lower limit. As used herein, methods of detection can include determination that the amount of analyte present is below the level of detection of the method. In the event of a conflict between an indicated target site and the nucleotide sequence for a sense or antisense strand, the indicated sequence takes precedence. 30 In the event of a conflict between a sequence and its indicated site on a transcript or other sequence, the nucleotide sequence recited in the specification takes precedence. Terms used herein may be preceded and / or followed by a single dash, or a double dash, "=", to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond or a pair of single bonds in the case of 35 a spiro-substituent. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read "left to right" unless a dash indicates otherwise. For example, C1-6alkoxycarbonyloxy and -OC(O)C1-66alkyl indicate the same functionality; similarly arylalkyl, arylalkyl-, and -alkylaryl indicate the same functionality. 14 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO Further, certain terms herein may be used as both monovalent and divalent linking radicals as would be familiar to those skilled in the art, and by their presentation linking between two other moieties. For example, an alkyl group can be both a monovalent radical or divalent radical; in the latter case, it would be apparent to one skilled in the art that an additional hydrogen atom is removed from a 5 monovalent alkyl radical to provide a suitable divalent moiety. Throughout the disclosure, is used to represent an oligonucleotide; such oligonucleotides may be an RNA, a DNA, a single-stranded RNA, such as an antisense oligonucleotide (ASO), a double-stranded RNA, such as an siRNA, and oligonucleotide derivatives such as phosphorodiamidate morpholino oligomers (PMOs). 10 The term “conjugated”, as used herein in reference, e.g., to a moiety conjugated to a dsRNA agent of the disclosure, e.g., at least one αvβ6 integrin targeting ligand conjugated to at least one strand of a dsRNA agent of the disclosure, or at least one in vivo delivery enhancing moiety conjugated to at least one strand of a dsRNA agent of the disclosure, means that the moiety is covalently attached to a dsRNA agent directly or via a linker or via a carrier or via an internucleotide phosphate linkage. 15 The term "alkenyl" as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2- propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and 3,7- dimethylocta-2,6-dienyl. 20 The term “alkynyl” as used herein means a straight or branched hydrocarbon chain containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, 1-butynyl, 2-butynyl, 1-propynyl and the like. The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the 25 parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, 2-propoxy, n-butoxy, tert-butoxy, n-pentyloxy, and n-hexyloxy. The term "alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec -butyl, iso-butyl, tert-butyl, n-pentyl, 30 isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an "alkyl" group is a divalent linking group between two other moieties, then it may also be a straight or branched chain; examples include, but are not limited to -CH2-, - CH2CH2-, -CH2CH2CHC(CH3)-, -CH2CH(CH2CH3)CH2-. The term "aryl," as used herein, means a phenyl (i.e., monocyclic aryl); naphthyl or azulenyl; a 35 bicyclic ring system containing a phenyl fused to a cycloalkyl, cycloalkenyl, or heterocyclyl ring. Representative examples of the bicyclic aryls include, but are not limited to, azulenyl, naphthyl, 2,3- dihydroinden-1-yl, 2,3-dihydroinden-2-yl, 2,3-dihydroinden-3-yl, 2,3-dihydroinden-4-yl, 2,3- 15 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO dihydroinden-5-yl, 2,3-dihydroindol-1-yl, indolin-2-yl, indolin-3-yl, indolin-4-yl, indolin-5-yl, indolin-6- yl, indolin-7-yl, inden-1-yl, inden-2-yl, inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen- 1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, 2,3- 5 dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3- dihydrobenzofuran-7-yl, 2,3-dihydrobenzothien-2-yl, 2,3-dihydrobenzothien-3-yl, 2,3- dihydrobenzothien-4-yl, 2,3-dihydrobenzothien-5-yl, 2,3-dihydrobenzothien-6-yl, 2,3- dihydrobenzothien-7-yl, 2,3-dihydrobenzothien-8-yl, benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl, 2H-chromen-2-on-3-yl, 2H-chromen-2-on-4-yl, 2H-chromen-2-on-5-yl, 2H-chromen-2-on-6-yl, 2H- 10 chromen-2-on-7-yl, 2H-chromen-2-on-8-yl, isoindoline-1,3-dion-2-yl,isoindoline-1,3-dion-4-yl, isoindoline-1,3-dion-5-yl, inden-1-on-2-yl, inden-1-on-3-yl, inden-1-on-4-yl, inden-1-on-5-yl, inden-1- on-6-yl, inden-1-on-7-yl, 2,3-dihydrobenzo[b][1,4]dioxan-2-yl, 2,3-dihydrobenzo[b][1,4]dioxan-5-yl, 2,3-dihydrobenzo[b][1,4]dioxan-6-yl, 2H-benzo[b][1,4]oxazin-3(4H)-on-5-yl, 2H-benzo[b][1,4]oxazin- 3(4H)-on-6-yl, 2H-benzo[b][1,4]oxazin-3(4H)-on-7-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-8-yl, 15 quinazolin-4(3H)-on-5-yl, quinazolin-4(3H)-on-6-yl, quinazolin-4(3H)-on-7-yl, quinazolin-4(3H)-on-8- yl, quinoxalin-2(1H)-on-5-yl, quinoxalin-2(1H)-on-6-yl, quinoxalin-2(1H)-on-7-yl, quinoxalin-2(1H)-on- 8-yl, benzo[d]thiazol-2(3H)-on-3-yl, benzo[d]thiazol-2(3H)-on-4-yl, benzo[d]thiazol-2(3H)-on-5-yl, benzo[d]thiazol-2(3H)-on-6-yl, and, benzo[d]thiazol-2(3H)-on-7-yl. In certain embodiments, the bicyclic aryl is (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 20 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5 or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. The term "arylalkyl," “aralkyl”, "-alkylaryl," and "arylalkyl-" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined25 herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3- phenylpropyl, and 2-naphth-2-ylethyl. The term “azido” means a -N3group. The term “carboxy” means a -COOH group. The terms "cyano" and "nitrile" as used herein, mean a -CN group. 30 The term "cycloalkyl" as used herein, means a monocyclic or a bicyclic cycloalkyl ring system. Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 10 carbon atoms, where such groups are saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring 35 where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form -(CH2)w-, where w is 1, 2, or 3). Representative examples of bridged bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, 16 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to a monocyclic cycloalkyl. Representative examples of fused bicyclic ring systems include, but are not limited to, decaliyl. Cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the fused bicyclic 5 cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to a 5 or 6 membered monocyclic cycloalkyl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia. "Cycloalkenyl" as used herein refers to a monocyclic or a bicyclic cycloalkenyl ring system. Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such 10 groups are unsaturated (i.e., containing at least one annular carbon-carbon double bond), but not aromatic. Examples of monocyclic ring systems include cyclopentenyl and cyclohexenyl. Bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of 15 the form -(CH2)w-, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct-2-enyl. Fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a monocyclic cycloalkyl or a monocyclic cycloalkenyl. Cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia. 20 The term “monocyclic ring”, as used herein, comprises monocyclic aryl, monocyclic cycloalkyl, monocyclic cycloalkenyl and monocyclic heterocyclyl. The term "halo" or "halogen" as used herein, means -CI, -Br, -I or -F. The term “H” means hydrogen. The term "haloalkyl" as used herein, means at least one halogen, as defined herein, appended to 25 the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl. The term "heteroaryl," as used herein, means a monocyclic heteroaryl or a bicyclic ring system containing at least one heteroaromatic ring (i.e., a monocyclic or bicyclic aromatic ring system containing 30 at least one heteroatom within the aromatic system). The monocyclic heteroaryl can be a 5 or 6 membered ring. The 5 membered ring consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom. The 6 membered ring consists of three double bonds and one, two, three or four nitrogen atoms. The 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. 35 Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, a monocyclic 17 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The fused cycloalkyl or heterocyclyl portion of the bicyclic heteroaryl group is optionally substituted with one or two groups which are independently oxo or thia. Representative examples of bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, 5 benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroquinolin-8-yl, 5,6-dihydroisoquinolin- 1-yl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, 5,6,7,8- tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8- tetrahydroquinolin-5-yl, 5,6,7,8-tetrahydroquinolin-6-yl, 5,6,7,8-tetrahydroquinolin-7-yl, 5,6,7,8- tetrahydroquinolin-8-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, thienopyridinyl, 4,5,6,7- 10 tetrahydrobenzo[c][1,2,5]oxadiazol-4-yl, and 6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl. In certain embodiments, the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroaryl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one 15 or two groups which are independently oxo or thia. The term "heteroarylalkyl" and "-alkylheteroaryl" as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heteroarylalkyl include, but are not limited to, fur-3-ylmethyl, 1H-imidazol- 2-ylmethylm 1H-imidazol-4-ylmethyl, 1-(pyridin-4-yl)ethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, 20 pyrimidin-5-ylmethyl, 2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl, and thien-3-ylmethyl. The term "heterocyclyl" as used herein, means a monocyclic heterocycle or a bicyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6, or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group 25 consisting of O, N and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one, or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxan-2-yl, 1,3-dioxolan-2-yl, 1,3-dithiolan-2-yl, 1,2- 30 dithiolan-3-yl, 1,2-dithiolan-4-yl, 1,3-dithian-2-yl, 1,2-dithian-3-yl, 1,2-dithian-4-yl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and 35 trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to either a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic heterocycle. Representative examples of bicyclic heterocyclyls include, but are not limited to, decahydroquinolinyl, decahydroisoquinolinyl, octahydro- 1H-indolyl, and octahydrobenzofuranyl. Heterocyclyl groups are optionally substituted with one or two 18 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5 or 6 membered monocyclic heterocyclyl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia. 5 The term "hydroxy" or “hydroxyl” as used herein means an -OH group. The term “thiol” as used herein means an –SH group. The term "hydroxyl protecting group," as used herein, refers to a labile chemical moiety which protects a hydroxyl group against undesired reactions during synthetic procedure(s). After the synthetic procedure(s), the hydroxy protecting group may be selectively removed. Hydroxy protecting groups as 10 known in the art are described generally in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include, but are not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4- bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl) 15 ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, l,l- dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2- trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, tert- 20 butyldimethylsilyl (TBDMS), trimethylsilyl, triethylsilyl, and triisopropylsilyl. In certain embodiments, hydroxyl protecting groups can be selected from acetyl (Ac or — C(O)CH3), benzoyl (Bz or — C(O)C6H5), and trimethylsilyl (TMS or -Si(CH3)3). The term "nitro" as used herein means a -NO2group. The term "oxo" as used herein means a =O group. 25 The term "saturated" as used herein means the referenced chemical structure does not contain any multiple carbon-carbon bonds. For example, a saturated cycloalkyl group as defined herein includes cyclohexyl, cyclopropyl, and the like. The term "thia" as used herein means a =S group. The term “amine” or “amino” encompasses compounds where a nitrogen atom is covalently 30 bonded to at least one carbon or heteroatom. The term “alkyl amino” includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group. The term “dialkyl amino” includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups. The term "unsaturated" as used herein means the referenced chemical structure contains at least one multiple carbon-carbon bond (i.e., double or triple bond, or both), but is not aromatic. For example, 35 an unsaturated cycloalkyl group as defined herein includes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like. The term “leaving group” as used herein means an atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate in a 19 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO specified reaction. For example, the specified reaction herein, unless otherwise noted, is an SN1 or an SN2 reaction as is understood by one skilled in the art. In certain embodimentns, the specified reaction herein, is an SN2 reaction. The term“substituted” as used herein, whether preceded by the term“optionally” or not, means 5 that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a“substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is 10 substituted, the substituent is either the same or different at each position. Suitable substituents include, but are not limited to, halogen, hydroxy, thiol, nitro, alkoxy, azido, carboxy, cyano, amino, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C1-6alkylamino.The term “support linking group as used herein means a divalent chemical moiety that covalent connects a surface-bound functional group of a solid support (e.g., an amino group of an amino-modified solid support) to another chemical moiety. 15 The term “reactive pair” as used herein means two functional groups known by one skilled in the art to be capable of reacting, alone or in the presence of other reagents, to form a covalent linkage between the two chemical entities which each contain one of member of the reactive pair, respectively; the latter, herein, is referred to as “linking group formed by a reactive pair”. In some embodiments, a reactive pair is a click pair, i.e., two functional groups capable of reacting in a click reaction to form a 20 covalent linkage. The term “Michael acceptor” as used herein means an alpha, beta-unsaturated compound capable of reacting with a nucleophile at the beta-carbon of the electrophilic alkene of the alpha, beta -unsaturated compound. Examples of alpha, beta-unsaturated compound include, but are not limited to, such as an alpha, beta-unsaturated aldehyde, ester, amide, sulfonyl, ketone, nitrile, or nitro. “Alpha, beta- 25 unsaturated” refers to the carbon-carbon multiple bond that connects the carbon atom that is immediately adjacent to the referenced aldehyde, ester, amide, sulfonyl, ketone, nitrile, or nitro group, to its adjacent carbon atom. Examples of Michael acceptor group include, but are not limited to, N-maleimide, acrylaldehyde, acrylonitrile, acrylic acid, acrylamide (e.g., N-isoproprylacrylamide), acrylate esters (e.g., methyl acrylate), vinyl sulfones, vinylsulfonates, and vinylsulfonamides. 30 The term “nitrogen protecting group” as used herein means those functional groups that are well known in the art and include those described in detail, for example, in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Suitable nitrogen protecting groups include but are not limited to, allyl (Alloc), acetyl (Ac), Adpoc (1-(1-Adamantyl)-1-methylethoxycarbonyl), Boc (tert-butyloxy 20 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO carbonyl), Dde Dnp (2,4-dinitrophenyl), Mmt (4-methoxytrityl), Mtt (4-methyltrityl), Teoc (2-trimethylsilylethoxycarbonyl, Tfa (trifluoroacetyl), optionally substituted trityl (e.g., trityl (Trt), 2-chlorotrityl (Clt), 4-methoxytrityl (Mmt), 4-methyltrityl (Mtt), 4,4’-dimethoxytrityl (DMT)), and 4,4’,4’’-trimethoxytrityl), optionally substituted 5 benzyloxycarbonyl (e.g., benzyloxycarbonyl (Z) or 2-chlorobenzyloxycarbonyl (2ClZ)), fluorenylmethoxycarbonyl (Fmoc), methoxyacetyl (mac), phenoxyacetyl (pac), 2-chlorophenoxyacetyl, 3-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2,4-dichlorophenoxyacetyl, 2-methylphenoxyacetyl, 3- methylphenoxyacetyl, 4-methylphenoxyacetyl, 4-chloro-2-methylphenoxyacetyl, 2-nitrophenoxyacetyl, 3-nitrophenoxyacetyl, 4-nitrophenoxyacetyl, 2-isopropylphenoxyacetyl, 3-isopropylphenoxyacetyl, 4- 10 isopropylphenoxyacetyl, 2-(t-butyl)phenoxyacetyl, 3-(t-butyl)phenoxyacetyl, 4-(t-butyl)phenoxyacetyl, 2-fluorophenoxyacetyl, 3-fluorophenoxyacetyl, 4-fluorophenoxyacetyl, 2,4-difluorophenoxyacetyl, 4- (trifluoromethoxy)phenoxyacetyl, 2-phenoxypropanoyl, 2-(4-chloro-2-methylphenoxy)propanoyl, and 2- (4-chlorophenoxy)propanoyl. As used herein, the term “remainder of the dsRNA agent”, refers to an oligonucleotide strand 15 (i.e. the sense strand or the antisense strand) that forms a dsRNA agent and any intervening linking group that connects the parent moiety (e.g., one or more αvβ6 integrin targeting ligand or one or more in vivo delivery enhancing moieties) to the oligonucleotide strand.. The terms “linker”, “linking group”, “carrier” and “carrier group”, in some embodiments, each refer to a chemical moiety connecting at least one αvβ6 integrin targeting ligand or at least one in vivo 20 delivery enhancing moiety to at least one strand of the dsRNA agent of the disclosure. As used herein, “target sequence” or “target nucleic acid” refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a target gene, including mRNA that is a product of RNA processing of a primary transcription product. In one embodment, the target portion of the sequence will be at least long enough to serve as a substrate for RNAi-directed 25 cleavage at or near that portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a target gene. In one embodiment, the target sequence is within the protein coding region of the target gene. In another embodiment, the target sequence is within the 3’ UTR of the target gene. The target nucleic acid can be a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or disease state. 30 The target sequence may be from about 9-36 nucleotides in length, e.g., about 15-30 nucleotides in length. For example, the target sequence can be about 15-30 nucleotides, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides in length. In some embodiments, the target sequence is about 19 to about 30 nucleotides in length. In other embodiments, the target sequence is about 19 to about 25 nucleotides in length. In still other embodiments, the target sequence is about 19 to about 23 nucleotides in length. In some embodiments, the target sequence is about 21 to about 23 nucleotides in 5 length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure. As used herein, the term “strand comprising a sequence” refers to an oligonucleotide comprising a chain of nucleotides that is described by the sequence referred to using the standard nucleotide nomenclature. 10 “G,” “C,” “A,” “T,” and “U” each generally stand for a nucleotide that contains guanine, cytosine, adenine, thymidine, and uracil as a base, respectively. However, it will be understood that the term “ribonucleotide” or “nucleotide” can also refer to a modified nucleotide, as further detailed below, or a surrogate replacement moiety (see, e.g., Table 1). The skilled person is well aware that guanine,cytosine, adenine, and uracil can be replaced by other moieties without substantially altering the base 15 pairing properties of an oligonucleotide comprising a nucleotide bearing such replacement moiety. It is understood that when a cDNA sequence is provided, the corresponding mRNA or RNAi agent would include a U in place of a T. For example, without limitation, a nucleotide comprising inosine as its base can base pair with nucleotides containing adenine, cytosine, or uracil. Hence, nucleotides containing uracil, guanine, or adenine can be replaced in the nucleotide sequences of dsRNA featured in the 20 disclosure by a nucleotide containing, for example, inosine. In another example, adenine and cytosine anywhere in the oligonucleotide can be replaced with guanine and uracil, respectively to form G-U Wobble base pairing with the target mRNA. Sequences containing such replacement moieties are suitable for the compositions and methods featured in the disclosure. Further, one of skill in the art that a T is a target gene sequence, or reverse complement thereof, would often be replaced by a U in an RNAi 25 agent of the disclosure. The terms “iRNA”, “RNAi agent,” “iRNA agent,” “RNA interference agent” as used interchangeably herein, refer to an agent that contains RNA as that term is defined herein, and which mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC) pathway. RNA interference (RNAi) is a process that directs the sequence-specific degradation of 30 mRNA. RNAi modulates, e.g., inhibits, the expression of a target gene in a cell, e.g., a cell within a subject, such as a mammalian subject. The terms “RNAi agent” and “dsRNA agent” may be used interchangeably herein. In one embodiment, an RNAi agent of the disclosure includes a single stranded RNAi that interacts with a target RNA sequence, e.g., a target mRNA sequence, to direct the cleavage of the target 35 RNA. Without wishing to be bound by theory it is believed that long double stranded RNA introduced into cells is broken down into double-stranded short interfering RNAs (siRNAs) comprising a sense strand and an antisense strand by a Type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev.15:485). Dicer, a ribonuclease-III-like enzyme, processes these dsRNA into 19-23 base pair short 22 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO interfering RNAs with characteristic two base 3' overhangs (Bernstein, et al., (2001) Nature 409:363). These siRNAs are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309). Upon binding to the appropriate target mRNA, one or 5 more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001) Genes Dev.15:188). Thus, in one aspect the disclosure relates to a single stranded RNA (ssRNA) (the antisense strand of a siRNA duplex) generated within a cell and which promotes the formation of a RISC complex to effect silencing of the target gene. Accordingly, the term “siRNA” is also used herein to refer to an RNAi as described above. 10 In another embodiment, the RNAi agent may be a single-stranded RNA that is introduced into a cell or organism to inhibit a target mRNA. Single-stranded RNAi agents bind to the RISC endonuclease, Argonaute 2, which then cleaves the target mRNA. The single-stranded siRNAs are generally 15-30 nucleotides and are chemically modified. The design and testing of single-stranded RNAs are described in U.S. Patent No.8,101,348 and in Lima et al., (2012) Cell 150:883-894, the entire contents of each of 15 which are hereby incorporated herein by reference. Any of the antisense nucleotide sequences described herein may be used as a single-stranded siRNA as described herein or as chemically modified by the methods described in Lima et al., (2012) Cell 150:883-894. In another embodiment, an “RNAi agent” for use in the compositions and methods of the disclosure is a double stranded RNA and is referred to herein as a “double stranded RNAi agent,” 20 “double stranded RNA (dsRNA) molecule,” “dsRNA agent,” or “dsRNA”. The term “dsRNA” refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary nucleic acid strands, referred to as having “sense” and “antisense” orientations with respect to a target RNA, i.e., a target mRNA sequence. In some embodiments of the disclosure, a double stranded RNA (dsRNA) triggers the degradation of a target RNA, e.g., an mRNA, 25 through a post-transcriptional gene-silencing mechanism referred to herein as RNA interference or RNAi. In general, a dsRNA molecule can include ribonucleotides, but as described in detail herein, each or both strands can also include one or more non-ribonucleotides, e.g., a deoxyribonucleotide, a modified nucleotide. In addition, as used in this specification, an “RNAi agent” may include ribonucleotides with chemical modifications; an RNAi agent may include substantial modifications at multiple nucleotides. 30 As used herein, the term “modified nucleotide” refers to a nucleotide having, independently, a modified sugar moiety, a modified internucleotide linkage, or a modified nucleobase. Thus, the term modified nucleotide encompasses substitutions, additions or removal of, e.g., a functional group or atom, to internucleoside linkages, sugar moieties, or nucleobases. The modifications suitable for use in the agents of the disclosure include all types of modifications disclosed herein or known in the art. Any such 35 modifications, as used in a siRNA type molecule, are encompassed by “RNAi agent” for the purposes of this specification and claims. 23 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In certain embodiments of the instant disclosure, inclusion of a deoxy-nucleotide – which is acknowledged as a naturally occurring form of nucleotide – if present within a RNAi agent can be considered to constitute a modified nucleotide. The duplex region may be of any length that permits specific degradation of a desired target 5 RNA through a RISC pathway, and may range from about 9 to 36 base pairs in length, e.g., about 15-30 base pairs in length, for example, about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 base pairs in length, such as about 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 10 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure. The two strands forming the duplex structure may be different portions of one larger RNA molecule, or they may be separate RNA molecules. Where the two strands are part of one larger 15 molecule, and therefore are connected by an uninterrupted chain of nucleotides between the 3’-end of one strand and the 5’-end of the respective other strand forming the duplex structure, the connecting RNA chain is referred to as a “hairpin loop.” A hairpin loop can comprise at least one unpaired nucleotide. In some embodiments, the hairpin loop can comprise at at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 23 or more unpaired nucleotides or nucleotides not directed to the 20 target site of the dsRNA. In some embodiments, the hairpin loop can be 10 or fewer nucleotides. In some embodiments, the hairpin loop can be 8 or fewer unpaired nucleotides. In some embodiments, the hairpin loop can be 4-10 unpaired nucleotides. In some embodiments, the hairpin loop can be 4-8 nucleotides. In certain embodiment, the two strands of double-stranded oligomeric compound can be linked together. The two strands can be linked to each other at both ends, or at one end only. By linking at one 25 end is meant that 5'-end of first strand is linked to the 3'-end of the second strand or 3'-end of first strand is linked to 5'-end of the second strand. When the two strands are linked to each other at both ends, 5'- end of first strand is linked to 3'-end of second strand and 3'-end of first strand is linked to 5'-end of second strand. The two strands can be linked together by an oligonucleotide linker including, but not limited to, (N)n; wherein N is independently a modified or unmodified nucleotide and n is 3-23. In some 30 embodiemtns, n is 3-10, e.g., 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, the oligonucleotide linker is selected from the group consisting of GNRA, (G)4, (U)4, and (dT)4, wherein N is a modified or unmodified nucleotide and R is a modified or unmodified purine nucleotide. Some of the nucleotides in the linker can be involved in base-pair interactions with other nucleotides in the linker. The two strands can also be linked together by a non-nucleosidic linker, e.g. a linker described herein. It will be 35 appreciated by one of skill in the art that any oligonucleotide chemical modifications or variations describe herein can be used in the oligonucleotide linker. Hairpin and dumbbell type oligomeric compounds will have a duplex region equal to or at least 14, 15, 15, 16, 17, 18, 19, 29, 21, 22, 23, 24, or 25 nucleotide pairs. The duplex region can be equal to or 24 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO less than 200, 100, or 50, in length. In some embodiments, ranges for the duplex region are 15-30, 17 to 23, 19 to 23, and 19 to 21 nucleotides pairs in length. The hairpin oligomeric compounds can have a single strand overhang or terminal unpaired region, in some embodiments at the 3', and in some embodiments on the antisense side of the hairpin. In 5 some embodiments, the overhangs are 1-4, more generally 2-3 nucleotides in length. The hairpin oligomeric compounds that can induce RNA interference are also referred to as "shRNA" herein. Where the two substantially complementary strands of a dsRNA are comprised by separate RNA molecules, those molecules need not, but can be covalently connected. Where the two strands are connected covalently by means other than an uninterrupted chain of nucleotides between the 3’-end of 10 one strand and the 5’-end of the respective other strand forming the duplex structure, the connecting structure is referred to as a “linker.” The RNA strands may have the same or a different number of nucleotides. The maximum number of base pairs is the number of nucleotides in the shortest strand of the dsRNA minus any overhangs that are present in the duplex. In addition to the duplex structure, an RNAi may comprise one or more nucleotide overhangs. 15 In one embodiment, an RNAi agent of the disclosure is a dsRNA, each strand of which is 24-30 nucleotides in length, that interacts with a target RNA sequence, e.g., a target mRNA sequence, to direct the cleavage of the target RNA. Without wishing to be bound by theory, long double stranded RNA introduced into cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev.15:485). Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base20 pair short interfering RNAs with characteristic two base 3' overhangs (Bernstein, et al., (2001) Nature 409:363). The siRNAs are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001) 25 Genes Dev.15:188). In one embodiment, an RNAi agent of the disclosure is a dsRNA agent, each strand of which comprises 19-23 nucleotides that interacts with a target mRNA sequence to direct the cleavage of the target RNA. Without wishing to be bound by theory, long double stranded RNA introduced into cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev. 30 15:485). Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pair short interfering RNAs with characteristic two base 3’ overhangs (Bernstein, et al., (2001) Nature 409:363). The siRNAs are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309). Upon binding to the appropriate target mRNA, one 35 or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001) Genes Dev.15:188). In one embodiment, an RNAi agent of the disclosure is a dsRNA of 24-30 nucleotides that interacts with a target mRNA sequence to direct the cleavage of the target RNA. 25 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO As used herein, the term “nucleotide overhang” refers to at least one unpaired nucleotide that protrudes from the duplex structure of a RNAi agent, e.g., a dsRNA. For example, when a 3'-end of one strand of a dsRNA extends beyond the 5'-end of the other strand, or vice versa, there is a nucleotide overhang. A dsRNA can comprise an overhang of at least one nucleotide; alternatively, the overhang can 5 comprise at least two nucleotides, at least three nucleotides, at least four nucleotides, at least five nucleotides or more. A nucleotide overhang can comprise or consist of a nucleotide / nucleoside analog, including a deoxynucleotide / nucleoside. The overhang(s) can be on the sense strand, the antisense strand or any combination thereof. Furthermore, the nucleotide(s) of an overhang can be present on the 5'-end, 3'-end or both ends of either an antisense or sense strand of a dsRNA. 10 In one embodiment of the dsRNA, at least one strand comprises a 3’ overhang of at least 1 nucleotide. In another embodiment, at least one strand comprises a 3’ overhang of at least 2 nucleotides, e.g., 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, or 15 nucleotides. In other embodiments, at least one strand of the RNAi agent comprises a 5’ overhang of at least 1 nucleotide. In certain embodiments, at least one strand comprises a 5’ overhang of at least 2 nucleotides, e.g., 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, or 15 15 nucleotides. In still other embodiments, both the 3’ and the 5’ end of one strand of the RNAi agent comprise an overhang of at least 1 nucleotide. In one embodiment, the antisense strand of a dsRNA has a 1-10 nucleotide, e.g., 0-3, 1-3, 2-4, 2- 5, 4-10, 5-10, e.g., a 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotide, overhang at the 3’-end or the 5’-end. In one embodiment, the sense strand of a dsRNA has a 1-10 nucleotide, e.g., a 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 20 nucleotide, overhang at the 3’-end or the 5’-end. In another embodiment, one or more of the nucleotides in the overhang is replaced with a nucleoside thiophosphate. In certain embodiments, the overhang on the sense strand or the antisense strand, or both, can include extended lengths longer than 10 nucleotides, e.g., 1-30 nucleotides, 2-30 nucleotides, 10-30 nucleotides, or 10-15 nucleotides in length. In certain embodiments, an extended overhang is on the sense 25 strand of the duplex. In certain embodiments, an extended overhang is present on the 3’end of the sense strand of the duplex. In certain embodiments, an extended overhang is present on the 5’end of the sense strand of the duplex. In certain embodiments, an extended overhang is on the antisense strand of the duplex. In certain embodiments, an extended overhang is present on the 3’end of the antisense strand of the duplex. In certain embodiments, an extended overhang is present on the 5’end of the antisense strand 30 of the duplex. In certain embodiments, one or more of the nucleotides in the overhang is replaced with a nucleoside thiophosphate. In certain embodiments, the overhang includes a self-complementary portion such that the overhang is capable of forming a hairpin structure that is stable under physiological conditions. The terms “blunt” or “blunt ended”, as used herein in reference to a dsRNA, mean that there are 35 no unpaired nucleotides or nucleotide analogs at a given terminal end of a dsRNA, i.e., no nucleotide overhang. One or both ends of a dsRNA can be blunt. Where both ends of a dsRNA are blunt, the dsRNA is said to be blunt ended. To be clear, a “blunt ended” dsRNA is a dsRNA that is blunt at both ends, i.e., 26 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO no nucleotide overhang at either end of the molecule. Most often such a molecule will be double stranded over its entire length. The term “antisense strand” or "guide strand" refers to the strand of an iRNA, e.g., a dsRNA, which includes a region that is substantially complementary to a target sequence, e.g., a target mRNA 5 sequence. As used herein, the term “region of complementarity” refers to the region on the antisense strand that is substantially complementary to a sequence, for example a target sequence, e.g., a target nucleotide sequence, as defined herein. Where the region of complementarity is not fully complementary to the target sequence, the mismatches can be in the internal or terminal regions of the molecule. Generally, the 10 most tolerated mismatches are in the terminal regions, e.g., within 5, 4, 3, or 2 nucleotides of the 5’- or 3’-terminus of the RNAi agent. As used herein, the term “internal position” refers to any position of the antisense strand or the sense strand that is not a terminal position, i.e., a 3’ terminal position or a 5’ terminal position. As used herein, the term “external position” refers to a terminal position of the antisense strand 15 or the sense strand, i.e., a 3’ terminal position or a 5’ terminal position. In some embodiments, a double stranded RNA agent of the disclosure includes a nucleotide mismatch in the antisense strand. In some embodiments, the antisense strand of the double stranded RNA agent of the disclosure includes no more than 4 mismatches with the target mRNA, e.g., the antisense strand includes 4, 3, 2, 1, or 0 mismatches with the target mRNA. In some embodiments, the 20 antisense strand double stranded RNA agent of the disclosure includes no more than 4 mismatches with the sense strand, e.g., the antisense strand includes 4, 3, 2, 1, or 0 mismatches with the sense strand. In some embodiments, a double stranded RNA agent of the disclosure includes a nucleotide mismatch in the sense strand. In some embodiments, the sense strand of the double stranded RNA agent of the disclosure includes no more than 4 mismatches with the antisense strand, e.g., the sense strand includes 4, 3, 2, 1, or 25 0 mismatches with the antisense strand. In some embodiments, the nucleotide mismatch is, for example, within 5, 4, 3 nucleotides from the 3’-end of the iRNA. In another embodiment, the nucleotide mismatch is, for example, in the 3’-terminal nucleotide of the iRNA agent. In some embodiments, the mismatch(s) is not in the seed region. Thus, an RNAi agent as described herein can contain one or more mismatches to the target 30 sequence. In one embodiment, a RNAi agent as described herein contains no more than 3 mismatches (i.e., 3, 2, 1, or 0 mismatches). In one embodiment, an RNAi agent as described herein contains no more than 2 mismatches. In one embodiment, an RNAi agent as described herein contains no more than 1 mismatch. In one embodiment, an RNAi agent as described herein contains 0 mismatches. In certain embodiments, if the antisense strand of the RNAi agent contains mismatches to the target sequence, the 35 mismatch can optionally be restricted to be within the last 5 nucleotides from either the 5’- or 3’-end of the region of complementarity. For example, in such embodiments, for a 23 nucleotide RNAi agent, the strand which is complementary to a region of a target gene, generally does not contain any mismatch within the central 13 nucleotides. The methods described herein or methods known in the art can be used 27 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO to determine whether an RNAi agent containing a mismatch to a target sequence is effective in inhibiting the expression of a target gene. Consideration of the efficacy of RNAi agents with mismatches in inhibiting expression of a target gene is important, especially if the particular region of complementarity in a target gene is known to vary.5 The term “sense strand” or "passenger strand" as used herein, refers to the strand of a RNAi agent that includes a region that is substantially complementary to a region of the antisense strand as that term is defined herein. As used herein, “substantially all of the nucleotides are modified” are largely but not wholly modified and can include not more than 5, 4, 3, 2, or 1 unmodified nucleotides. 10 As used herein, the term “cleavage region” refers to a region that is located immediately adjacent to the cleavage site. The cleavage site is the site on the target at which cleavage occurs. In some embodiments, the cleavage region comprises three bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage region comprises two bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage site specifically occurs at 15 the site bound by nucleotides 10 and 11 of the antisense strand, and the cleavage region comprises nucleotides 11, 12 and 13. As used herein, and unless otherwise indicated, the term “complementary,” when used to describe a first nucleotide sequence in relation to a second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize and form a 20 duplex structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence, as will be understood by the skilled person. Such conditions can be, for example, “stringent conditions”, where stringent conditions can include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50oC or 70oC for 12-16 hours followed by washing (see, e.g., “Molecular Cloning: A Laboratory Manual, Sambrook, et al. (1989) Cold Spring Harbor Laboratory Press). Other 25 conditions, such as physiologically relevant conditions as can be encountered inside an organism, can apply. The skilled person will be able to determine the set of conditions most appropriate for a test of complementarity of two sequences in accordance with the ultimate application of the hybridized nucleotides. Complementary sequences within an RNAi agent, e.g., within a dsRNA as described herein, 30 include base-pairing of the oligonucleotide or polynucleotide comprising a first nucleotide sequence to an oligonucleotide or polynucleotide comprising a second nucleotide sequence over the entire length of one or both nucleotide sequences. Such sequences can be referred to as “fully complementary” with respect to each other herein. However, where a first sequence is referred to as “substantially complementary” with respect to a second sequence herein, the two sequences can be fully complementary, or they can 35 form one or more, but generally not more than 5, 4, 3, or 2 mismatched base pairs upon hybridization for a duplex up to 30 base pairs, while retaining the ability to hybridize under the conditions most relevant to their ultimate application, e.g., inhibition of gene expression , in vitro or in vivo. However, where two oligonucleotides are designed to form, upon hybridization, one or more single stranded overhangs, such 28 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO overhangs shall not be regarded as mismatches with regard to the determination of complementarity. For example, a dsRNA comprising one oligonucleotide 21 nucleotides in length and another oligonucleotide 23 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 21 nucleotides that is fully complementary to the shorter oligonucleotide, can yet be referred to as “fully complementary” for 5 the purposes described herein. “Complementary” sequences, as used herein, can also include, or be formed entirely from, non- Watson-Crick base pairs or base pairs formed from non-natural and modified nucleotides, in so far as the above requirements with respect to their ability to hybridize are fulfilled. Such non-Watson-Crick base pairs include, but are not limited to, G:U Wobble or Hoogsteen base pairing. 10 The terms “complementary,” “fully complementary” and “substantially complementary” herein can be used with respect to the base matching between the sense strand and the antisense strand of a dsRNA, or between two oligonucleotides or polynucleotides, such as the antisense strand of a RNAi agent and a target sequence, as will be understood from the context of their use. As used herein, a polynucleotide that is “substantially complementary to at least part of” a 15 messenger RNA (mRNA) or target sequence refers to a polynucleotide that is substantially complementary to a contiguous portion of the mRNA of interest or target sequence (e.g., an mRNA encoding a target gene). For example, a polynucleotide is complementary to at least a part of a target RNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding a target gene. 20 Accordingly, in some embodiments, the antisense strand polynucleotides disclosed herein are fully complementary to the target gene sequence. In other embodiments, the antisense polynucleotides disclosed herein are substantially complementary to the target sequence and comprise a contiguous nucleotide sequence which is at least 80% complementary over its entire length to the equivalent region of the nucleotide sequence of the target sequence, such as about 85%, about 90%, about 91%, about 92%, 25 about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% complementary. Exemplary target genes include, for example, adrenoceptor beta 1 (ADRB1); calcium voltage- gated channel subunit alpha1 C (CACNA1C); calcium voltage-gated channel subunit alpha1 G (CACNA1G) (T type calcium cchannel); angiotensin II receptor type 1(AGTR1); Sodium Voltage-Gated Channel Alpha Subunit 2 (SCN2A); Hyperpolarization Activated Cyclic Nucleotide Gated Potassium 30 Channel 1 (HCN1); Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4 (HCN4); Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 3 (HCN3); Potassium Voltage- Gated Channel Subfamily A Member 5 (KCNA5); Potassium Inwardly Rectifying Channel Subfamily J Member 3 (KCNJ3); Potassium Inwardly Rectifying Channel Subfamily J Member 4 (KCNJ4); phospholamban (PLN); calcium / calmodulin dependent protein kinase II delta (CAMK2D); or 35 Phosphodiesterase 1 (PDE1). Additional exemplary target genes also include, for example, myostatin (MSTN); Cholinergic Receptor Nicotinic Alpha 1 Subunit (CHRNA1); Cholinergic Receptor Nicotinic Beta 1 Subunit (CHRNB1); Cholinergic Receptor Nicotinic Delta Subunit (CHRND); Cholinergic Receptor Nicotinic 29 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO Epsilon Subunit (CHRNE); Cholinergic Receptor Nicotinic Gamma Subunit (CHRNG); Collagen Type XIII Alpha 1 Chain (COL13A1); Docking Protein 7 (DOK7); LDL Receptor Related Protein 4 (LRP4); Muscle Associated Receptor Tyrosine Kinase (MUSK); Receptor Associated Protein Of The Synapse (RAPSN); Sodium Voltage-Gated Channel Alpha Subunit 4 (SCN4A); Double Homeobox 4 (DUX4), 5 dystrophy myotonic protein kinase (DMPK), glycogen synthase 1 (GYS1), survival of motor neuron 1 (SMN1), and alpha-glucosidase (GAA). As used herein, “adrenoceptor beta 1,” used interchangeably with the term “ADRB1,” refers to a member of the adrenergic receptor family. ADRB1 is also known as ADRB1R, beta-1 adrenergic receptor, B1AR, BETA1AR, FNSS2, or RHR. 10 In one embodiment, the target gene is calcium voltage-gated channel subunit alpha1 C (CACNA1C). As used herein, “calcium voltage-gated channel subunit alpha1 C,” used interchangeably with the term “CACNA1C,” refers to an alpha-1 subunit of a voltage-dependent calcium channel. CACNA1C is also known as calcium channel, voltage-dependent, L type, alpha 1C subunit; voltage-dependent L-type 15 calcium channel subunit alpha-1C; voltage-gated L-type calcium channel Cav1.2 alpha 1 subunit, splice variant 10; calcium channel, L type, alpha-1 polypeptide, isoform 1, cardiac muscle; calcium channel, cardic dihydropyridine-sensitive, alpha-1 subunit; voltage-dependent L-type Ca2+ channel alpha 1 subunit; voltage-gated calcium channel subunit alpha CaV1.2; DHPR, alpha-1 subunit; CACH2, CACN2, CACNL1A1, CCHL1A1, CaV1.2, LQT8, TS, or TS. LQT8 20 As used herein, “calcium voltage-gated channel subunit alpha1 G,” used interchangeably with the term “CACNA1G,” refers to a T-type, low-voltage activated calcium channel. CACNA1G is also known as calcium channel, voltage-dependent, T type, alpha 1G subunit; voltage-dependent T-type calcium channel subunit alpha-1G; voltage-gated calcium channel subunit alpha Cav3.1; NBR13 ; Cav3.1c; Ca(V)T.1; KIAA1123; SCA42ND; or SCA42. 25 As used herein, “angiotensin II receptor type 1,” used interchangeably with the term “AGTR1,” refers to a receptor for the vasoconstricting peptide angiotensin II. AGTR1 is also known as angiotensin receptor 1B, AT1, AT2R1, AGTR1A, AT2R1B, AGTR1B, HAT1R, AG2S, AT1B, AT2R1A, AT1AR, AT1BR, or AT1R. As used herein, “Sodium Voltage-Gated Channel Alpha Subunit 2,” used interchangeably with 30 the term “SCN2A,” refers to a member of the voltage-gated sodium channel family. SCN2A is also known as Nav1.2, HBSCII, SCN2A1, SCN2A2, HBSCI, EIEE11, BFIC3, BFIS3, BFNIS, DEE11, EA9, or HBA. As used herein, “Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 1,” used interchangeably with the term “HCN1,” refers to a member of the hyperpolarization-activated cyclic 35 nucleotide-gated (HCN) channel family. HCN1 is also known as potassium channel 1, BCNG-1, HAC-2, BCNG1, Potassium / Sodium Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 1; Brain Cyclic Nucleotide-Gated Channel 1; Hyperpolarization Activated Cyclic Nucleotide-Gated Potassium Channel 1; GEFSP10, EIEE24, or DEE24. 30 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO As used herein, “Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4,” used interchangeably with the term “HCN4,” refers to a member of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel family. HCN4 is also known as Potassium / Sodium Hyperpolarization- Activated Cyclic Nucleotide-Gated Channel 4, Hyperpolarization Activated Cyclic Nucleotide-Gated 5 Potassium Channel 4, Hyperpolarization Activated Cyclic Nucleotide-Gated Cation Channel 4 or SSS2. As used herein, “Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 3,” used interchangeably with the term “HCN3,” refers to a member of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel family. HCN3 is also known as Potassium / Sodium Hyperpolarization- Activated Cyclic Nucleotide-Gated Channel 3, Hyperpolarization Activated Cyclic Nucleotide-Gated 10 Potassium Channel 3, or KIAA1535. As used herein, “Potassium Voltage-Gated Channel Subfamily A Member 5,” used interchangeably with the term “KCNA5,” refers to a member of the voltage-gated potassium channel family. KCNA5 is also known as HPCN1, HK2, Potassium Voltage-Gated Channel, Shaker-Related Subfamily, Member 5; Voltage-Gated Potassium Channel Subunit Kv1.5; Voltage-Gated Potassium 15 Channel HK2; Kv1.5; Insulinoma And Islet Potassium Channel; Cardiac Potassium Channel; Potassium Channel 1; ATFB7, HCK1 or PCN1. As used herein, “Potassium Inwardly Rectifying Channel Subfamily J Member 3,” used interchangeably with the term “KCNJ3,” refers to an integral membrane protein and an inward-rectifier type potassium channel. KCNJ3 is also known as GIRK1, G Protein-Activated Inward Rectifier 20 Potassium Channel 1, KGA; Potassium Channel, Inwardly Rectifying Subfamily J Member 3; Inward Rectifier K(+) Channel Kir3.1; or Potassium Inwardly-Rectifying Channel Subfamily J Member 3 Splice Variant 1e. As used herein, “Potassium Inwardly Rectifying Channel Subfamily J Member 4,” used interchangeably with the term “KCNJ4,” refers to an integral membrane protein and inward-rectifier type 25 potassium channel. KCNJ4 is also known as HIRK2, HRK1, IRK3, HIR, Kir2.3, inward rectifier potassium channel 4; Inward Rectifier K(+) Channel Kir2.3; Potassium Voltage-Gated Channel Subfamily J Member 4; Hippocampal Inward Rectifier Potassium Channel; or Hippocampal Inward Rectifier. As used herein, “Phosphodiesterase 1,” used interchangeably with the term “PDE1,” refers to a 30 member of the cyclic nucleotide phosphodiesterases families. PDE1 is also known as Calcium / Calmodulin-Dependent 3',5'-Cyclic Nucleotide Phosphodiesterase 1; Calcium / Calmodulin- Stimulated Cyclic Nucleotide Phosphodiesterase; CAM-PDE 1, HSPDE1, HCAM1, or EC 3.1.4. As used herein, “myostatin,” used interchangeably with the term “MSTN,” refers to a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Myostatin is also 35 known as GDF8, Growth / Differentiation Factor 8, or MSLHP. As used herein, “Cholinergic Receptor Nicotinic Alpha 1 Subunit,” used interchangeably with the term “CHRNA1,” refers to an alpha subunit of the muscle acetylcholine receptor (AChR). CHRNA1 is also known as Cholinergic Receptor, Nicotinic, Alpha Polypeptide 1; Acetylcholine Receptor, 31 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO Nicotinic, Alpha 1 (Muscle); ACHRA; CHRNA; Muscle Nicotinic Acetylcholine Receptor; CMS1A, CMS1B, CMS2A, FCCMS, SCCMS, or ACHRD. As used herein, “Cholinergic Receptor Nicotinic Beta 1 Subunit,” used interchangeably with the term “CHRNB1,” refers to a beta subunit of the muscle acetylcholine receptor (AChR). CHRNB1 is 5 associated with diseases associated such as Myasthenic Syndrome. CHRNB1 is also known as Cholinergic Receptor, Nicotinic, Beta Polypeptide 1; Acetylcholine Receptor, Nicotinic, Beta 1 (Muscle); ACHRB; CHRNB; CMS1D, CMS2C, CMS2A, or SCCMS. As used herein, “Cholinergic Receptor Nicotinic Delta Subunit,” used interchangeably with the term “CHRND,” refers to a delta subunit of the muscle acetylcholine receptor (AChR). CHRND is also 10 known as ACHRD, Cholinergic Receptor, Nicotinic, Delta Polypeptide; Acetylcholine Receptor, Nicotinic, Delta (Muscle); CMS2A; CMS3A, CMS3B, CMS3C, FCCMS, or SCCMS. As used herein, “Cholinergic Receptor Nicotinic Epsilon Subunit,” used interchangeably with the term “CHRNE,” refers to a subunit of the acetylcholine receptor. CHRNE is also known as Cholinergic Receptor, Nicotinic, Epsilon; Acetylcholine Receptor, Nicotinic, Epsilon; ACHRE; CMS1D, CMS1E, 15 CMS2A, CMS4A, CMS4B, CMS4C, FCCMS, or SCCMS. As used herein, “Cholinergic Receptor Nicotinic Gamma Subunit,” used interchangeably with the term “CHRNG,” refers to a subunit of the acetylcholine receptor. CHRNG is also known as Cholinergic Receptor, Nicotinic, Gamma; Acetylcholine Receptor, Nicotinic, Gamma; or ACHRG. As used herein, “Collagen Type XIII Alpha 1 Chain,” used interchangeably with the term 20 “COL13A1,” refers to a synaptic extracellular-matrix protein involved in the formation and maintenance of the neuromuscular synapse. COL13A1 is also known as COLXIIIA1, Collagen Alpha-1(XIII) Chain, or CMS19. As used herein, “Docking Protein 7,” used interchangeably with the term “DOK7,” refers to a protein that is essential for neuromuscular synaptogenesis. DOK7 is also known as C4orf25, Downstream 25 Of Tyrosine Kinase 7, FLJ33718, FLJ39137, Chromosome 4 Open Reading Frame 25, CMS10, CMS1B, or FADS3. As used herein, “LDL Receptor Related Protein 4,” used interchangeably with the term “LRP4,” refers to a member of the low-density lipoprotein receptor-related protein family. LRP4 is also known as MEGF7, LRP-4, SOST2, CLSS, Low-Density Lipoprotein Receptor-Related Protein 4, Multiple 30 Epidermal Growth Factor-Like Domains 7, LRP10, KIAA0816, or CMS17. As used herein, “Muscle Associated Receptor Tyrosine Kinase,” used interchangeably with the term “MUSK,” refers to a muscle-specific tyrosine kinase receptor, which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle. MUSK is also known as EC 2.7.10.1, FADS1, CMS9, FADS, Muscle, 35 Skeletal Receptor Tyrosine-Protein Kinase, or Muscle-Specific Kinase Receptor. As used herein, “Receptor Associated Protein Of The Synapse,” used interchangeably with the term “RAPSN,” refers to a member of a family of proteins that are receptor associated proteins of the synapse. RAPSN is also known as RNF205, 43 KDa Receptor-Associated Protein Of The Synapse, 32 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO RING Finger Protein 205, CMS1D, CMS1E, Acetylcholine Receptor-Associated 43 Kda Protein, RAPSYN, CMS11, CMS4C, FADS2, or FADS. As used herein, “Sodium Voltage-Gated Channel Alpha Subunit 4,” used interchangeably with the term “SCN4A,” refers to a member of the voltage-gated sodium channel family. SCN4A is also 5 known as SkM1, Nav1.4, HYPP, Sodium Channel Protein Skeletal Muscle Subunit Alpha, Voltage- Gated Sodium Channel Subunit Alpha Nav1.4, HYKPP, Skeletal Muscle Voltage-Dependent Sodium Channel Type IV Alpha Subunit, CTC-264K15.6, Na(V)1.4, HOKPP2, CMS16, or NAC1A. As used herein, “Double Homeobox 4,” used interchangeably with the term “DUX4,” refers to a transcriptional activator of many genes. DUX4 is also known as Double Homeobox Protein 10, Double 10 Homeobox Protein 4, Double Homeobox Protein 4 / 10, DUX4L, and DUX10. As used herein, “phospholamban,” used interchangeably with the term “PLN,” refers to a crucial regulator of cardiac contractility. PLN is also known as CMD1P, PLB, Cardiac Phospholamban, or CMH. As used herein, “calcium / calmodulin dependent protein kinase II delta,” used interchangeably 15 with the term “CAMK2D,” refers to a member of the serine / threonine protein kinase family and the Ca(2+) / calmodulin-dependent protein kinase subfamily. CAMK2D is also known as Calcium / Calmodulin-Dependent Protein Kinase Type II Delta Chain, CaM Kinase II Delta Subunit, CaM Kinase II Subunit Delta, CAMKD, EC 2.7.11.17, or EC 2.7.11. As used herein, “dystrophy myotonic protein kinase,” used interchangeably with the term 20 “DMPK,” refers to a non-receptor serine / threonine protein kinase which is necessary for the maintenance of skeletal muscle structure and function. DMPK is also known as DM1 protein kinase, DM1PK, DM1, MT-PK, MDPK, DMK, myotonin-protein kinase, myotonic dystrophy associated protein kinase, dystrophia myotonica protein kinase, myotonin protein kinase A, thymopoietin homolog, or EC 2.7.11.1. As used herein, “glycogen synthase 1,” used interchangeably with the term “GYS1,” refers to an 25 enzyme that catalyzes the addition of glucose monomers to the growing glycogen molecule. GYS1 is also known as muscle glycogen synthase, GSY, GYS, or EC 2.4.1.11. As used herein, “survival of motor neuron 1,” used interchangeably with the term “SMN1,” refers to one of a group of proteins called the SMN complex, which is important for the maintenance of specialized nerve cells called motor neurons. SMN1 is also known as SMNT, TDRD16A, Gemin-1, 30 BCD541, GEMIN1, SMA1, SMA2, SMA3, SMA4, SMN, SMNT, tudoe domain containing 16A, complement of gems 1, or SMNC. As used herein, “alpha-glucosidase,” used interchangeably with the term “GAA,” refers to an enzyme responsible for the degradation of glycogen to glucose in lysosomes. GAA is also known as lysosomal alpha-glucosidase, acid maltase, EC 3.2.1.20, glycogen storage disease type II, or LYAG. 35 Examples of target mRNA sequences, and variations thereof (e.g., variants provided in the SNP database) are readily available through publicly available databases, e.g., GenBank, UniProt, OMIM, UCSC Genome Browser, NCBI dbSNP, and the Macaca genome project website. 33 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments, the double-stranded region of a dsRNA agent is equal to or at least, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 23, 24, 25, 26, 27, 28, 29, 30 or more nucleotide pairs in length. In some embodiments, the antisense strand of a dsRNA agent is equal to or at least 14, 15, 16, 5 17, 18, 19, 20, 21, 22, 23, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, the sense strand of a dsRNA agent is equal to or at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In one embodiment, the sense and antisense strands of the dsRNA agent are each independently 15 to 30 nucleotides in length. 10 In one embodiment, the sense and antisense strands of the dsRNAagent are each independently 19 to 25 nucleotides in length. In one embodiment, the sense and antisense strands of the dsRNAagent are each independently 21 to 23 nucleotides in length. In one embodiment, the sense strand of the dsRNA agent is 21-nucleotides in length, and the 15 antisense strand is 23-nucleotides in length, wherein the strands form a double-stranded region of 21 consecutive base pairs having a 2-nucleotide long single stranded overhangs at the 3’-end. In one aspect of the disclosure, an agent for use in the methods and compositions of the disclosure is a single-stranded antisense nucleic acid molecule that inhibits a target mRNA via an antisense inhibition mechanism. The single-stranded antisense RNA molecule is complementary to a 20 sequence within the target mRNA. The single-stranded antisense oligonucleotides can inhibit translation in a stoichiometric manner by base pairing to the mRNA and physically obstructing the translation machinery, see Dias, N. et al., (2002) Mol Cancer Ther 1:347-355. The single-stranded antisense RNA molecule may be about 15 to about 30 nucleotides in length and have a sequence that is complementary to a target sequence. For example, the single-stranded antisense RNA molecule may comprise a 25 sequence that is at least about 15, 16, 17, 18, 19, 20, or more contiguous nucleotides from any one of the antisense sequences described herein. In one embodiment, at least partial suppression of the expression of a target gene, is assessed by a reduction of the amount of target mRNA which can be isolated from or detected in a first cell or group of cells in which a target gene is transcribed and which has or have been treated such that the expression 30 of a target gene is inhibited, as compared to a second cell or group of cells substantially identical to the first cell or group of cells but which has or have not been so treated (control cells). The degree of inhibition may be expressed in terms of: (mRNA in control cells) - (mRNA in treated cells) (mRNA in control cells) 100% 35 In one embodiment, inhibition of expression is determined by the dual luciferase method wherein the RNAi agent is present at 10 nM. The phrase “contacting a cell with an RNAi agent,” such as a dsRNA, as used herein, includes contacting a cell by any possible means. Contacting a cell with an RNAi agent includes contacting a cell 34 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO in vitro with the RNAi agent or contacting a cell in vivo with the RNAi agent. The contacting may be done directly or indirectly. Thus, for example, the RNAi agent may be put into physical contact with the cell by the individual performing the method, or alternatively, the RNAi agent may be put into a situation that will permit or cause it to subsequently come into contact with the cell. 5 Contacting a cell in vitro may be done, for example, by incubating the cell with the RNAi agent. Contacting a cell in vivo may be done, for example, by injecting the RNAi agent into or near the tissue where the cell is located, or by injecting the RNAi agent into another area, or to the bloodstream or the subcutaneous space, such that the agent will subsequently reach the tissue where the cell to be contacted is located. In some embodiments, the RNAi agent may contain or be coupled to a ligand, e.g., one or 10 more alpha-v-beta-6 (αvβ6) integrin targeting ligand. An “alpha-v-beta-6 (αvβ6) integrin targeting ligand”, as used herein, includes any moiety (e.g., peptides and small molecules) which bind an αvβ6 integrin and are able to mediate delivery of a dsRNA agent to which they are attached to skeletal muscle (e.g., a skeletal muscle cell or skeletal muscle tissue) and / or cardiac muscle (e.g., a cardiac muscle cell or cardiac muscle tissue). The αvβ6 integrin targeting 15 ligands bind αvβ6 integrin or the αvβ6 integrin receptor on skeletal muscle / cardiac myocytes (cells). Exemplary αvβ6 integrin targeting ligands are described in Section II below. Exemplary αvβ6 integrin targeting ligands are also described in WO2024 / 086633, incorporated by reference herein. In one embodiment, contacting a cell with an RNAi agent includes “introducing” or “delivering the RNAi agent into the cell” by facilitating or effecting uptake or absorption into the cell. Absorption or 20 uptake of a RNAi agent can occur through unaided diffusive or active cellular processes, or by auxiliary agents or devices. Introducing a RNAi agent into a cell may be in vitro or in vivo. For example, for in vivo introduction, a RNAi agent can be injected into a tissue site or administered systemically. In vitro introduction into a cell includes methods known in the art such as electroporation and lipofection. Further approaches are described herein below or are known in the art. 25 As used herein, a “subject” is an animal, such as a mammal, including a primate (such as a human, a non-human primate, e.g., a monkey, and a chimpanzee), or a non-primate (such as a a cow, a pig, a horse, a goat, a rabbit, a sheep, a hamster, a guinea pig, a cat, a dog, a rat, or a mouse), or a bird that expresses the target gene, either endogenously or heterologously. In one embodiment, the subject is a human, such as a human being treated or assessed for a disease, disorder, or condition that would benefit 30 from reduction in target gene expression; a human at risk for a disease, disorder, or condition that would benefit from reduction in target gene expression; a human having a disease, disorder, or condition that would benefit from reduction in target gene expression; or human being treated for a disease, disorder, or condition that would benefit from reduction in target gene expression as described herein. In some embodiments, the subject is a female human. In other embodiments, the subject is a male human. In one 35 embodiment, the subject is an adult subject. In another embodiment, the subject is a pediatric subject. As used herein, the terms “treating” or “treatment” refer to a beneficial or desired result including, but not limited to, alleviation or amelioration of one or more signs or symptoms associated with target gene expression or target gene protein production, e.g., a target gene-associated disease, e.g., 35 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO a muscle disorder, e.g., a skeletal muscle disorder, and / or a cardiac muscle disorder, or symptoms associated with unwanted target gene expression; diminishing the extent of unwanted target activation or stabilization; amelioration or palliation of unwanted target activation or stabilization. “Treatment” can also mean prolonging survival as compared to expected survival in the absence of treatment. 5 The term “lower” in the context of the level of a target gene in a subject or a disease marker or symptom refers to a statistically significant decrease in such level. The decrease can be, for example, at least 10%, 15%, 20%, 25%, 30%, %, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more. In certain embodiments, a decrease is at least 20%. In certain embodiments, the decrease is at least 50% in a disease marker, e.g., protein or gene expression level. “Lower” in the context of the 10 level of a target gene in a subject is a decrease to a level accepted as within the range of normal for an individual without such disorder. In certain embodiments, the expression of the target is normalized, i.e., decreased towards or to a level accepted as within the range of normal for an individual without such disorder, e.g., blood glucose level, blood uric acid level, blood lipid level, blood oxygen level, white blood cell count, kidney function, spleen function, liver function. As used here, “lower” in a subject can 15 refer to lowering of gene expression or protein production in a cell in a subject does not require lowering of expression in all cells or tissues of a subject. For example, as used herein, lowering in a subject can include lowering of gene expression or protein production in a subject. The term “lower” can also be used in association with normalizing a symptom of a disease or condition, i.e. decreasing the difference between a level in a subject suffering from a target gene- 20 associated disease towards or to a level in a normal subject not suffering from a target gene-associated disease. As used herein, if a disease is associated with an elevated value for a symptom, “normal” is considered to be the upper limit of normal. If a disease is associated with a decreased value for a symptom, “normal” is considered to be the lower limit of normal. As used herein, “prevention” or “preventing,” when used in reference to a disease, disorder, or 25 condition thereof, that would benefit from a reduction in expression of a target gene or production of a target protein, refers to a reduction in the likelihood that a subject will develop a symptom associated with such a disease, disorder, or condition, e.g., a symptom of a target gene-associated disease. The failure to develop a disease, disorder, or condition, or the reduction in the development of a symptom associated with such a disease, disorder, or condition (e.g., by at least about 10% on a clinically accepted 30 scale for that disease or disorder), or the exhibition of delayed symptoms delayed (e.g., by days, weeks, months or years) is considered effective prevention. As used herein, the term “target gene-associated disease,” is a disease or disorder that would benefit from reduction in the expression or activity of the target gene. The term “target gene-associated disease,” is a disease or disorder that is caused by, or associated with expression or protein production of 35 the target gene. The term "target gene-associated disease” includes a disease, disorder or condition that would benefit from a decrease in expression or protein activity of the target gene. Additional information regarding specific target genes and disease that would benefit from reduction in expression of the target gene are descrived below. 36 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In one embodiment, the target gene-associated disease is a muscle disorder. Exemplary muscle disorders include Myostatin-related muscle hypertrophy, congenital myasthenic syndrome, facioscapulohumeral muscular dystrophy (FSHD), Spinal Muscular Atrophy (SMA), Myotonic Dystrophy Type 1 (DM1), Pompe disease, PLN cardiomyopathy, spasticity, 5 obstructive hypertrophic cardiomyopathy (HOCM); familial hypertrophic cardiomyopathy (FHC); Heart failure with preserved ejection fraction (HFPEF); atrial fibrillation (AFIB); ventricular fibrillation (VFIB); angina; myocardial infarction (MI); heart failure or heart failure with reduced ejection fraction (HFREF); supraventricular tachycardia (SVT); hypertrophic cardiomyopathy (HCM); and PLN cardiomyopathy. 10 In one embodiment, the target gene-associated disease is a skeletal muscle disease or disorder. In one embodiment, the target gene-associated disease is a cardiac muscle disease or disorder. Exemplary cardiac muscle disorders include obstructive hypertrophic cardiomyopathy (HOCM); familial hypertrophic cardiomyopathy (FHC); Heart failure with preserved ejection fraction (HFPEF); atrial fibrillation (AFIB); ventricular fibrillation (VFIB); angina; myocardial infarction (MI); heart failure 15 or heart failure with reduced ejection fraction (HFREF); supraventricular tachycardia (SVT); hypertrophic cardiomyopathy (HCM); and PLN cardiomyopathy. “Heart failure” (“HF”) or “congestive heart failure” (“CHF”) is a chronic condition in which the heart does not pump blood as well as it should. Heart failure can occur when the heart’s capacity to pump blood cannot keep up with the body’s need. Heart failure can occur if the heart cannot pump 20 (systolic) or fill (diastolic) adequately. The term “congestive” refers to the resulting buildup of fluid in the ankles and feet, arms, lungs, and / or other organs. One type of heart failure is “heart failure with preserved left ventricular function” (“HF-pEF”) also known as “heart failure with preserved ejection fraction” (“HF-pEF”) is a condition in which the heart contracts and pumps normally, but the ventricles are thicker and stiffer than normal.. 25 A common cause of congestive heart failure is coronary artery disease. Risk factors for coronary artery disease can include high levels of cholesterol and / or triglyceride, high blood pressure, poor diet, a sedentary lifestyle, diabetes, smoking, being overweight or obese, and stress. In addition to coronary artery disease, several other conditions can damage the heart muscles, including inherited and genetic factors, some infections and autoimmune diseases and some treatments such as chemotherapy. 30 Symptoms of CHF can include shortness of breath, fatigue, swollen legs, and rapid heartbeat. “Hypertrophic cardiomyopathy” (“HCM”) refers to impaired heart function associated with abnormally thick heart muscle in the absence of other heart disease; e.g., valvular heart disease. “Hypertrophic obstructive cardiomyopathy” (“HOCM”) is a subtype of HCM, where the wall (septum) between the two bottom chambers of the heart thickens. The walls of the pumping chamber can also 35 become stiff. The thickened septum may cause a narrowing that can block or reduce the blood flow from the left ventricle to the aorta, which is a condition called “outflow tract obstruction.” Both HCM and HOCM can be caused by heart muscle gene mutation, which may be inherited. 37 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO “Familial hypertrophic cardiomyopathy” is an autosomal dominant disease characterized mainly by left ventricular hypertrophy. Thickening usually occurs in the interventricular septum. In some, thickening of the interventricular septum impedes the flow of oxygen-rich blood from the heart, which may lead to an abnormal heart sound during a heartbeat (heart murmur) and other signs and symptoms of 5 the condition. Familial hypertrophic cardiomyopathy can cause abnormal heart rhythms (arrhythmias) that can be life threatening. People with familial hypertrophic cardiomyopathy have an increased risk of sudden death, even if they have no other symptoms of the condition. A small number of affected individuals develop potentially fatal heart failure, which may require heart transplantation. 10 Mutations in one of several genes can cause familial hypertrophic cardiomyopathy; the most commonly involved genes are MYH7, MYBPC3, TNNT2, and TNNI3. Other genes, including some that have not been identified, may also be involved in this condition. “Atrial fibrillation” (“AFIB”) is when the atria beat chaotically and irregularly - out of coordination with the ventricles. The result can be a fast and irregular heart rhythm. The heart rate in 15 atrial fibrillation can range from 100 to 175 beats a minute. The normal range for a heart rate is 60 to 100 beats a minute. “Ventricular fibrillation” (“VFIB”) is a type of abnormal heart rhythm (arrhythmia). During ventricular fibrillation, disorganized heart signals cause the ventricles to twitch (quiver) uselessly. As a result, the heart does not pump blood to the rest of the body. 20 Ventricular fibrillation is an emergency that requires immediate medical attention. A “myocardial infarction” or “MI” occurs when the flow of blood to the heart is blocked. The blockage can be a buildup of fat, cholesterol and other substances, which form a plaque in the arteries that feed the heart (coronary arteries). “Supraventricular tachycardia” (“SVT”) is as an abnormally fast or erratic heartbeat that affects 25 the heart's atria. During an episode of SVT, the heart beats about 150 to 220 times per minute, but it can occasionally beat faster or slower. Things that may cause an SVT episode include age, coronary artery disease, previous heart surgery, heart disease, heart failure, other heart problems, such as Wolff-Parkinson-White syndrome, chronic lung disease, consuming too much caffeine, drinking too much alcohol, drug use, particularly 30 stimulants such as cocaine and methamphetamines, pregnancy, smoking, thyroid disease, tobacco, sleep apnea, diabetes, and certain medications, including asthma medications and over-the-counter cold and allergy drugs. “Hypertrophic cardiomyopathy” (“HCM”) is a disease in which the heart muscle becomes abnormally thick (hypertrophied). The thickened heart muscle can make it harder for the heart to pump 35 blood. “Angina” is a type of chest pain caused by reduced blood flow to the heart. Angina is a symptom of coronary artery disease. 38 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO Angina, also called angina pectoris, can be described as squeezing, pressure, heaviness, tightness or pain in the chest. Phospholamban (PLN) cardiomyopathy, as used herein, refers to a specific subtype of hereditary cardiomyopathy caused by PLN p.(Arg14del), a pathogenic variant in the gene encoding PLN, which is a 5 protein with a central role in calcium homeostasis in cardiac tissue. This protein ensures proper contraction and relaxation of the human heart. Carriers of this pathogenic variant have a high risk of developing dilated cardiomyopathy (DCM), arrhythmic cardiomyopathy (ACM), or both. They commonly have a high arrhythmic burden, with premature ventricular contractions (PVCs) and ventricular tachycardia, remarkable low-voltage electrocardiograms (ECGs), left ventricular dysfunction, 10 and a positive family history for sudden cardiac death. PLN p.(Arg14del) cardiomyopathy has been found in several European countries, but also in the United States, Canada, and China. On a global scale it is a rare disease, but it is particularly common in The Netherlands, with the pathogenic variant being present in 12% of all ACM patients and 15% of all DCM patients. Exemplary skeletal muscle disorders include Myostatin-related muscle hypertrophy, congenital 15 myasthenic syndrome, facioscapulohumeral muscular dystrophy (FSHD), Spinal Muscular Atrophy (SMA), Myotonic Dystrophy Type 1 (DM1), Pompe disease, PLN cardiomyopathy, and spasticity. Myostatin-related muscle hypertrophy is a rare condition characterized by reduced body fat and increased muscle size. Affected individuals have up to twice the usual amount of muscle mass in their bodies. They also tend to have increased muscle strength. Myostatin-related muscle hypertrophy is 20 caused by mutations in the MSTN gene. It follows an incomplete autosomal dominant pattern of inheritance. Congenital myasthenic syndromes (CMS) are a heterogeneous group of early-onset genetic neuromuscular transmission disorders due to mutations in proteins involved in the organisation, maintenance, function, or modification of the motor endplate (endplate myopathies), e.g., CHRNA1, 25 CHRNB1, CHRBD, CHRNE, CHRNG, COL13A1, DOX7, LRP4, MUSK, RAPSN, or SCN4A. CMS are clinically characterised by abnormal fatigability, or transient or permanent weakness of extra-ocular, facial, bulbar, truncal, respiratory, or limb muscles. Onset of endplate myopathy is intrauterine, congenital, in infancy, or childhood, and rarely in adolescence. Severity ranges from mild, phasic weakness, to disabling, permanent muscle weakness, respiratory insufficiency, and early death. All 30 subtypes of CMS share the clinical features of fatigability and muscle weakness, but age of onset, presenting symptoms, and response to treatment vary depending on the molecular mechanism that results from the underlying genetic defect. The term CMS is misleading since not all CMS are congenital. See, Finsterer (2019) Orphanet J Rare Dis.14: 57 for a review. Facioscapulohumeral muscular dystrophy (FSHD) type 1 is an autosomal dominant condition 35 caused by mutations in DUX4. FSHD typically presents before age 20 years with weakness of the facial muscles and the stabilizers of the scapula or the dorsiflexors of the foot. There is extreme clinical variability. In some cases, congenital facial weakness may be present. In FSHD, the muscle weakness is 39 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO slowly progressive and approximately 20% of affected individuals eventually require a wheelchair. Life expectancy is not shortened. The incidence is approximately 4 individuals affected per 100,000 people. Spinal muscular atrophy, as used herein, refers to a genetic disorder characterized by weakness and wasting (atrophy) in muscles used for movement (skeletal muscles). It is caused by a loss of 5 specialized nerve cells, called motor neurons that control muscle movement. The weakness can be more severe in the muscles that are close to the center of the body (proximal) compared to muscles away from the body's center (distal). The muscle weakness usually worsens with age. There are many types of spinal muscular atrophy that are caused by changes in the same genes. The types differ in age of onset and severity of muscle weakness; however, there is overlap between the types. Other forms of spinal 10 muscular atrophy and related motor neuron diseases, such as spinal muscular atrophy with progressive myoclonic epilepsy, spinal muscular atrophy with lower extremity predominance, X-linked infantile spinal muscular atrophy, and spinal muscular atrophy with respiratory distress type 1 are caused by mutations in other genes. Mutations in the SMN1 gene cause all types of spinal muscular atrophy described above. The 15 number of copies of the SMN2 gene modifies the severity of the condition and helps determine which type develops. The SMN1 and SMN2 genes both provide instructions for making a protein called the survival motor neuron (SMN) protein. Normally, most functional SMN protein is produced from the SMN1 gene, with a small amount produced from the SMN2 gene. Several different versions of the SMN protein are produced from the SMN2 gene, but only one version is functional; the other versions are 20 smaller and quickly broken down. The SMN protein is one of a group of proteins called the SMN complex, which is important for the maintenance of motor neurons. Motor neurons transmit signals from the brain and spinal cord that tell skeletal muscles to tense (contract), which allows the body to move. Myotonic dystrophy, as used herein, refers to a part of a group of inherited disorders called muscular dystrophies. It is the most common form of muscular dystrophy that begins in adulthood. 25 Myotonic dystrophy is characterized by progressive muscle wasting and weakness. People with this disorder often have prolonged muscle contractions (myotonia) and are not able to relax certain muscles after use. Other signs and symptoms of myotonic dystrophy include clouding of the lens of the eye (cataracts) and abnormalities of the electrical signals that control the heartbeat (cardiac conduction defects). Some affected individuals develop a condition called diabetes mellitus, in which blood sugar 30 levels can become dangerously high. The features of myotonic dystrophy often develop during a person's twenties or thirties, although they can occur at any age. The severity of the condition varies widely among affected people, even among members of the same family. There are two major types of myotonic dystrophy: type 1 and type 2. Their signs and symptoms overlap, although type 2 tends to be milder than type 1. The muscle weakness associated with type 1 particularly affects muscles farthest from the center 35 of the body (distal muscles), such as those of the lower legs, hands, neck, and face. Muscle weakness in type 2 primarily involves muscles close to the center of the body (proximal muscles), such as the those of the neck, shoulders, elbows, and hips. The two types of myotonic dystrophy are caused by mutations in different genes. 40 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO Myotonic dystrophy type 1 is caused by mutations in the DMPK gene, while type 2 results from mutations in the CNBP gene. The protein produced from the DMPK gene likely plays a role in communication within cells. It appears to be important for the correct functioning of cells in the heart, brain, and skeletal muscles (which are used for movement). The protein produced from the CNBP gene is 5 found primarily in the heart and in skeletal muscles, where it helps regulate the function of other genes. Similar changes in the structure of the DMPK and CNBP genes cause myotonic dystrophy type 1 and type 2. In each case, a segment of DNA is abnormally repeated many times, forming an unstable region in the gene. The gene with the abnormal segment produces an unusually long messenger RNA, which is a molecular blueprint of the gene that guides the production of proteins. The unusually long messenger 10 RNA forms clumps inside the cell that interfere with the production of many other proteins. These changes prevent muscle cells and cells in other tissues from functioning normally, which leads to the signs and symptoms of myotonic dystrophy. If these changes affect the DMPK gene, the result is myotonic dystrophy type 1, if the CNBP gene is affected, the result is myotonic dystrophy type 2. Pompe disease, as used herein, refers to an inherited disorder caused by the buildup of a complex 15 sugar called glycogen in the body's cells. The accumulation of glycogen in certain organs and tissues, especially muscles, impairs their ability to function normally. There are three types of Pompe disease, which differ in severity and the age at which they appear. These types are known as classic infantile- onset, non-classic infantile-onset, and late-onset. The classic form of infantile-onset Pompe disease begins within a few months of birth. Infants with this disorder typically experience muscle weakness 20 (myopathy), poor muscle tone (hypotonia), an enlarged liver (hepatomegaly), and heart defects. Affected infants may also fail to gain weight and grow at the expected rate (failure to thrive) and have breathing problems. If untreated, this form of Pompe disease leads to death from heart failure in the first year of life. The non-classic form of infantile-onset Pompe disease usually appears by age 1. It is characterized by delayed motor skills (such as rolling over and sitting) and progressive muscle weakness. The heart 25 may be abnormally large (cardiomegaly), but affected individuals usually do not experience heart failure. The muscle weakness in this disorder leads to serious breathing problems, and most children with non- classic infantile-onset Pompe disease live only into early childhood. The late-onset type of Pompe disease may not become apparent until later in childhood, adolescence, or adulthood. Late-onset Pompe disease is usually milder than the infantile-onset forms of this disorder and is less likely to involve the 30 heart. Most individuals with late-onset Pompe disease experience progressive muscle weakness, especially in the legs and the trunk, including the muscles that control breathing. As the disorder progresses, breathing problems can lead to respiratory failure. Mutations in the GAA gene cause Pompe disease. The GAA gene provides instructions for producing an enzyme called acid alpha-glucosidase (also known as acid maltase). This enzyme is active 35 in lysosomes, which are structures that serve as recycling centers within cells. The enzyme normally breaks down glycogen into a simpler sugar glucose, which is the main energy source for most cells. Mutations in the GAA gene prevent acid alpha-glucosidase from breaking down glycogen effectively, which allows this sugar to build up to toxic levels in lysosomes. This buildup damages organs and tissues 41 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO throughout the body, particularly the muscles, leading to the progressive signs and symptoms of Pompe disease. Spasticity, as used herein, refers to a condition in which muscles stiffen or tighten, preventing normal fluid movement. The muscles remain contracted and resist being stretched, thus affecting 5 movement, speech and gait. Spasticity is generally caused by damage or disruption to the area of the brain and spinal cord that are responsible for controlling muscle and stretch reflexes. These disruptions can be due to an imbalance in the inhibitory and excitatory signals sent to the muscles, causing them to lock in place. Spasticity can be harmful to growing children as it can affect muscles and joints. People with brain injury, spinal cord injury, cerebral palsy or multiple sclerosis can have varying degrees of 10 spasticity. "Therapeutically effective amount," as used herein, is intended to include the amount of an RNAi agent that, when administered to a subject having a target gene-associated disease, is sufficient to effect treatment of the disease (e.g., by diminishing, ameliorating, or maintaining the existing disease or one or more symptoms of disease). The "therapeutically effective amount" may vary depending on the RNAi 15 agent, how the agent is administered, the disease and its severity and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the subject to be treated. “Prophylactically effective amount,” as used herein, is intended to include the amount of a RNAi agent that, when administered to a subject having a target gene-associated disorder, e.g., gout or diabetes, 20 is sufficient to prevent or ameliorate the disease or one or more symptoms of the disease. Ameliorating the disease includes slowing the course of the disease or reducing the severity of later-developing disease. The "prophylactically effective amount" may vary depending on the RNAi agent, how the agent is administered, the degree of risk of disease, and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of 25 the patient to be treated. A "therapeutically-effective amount" or “prophylacticaly effective amount” also includes an amount of a RNAi agent that produces some desired local or systemic effect at a reasonable benefit / risk ratio applicable to any treatment. A RNAi agent employed in the methods of the present disclosure may be administered in a sufficient amount to produce a reasonable benefit / risk ratio applicable to such 30 treatment. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human subjects and animal subjects without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable 35 benefit / risk ratio. The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent 42 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject being treated. Some examples of materials which can serve as pharmaceutically-acceptable carriers 5 include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium state, sodium lauryl sulfate and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and 10 soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids (23) serum 15 component, such as serum albumin, HDL and LDL; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. Pharmaceutically acceptable carriers for pulmonary delivery are known in the art and will vary depending on the desired location for deposition of the agent, e.g., upper or lower respiratory system, and the type of device to be used for delivery, e.g., sprayer, nebulizer, dry powder inhaler. 20 “Pharmaceutically acceptable salts” of each of RNAi agents herein include, but are not limited to, a sodium salt, a calcium salt, a lithium salt, a potassium salt, an ammonium salt, a magnesium salt, an mixtures thereof. One skilled in the art will appreciate that the RNAi agent, when provided as a polycationic salt having one cation per free acid group of the optionally modified phosophodiester backbone and / or any other acidic modifications (e.g., 5’-terminal phosphonate groups). For example, an 25 oligonucleotide of “n” nucleotides in length contains n-1 optionally modified phosophodiesters, so that an oligonucleotide of 21 nt in length may be provided as a salt having up to 20 cations (e.g., 20 sodium cations). Similarly, an RNAi agentshaving a sense strand of 21 nt in length and an antisense strand of 23 nt in length may be provided as a salt having up to 42 cations (e.g., 42 sodium cations). In the preceding example, where the RNAi agent also includes a 5’-terminal phosphate or a 5’-terminal vinylphosphonate 30 group, the RNAi agent may be provided as a salt having up to 44 cations (e.g., 44 sodium cations). The term “sample,” as used herein, includes a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Examples of biological fluids include blood, serum and serosal fluids, plasma, bronchial fluids, sputum, cerebrospinal fluid, ocular fluids, lymph, urine, saliva, sputum, and the like. Tissue samples may include samples from tissues, 35 organs or localized regions. For example, samples may be derived from particular organs, parts of organs, or fluids or cells within those organs. 43 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO II. In Vivo Delivery Enhancing Moiety Conjugated to dsRNA agent The present disclosure provides dual conjugated dsRNA agents for inhibiting expression of a target gene. In some embodiments, a dsRNA agent comprises an antisense strand and a sense strand; at 5 least one αvβ6 integrin targeting ligand that mediates delivery to muscle tissue conjugated to at least one strand; and at least one in vivo delivery enhancing moiety conjugated to at least one strand. The at least one in vivo delivery enhancing moiety may be conjugated to any internal position of the antisense strand or the sense strand. In some embodiments, the at least one in vivo delivery enhancing moiety may be conjugated to a position that is not an external position of the antisense strand 10 or the sense strand. In other embodiments, the at least one in vivo delivery enhancing moiety may be conjugated to an external positon of the antisense strand or the sense strand. As used herein, the term “in vivo delivery enhancing moiety” refers to a moiety which, when conjugated to a dsRNA agent, enhances delivery of the dsRNA agent to a target tissue, e.g., muscle, or a cell type, such as a muscle cell (e.g., a skeletal muscle cell or a cardiac muscle cell). In some 15 embodiments, the in vivo delivery enhancing moiety has pharmacokinetic (PK) enhancing properties, such as increasing the residence time in the blood of the dsRNA agent, and / or increasing tissue PK, including increasing tissue exposure of the dsRNA agent. In some embodiments, the in vivo delivery enhancing moiety can have a cooperative or synergistic effect with an αvβ6 compound in increasing tissue exposure when both elements are conjugated to the dsRNA agent. 20 In some embodiments, the in vivo delivery enhancing moiety is lipophilic. Thus, when conjugated to one or more internal position(s) of the dsRNA agent of the disclosure, the in vivo enhancing moiety increases lipophilicity of the dsRNA agent and provides optimal hydrophobicity for the enhanced in vivo delivery of dsRNA to muscle tissue, e.g., skeletal muscle tissue or cardiac muscle tissue. 25 One way to characterize lipophilicity is by the octanol-water partition coefficient, logKow, where Kow is the ratio of a chemical’s concentration in the octanol-phase to its concentration in the aqueous phase of a two-phase system at equilibrium. The octanol-water partition coefficient is a laboratory- measured property of a substance. However, it may also be predicted by using coefficients attributed to the structural components of a chemical which are calculated using first-principle or empirical methods 30 (see, for example, Tetko et al., J. Chem. Inf. Comput. Sci.41:1407-21 (2001), which is incorporated herein by reference in its entirety). It provides a thermodynamic measure of the tendency of the substance to prefer a non-aqueous or oily milieu rather than water (i.e. its hydrophilic / lipophilic balance). In principle, a chemical substance is lipophilic in character when its logKowexceeds 0. Typically, the lipophilic moiety possesses a logKowexceeding 1, exceeding 1.5, exceeding 2, exceeding 3, exceeding 4, 35 exceeding 5, or exceeding 10. For instance, the logKowof 6-amino hexanol, for instance, is predicted to 44 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO be approximately 0.7. Using the same method, the logKowof cholesteryl N-(hexan-6-ol) carbamate is predicted to be 10.7. The lipophilicity of a molecule can change with respect to the functional group it carries. For instance, adding a hydroxyl group or amine group to the end of a hydrocarbon chain, e.g., a C225 hydrocarbon chain, can increase or decrease the partition coefficient (e.g., logKow) value of the hydrocarbon chain. Alternatively, the hydrophobicity of the dsRNA agent conjugated to at least one in vivo delivery enhancing moiety can be measured by its protein binding characteristics. For instance, the unbound fraction in the plasma protein binding assay of the dsRNA agent can be determined to positively correlate 10 to the relative hydrophobicity of the dsRNA agent, which can positively correlate to the silencing activity of the dsRNA agent. In one embodiment, the plasma protein binding assay determined is an electrophoretic mobility shift assay (EMSA) using human serum albumin protein. In some embodiments, the hydrophobicity of the dsRNA agent, measured by fraction of unbound dsRNA agent in the binding assay, exceeds 0.15, 15 exceeds 0.2, exceeds 0.25, exceeds 0.3, exceeds 0.35, exceeds 0.4, exceeds 0.45, or exceeds 0.5 for an enhanced in vivo delivery of dsRNA agent. The at least one in vivo delivery enhancing agent may be attached to the dsRNA agent of the disclosure by any method known in the art, including via a functional grouping already present in the in vivo delivery enhancing moiety or introduced into the dsRNA agent, such as a hydroxy group (e.g., — 20 CO—CH2—OH). The functional groups already present in the in vivo delivery enhancing moiety or introduced into the dsRNA agent include, but are not limited to, hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne. Conjugation of the dsRNA agent and the in vivo delivery enhancing moiety may occur, for example, through formation of an ether or a carboxylic or carbamoyl ester linkage between the hydroxy 25 and an alkyl group R—, an alkanoyl group RCO— or a substituted carbamoyl group RNHCO—. The alkyl group R may be cyclic (e.g., cyclohexyl) or acyclic (e.g., straight-chained or branched; and saturated or unsaturated). Alkyl group R may be a butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl group, or the like. In certain embodiments, more than one in vivo delivery enhancing moiety can be conjugated to 30 the dsRNA agent of the disclosure. In one embodiment, two or more in vivo delivery enhancing moieties are conjugated to the same strand of the dsRNA agent. In one embodiment, each strand of the dsRNA agent is conjugated to one or more in vivo delivery enhancing moieties. In one embodiment, two or more in vivo delivery enhancing moieties are conjugated to the same position (i.e., the same nucleobase, same sugar moiety, or same internucleosidic linkage) of the dsRNA agent. This can be achieved by, e.g., 35 conjugating the two or more in vivo delivery enhancing moieties via a carrier, and / or conjugating the two or more in vivo delivery enhancing moieties via a branched linker, and / or conjugating the two or more in 45 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO vivo delivery enhancing moieties via one or more linkers, with one or more linkers linking the in vivo delivery enhancing moieties consecutively. In some embodiments, the in vivo delivery enhancing moiety may comprise at least one C10-C26hydrocarbon chain, e.g., a C10hydrocarbon chain, a C11hydrocarbon chain, a C12hydrocarbon chain, a 5 C13hydrocarbon chain, a C14hydrocarbon chain, a C15hydrocarbon chain, a C16hydrocarbon chain, a C17hydrocarbon chain, a C18hydrocarbon chain, a C19hydrocarbon chain, a C20hydrocarbon chain, a C21hydrocarbon chain, a C22hydrocarbon chain, a C23hydrocarbon chain, a C24hydrocarbon chain, a C25hydrocarbon chain or a C26hydrocarbon chain. In some embodiments, the C10-C26hydrocarbon chain may be a straight hydrocarbon chain. In other embodiments, the C10-C26hydrocarbon chain may be a 10 branched hydrocarbon chain. In some embodiments, the C10-C26hydrocarbon chain may be a saturated hydrocarbon chain. In other embodiments, the C10-C26hydrocarbon chain may be an unsaturated hydrocarbon chain, e.g., comprising one or more double bonds and / or one or more triple bonds. In one embodiment, the in vivo delivery enhancing moiety may comprise at least one C11hydrocarbon chain. In one embodiment, the at least one in vivo delivery enhancing moiety may comprise 15 at least one C17hydrocarbon chain. In one embodiment, the in vivo delivery enhancing moiety may comprise at least one C22hydrocarbon chain. In some embodiments, the C10-C26hydrocarbon chain may be unsubstituted. In other embodiments, the C10-C26hydrocarbon chain may be substituted with at least one functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, 20 and alkyne. In one embodiment, the C10-C26hydrocarbon chain is substituted with a carboxylic acid group. In some embodiments, the C10-C26hydrocarbon chain is represented by –(CH2)n-, wherein n is a number from 10 to 26, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26; and – is a bond connecting the C10-C26hydrocarbon chain to other portions of the in vivo delivery enhancing 25 moiety. In this embodiment, the C10-C26hydrocarbon chain is connected at both ends to the remainder of the in vivo delivery enhancing moiety. In some embodiments, the C10-C26hydrocarbon chain is represented by the following structure: – linker-(CH2)n(CH3), wherein n is a number from 10 to 25, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25; the linker is as described hereinbelow; and – is a bond connecting the C10-C2630 hydrocarbon chain to other portions of the in vivo delivery enhancing moiety. In this embodiment, the C10-C26hydrocarbon chain is connected at one end to other portions of the in vivo delivery enhancing moiety. In some embodiments, the C10-C26hydrocarbon chain is represented by the following structure: – linker-(CH2)n-A, wherein n is a number from 10 to 26, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 35 22, 23, 24, 25 or 26; the linker as described herein below and A is a functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne; or A1 or A2 with a structure shown below: 46 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In one embodiment, A is carboxylic acid. In one embodiment, A is A1. In one embodiment, A is 5 A2. Exemplary in vivo delivery enhancing moieties useful in the context of the present disclosure are described, e.g., in WO 2023 / 064530, the entire contents of which are incorporated herein by reference. Lipophilic Moiety As noted above, the in vivo delivery enhancing moietycomprises a lipophilic moiety, such as at 10 least one C10-C26hydrocarbon chain. In some embodiments, the in vivo delivery enhancing moiety comprises a C22hydrocarbon chain, e.g., one or more C22hydrocarbon chains. In some embodiments, the C22hydrocarbon chain is a C22acid, e.g., a C22acid selected from the group consisting of docosanoic acid, 6-octyltetradecanoic acid, 10-hexylhexadecanoic acid, all-cis-7,10,13,16,19-docosapentaenoic acid, all-cis-4,7,10,13,16,19-docosahexaenoic acid, all-cis-13,16-docosadienoic acid, all-cis-7,10,13,16- 15 docosatetraenoic acid, all-cis-4,7,10,13,16-docosapentaenoic acid, and cis-13-docosenoic acid. In one embodiment, the C22 hydrocarbon chain is a C22 alcohol, e.g. the C22 alcohol selected from the group consisting of 1-docosanol, 6-octyltetradecan-1-ol, 10-hexylhexadecan-1-ol, cis-13-docosen-1- ol, docosan-9-ol, docosan-2-ol, docosan-10-ol, docosan-11-ol, and cis-4,7,10,13,16,19-docosahexanol. 20 In one embodiment, the C22hydrocarbon chain is a C22amide, e.g., the C22amide selected from the group consisting of (E)-Docos-4-enamide, (E)-Docos-5-enamide, (Z)-Docos-9-enamide, (E)-Docos- 11-enamide,12-Docosenamide, (Z)-Docos-13-enamide, (Z)-N-Hydroxy-13-docoseneamide, (E)-Docos- 14-enamide, 6-cis-Docosenamide, 14-Docosenamide Docos-11-enamide, (4E,13E)-Docosa-4,13- 25 dienamide, and (5E,13E)-Docosa-5,13-dienamide. In one embodiment, the C22hydrocarbon chain includes, but are not limited to, 47 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO docosan-2-yl, docosan-3-yl, docosan-4-yl, docosan-5-yl, docosan-6-yl, docosan-7-yl, docosan-8-yl, docosan-9-yl, docosan-10-yl, docosan-11-yl, 2-(decyl)dodecan-1-yl, 2-(nonyl)tridecan-1-yl, 2- (octyl)tetradecan-1-yl, 2-(heptyl)pentadecan-1-yl, 2-(hexyl)hexadecan-1-yl, 2-(pentyl)heptadecan-1-yl, 2- (butyl)octadecan-1-yl, 2-(propyl)nonadecan-1-yl, 2-(ethyl)eicosan-1-yl, 2-(methyl)henicosan-1-yl, 3- 5 (nonyl)tridecan-1-yl, 3-(octyl)tetradecan-1-yl, 3-(heptyl)pentadecan-1-yl, 3-(hexyl)hexadecan-1-yl, 3- (pentyl)heptadecan-1-yl, 3-(butyl)octadecan-1-yl, 3-(propyl)nonadecan-1-yl, 3-(ethyl)eicosan-1-yl, 3- (methyl)henicosan-1-yl, 4-(octyl)tetradecan-1-yl, 4-(heptyl)pentadecan-1-yl, 4-(hexyl)hexadecan-1-yl, 4- (pentyl)heptadecan-1-yl, 4-(butyl)octadecan-1-yl, 4-(propyl)nonadecan-1-yl, 4-(ethyl)eicosan-1-yl, 4- (methyl)henicosan-1-yl, 5-(heptyl)pentadecan-1-yl, 5-(hexyl)hexadecan-1-yl, 5-(pentyl)heptadecan-1-yl,10 5-(butyl)octadecan-1-yl, 5-(propyl)nonadecan-1-yl, 5-(ethyl)eicosan-1-yl, 5-(methyl)henicosan-1-yl, 6- (hexyl)hexadecan-1-yl, 6-(pentyl)heptadecan-1-yl, 6-(butyl)octadecan-1-yl, 6-(propyl)nonadecan-1-yl, 6- (ethyl)eicosan-1-yl, 6-(methyl)henicosan-1-yl, 7-(pentyl)heptadecan-1-yl, 7-(butyl)octadecan-1-yl, 7- (propyl)nonadecan-1-yl, 7-(ethyl)eicosan-1-yl, 7-(methyl)henicosan-1-yl, 8-(butyl)octadecan-1-yl, 8- (propyl)nonadecan-1-yl, 8-(ethyl)eicosan-1-yl, 8-(methyl)henicosan-1-yl, 9-(propyl)nonadecan-1-yl, 9- 15 (ethyl)eicosan-1-yl, 9-(methyl)henicosan-1-yl, 10-(ethyl)eicosan-1-yl, 10-(methyl)henicosan-1-yl, and 11-(methyl)henicosan-1-yl, which is substituted at the 2’-oxygen of a nucleoside of an oligonucleotide herein. In some embodiments, the at least one C10-C26 hydrocarbon chain comprised in the in vivo delivery enhancing moiety may be conjugated to the remainder of the dsRNA agent via a linker or via a 20 carrier or via an internucleotide phosphate linkage. In one embodiments, the at least one C10-C26 hydrocarbon chain is conjugated to the remainder of the dsRNA agent via a linker. In some embodiments, the linker may be a cleavable linker, i.e., the linker comprises a portion that can be cleavable chemically or enzymatically. For example, amide linkages can be enzymatically cleavable. In some embodiments, the linker comprises –(CH2)n-NH-C(O)- or –(CH2)n-NH-C(O)-(CH2)2-C(COOH)- 25 NH-C(O)-, wherein n is a number from 1 to 20, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In one embodiment, the linker comprises –(CH)2-O-(CH2CH2)-(O)-(CH2CH2)-NH-C(O)-. In other embodiments, the in vivo delivery enhancing moiety comprises a naturally occurring lipophilic compound such as a steroid (e.g., cholesterol), Vitamin E, retinol, or retinoic acid. In some embodiments, the linker may comprise a group selected from the group consisting of an 30 ether, a thioether, a urea, a carbonate, an amine, an amide, a maleimide-thioether, a disulfide, a phosphodiester, a sulfonamide linkage, a product of a click reaction, and a carbamate. In some embodiments, the linker may be selected from the group consisting of -(CH2)nNH-; -C(O)(CH2)nNH-; - NR’’’’(CH2)nNH-, -C(O)-(CH2)n-C(O)-; -C(O)-(CH2)n-C(O)O-; -C(O)-O-; -C(O)-(CH2)n-NH-C(O)-; - C(O)-(CH2)n-; -C(O)-NH-; -C(O)-; -(CH2)n-C(O)-; -(CH2)n-C(O)O-; -(CH2)n-; and -(CH2)n-NH-C(O)-; 35 wherein n is a number from 1 to 20; and R’’’’ is C1-C6 alkyl, e.g., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, 48 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO C5 alkyl or C6 alkyl. In some embodiments, n may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19 or 20. In some embodiments, the αvβ6 integrin targeting ligand is linked to the remainder of the dsRNA agent as shown in the exemplary schematics below, wherein “2’-N6” refers to attachment of a lipophilic 5 moiety (e.g., C22) at the 2’ position on the nucleotide at position 6 on the sense strand (counting from the 5’ end): 10 In some embodiments, the in vivo delivery enhancing moiety that may be conjugated to the dsRNA agent of the disclosure is represented by the following structure: , 49 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO , wherein * represents the bond to the remainder of the dsRNA agent (e.g., to a 2’-oxygen of a nucleoside). The in vivo delivery enhancing moiety may be attached to the remainder of the dsRNA agent at a 2’ position on an internal nucleotide. 50 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO The at least one in vivo delivery enhancing moiety may be conjugated to the dsRNA agent via a direct attachment to the ribosugar of the dsRNA agent, e.g., an antisense strand or a sense strand. Alternatively, the at least one in vivo delivery enhancing moiety may be conjugated to the dsRNA agent via a linker or a carrier. 5 In certain embodiments, at least one in vivo delivery enhancing moiety may be conjugated to the iRNA agent via one or more linkers (tethers). In one embodiment, the at least one in vivo delivery enhancing moiety is conjugated to the dsRNA agent via a linker containing an ether, thioether, urea, carbonate, amine, amide, maleimide- thioether, disulfide, phosphodiester, sulfonamide linkage, a product of a click reaction (e.g., a triazole 10 from the azide-alkyne cycloaddition), or carbamate. In some embodiments, the in vivo delivery enhancing moiety and the targeting moiety are independently present within: (a) an internally-modified nucleosides such as, 15 (b) a modified internucleotide linkage such as, -OP(Y)(X)O-, wherein Y is O or S (e.g., O), and (c) a 5’-terminal modification such as 20 P(Y’)(OH)-O-; or (ii) -P(Y)(OH)O-RL3or -C(O)N(H)RL3, wherein Y is O or S; and (iii) -RL3, -C(O)RL3, -C(O)N(H)RL3, -S(O)2RL3, -S(O)2N(H)RL3or (d) a 3’-terminal modification such as 51 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (i) -P(Y)(OH)-R3, wherein ; or (ii) -RL3, -C(O)RL3, -C(O)N(H)RL3, -S(O)2RL3, -S(O)2N(H)RL3; wherein: 5 B is an optionally modified nucleobase; B1is a nucleobase modified with a lipophilic moiety or a targeting moiety (e.g., a pyrimidine nucleobase modified at the 5-position); RL3, RL1, and RL2are each a group containing a lipophilic moiety or a targeting moiety; R2’ or R3’ may be any functional group that is an acceptable 2’-modification for a ribose sugar. 10 Examples of suitable R2’ or R3’groups include, but are not limited to, hydrogen, halogen (e.g., 2’-fluoro), hydroxy, 2’-O-alkyl (e.g., 2’-OMethyl), 2’-O-methoxyalkyl (e.g., 2’-O-methoxymethyl, 2’-O- methoxyethyl, or 2’-O-2-methoxypropanyl) modification, 2’-O-allyl modification, 2’-C-allyl modification, 2'-O-N-methylacetamido (2'-O-NMA, i.e. -OCH2C(O)N(H)Me) modification, 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) modification, 2'- 15 O-aminopropyl (2'-O-AP) modification, or 2'-ara-F modification. For instance, R2’ or R3’ may be H, OH, F, OMe, O-methoxyalkyl, O-allyl, O-N-methylacetamido, O-dimethylaminoethoxyethyl, or O- aminopropyl. In one embodiment, RL1, RL2and RL3are each a group containing a lipophilic moiety, such as a C10-26saturated or unsaturated hydrocarbon chain. In one embodiment, RL1, RL2and RL3are each a group 20 containing a C12-26saturated or unsaturated hydrocarbon chain. In one embodiment, RL1, RL2and RL3are each a group containing a C12-24saturated or unsaturated hydrocarbon chain. In one embodiment, RL1, RL2and RL3are each a group containing a C14-24saturated or unsaturated hydrocarbon chain. In one embodiment, RL1, RL2and RL3are each a group containing a C14-18 saturated or unsaturated hydrocarbon chain. In one embodiment, RL1, RL2and RL3are each a group containing a C16 saturated or unsaturated 25 hydrocarbon chain. In one embodiment, RL1, RL2and RL3are each a group containing a saturated or unsaturated C22-hydrocarbon chain. In other embodiments RL1, RL2and RL3are each a group containing a lipophilic moiety, such as a lipophilic vitamin or steroid, including, but not limited to, Vitamin E, Vitamin A (retinol, retinoic acid), and cholesterol. 30 In one embodiment, when RL3comprises a lipophilic moiety, then RL3can be selected from the group consisting of: 52 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO wherein integer m is 0-10 (e.g., 0; or 1-10 or 1-8; or 0-6; or 1; or 2; or 3; or 4; or 5; or 6; or 7; or 8); integer n is 1-21 (e.g., 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2; or 2 or 3 or 4 or 5 or 6); 5 W is C1-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl); R and R’ are each independently H or C1-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, or t- butyl); G is G1 or a saturated or unsaturated C10-26 saturated or unsaturated hydrocarbon chain (e.g.,a C21 hydrocarbon chain e., G together with the carbonyl to which it is attached may form a group with 22 10 carbons) (for instance, G may be a linear or branched C21 alkyl group), wherein G is optionally substituted with one or two groups selected from the group consisting of halogen, -ORG, -SRG, -N(RG)2, - C(O)ORG, -OC(O)RG, -C(O)N(RG) 2, -N(RG)C(O)RG, -N(RG)C(O)ORG, -N(RG)SO2(RG), or -SO2N(RG)2, wherein each RGis independently hydrogen or C1-C6 alkyl (for instance, G is optionally substituted with a -ORG, -C(O)ORG, or -N(RG)C(O)RG); and 15 G1 is a saturated or unsaturated C10-26 saturated or unsaturated hydrocarbon chain (e.g., a C22 hydrocarbon chain,for instance, G1 may be a linear or branched C22 alkyl group), wherein G1is optionally substituted with one or two groups selected from the group consisting of halogen, -ORG1, -SRG1, - N(RG1)2, -C(O)ORG1, -OC(O)RG1, -C(O)N(RG1)2, -N(RG1)C(O)RG1, -N(RG1)C(O)ORG1, -N(RG1)SO2(RG1), or -SO2N(RG1)2, wherein each RG1is independently hydrogen or C1-C6 alkyl (for instance, G1 is optionally 20 substituted with a -ORG1, -C(O)ORG1, or -N(RG1)C(O)RG1). Examples of RL3include, but are not limited to the following structures: 53 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO 54 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO Other examples of RL3include, but are not limited to the following structures: Further examples of RL3include, but are not limited to the following structures: 55 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO . In another embodiment, RL1can be selected from the group consisting of -G1and - S(O)2G1.Examples of RL1include, but are not limited to, the following structures: Further examples of RL1include, but are not limited to, the following structures: 5 In another embodiment, RL2is -C(O)RL3, wherein RL3is according to any of the preceding embodiments thereof. For example, RL2can be selected from the group consisting of the following structures: 56 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO integer m is 0-8 (for instance, m is 0; or m is 1-8; or m is 0-6; or m is 1; or 2; or 3; or 4; or 5; or 6; or 7; or 8); integer n is 1-21 (for instance, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2; or 2 or 3 or 4 or 5 or 6); 5 R and R’ are each independently H or an alkyl group such as a C1-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, t-butyl); G is G1 or a saturated or unsaturated C10-26 saturated or unsaturated hydrocarbon chain (e.g.,a C21 hydrocarbon chain,i.e., G together with the carbonyl to which it is attached may form a group with 22 carbons); for instance, G may be a linear or branched C21 alkyl group), wherein G is optionally 10 substituted with one or two groups selected from the group consisting of halogen, -ORG, -SRG, -N(RG)2, - C(O)ORG, -OC(O)RG, -C(O)N(RG) 2, -N(RG)C(O)RG, -N(RG)C(O)ORG, -N(RG)SO2(RG), or -SO2N(RG)2, wherein each RGis independently hydrogen or C1-C6 alkyl (for instance, G is optionally substituted with a -ORG, -C(O)ORG, or -N(RG)C(O)RG); and G1 is a saturated or unsaturated C10-26 saturated or unsaturated hydrocarbon chain (e.g.,a C22 15 hydrocarbon chain,(for instance, G1 may be a linear or branched C22 alkyl group), wherein G1is optionally substituted with one or two groups selected from the group consisting of halogen, -ORG1, - SRG1, -N(RG1)2, -C(O)ORG1, -OC(O)RG1, -C(O)N(RG1)2, -N(RG1)C(O)RG1, -N(RG1)C(O)ORG1, - N(RG1)SO2(RG1), or -SO2N(RG1)2, wherein each RG1is independently hydrogen or C1-C6 alkyl (for instance, G1 is optionally substituted with a -ORG1, -C(O)ORG1, or -N(RG1)C(O)RG1). 20 Additional examples of RL2include, but are not limited to the following structures: 57 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO Further examples of RL2include, but are not limited to the following structures: In some embodiments, B1 is a nucleobase modified with a G or G1 group, wherein G and G1are 5 as defined above (e.g., a pyrimidine nucleobase modified at the 5’-position with a group comprising G or G1). Examples of B1 include, , wherein t is selected from 0 – 20 (e.g., 1-12, or 1-10, or 3-12, or 3-10). In some embodiments, in vivo delivery enhancing moiety is present within a modified nucleoside of the formula: 10 wherein: B is an optionally modified nucleobase; 58 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO G3is a saturated or unsaturated C1-20hydrocarbon group (e.g., C1-6alkylene; C2-6alkylene; or hexylene); LKis a linking group such as -O-, -N(H)-, -S-, -S-S-, -C(O)O-, OC(O)-, -C(O)N(H)-, -N(H)C(O), -OC(O)N(H)-, -N(H)C(O)O-, -S(O)2-, -S(O)2O-, -S(O)2N(H)-, -P(O)(OH)O-, -OP(O)(OH)-, - 5 P(S)(OH)O-, -OP(S)(OH)-, -OP(O)(OH)O-, -OP(S)(OH)O-, G2is a saturated or unsaturated C10-26hydrocarbon group (e.g., a C14-C24hydrocarbon group, a C16-C22hydrocarbon group, or a C21-C22hydrocarbon group; and RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2.In one embodiment, when LKcontains a carbonyl attached to G2 (e.g., (-N(H)C(O)- or -OC(O)-), 10 then G2 is a C21 hydrocarbon group. In another embodiment, when LKdoes not contain a carbonyl attached to G2, then G2 is a C22 hydrocarbon group. In one embodiment, RGis hydrogen. In another embodiment, RGis OH, In one embodiment, RGis COOH. In another embodiment, RGis CONH2. In one embodiment, RGis amino. In the above structures for the lipophilic monomers, the monomers may also contain one or more 15 asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of the monomers are expressly included. Further, in the preceding and throughout the present application, where a modified internucleotide linkage is shown with substituent atoms fully described at the phosphorous atom, e.g., , where C’ is the 2’-carbon or 3’-carbon atom of a ribose ring, it is understood that the 20 oxygen having the broken bond is the 5'-oxygen of the subsequent nucleotide. In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula: ,wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), such .59 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula: , , wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), such .In one embodiment, the in vivo delivery enhancing moiety is present within a modified 5 nucleoside of the formula: wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), and RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2, such as . In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula: , wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13,10 14 ,15, 16, 17, 18, 19, 20, or 21), and RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2, such as . In some embodiments, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula: , wherein n is an integer of 1-21, for instance, 1-12, 1- 10, 1-8, 1-6, 1-4, or 1-2, or 2 or 3 or 4 or 5 or 6); G is a C10-C22 hydrocarbon chain (e.g., a C16-C22 alkyl 15 chain, or a C16 alkyl chain, or a C22 alkyl chain)., optionally substituted with one or two groups selected from the group consisting of halogen, -ORG, -SRG, -N(RG)2, -C(O)ORG, -OC(O)RG, -C(O)N(RG)2, - N(RG)C(O)RG, -N(RG)C(O)ORG, -N(RG)SO2(RG), or -SO2N(RG)2, wherein each RGis independently hydrogen or C1-C6 alkyl; and nucleobase B is a modified or unmodified nucleobase. In one embodiment, 60 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO n is 1. In one embodiment, n is 2-6. In one embodiment, n is 6. In one embodiment, G is a C22alkyl chain. In one embodiment, G is a C16alkyl chain In some embodiments, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula: , wherein n is an integer of 1-21, for instance, 1-12, 1-10, 5 1-8, 1-6, 1-4, or 1-2, or 2 or 3 or 4 or 5 or 6); G is a C22 hydrocarbon chain, optionally substituted with one or two groups selected from the group consisting of halogen, -ORG, -SRG, -N(RG)2, -C(O)ORG, - OC(O)RG, -C(O)N(RG) 2, -N(RG)C(O)RG, -N(RG)C(O)ORG, -N(RG)SO2(RG), or -SO2N(RG)2, wherein each RGis independently hydrogen or C1-C6 alkyl; and nucleobase B is a modified or unmodified nucleobase. In one embodiment, n is 1. In one embodiment, n is 2-6. In one embodiment, n is 6. In one 10 embodiment, G is C10-C22 alkyl chain (e.g., a C14-C24 alkyl chain, C16-C22 alkyl chain, or a C16 alkyl chain, or a C22 alkyl chain). In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula: one embodiment, the in vivodelivery enhancing moiety is present within a modified nucleoside of the formula: 15 . In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), such one embodiment, thein vivo delivery enhancing moiety is present within a modified nucleoside of the formula ,61 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), such as . In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula 62 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments, the in vivo delivery enhancing moiety is present within a modified internucleotide linkage of the form, -OP(Y)(X)O-, wherein Y is O or S (e.g., O), and X is -N(H)(RL1), wherein RL1is -G1or S(O)2-G1, each as defined above, wherein the phosphorous atom in the internucleotide linkage is optionally enriched in the Sp or Rp isomer, or is racemic. 5 In some embodiments, the in vivo delivery enhancing moiety is present within a modified internucleotide linkage of the form, -OP(O)(X)O-, wherein X is -N(H)(RL1), wherein RL1is 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21) and the phosphorous atom in the internucleotide linkage is optionally enriched in the Sp or Rp isomer, or is racemic. 10 In some embodiments, the in vivo delivery enhancing moiety is present within a amodified internucleotide linkage of the form, (such as ) , whereinn is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21) and the 3’-O is from the preceding nucleoside and the 5’-O is from the subsequent nucleoside, and wherein the phosphorous atom in the internucleotide linkage is optionally enriched in the Sp or Rp isomer, or is racemic. In certain 15 embodiments, the preceding nucleotide contains a 2’-fluoro modification. In certain embodiments, the preceding nucleotide contains a 2’-O-methyl modification. In certain embodiments, the preceding nucleotide contains a 2’-H modification. In some embodiments, the in vivo delivery enhancing moiety is present within a 63 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO amodified internucleotide linkage of the form , (such wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21) and the 3’-O is from the preceding nucleoside and the 5’-O is from the subsequent nucleoside, and wherein the phosphorous atom in the internucleotide linkage is optionally enriched in the Sp or Rp isomer, or is 5 racemic. In certain embodiments, the preceding nucleotide contains a 2’-fluoro modification. In certain embodiments, the preceding nucleotide contains a 2’-O-methyl modification. In certain embodiments, the preceding nucleotide contains a 2’-H modification. In some embodiments, the in vivo delivery enhancing moiety is present within a a modified internucleotide linkage of the form, -OP(Y)(X)O-, whereinY 10 wherein G1 is defined above, such a wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, In some embodiments, in vivo delivery enhancing moiety is conjugated to the 3’-end or 5’-end of one of the sense and antisense strands via a direct bond or through a carrier or linker. In some embodiments, in vivo delivery enhancing moiety is conjugated to the 3’-end of the sense or antisense 15 strand via a direct bond or through a carrier or linker. In some embodiments, in vivo delivery enhancing moiety is conjugated to the 5’-end of the sense or antisense strand via a direct bond or through a carrier or linker. In some embodiments, in vivo delivery enhancing moiety is conjugated to the 5’-end of one of the sense and antisense strands (e.g., sense strand) and is of the formula , wherein X is O or 20 S (e.g., S); and RL3is according to any of the preceding embodiments there. For example, RL3can be , wherein n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23). In another 64 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO example, RL3 can wherein m is selected from 1-6, and n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23). For example, m can be 2-5, or 1, or 2, or 3, or 4 or 5. 5 In some embodiments, in vivo delivery enhancing moiety is conjugated to the 5’-end of one of the sense and antisense strands (e.g., sense strand) and is of the formula -RL3, wherein RL3is according to 10 15 to the alpha-amino acid carbon, Ph is phenyl, Y is =O or =S, p is selected from 1 – 6; and ZZ1is a group formed by reaction of a reactive pairFor example, m can be 2-5, or 1, or 2, or 3, or 4 or 5. In another example, RL3can be 20 selected from 1-6, and n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23). For example, m can be 2-5, or 1, or 2, or 3, or 4 or 5. In some embodiments, in vivo delivery enhancing moiety is conjugated to the 5’-end of one of the sense and antisense strands (e.g., sense strand) and is of the formula: , or a salt thereof, 65 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO wherein X is O or S (e.g., S); L is a divalent linking group (e.g., C1-20alkyl or C1-10alkyl-S-S-C1-10alkyl). In one embodiment, in vivo delivery enhancing moiety is conjugated to the 5’-end of one of the sense and antisense strands and is of the formula (such as ), ora salt thereof, wherein q is selected from 0 – 18 (e.g., 1-11 or 1-8, or 3-11, or 3-8) and X is O or S (e.g., S). 5 (e.g.,11 – 21, or 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21); and a, b, and c are independently selected from 1- 22, provided that the sum of a + b + c is selected from 2 to 22. In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’- 10 terminal nucleotide, and is of the formula 15 20 to the alpha-amino acid carbon, Ph is phenyl, Y is =O or =S, p is selected from 1 – 6; RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2; and ZZ1is a group formed by reaction of a reactive pair (e.g., a reaction between an azide and an alkyne or a cycloalkyne). 66 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’- terminal nucleotide, and is of the formula wherein m is selected from 1-10 (e.g., 3-6, or 3); RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2, and n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 5 19, or 20, or 21, or 22, or 23). For example, m can be 3-6 and RGis hydrogen; or m can be 3-6 and RGis COOH. In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’- terminal nucleotide, and the 5’-terminal nucleotide is of the formula: 10 67 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’- 5 terminal nucleotide, and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5is: . In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’- terminal nucleotide, and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5is , wherein 10 RL2selected from: , 68 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO 5 10 69 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In one embodiment, in vivo delivery enhancing moiety is bonded to the 3’-oxygen of the 3’- terminal nucleotide, and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3is: 5 In one embodiment, in vivo delivery enhancing moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide, and is of the formula -P(Y)(OH)-R3, wherein , whereinRL2selected from: 10 70 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments, in vivo delivery enhancing moiety is conjugated to the 3’-end or 5’-end of one of the sense and antisense strands via a carrier or linker, and the carrier or linker is an inverted abasic 5 nucleotide, such as an inverted abasic deoxyribonucleotide or an inverted abasic ribonucleotide, each connected to the remainder of the oligonucleotide via a phosphodiester (PO) or phosphorothioate (PS) linkage. Examples include, but are not limited to, , wherein Q2is a bond, C(O), S(O)2, or -P(Y’)(OH)-O-, Y and Y’ are independently O or S; and RL3is as defined above. In some embodiments, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’- 10 terminal nucleotide and is of the formula salt thereof, wherein each X is independently O or S (e.g., each is S); Rligand is selected from the groups listed in Table R-1; and L is adivalent linking group (e.g., C1-20 alkyl or C1-10 alkyl-S-S-C1-10 alkyl). For example, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula 15 salt thereof, wherein each X is independently O or S (e.g., each is S) and Rligandis selected from a , wherein n is 7-23 (e.g.,11 – 21, or 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21). In some embodiments, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’- terminal nucleotide, and is of the formula 71 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO salt thereof, wherein each X is independently O or S (e.g., each is S) and Rligand is selected from a ,wherein n is 7-23 (e.g.,11 – 21,or 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21).and L is a divalent linking group (e.g., C1-20 alkyl or C1-10alkyl-S-S-C1-10 alkyl. 5 In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’- terminal nucleotide, and is of the formula salt thereof, wherein each X is O or S (e.g., each is S) and Rligand is selected from a ,,wherein n is 7-23 (e.g.,11 – 21, or 11, 12,13, 14, 15, 16, 17, 18, 19, 20, or 21). 10 In another embodiment, RL1, RL2, and RL3are each a group containing at least one targeting moiety, such as an αvβ6 integrin targeting ligand described herein. In one embodiment, the targeting moiety can be selected from: 72 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In one embodiment, the broken bond is connected to a group of the formula **-L-ZZ-L’- , wherein ** represents the bond to the targeting ligand. ZZ is a bridging group that may be formed, for example, by reaction of two functional groups, and can be selected from the group consisting of, -C(H)=N-, -C(H)=N-N(H)-, -C(H)=N-N(H)C(O)-, -5 C(H)=N-N(R)-, -C(H)=N-N(R)C(O)-, -C(H)=N-O-, -C(O)N(H)-, -C(O)N(H)-N(H)-, -C(O)N(H)-N(R)-, - C(O)N(R)-, -C(O)O-, -C(O)S-, -C(O)N(H)-, -C(O)N(H)-N(H)-, -C(O)N(H)-N(R)-, -C(O)N(R)-, - C(S)N(H)-, -C(S)N(R)-, -C(S)O-, -C(S)S-, -C(S)N(H)-, -C(S)N(R)-, -N(H)C(O)N(H)-, -N(H)C(O)N(R)-, 73 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO -N(H)C(O)O-, -N(H)C(O)S-, -N(H)C(S)N(H)-, -N(H)C(S)N(R)-, -N(H)C(S)O-, -N(H)C(S)S-, -S-S-, - CH2-S-, -CH2-O-, -CH2-N(H)-, -CH=CH-, and a click adduct, for example, selected from the following structures: wherein each R is independently C1-10alkyl (e.g., methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, butyl, 5 or hexyl); and RLais hydrogen, C1-10alkyl (e.g., methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, butyl, or hexyl), C3-8cycloalkyl, 3-8 membered heterocyclyl, aryl (e.g., phenyl), or heteroaryl (e.g., 2-pyridyl). The term “click adduct”, as used herein, includes those adducts formed by a copper(I)-catalyzed azide-alkyne cycloaddition reaction, a strain-promoted azide-alkyne cycloaddition, a strain-promoted azide-trans-cycloalkene cycloaddition, and a thiol-maleimide Michael-addition reaction including, for 10 example, (i) an azide with a terminal alkyne or cycloalkyne (e.g. cyclooctyne, BCN, or DBCO); (ii) a tetrazine with a terminal alkyne or cycloalkyne (e.g. cyclooctyne); (iii) a thiol and maleimide (with or without hydrolysis of the product). In some embodiments, L and L’ are independently one of: (a) -L1-[G-L2]q-G-L3-* wherein q is 0 or an integer selected from 1-10;15 (b) -L1-G-L2-G-L3-*;74 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (c) -L1-G-L3-*;(d) -G-L3-*;(e) -L1-G-*; or(f) -G-*.5 wherein in each of (a) -(f), * represent the bond to ZZ; L1is selected from one of the following groups: (a) a bond, C(O), C(S), C(NRN), S(O)2, P(O)(OH), or P(S)(OH), wherein and RNis hydrogen or C1-6alkyl; (b) a bond, C(O), P(O)(OH), or P(S)(OH); 10 (c) a bond; (d) C(O); (e) P(O)(OH); or (f) P(S)(OH); each L2and L3is independently selected from one of the following groups:15 (a) -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -OP(O)(OH)O- ,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (b) -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1- 20 6alkyl; or (c) -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-,and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (d) -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN isindependently hydrogen or C1-6alkyl; or25 (e) -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independentlyhydrogen or C1-6alkyl; and each G is independently selected from one of the following groups: (a) C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl,or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; or30 (b) C1-10alkyl, optionally substituted with 1, 2, or 3 R groups (e.g., 1 or 2 R groups; or 1 Rgroup); or wherein each R group is independently selected from the group consisting of R’, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkylC1-6alkyl, heterocyclylC1-6alkyl, aryl C1-6alkyl, and heteroarylC1-6alkyl, each of which, other than R’, is 35 optionally substituted with 1, 2, or 3 R’ groups, wherein 75 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO each R’ is independently halogen, cyano, azido, nitro, -N(Rb)2, -O(Ra), -S(R0), -C(O)OR0, - C(O)R0, -C(O)N(R0)2, -C(NR0)OR0, -C(NR0)R0, -C(NR0)N(R0)2, -C(S)OR0, -C(S)R0, -C(S)N(R0) 2, -S(O)2R0, -S(O)2OR0, -S(O)2N(R0)2, -N(R0)C(O)OR0, -N(R0)C(O)R0, -N(R0)C(O)N(R0)2, -N(R0)S(O)2R0, -N(R0)S(O)2OR0, -N(R0)S(O)2N(R0)2, -OC(O)OR0, -OC(O)R0, -OC(O)N(R0)2, - 5 OS(O)2R0, -OS(O)2OR0, -OS(O)2N(R0)2, or -SC(O)R0, wherein each R0is independently hydrogen or C1-6alkyl; each Rais independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; and each Rbis independently hydrogen, C1-6alkyl, or a nitrogen protecting group. In one embodiment of L or L’, q is 0, 1, 2, 3, 4, or 5. In another embodiment of L or L’, q is 0, 1, 10 2, 3, or 4. In another embodiment of L or L’, q is 0, 1, 2, or 3. In another embodiment of L or L’, q is 0, 1, or 2. In another embodiment of L or L’, q is 1, 2, 3, 4, or 5, In another embodiment of L or L’, q is 1, 2, 3, or 4. In another embodiment of L or L’, q is 1, 2, or 3. In another embodiment of L or L’, q is 1 or 2. In another embodiment of L or L’, q is 4. In another embodiment of L or L’, q is 3. In another embodiment of L or L’, q is 2. 15 In some embodiments, L is one of: (a) , wherein k is an integer from 1 to 10; L1 is bond, C(O), C(S), C(NRN), S(O)2,P(O)(OH), or P(S)(OH) (e.g., L1is a bond, C(O), P(O)(OH), or P(S)(OH)); and RNis hydrogen or C1-6alkyl; (b) , wherein k is an integer from 1 to 10; or an integer from 2 to 10; or an integer from20 3 to 10; or an integer from 4 to 10; or an integer from 5 to 10; or an integer from 5 to 9; or an integer from 5 to 8; or an integer from 5 to 7; (c) , wherein t is an integer from 0 to 10 (e.g., an integer from 1 to 5; or1; or 2; or 3); (d) , wherein t is an integer from 0 to 10 (e.g., an integer from 1 to 5 or 1; or 2; or25 3); a is an integer from 1 to 3; and s and s’ are each independently an integer from 1 to 24 (e.g., an integer from 1 to 16; an integer from 1 to 10; an integer from 3 to 10; an integer from 3 to 7; or an integer from 4 to 6); 76 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (e) wherein and s, s’, and s’’ areindependently is an integer from 1 to 24 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7, or an integer from 4 to 6); 5 independently is an integer from 1 to 20 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an integer from 4 to 6); and w is an integer from 1 to 20 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an integer from 4 to 6); or and wherein in each of the preceding embodiments of L, * represents the bond to ZZ.10 In some embodiments, L’ is one of:(a)*-G-L1-, wherein L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; or L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and G is C1-10alkyl; (b)*-G-[L2-G]q-L1-, wherein L1is a bond, CH2, C(O), S(O)2, P(O)(OH), or P(S)(OH); each L2is 15 independently -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein RNis hydrogen or C1-6alkyl each B is independently a bond, CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); each G is independently C1-10alkyl; (c) -[G-L2]q-G-L3-*, wherein each L2is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O, wherein each RNis independently hydrogen or C1-206alkyl; each G is independently C1-10alkyl or C2-10alkenyl, each of which is optionally substituted with 1 or 2 R groups; or each L2is independently C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O wherein each RNis independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl, each of which is optionally substituted with 1 or 2 R groups; (d) *-L3-G-L1-, wherein L3is -C(O)O- or C(O)N(RN)-, wherein RNis hydrogen or C1-6alkyl; L1is -25 OP(O)(OH)O- or -OP(S)(OH)O-; and G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, or 3 R groups (e.g., 1 or no R groups); (e) -L1-[G-L2]q-G-*, wherein L1is a bond or -B-A-; each L2is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O, wherein each RNis independently 30 hydrogen or C1-6alkyl; and each G is independently C1-10alkyl or C2-10alkenyl, each of which is optionally substituted with 1 or 2 R groups; 77 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (f) -[G-L2]q-G-*, wherein each L2is independently C(O)(NRN) , N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O wherein each RNis independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl, each of which is optionally substituted with 1 or 2 R groups; (g) -C2-30alkyl-*, such as -C5-20alkyl-* or -C10-20alkyl-*; 5 (h) -C1-10alkyl-*, optionally substituted with 1 or 2 R groups; (i) -C(O)-C2-30alkyl-*, such as -C(O)-C5-20alkyl-* or -C(O)-C10-20alkyl-*; wherein in each of (a) - (i), * is the bond to ZZ, and q, when present, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3; or 0, 1, 2, or 3; or 0, 1, or 2; or 0 or 1; or 0; or 1; or 2). 10 Examples of RL1and RL3that comprise a targeting ligand include, but are not limited to the following structures: Additional examples of RL1and RL3that comprise a targeting ligand include, but are not limited to the following structures: 78 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO Examples of RL2that comprise a targeting ligand include, but are not limited to the following structures: Additional examples of RL2that comprise a targeting ligand include, but are not limited to the 5 following structure: 79 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In one embodiment of any of the preceding structures comprising a targeting moiety, each RXis an integrin-receptor targeting ligand such as, 5 . In one embodiment, RL2is . In some embodiments, targeting moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide,10 and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3is: In some embodiments, targeting moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide,and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5is: 80 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO . In another embodiment, multiple targeting ligands may be connected to a branched multivalent linker In certain embodiments, RL1, RL2and RL3can comprise a branched linking group (Δ) capable of 5 supporting multiple targeting ligands (e.g., at least 2; or 2-8; or 2-6; or 2-4; or 2; or 3). For example, in one embodiment, the mutiple targeting moieties can be connected through an RL1, RL2, and RL3of the form, (RX-L-ZZ-)z-Δ-T- , wherein each RXis a targeting moiety; z is at least 2; or 2-8; or 2-6; or 2-4; or 2; or 3, 10 T is -L’-T’-**, wherein ** is the bond to Δ, and T’ is O, S, N(H), C(O), S(O)2, C(O)N(H), N(H)C(O), OC(O), OC(O), -P(O)(OH)-, -P(S)(OH)-, -OP(O)(OH)-, -OP(S)(OH)-, -P(O)(OH)O-, - P(S)(OH)O-, -OP(O)(OH)O-, or -OP(S)(OH)O-; and L , L’, and ZZ are each as described above, and each * represents the bond to the targeting ligand. 15 In some embodiments, T is selected from the following, wherein ** is the bond to Δ: (a) -C(O)-X1-L5-X2-C(O)-**, wherein X1 and X2 are each independently C1-10alkyl; or C2-10alkyl; or C4-10alkyl; or C6-10alkyl; or C2-8alkyl; or C2-6alkyl; or C2-4alkyl; (b) -C(O)-C2-20alkyl-C(O)-**, such as -C(O)-C2-12alkyl-C(O)-**,(c) -C(O)-C6-20alkyl-C(O)-**, such as -C(O)-C6-12alkyl-C(O)-**,20 (d) -C(O)-C10alkyl-C(O)-** and wherein each L5is a bond, ZZ, or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond; or ZZ), wherein each A1is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1is independently hydrogen or C1-6alkyl; and each B1is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); 25 and ZZ is as described above (such as -C(O)N(H)-, N(H)C(O)-, -OP(O)(OH)O-, -OP(S)(OH)O-, or a click adduct). In some embodiments, T is selected from the following, ** is the bond to Δ: (f) -N(H)C(O)-C2-20alkyl-C(O)-**,(g) - N(H)C(O)-C6-20alkyl-C(O)-**, such as - N(H)C(O)-C6-12alkyl-C(O)-**,30 (h) - N(H)C(O)-C10alkyl-C(O)-**,(i) -C(O)-C2-20alkyl-C(O)N(H)-**,(j) -C(O)-C6-20alkyl-C(O)N(H)-**,81 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (k) -C(O)-C6-12alkyl-C(O)N(H)-**,(l) -C(O)-C10alkyl-C(O)N(H)-**,(m) -N(H)C(O)-C2-20alkyl-C(O)N(H)-**,(n) - N(H)C(O)-C6-20alkyl-C(O)N(H)-**,5 (o) - N(H)C(O)-C6-12alkyl-C(O)N(H)-**, and(p) - N(H)C(O)-C10alkyl-C(O)N(H)-**.In some embodiments, T is selected from the following, ** is the bond to Δ: (a) -N(H)C(O)-X3-ZZ-X4-C(O)-**,(b) -C(O)-X3-ZZ-X4-C(O)N(H)-**,10 (c) N(H)C(O)-X3-ZZ- X4-C(O)N(H)-**,wherein X3and X4are independently C2-12alkyl; or C4-10alkyl; or C6-10alkyl; or C4-8alkyl; and ZZ is as described above (such as -C(O)N(H)-, N(H)C(O)-, -OP(O)(OH)O-, -OP(S)(OH)O-, or a click adduct). In some embodiments, , T is selected from the following (w) -L6-[G5-O]q5-G5-L4-**, wherein L4and L6are independently -A1-B1-A1-, wherein each A115 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1is hydrogen or C1-6alkyl; each B1is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); each G5is independently C1-10alkyl; (x) -C(O)-[CH2CH2-O]q5-G5-L4-**, L4is -A1-B1-A1-, wherein each A1is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1is hydrogen or C1-6alkyl; each B1is independently a 20 bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); G5is C1-10alkyl. (y) -C(O)-[CH2CH2-O]q5-G5-L4-**, L4is -A1-B1or -B1-A1-, wherein each A1is independently -O- or -N(H)-, and each B1is independently C(O), G5is C1-10alkyl (e.g., C2- 10alkyl or C2-6alkyl); and (z) -C(O)-[CH2CH2-O]q5- C2-10alkyl-C(O)N(H)-**; 25 wherein in each of the preceding ** is the bond to Δ, and q5, when present, is an integer selected from 1 to 20 (e.g., 1 to 10, or 2 to 10; or 2 – 8; or 1; or 2; or 3; or 4.) Examples of branched linking group (Δ) include, but are not limited to, 82 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO wherein the broken bond is the bond to L’. Examples of -T1-Δ- include, but are not limited to, , 5 Examples of RL1and RL3that comprise a branched linker to a targeting ligand include, but are not limited to the following structures: 83 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO Examples of branched RL1and RL3include, but are not limited to, the following structures: 5 84 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO Examples of branched RL2include, but are not limited to, the following structures: 5 . In some embodiments, targeting moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide,and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3is: 10 ( .g., ; . 85 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments, targeting moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide,and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3is: . In some embodiments, targeting moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide,5 and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3is: . In some embodiments, targeting moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide,and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5is: wherein , r is an integer 10 selected from 1 - 10 (e.g., r is 7); and each R is: , wherein RXis a targeting ligand. In some embodiments, targeting moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide,and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5is: 15 ligand. In one embodiment of any of the preceding structures comprising a targeting moiety, each RXis an integrin-receptor targeting ligand such as, 86 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO . In some embodiments, the dsRNA agent comprises a double-stranded region formed between the sense and antisense strands and optionally one or two single-stranded non-loop overhang, and wherein the one or more lipophilic moieties are conjugated to either the double-stranded region or the non-loop 5 overhang. In some embodiments, the dsRNA agent does not contain a loop (e.g., stem loop) region. In some embodiments, the dsRNA agent contains a loop (e.g., stem loop) region, and the one or more lipophilic moieties are not conjugated to the loop (e.g., stem loop) region. In some embodiments, the dsRNA agent comprises a sense strand of 10 to 53 nucleotides in length, in which the sense strand forms a duplex region with the antisense strand. For instance, the sense 10 strand may be 10 to 49, 12 to 49, 12 to 45, 12 to 42, 12 to 40, 15 to 49, 15 to 45, 15 to 42, 15 to 40, 15 to 38, or 15 to 36 nucleotides in length. In some embodiments, the duplex region is at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 nucleotides in length. In some embodiments, the region of complementarity to the target sequence is at least 19 contiguous nucleotides in length. In some embodiments, the sense strand comprises at its 3′-end a stem-loop set forth as: S1-L-S2, 15 in which S1 is complementary to S2, and in which L forms a loop between S1 and S2. In some embodiments, the first 17 to 25 nucleotides counting from 5’ end of the sense strand forms a duplex region with the antisense strand, and the last 11 to 28 counting from 5’ end of the sense strand forms a 3′-end a stem-loop set forth as: S1-L-S2. In some embodiments, the length of the stem loop S1-L-S2 is 11 to 28, 13 to 26, or 15 to 24 20 nucleotides in length. In one embodiment, the stem loop S1-L-S2 is 16 nucleotides in length. In some embodiments, the stem loop S1-L-S2 comprises a sequence of GCAGCCGAAAGGCUGC (SEQ ID NO: 1). In some embodiments, L is at least 3, 4, or 5 nucleotides in length. In some embodiments, L comprises a sequence of GAAA. 25 In some embodiments, the sense strand is 36 nucleotides in length, the first 20 nucleotide counting from 5’ end of the sense strand forms a duplex region with the antisense strand, and the last 16 nucleotides forms a stem loop S1-L-S2. In one embodiment, the 16-nucleotide stem loop S1-L-S2has the sequence of GCAGCCGAAAGGCUGC (SEQ ID NO: 2), wherein L is GAAA. In some embodiments, the one or more lipophilic moieties are conjugated to a non-terminal 30 position of the sense strand. 87 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments, the one or more lipophilic moieties are conjugated to one or more nucleotides of the stem loop S1-L-S2. In some embodiments, the one or more lipophilic moieties are conjugated to one or more nucleotides of the loop L. In some embodiments, S1and S2are complementary and contain 4-10 nucelotides, e.g., S1and S25 each contain 6 complementary nucelotides. In some embodiments, S1and S2are complementary and contain 4-10 nucelotides and L is GAAA, e.g., S1and S2each contain 6 complementary nucelotides and L is GAAA. In some embodiments, the one or more lipophilic moieties containing one or more saturated or unsaturated C22 hydrocarbon chains are conjugated to one or more internal positions on at least one strand 10 of the dsRNA agent. Dual Conjugation In another embodiment, in vivo delivery enhancing moiety is connected in series with a targeting moiety, e.g., αvβ6 integrin targeting ligand, as described herein. For example, a sense or antisense strand 15 can contain a series modification at the 3’-end or 5’-end of the oligonucleotide, . such that one of L1 and L2 comprises the in vivo delivery enhancing moiety and the other comprises the targeting moiety, e.g., αvβ6 integrin targeting ligand as described herein.In one embodiment, the series modification is of the form, , wherein Q is selected20 wherein RL2 is according to any preceding embodiment,wherein one of the broken bonds connects to a 5’-oxygen of a nucleoside or a 3’-oxygen of a nucleoside and the other connects to a 5’-terminal or 3’-terminal modification as described herein. In another example, a sense or antisense strand can contain a series modification of the form, wherein RL2 is25 according to any preceding embodiment, each Y is independently O or S; one of the broken bonds 88 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO connects to a 5’-oxygen of a nucleoside or a 3’-oxygen of a nucleoside and the other connects any of the 5’-terminal modifications described above or 3’-terminal modifications described above. In one embodiment, a sense or antisense strand can contain a series modification of the form, , wherein the broken bond connects to the 5’-oxygen of a 5’-terminal 5 nucleoside; each Y is independently O or S; one of R51and R52comprises a lipophilic group (e.g., an in vivo delivery enhancing moiety) and the other comprises a second ligand moiety (e.g., a targeting moiety, such as a αvβ6 integrin targeting ligand as described herein). In another embodiment, a sense or antisense strand can contain a series modification of the form , wherein the broken bond connects to the 5’-oxygen of a 5’-terminal nucleoside; 10 each Y is independently O or S; one of R51and R52comprises a lipophilic group (e.g., an in vivo delivery enhancing moiety, such as any of RLor RL2above) and the other comprises a second ligand moiety (e.g., a targeting moiety). For example an oligonucleotide may have a series modification at the 5’-end of the formula: 15 is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21); and each Y is independently O or S and R510and R520are 89 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO wherein each Y is independently O or S. In another embodiment, a sense or antisense strand can contain a series modification of the form, , wherein the broken bond connects to the 3’-oxygen of a 3’- 5 terminal nucleoside; each Y is independently O or S; one of R31and R32comprises a lipophilic group (e.g., an in vivo delivery enhancing moiety, such as any of RL2above) and the other comprises a second ligand moiety (e.g., a targeting ligand). For example an oligonucleotide may have a series modification at the 3’-end of the formula: wherein n is selected from 7-2310 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21); and each Y is independently O or S and R310and R320are wherein each Y is indepedently O or S. 90 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In another embodiment, can contain a single modification at the 5’-end, the 3’-end or at an internal position that contains both the in vivo delivery enhancing moiety and the targeting moiety.In one embodiment, single modification is bonded to the 3’-oxygen of the 3’-terminal nucleotide, and is of the formula -P(Y)(OH)-R3, wherein 5 wherein , wherein RL2and RL3comprises the in vivo delivery enhancing moiety (e.g., according to any in vivo delivery enhancing moiety embodiment of RL2or RL3above); RTGcomprises the targeting moiety (e.g., RTGis according to Formula (X) (below), wherein R5is -L-ZZ-L’-, where L, ZZ, and L’ are defined for Formula (X) or an embodiment thereof; E is -C(O)N(H)-(CH2)p-*, -N(H)C(O)-(CH2)p-*, -C(O)O-(CH2)p-*, -OC(O)-(CH2)p-*, - 10 -O-N(H)-(CH2)p-, wherein * is the bond to the alpha-amino acid carbon, Ph is phenyl, Y is =O or =S, p is selected from 1 – 6; RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2; and ZZ1is a group formed by reaction of a reactive pair (e.g., a reaction between an azide and an alkyne or a cycloalkyne); 15 E1is -O-, -S-, or -N(H)-; T is a bond or -L6-G1-[L5-G1]q1-L4-**, wherein ** is the bond to E; q1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each L4, L5, and L6are independently a bond, -A1-B1-A1- or ZZ1; ZZ1is a group formed by reaction of a reactive pair (e.g., a reaction between an azide and an alkyne or a cycloalkyne); each G1is independently -D1-E1-F1-, wherein D1, E1, and F1are independently a bond, C1-10alkyl, 20 C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, or 3 R groups; each A1is independently a bond, -O-, -S-, or -N(RN1)-; each B1is independently a bond, C(O), C(S), C(NRN1), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); 25 each RN1is independently hydrogen or C1-6alkyl, or two RN1within an -A1-B1-A1- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl. 91 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In one embodiment, the single modification is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula -P(Y)(OH)-R5, wherein wherein RDis as defined above. In one embodiment of the 3’- or 5’-modification, . 5 embodiment of the 3’- or 5’-modification, r example, G1can be C1-10alkyl. In one embodiment of the 3’- or 5’-modification, RDis 10 15 92 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO nitrogen. 5In one embodiment of the 3’- or 5’-modification, RD is . In one embodiment ofthe 3’- or 5’-modification, RD is . In one embodiment of the 3’- or 5’-modification, RD is ; for example, G1 can be C2-20alkyl. In one embodiment of the 3’- or 5’-modification, wherein n is selected from 7-23 (e.g., 11-23, or 11 –21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 10 21, or 22, or 23); RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2; G1is C2-20alkyl. In one embodiment of the 3’- or 5’-modification, wherein nis selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23); RGis hydrogen, hydroxy, amino, -COOH, or - C(O)NH2; G1is C2-20alkyl, and -C(O)-RTGis 93 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO broken bond is the bond between RTGand the nitrogen. 5 In another embodiment, a sense or antisense strand can contain two different ligand modifications, one at the 3'-end of the strand and the other at the 5'-end of the strand: such that one of L1 and L2 comprises the in vivo delivery enhancing moiety and the other comprises the targeting moiety, e.g., αvβ6 integrin targeting ligand as described herein.10 In another embodiment, a sense or antisense strand can contain two different ligand modifications, one is an internal modified nuceloside or modified internucleotide linkage of the strand and the other at the 3’-end or 5'-end of the strand: such that one of L1 and L2 comprises the in vivo delivery enhancing moiety and the other comprises the15 targeting moiety, e.g., αvβ6 integrin targeting ligand as described herein. The modified nucelosiderepresented by L1 can be located at a position in the strand selected from positions 2 to n-1, where the strand contains n nucleotides (e.g., n-1 is 20 when n is 21). For example, when L1 is at position 6, then segment (1) of the strand contains 5 nucleotides and segment (2) contains the remainder of the nucleotides within the strand. “Position” herein, when referring to a modified nucleotide, nucleoside, or 20 internucleotide linkage is counted from the 5’-end of the strand, for example, position 6 includes the 6th nucleotide from the 5’-end of the strand and the 6th internucleotide linkage counting from the 5’-end of the strand. 94 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In one embodiment, L1 comprises the in vivo delivery enhancing moiety (e.g., C10-C26saturated or unsaturated hydrocarbon, such as a C10-C26alkyl group, or a C14-C24alkyl group, or a C16-C22alkyl group, or a C16alkyl group, or a C22alkyl group) and a sense or antisense strand can be represented by one of: 5 wherein B is an optionally modified nucleobase (e.g., A, C, G, U, or T); RL3or RL1comprises the in vivo delivery enhancing moiety, L2 comprises the targeting moiety. In one embodiment, RL3is selected from the group consisting of: , , , and wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21); for example, in one embodiment, n is 13; and in another embodiment, n is 19. 10 In one embodiment, RL1is selected from the group consisting of: a , wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21); for example, in one embodiment, n is 7; and in another embodiment, n is 10. 95 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In another embodiment, RL3is selected from the group consisting of: another embodiment, RL1is selected from the group consisting of: . 1. Linkers / Tethers5 Linkers / Tethers are connected to the at least one in vivo delivery enhancing moiety at a “tethering attachment point (TAP).” Linkers / Tethers may include any C1-C100carbon-containing moiety, (e.g. C1-C75, C1-C50, C1-C20, C1-C10; C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10), and may have at least one nitrogen atom. In certain embodiments, the nitrogen atom forms part of a terminal amino or amido (NHC(O)-) group on the linker / tether, which may serve as a connection point for the lipophilic moiety. 10 Non-limited examples of linkers / tethers (underlined) include TAP- nNH-; TAP-C(O)(CH2)nNH-; TAP-NR’’’’(CH2)nNH-, TAP-C(O)-(CH2)n-C(O)-; TAP-C(O)-(CH2)n-C(O)O-; TAP-C(O)-O-; TAP- C(O)-(CH2)n-NH-C(O)-; TAP-C(O)-(CH2)n-; TAP-C(O)-NH-; TAP-C(O)-; TAP-(CH2)n-C(O)-; TAP- (CH2)n-C(O)O-; TAP-(CH2)n-; or TAP-(CH2)n-NH-C(O)-; in which n is 1-20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) and R’’’’ is C1-C6 alkyl. Preferably, n is 5, 6, or 11. In other 15 embodiments, the nitrogen may form part of a terminal oxyamino group, e.g., -ONH2, or hydrazino group, -NHNH2. The linker / tether may optionally be substituted, e.g., with hydroxy, alkoxy, perhaloalkyl, and / or optionally inserted with one or more additional heteroatoms, e.g., N, O, or S. Preferred tethered ligands may include, e.g., TAP-(CH2)nNH(LIGAND); TAP- C(O)(CH2)nNH(LIGAND); TAP-NR’’’’(CH2)nNH(LIGAND); TAP-(CH2)nONH(LIGAND); TAP-20 C(O)(CH2)nONH(LIGAND); TAP-NR’’’’(CH2)nONH(LIGAND); TAP-(CH2)nNHNH2(LIGAND), TAP- C(O)(CH2)nNHNH2(LIGAND); TAP-NR’’’’(CH2)nNHNH2(LIGAND); TAP-C(O)-(CH2)n- C(O)(LIGAND); TAP-C(O)-(CH2)n-C(O)O(LIGAND); TAP-C(O)-O(LIGAND); TAP-C(O)-(CH2)n-NH- C(O)(LIGAND); TAP-C(O)-(CH2)n(LIGAND); TAP-C(O)-NH(LIGAND); TAP-C(O)(LIGAND); TAP- (CH2)n-C(O) (LIGAND); TAP-(CH2)n-C(O)O(LIGAND); TAP-(CH2)n(LIGAND); or TAP-(CH2)n-NH- 25 C(O)(LIGAND). In some embodiments, amino terminated linkers / tethers (e.g., NH2, ONH2, NH2NH2) can form an imino bond (i.e., C=N) with the ligand. In some embodiments, amino terminated linkers / tethers (e.g., NH2, ONH2, NH2NH2) can acylated, e.g., with C(O)CF3. In some embodiments, the linker / tether can terminate with a mercapto group (i.e., SH) or an olefin (e.g., CH=CH2). For example, the tether can be TAP-(CH2)n-SH, TAP-C(O)(CH2)nSH, TAP- 30 (CH2)n-(CH=CH2), or TAP-C(O)(CH2)n(CH=CH2), in which n can be as described elsewhere. The tether may optionally be substituted, e.g., with hydroxy, alkoxy, perhaloalkyl, and / or optionally inserted with one or more additional heteroatoms, e.g., N, O, or S. The double bond can be cis or trans or E or Z. 96 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In other embodiments, the linker / tether may include an electrophilic moiety, preferably at the terminal position of the linker / tether. Exemplary electrophilic moieties include, e.g., an aldehyde, alkyl halide, mesylate, tosylate, nosylate, or brosylate, or an activated carboxylic acid ester, e.g. an NHS ester, or a pentafluorophenyl ester. Preferred linkers / tethers (underlined) include TAP-(CH2)nCHO; TAP- 5 C(O)(CH2)nCHO; or TAP-NR’’’’(CH2)nCHO, in which n is 1-6 and R’’’’ is C1-C6alkyl; or TAP- (CH2)nC(O)ONHS; TAP-C(O)(CH2)nC(O)ONHS; or TAP-NR’’’’(CH2)nC(O)ONHS, in which n is 1-6 and R’’’’ is C1-C6alkyl; TAP-(CH2)nC(O)OC6F5; TAP-C(O)(CH2)nC(O) OC6F5; or TAP-NR’’’’(CH2) nC(O) OC6F5, in which n is 1-11 and R’’’’ is C1-C6alkyl; or -(CH2)nCH2LG; TAP-C(O)(CH2)nCH2LG; or TAP-NR’’’’(CH2)nCH2LG, in which n can be as described elsewhere and R’’’’ is C1-C6 alkyl (LG can 10 be a leaving group, e.g., halide, mesylate, tosylate, nosylate, brosylate). Tethering can be carried out by coupling a nucleophilic group of a ligand, e.g., a thiol or amino group with an electrophilic group on the tether. In other embodiments, it can be desirable for the monomer to include a phthalimido group (K) at the terminal position of the l .15 In other embodiments, other protected amino groups can be at the terminal position of the linker / tether, e.g., alloc, monomethoxy trityl (MMT), trifluoroacetyl, Fmoc, or aryl sulfonyl (e.g., the aryl portion can be ortho-nitrophenyl or ortho, para-dinitrophenyl). Any of the linkers / tethers described herein may further include one or more additional linking groups, e.g., -O-(CH2)n-, -(CH2)n-SS-, -(CH2)n-, or -(CH=CH)-. 20 2. Cleavable linkers / tethersIn some embodiments, at least one of the linkers / tethers can be a redox cleavable linker, an acid cleavable linker, an esterase cleavable linker, a phosphatase cleavable linker, or a peptidase cleavable linker. 25 In one embodiment, at least one of the linkers / tethers can be a reductively cleavable linker (e.g., a disulfide group). In one embodiment, at least one of the linkers / tethers can be an acid cleavable linker (e.g., a hydrazone group, an ester group, an acetal group, or a ketal group). In one embodiment, at least one of the linkers / tethers can be an esterase cleavable linker (e.g., an 30 ester group). In one embodiment, at least one of the linkers / tethers can be a phosphatase cleavable linker (e.g., a phosphate group). 97 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In one embodiment, at least one of the linkers / tethers can be a peptidase cleavable linker (e.g., a peptide bond). Cleavable linking groups are susceptible to cleavage agents, e.g., pH, redox potential or the presence of degradative molecules. Generally, cleavage agents are more prevalent or found at higher 5 levels or activities inside cells than in serum or blood. Examples of such degradative agents include: redox agents which are selected for particular substrates or which have no substrate specificity, including, e.g., oxidative or reductive enzymes or reductive agents such as mercaptans, present in cells, that can degrade a redox cleavable linking group by reduction; esterases; endosomes or agents that can create an acidic environment, e.g., those that result in a pH of five or lower; enzymes that can hydrolyze or degrade 10 an acid cleavable linking group by acting as a general acid, peptidases (which can be substrate specific), and phosphatases. A cleavable linkage group, such as a disulfide bond, can be susceptible to pH. The pH of human serum is 7.4, while the average intracellular pH is slightly lower, ranging from about 7.1-7.3. Endosomes have a more acidic pH, in the range of 5.5-6.0, and lysosomes have an even more acidic pH at around 15 5.0. Some tethers will have a linkage group that is cleaved at a preferred pH, thereby releasing the iRNA agent from a ligand (e.g., a targeting or cell-permeable ligand, such as cholesterol) inside the cell, or into the desired compartment of the cell. A chemical junction (e.g., a linking group) that links a ligand to an iRNA agent can include a disulfide bond. When the iRNA agent / ligand complex is taken up into the cell by endocytosis, the acidic 20 environment of the endosome will cause the disulfide bond to be cleaved, thereby releasing the iRNA agent from the ligand (Quintana et al., Pharm Res.19:1310-1316, 2002; Patri et al., Curr. Opin. Curr. Biol.6:466-471, 2002). The ligand can be a targeting ligand or a second therapeutic agent that may complement the therapeutic effects of the iRNA agent. A tether can include a linking group that is cleavable by a particular enzyme. The type of linking 25 group incorporated into a tether can depend on the cell to be targeted by the iRNA agent. Tethers that contain peptide bonds can be conjugated to iRNA agents target to cell types rich in peptidases. In general, the suitability of a candidate cleavable linking group can be evaluated by testing the ability of a degradative agent (or condition) to cleave the candidate linking group. It will also be desirable to also test the candidate cleavable linking group for the ability to resist cleavage in the blood or 30 when in contact with other non-target tissue, e.g., tissue the iRNA agent would be exposed to when administered to a subject. Thus one can determine the relative susceptibility to cleavage between a first and a second condition, where the first is selected to be indicative of cleavage in a target cell and the second is selected to be indicative of cleavage in other tissues or biological fluids, e.g., blood or serum. The evaluations can be carried out in cell free systems, in cells, in cell culture, in organ or tissue culture, 35 or in whole animals. It may be useful to make initial evaluations in cell-free or culture conditions and to confirm by further evaluations in whole animals. In preferred embodiments, useful candidate compounds 98 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO are cleaved at least 2, 4, 10 or 100 times faster in the cell (or under in vitro conditions selected to mimic intracellular conditions) as compared to blood or serum (or under in vitro conditions selected to mimic extracellular conditions). 53. Redox Cleavable Linking GroupsOne class of cleavable linking groups are redox cleavable linking groups that are cleaved upon reduction or oxidation. An example of reductively cleavable linking group is a disulphide linking group (—S—S—). To determine if a candidate cleavable linking group is a suitable “reductively cleavable linking group,” or for example is suitable for use with a particular iRNA moiety and particular in vivo 10 delivery enhancing moiety, one can look to methods described herein. For example, a candidate can be evaluated by incubation with dithiothreitol (DTT), or other reducing agent using reagents know in the art, which mimic the rate of cleavage which would be observed in a cell, e.g., a target cell. The candidates can also be evaluated under conditions which are selected to mimic blood or serum conditions. In a preferred embodiment, candidate compounds are cleaved by at most 10% in the blood. In preferred 15 embodiments, useful candidate compounds are degraded at least 2, 4, 10 or 100 times faster in the cell (or under in vitro conditions selected to mimic intracellular conditions) as compared to blood (or under in vitro conditions selected to mimic extracellular conditions). The rate of cleavage of candidate compounds can be determined using standard enzyme kinetics assays under conditions chosen to mimic intracellular media and compared to conditions chosen to mimic extracellular media. 20 4. Phosphate-Based Cleavable Linking GroupsPhosphate-based linking groups are cleaved by agents that degrade or hydrolyze the phosphate group. An example of an agent that cleaves phosphate groups in cells are enzymes such as phosphatases in cells. Examples of phosphate-based linking groups are —O—P(O)(ORk)-O—, —O—P(S)(ORk)-O—25 , —O—P(S)(SRk)-O—, —S—P(O)(ORk)-O—, —O—P(O)(ORk)-S—, —S—P(O)(ORk)-S—, —O— P(S)(ORk)-S—, —S—P(S)(ORk)-O—, —O—P(O)(Rk)-O—, —O—P(S)(Rk)-O—, —S—P(O)(Rk)- O—, —S—P(S)(Rk)-O—, —S—P(O)(Rk)-S—, —O—P(S)(Rk)-S—. Preferred embodiments are —O— P(O)(OH)—O—, —O—P(S)(OH)—O—, —O—P(S)(SH)—O—, —S—P(O)(OH)—O—, —O— P(O)(OH)—S—, —S—P(O)(OH)—S—, —O—P(S)(OH)—S—, —S—P(S)(OH)—O—, —O— 30 P(O)(H)—O—, —O—P(S)(H)—O—, —S—P(O)(H)—O—, —S—P(S)(H)—O—, —S—P(O)(H)—S— , —O—P(S)(H)—S—. A preferred embodiment is —O—P(O)(OH)—O—. These candidates can be evaluated using methods analogous to those described above. 5. Acid Cleavable Linking Groups35 Acid cleavable linking groups are linking groups that are cleaved under acidic conditions. In preferred embodiments acid cleavable linking groups are cleaved in an acidic environment with a pH of 99 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO about 6.5 or lower (e.g., about 6.0, 5.5, 5.0, or lower), or by agents such as enzymes that can act as a general acid. In a cell, specific low pH organelles, such as endosomes and lysosomes can provide a cleaving environment for acid cleavable linking groups. Examples of acid cleavable linking groups include but are not limited to hydrazones, ketals, acetals, esters, and esters of amino acids. Acid 5 cleavable groups can have the general formula —C═NN—, C(O)O, or —OC(O). A preferred embodiment is when the carbon attached to the oxygen of the ester (the alkoxy group) is an aryl group, substituted alkyl group, or tertiary alkyl group such as dimethyl pentyl or t-butyl. These candidates can be evaluated using methods analogous to those described above.10 6. Ester-Based Linking GroupsEster-based linking groups are cleaved by enzymes such as esterases and amidases in cells. Examples of ester-based cleavable linking groups include but are not limited to esters of alkylene, alkenylene and alkynylene groups. Ester cleavable linking groups have the general formula —C(O)O—, or —OC(O)—. These candidates can be evaluated using methods analogous to those described above. 15 7. Peptide-Based Cleaving GroupsPeptide-based linking groups are cleaved by enzymes such as peptidases and proteases in cells. Peptide-based cleavable linking groups are peptide bonds formed between amino acids to yield oligopeptides (e.g., dipeptides, tripeptides etc.) and polypeptides. Peptide-based cleavable groups do not 20 include the amide group (—C(O)NH—). The amide group can be formed between any alkylene, alkenylene or alkynelene. A peptide bond is a special type of amide bond formed between amino acids to yield peptides and proteins. The peptide based cleavage group is generally limited to the peptide bond (i.e., the amide bond) formed between amino acids yielding peptides and proteins and does not include the entire amide functional group. Peptide cleavable linking groups have the general formula — 25 NHCHR1C(O)NHCHR2C(O)—, where R1and R2are the R groups of the two adjacent amino acids. These candidates can be evaluated using methods analogous to those described above. H. Biocleavable linkers / tethers The linkers can also include biocleavable linkers that are nucleotide and non-nucleotide linkers 30 or combinations thereof that connect two parts of a molecule. The non-nucleotide linkers include tethers or linkers derived from monosaccharides, disaccharides, oligosaccharides, and derivatives thereof, aliphatic, alicyclic, hetercyclic, and combinations thereof. In some embodiments, at least one of the linkers (tethers) is a bio-clevable linker selected from the group consisting of DNA, RNA, disulfide, amide, functionalized monosaccharides or 35 oligosaccharides of galactosamine, glucosamine, glucose, galactose, and mannose, and combinations thereof. 100 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In one embodiment, the bio-cleavable carbohydrate linker may have 1 to 10 saccharide units, which have at least one anomeric linkage capable of connecting two siRNA units. When two or more saccharides are present, these units can be linked via 1-3, 1-4, or 1-6 sugar linkages, or via alkyl chains. Exemplary bio-cleavable linkers include: 5 101 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO 102 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO . More discussion about the biocleavable linkers may be found in WO2018136620, entitled 5 “Endosomal Cleavable Linkers,” the entire contents of which are incorporated herein by reference. 8. CarriersIn certain embodiments, the at least one in vivo delivery enhancing moiety is conjugated to the dsRNA agent via a carrier that replaces one or more nucleotide(s). 10 The carrier can be a cyclic group or an acyclic group. In one embodiment, the cyclic group is selected from the group consisting of pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3]dioxolane, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuryl, and decalin. In one embodiment, the acyclic group is a moiety based on a serinol backbone or a diethanolamine backbone. 15 In some embodiments, the carrier replaces one or more nucleotide(s) in the internal position(s) of the dsRNA agent. In other embodiments, the carrier replaces the nucleotides at the terminal end of the sense strand or antisense strand. In one embodiment, the carrier replaces the terminal nucleotide on the 3’ end of the sense strand, thereby functioning as an end cap protecting the 3’ end of the sense strand. In one 20 embodiment, the carrier is a cyclic group having an amine, for instance, the carrier may be pyrrolidinyl, 103 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3]dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuranyl, or decalinyl. A ribonucleotide subunit in which the ribose sugar of the subunit has been so replaced is referred 5 to herein as a ribose replacement modification subunit (RRMS). The carrier can be a cyclic or acyclic moiety and include two “backbone attachment points” (e.g., hydroxyl groups) and a ligand (e.g., the lipophilic moiety). The one or more C22hydrocarbon chains can be directly attached to the carrier or indirectly attached to the carrier by an intervening linker / tether, as described above. 10 The ligand-conjugated monomer subunit may be the 5’ or 3’ terminal subunit of the iRNA molecule, i.e., one of the two “W” groups may be a hydroxyl group, and the other “W” group may be a chain of two or more unmodified or modified ribonucleotides. Alternatively, the ligand-conjugated monomer subunit may occupy an internal position, and both “W” groups may be one or more unmodified or modified ribonucleotides. More than one ligand-conjugated monomer subunit may be present in an 15 iRNA agent. (i) Sugar Replacement-Based Monomers, e.g., Ligand-ConjugatedMonomers (Cyclic) Cyclic sugar replacement-based monomers, e.g., sugar replacement-based ligand-conjugated 20 monomers, are also referred to herein as RRMS monomer compounds. The carriers may have the general formula (LCM-2) provided below (in that structure preferred backbone attachment points can be chosen from R1or R2; R3or R4; or R9and R10if Y is CR9R10(two positions are chosen to give two backbone attachment points, e.g., R1and R4, or R4and R9)). Preferred tethering attachment points include R7; R5or R6when X is CH2. The carriers are described below as an entity, which can be 25 incorporated into a strand. Thus, it is understood that the structures also encompass the situations wherein one (in the case of a terminal position) or two (in the case of an internal position) of the attachment points, e.g., R1or R2; R3or R4; or R9or R10(when Y is CR9R10), is connected to the phosphate, or modified phosphate, e.g., sulfur containing, backbone. E.g., one of the above-named R 104 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO groups can be -CH2-, wherein one bond is connected to the carrier and one to a backbone atom, e.g., a linking oxygen or a central phosphorus atom. (LCM-2) 5 wherein: X is N(CO)R7, NR7or CH2; Y is NR8, O, S, CR9R10; Z is CR11R12or absent; Each of R1, R2, R3, R4, R9, and R10is, independently, H, ORa, or (CH2)nORb, provided 10 that at least two of R1, R2, R3, R4, R9, and R10are ORaand / or (CH2)nORb; Each of R5, R6, R11, and R12is, independently, a ligand, H, C1-C6alkyl optionally substituted with 1-3 R13, or C(O)NHR7; or R5and R11together are C3-C8 cycloalkyl optionally substituted with R14; R7can be a ligand, e.g., R7can be Rd, or R7can be a ligand tethered indirectly to the 15 carrier, e.g., through a tethering moiety, e.g., C1-C20 alkyl substituted with NRcRd; or C1-C20 alkyl substituted with NHC(O)Rd; R8is H or C1-C6 alkyl; R13is hydroxy, C1-C4 alkoxy, or halo; R14is NRcR7; 20 R15is C1-C6 alkyl optionally substituted with cyano, or C2-C6 alkenyl; R16is C1-C10 alkyl; R17is a liquid or solid phase support reagent; L is -C(O)(CH2)qC(O)-, or -C(O)(CH2)qS-; Rais a protecting group, e.g., CAr3; (e.g., a dimethoxytrityl group) or Si(X5’)(X5”)(X5”’) 25 in which (X5’),(X5”), and (X5”’) are as described elsewhere. Rbis P(O)(O-)H, P(OR15)N(R16)2 or L-R17; Rcis H or C1-C6 alkyl; Rdis H or a ligand; Each Ar is, independently, C6-C10 aryl optionally substituted with C1-C4 alkoxy; 30 n is 1-4; and q is 0-4. Exemplary carriers include those in which, e.g., X is N(CO)R7or NR7, Y is CR9R10, and Z is absent; or X is N(CO)R7or NR7, Y is CR9R10, and Z is CR11R12; or X is N(CO)R7or NR7, Y is NR8, and Z is CR11R12; or X is N(CO)R7or NR7, Y is O, and Z is CR11R12; or X is CH2; Y is CR9R10; Z is CR11R12, 105 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO and R5and R11together form C6cycloalkyl (H, z = 2), or the indane ring system, e.g., X is CH2; Y is CR9R10; Z is CR11R12, and R5and R11together form C5cycloalkyl (H, z = 1). In certain embodiments, the carrier may be based on the pyrroline ring system or the 4-hydroxyproline ring system, e.g., X is N(CO)R7or NR7, Y is CR9R10, and Z is absent (D). 5 . OFG1is preferably attached to a primary carbon, e.g., an exocyclic alkylene group, e.g., a methylene group, connected to one of the carbons in the five-membered ring (-CH2OFG1in D). OFG2is preferably attached directly to one of the carbons in the five-membered ring (-OFG2in D). For the pyrroline-based carriers, -CH2OFG1may be attached to C-2 and OFG2may be attached to C-3; or - CH2OFG1may be attached to C-3 and OFG2may be attached to C-4. In certain embodiments, CH2OFG110 and OFG2may be geminally substituted to one of the above-referenced carbons. For the 3- hydroxyproline-based carriers, -CH2OFG1may be attached to C-2 and OFG2may be attached to C-4. The pyrroline- and 4-hydroxyproline-based monomers may therefore contain linkages (e.g., carbon- carbon bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring. Thus, CH2OFG1and OFG2may be cis or trans with respect to one another 15 in any of the pairings delineated above Accordingly, all cis / trans isomers are expressly included. The monomers may also contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of the monomers are expressly included (e.g., the centers bearing CH2OFG1and OFG2can both have the R configuration; or both have the S configuration; or one center can have the R configuration 20 and the other center can have the S configuration and vice versa). The tethering attachment point is preferably nitrogen. Preferred examples of carrier D include the following: 106 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO . In certain embodiments, the carrier may be based on the piperidine ring system (E), e.g., X is . 5 OFG1is preferably attached to a primary carbon, e.g., an exocyclic alkylene group, e.g., a methylene group (n=1) or ethylene group (n=2), connected to one of the carbons in the six-membered ring [-(CH2)nOFG1in E]. OFG2is preferably attached directly to one of the carbons in the six-membered ring (-OFG2in E). -(CH2)nOFG1and OFG2may be disposed in a geminal manner on the ring, i.e., both groups may be attached to the same carbon, e.g., at C-2, C-3, or C-4. Alternatively, -(CH2)nOFG1and 10 OFG2may be disposed in a vicinal manner on the ring, i.e., both groups may be attached to adjacent ring carbon atoms, e.g., -(CH2)nOFG1may be attached to C-2 and OFG2may be attached to C-3; -(CH2)nOFG1may be attached to C-3 and OFG2may be attached to C-2; -(CH2)nOFG1may be attached to C-3 and OFG2may be attached to C-4; or -(CH2)nOFG1may be attached to C-4 and OFG2may be attached to C- 3. The piperidine-based monomers may therefore contain linkages (e.g., carbon-carbon bonds) wherein 15 bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring. Thus, -(CH2)nOFG1and OFG2may be cis or trans with respect to one another in any of the pairings delineated above. Accordingly, all cis / trans isomers are expressly included. The monomers may also contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of the 20 monomers are expressly included (e.g., the centers bearing CH2OFG1and OFG2can both have the R configuration; or both have the S configuration; or one center can have the R configuration and the other center can have the S configuration and vice versa). The tethering attachment point is preferably nitrogen. In certain embodiments, the carrier may be based on the piperazine ring system (F), e.g., X is25 N(CO)R7 or NR7, Y is NR8, and Z is CR11R12, or the morpholine ring system (G), e.g., X is N(CO)R7 orNR7, Y is O, and Z is CR11R12. 107 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO . OFG1is preferably attached to a primary carbon, e.g., an exocyclic alkylene group, e.g., a methylene group, connected to one of the carbons in the six-membered ring (-CH2OFG1in F or G). OFG2is preferably attached directly to one of the carbons in the six-membered rings (-OFG2in F or G). 5 For both F and G, -CH2OFG1may be attached to C-2 and OFG2may be attached to C-3; or vice versa. In certain embodiments, CH2OFG1and OFG2may be geminally substituted to one of the above- referenced carbons.The piperazine- and morpholine-based monomers may therefore contain linkages (e.g., carbon-carbon bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring. Thus, CH2OFG1and OFG2may be cis or trans with 10 respect to one another in any of the pairings delineated above. Accordingly, all cis / trans isomers are expressly included. The monomers may also contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of the monomers are expressly included (e.g., the centers bearing CH2OFG1and OFG2can both have the R configuration; or both have the S configuration; or one center 15 can have the R configuration and the other center can have the S configuration and vice versa). R’’’ can be, e.g., C1-C6 alkyl, preferably CH3. The tethering attachment point is preferably nitrogen in both F and G. In certain embodiments, the carrier may be based on the decalin ring system, e.g., X is CH2; Y is CR9R10; Z is CR11R12, and R5and R11together form C6cycloalkyl (H, z = 2), or the indane ring system, 20 e.g., X is CH2; Y is CR9R10; Z is CR11R12, and R5and R11together form C5cycloalkyl (H, z = 1). . OFG1is preferably attached to a primary carbon, e.g., an exocyclic methylene group (n=1) or ethylene group (n=2) connected to one of C-2, C-3, C-4, or C-5 [-(CH2)nOFG1in H]. OFG2is preferably attached directly to one of C-2, C-3, C-4, or C-5 (-OFG2in H). -(CH2)nOFG1and OFG2may be disposed 25 in a geminal manner on the ring, i.e., both groups may be attached to the same carbon, e.g., at C-2, C-3, C-4, or C-5. Alternatively, -(CH2)nOFG1and OFG2may be disposed in a vicinal manner on the ring, i.e., both groups may be attached to adjacent ring carbon atoms, e.g., -(CH2)nOFG1may be attached to C-2 and OFG2may be attached to C-3; -(CH2)nOFG1may be attached to C-3 and OFG2may be attached to C- 108 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO 2; -(CH2)nOFG1may be attached to C-3 and OFG2may be attached to C-4; or -(CH2)nOFG1may be attached to C-4 and OFG2may be attached to C-3; -(CH2)nOFG1may be attached to C-4 and OFG2may be attached to C-5; or -(CH2)nOFG1may be attached to C-5 and OFG2may be attached to C-4. The decalin or indane-based monomers may therefore contain linkages (e.g., carbon-carbon bonds) wherein 5 bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring. Thus, -(CH2)nOFG1and OFG2may be cis or trans with respect to one another in any of the pairings delineated above. Accordingly, all cis / trans isomers are expressly included. The monomers may also contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of the 10 monomers are expressly included (e.g., the centers bearing CH2OFG1and OFG2can both have the R configuration; or both have the S configuration; or one center can have the R configuration and the other center can have the S configuration and vice versa). In a preferred embodiment, the substituents at C-1 and C-6 are trans with respect to one another. The tethering attachment point is preferably C-6 or C-7. Other carriers may include those based on 3-hydroxyproline (J). 15 . Thus, -(CH2)nOFG1and OFG2may be cis or trans with respect to one another. Accordingly, all cis / trans isomers are expressly included. The monomers may also contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of the monomers are expressly included (e.g., the 20 centers bearing CH2OFG1and OFG2can both have the R configuration; or both have the S configuration; or one center can have the R configuration and the other center can have the S configuration and vice versa). The tethering attachment point is preferably nitrogen. Details about more representative cyclic, sugar replacement-based carriers can be found in U.S. Patent Nos.7,745,608 and 8,017,762, which are herein incorporated by reference in their entireties. 25 (ii) Sugar Replacement-Based Monomers (Acyclic)Acyclic sugar replacement-based monomers, e.g., sugar replacement-based ligand-conjugated monomers, are also referred to herein as ribose replacement monomer subunit (RRMS) monomer compounds. Preferred acyclic carriers can have formula LCM-3 or LCM-4: 109 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO . In some embodiments, each of x, y, and z can be, independently of one another, 0, 1, 2, or 3. In formula LCM-3, when y and z are different, then the tertiary carbon can have either the R or Sconfiguration. In preferred embodiments, x is zero and y and z are each 1 in formula LCM-3 (e.g., based 5 on serinol), and y and z are each 1 in formula LCM-3. Each of formula LCM-3 or LCM-4 below can optionally be substituted, e.g., with hydroxy, alkoxy, perhaloalkyl. Details about more representative acyclic, sugar replacement-based carriers can be found in U.S. Patent Nos.7,745,608 and 8,017,762, which are herein incorporated by reference in their entireties. The at least one in vivo delivery enhancing moiety may be conjugated to one or more internal 10 positions on at least one strand, e.g., a sense strand or an antisense strand. Internal positions of a strand refers to the nucleotide on any position of the strand, except the terminal position from the 3’ end and 5’ end of the strand (e.g., excluding 2 positions: position 1 counting from the 3’ end and position 1 counting from the 5’ end). In one embodiment, the at least one in vivo delivery enhancing moiety may be conjugated to one 15 or more internal positions on at least one strand, which include all positions except the terminal two positions from each end of the strand (e.g., excluding 4 positions: positions 1 and 2 counting from the 3’ end and positions 1 and 2 counting from the 5’ end). In one embodiment, the at least one in vivo delivery enhancing moiety is conjugated to one or more internal positions on at least one strand, which include all positions except the terminal three positions from each end of the strand (e.g., excluding 6 positions: 20 positions 1, 2, and 3 counting from the 3’ end and positions 1, 2, and 3 counting from the 5’ end). In one embodiment, the at least one in vivo delivery enhancing moiety may be conjugated to one or more internal positions on at least one strand, except the cleavage site region of the sense strand, for instance, the at least one in vivo delivery enhancing moiety is not conjugated to positions 9-12 counting from the 5’-end of the sense strand, for example, the at least one in vivo delivery enhancing moiety is not 25 conjugated to positions 9-11 counting from the 5’-end of the sense strand. Alternatively, the internal positions exclude positions 11-13 counting from the 3’-end of the sense strand. In one embodiment, the at least one in vivo delivery enhancing moiety may be conjugated to one or more internal positions on at least one strand, which exclude the cleavage site region of the antisense strand. For instance, the internal positions exclude positions 12-14 counting from the 5’-end of the 30 antisense strand. In one embodiment, the at least one in vivo delivery enhancing moiety may be conjugated to one or more internal positions on at least one strand, which exclude positions 11-13 on the sense strand, counting from the 3’-end, and positions 12-14 on the antisense strand, counting from the 5’-end. 110 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In one embodiment, the at least one in vivo delivery enhancing moiety may be conjugated to one or more of the following internal positions: positions 4-8 and 13-18 on the sense strand, and positions 6- 10 and 15-18 on the antisense strand, counting from the 5’end of each strand. In one embodiment, the at least one in vivo delivery enhancing moiety may be conjugated to one 5 or more of the following internal positions: positions 5, 6, 7, 15, and 17 on the sense strand, and positions 15 and 17 on the antisense strand, counting from the 5’end of each strand. In one embodiment, the at least one in vivo delivery enhancing moiety may be conjugated to position 6 on the sense strand, counting from the 5’end of each strand. In some embodiments, the at least one in vivo delivery enhancing moiety may be conjugated to a10 nucleobase, sugar moiety, or internucleosidic phosphate linkage of the dsRNA agent. In one embodiment, the at least one in vivo delivery enhancing moiety is conjugated to a sugar moiety of the dsRNA agent. In a further embodiment, the at least one in vivo delivery enhancing moiety is conjugated to the 2’ position of a ribose sugar of the dsRNA agent. 15 III. Alpha-v-Beta-6 (αvβ6) Integrin Targeting Ligands The present disclosure provides dual conjugated dsRNA agents for inhibiting expression of a target gene. In some embodiments, a dsRNA agent comprises an antisense strand and a sense strand; at least one αvβ6 integrin targeting ligand that mediates delivery to muscle tissue conjugated to at least one 20 strand; and at least one in vivo delivery enhancing moiety conjugated to at least one strand. Integrins are cell surface receptors that, upon ligand binding, activate signal transduction pathways including signaling pathways involved in cytoskeleton organization and cell cycle regulation. Integrins are also involved in cell attachment to the extracellular matrix and the integrin ligands comprise common extracellular matrix components, including fibronectin, collagen, laminin, fibrinogen, 25 thrombospondin, and glycoproteins (e.g., tenascin C, osteopontin, and nefronectin). In humans there are at least twenty-four known integrin heterodimers composed of an alpha and a beta subunit, e.g., αvβ6. It is the combination of the alpha and beta subunits which determines the ligand specificity and function of the integrin. Nearly all cells express at least one integrin and the expression and / or activity of integrins can be influenced by other signal inducing molecules, such as cytokines or steroids. 30 The main function of αvβ6 is the activation of cytokine transforming growth factor-b1 (TGF-β1). Latent-TGF-β1 is bound to the extracellular matrix, covered by its pro-peptide latency associated peptide (LAP). αvβ6 binds LAP, and through cytoskeletal force releases TGF-β1. TGF-β1 regulates multiple processes including cell proliferation, differentiation, angiogenesis, epithelial-mesenchymal-transition (EMT) and immune suppression. These processes combine to heal wounds but when uncontrolled can 35 promote tissue pathologies. 111 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO The present disclosure provides dual conjugated dsRNA agents for inhibiting expression of a target gene that comprise an antisense strand and a sense strand; at least one αvβ6 integrin targeting ligand that mediates delivery to muscle tissue conjugated to at least one strand; and at least one in vivo delivery enhancing moiety conjugated to at least one strand. 5 A. Alpha-v-Beta-6 (αvβ6) Integrin Targeting Ligands Conjugated to dsRNA agentsIn one aspect, the dsRNA agent of the present disclosure is conjugated to at least one αvβ6 integrin targeting ligand. The at least one αvβ6 integrin targeting ligand may be conjugated to the dsRNA agent via a direct attachment to the dsRNA agent, e.g., a ribosugar of the dsRNA agent. 10 Alternatively, the at least one αvβ6 integrin targeting ligand may be conjugated to the dsRNA agent via a linker or a carrier as described herein. Exemplary αvβ6 integrin targeting ligands that can conjugated to the dsRNA agents of the disclosure can be found, e.g., in U.S. Patent Nos 10,023,568, 10,450,312, 10,144,733, 10,487,080, 105,13,517, and 10,000,489, as well as in International Patent Application No. PCT / US2023 / 083947, 15 filed on December 14, 2023, the entire contents of each of which are incorporated herein by reference. In one embodiment, the αvβ6 integrin targeting ligand may be conjugated to the dsRNA agent via a linker comprising a compound of the structure L333 N-(aminocaproyl-DBCO)-4-hydroxyprolinol, wherein * represents the bond to the remainder of the 20 dsRNA agent. In one embodiment, the αvβ6 integrin targeting ligand comprises the structure: wherein 112 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO 5 bond from RLigto the nitrogen, # is the bond to the integrin ligand, and * represents the bond to the remainder of the dsRNA agent. 113 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In one embodiment, the αvβ6 integrin targeting ligand comprises the structure: 5 In one embodiment, the αvβ6 integrin targeting ligand comprises the structure: 10 114 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO 5 , the bond from RLigto the nitrogen, # is the bond to the integrin ligand, and * represents the bond to the remainder of the dsRNA agent. In one embodiment, the αvβ6 integrin targeting ligand comprises the structure: 10 wherein wherein 115 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO 5 bond from RLigto the nitrogen, # is the bond to the integrin ligand, and * represents the bond to the remainder of the dsRNA agent. 116 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In one embodiment, the αvβ6 integrin targeting ligand comprises the structure: to the re 5 In some embodiments, the αvβ6 integrin targeting ligand or the the αvβ6 integrin targeting ligand to the dsRNA agent of the present disclosure comprises a structure selected from the table below: 117 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO 118 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO wherein Z1 is a linker linking the αvβ6 integrin targeting ligand to the remainder of the dsRNA agent and wherein * represents the bond to the remainder of the dsRNA agent. 119 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO B. Alpha-v-Beta-6 (αvβ6) Integrin Targeting Ligands Conjugated to a Carrier Group In some embodiments, the alpha-v-beta-6 (αvβ6) integrin targeting ligand may be conjugated to the dsRNA agent of the disclosure, e.g., to at least one strand of the dsRNA agent of the disclosure, via a 5 carrier group. In some embodiments, the alpha-v-beta-6 (αvβ6) integrin targeting ligand conjugated to the dsRNA agent of the disclosure, e.g., to at least one strand of the dsRNA agent of the disclosure, is represented by a compound of the Formula (X): or a salt thereof, wherein: Y is O, N(H), S, or CH2; (e.g., O or CH2) 10 , wherein m is 0, 1, 2, 3, or 4; and each R2is independently R, or two R2groups on adjacent carbon atoms taken together with the atoms to which they are bound form a fused 4 – 8 membered ring (e.g,. cycloalkyl or heterocyclyl ring) that is optionally substituted by 1, 2, 3 or 4 groups 15 independently selected from group consisting of R and a nitrogen protecting group; A is an 5-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, fluoro, hydroxymethyl, 2-hydroxypropan-2-yl, trifluoromethyl, difluoromethyl, and fluoromethyl; Q is -COOR1or tetrazolyl (e.g., 1,2,3,4-tetrazol-5-yl), wherein R1is hydrogen or C1-6alkyl (e.g., 20 methyl);and RLis -N(R3)(R4), -O(R5), -S(R5), or -R5, wherein R3and R4are either (i) R3 is hydrogen or C1-6alkyl and R4 is R5; or(ii) R3 and R4 taken together with the nitrogen atom to which they are25 attached form a 4 – 8 membered monocyclic heterocyclyl group that is substituted with R5; and R5is -L-ZZ-L’-RTwherein L and L’ are independently -L1-[G-L2]q-G-L3-*, wherein 120 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO * is the bond to ZZ; q is 0 or an integer selected from 1 – 25; (e.g., 1-20, or 1-15); L1is a bond or -B-A-; each L2is independently -A-B-A-; 5 L3is a bond or -A-B-A-; each G is independently -D-E-F-, wherein D, E, and F are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; 10 each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RNis independently hydrogen or C1-6alkyl, or two RNwithin an -A- B-A- group taken together with the atoms to which they are connected 15 from a 4-8 membered heterocyclyl; and ZZ is -A’-B’-A’- or a linking group formed by a reactive pair, wherein each A’ is independently a bond, -O-, -S-, or -N(RN3)-; each B’ is independently a bond, CH2, C(O), C(S), C(NRN3), -C=N-, S(O), 20 S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RN3is independently hydrogen or C1-6alkyl, or two RN3within the -A’-B’- A’- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; RTis -G0-ORT1, wherein 25 G0is absent or -D0-E0-F0-, wherein D0, E0, and F0are independently a bond, C1- 10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; and 30 RT1is LL-oligonucleotide, wherein LLis an oligonucleotide linking group connecting the αvβ6 integrin targeting ligand to oligonucleotide comprised in the dsRNA agent; and each R group is independently selected from the group consisting of R’, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkylC1-6alkyl, 35 heterocyclylC1-6alkyl, aryl C1-6alkyl, heteroarylC1-6alkyl, each of which, other than R’, is optionally substituted with 1, 2, or 3 R’ groups, wherein 121 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO each R’ is independently halogen, cyano, azido, nitro, -N(Rb)2, -O(Ra), -S(R0), - C(O)OR0, - C(O)R0, -C(O)N(R0)2, -C(NR0)OR0, -C(NR0)R0, -C(NR0)N(R0)2, -C(S)OR0, -C(S)R0, -C( S)N(R0)2, -S(O)2R0, -S(O)2OR0, -S(O)2N(R0)2, -N(R0)C(O)OR0, -N(R0)C(O)R0, -N(R0)C( 5 O)N(R0)2, -N(R0)S(O)2R0, -N(R0)S(O)2OR0, -N(R0)S(O)2N(R0)2, -OC(O)OR0, -OC(O)R0, -OC(O)N(R0)2, -OS(O)2R0, -OS(O)2OR0, -OS(O)2N(R0)2, or -SC(O)R0, wherein each R0is independently hydrogen or C1-6alkyl; each Rais independently hydrogen or C1-6alkyl; and each Rbis independently hydrogen, C1-6alkyl, or a nitrogen protecting group. 10 In some embodiments, in each -D-E-F- group, at least one of D, E, and F is not a bond; and RLis not N-morpholinyl. In some embodiments of Formula (X), in -N(R3)(R4), R3and R4do not form a morpholino ring. In some embodiments of Formula (X), in each -A-B-A- group, B is only a bond when one of the A groups is not a bond. 15 In some embodiments, each R group is independently selected from the group consisting of R’, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3- 8cycloalkylC1-6alkyl, heterocyclylC1-6alkyl, aryl C1-6alkyl and heteroaryl1-6alkyl, each of which, other than R’, is optionally substituted with 1, 2, or 3 R’ groups, wherein each R’ is independently halogen, cyano, azido, nitro, -N(Rb)2, -O(Ra), -S(R0), -C(O)OR0, -C(O)R0, -C(O)N(R0)2, -N(R0)C(O)R0, -OC(O)OR0, or - 20 OC(O)R0, wherein each R0is independently hydrogen or C1-6alkyl; each Rais independently hydrogen or C1-6alkyl; and each Rbis independently hydrogen, C1-6alkyl, or a nitrogen protecting group. In some embodiments, each R group is independently selected from the group consisting of R’, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and benzyl, each of which, other than R’, is optionally substituted with 1, 2, or 325 R’ groups, wherein each R’ is independently halogen, cyano, azido, nitro, -N(Rb)2, -O(Ra), -S(R0), - C(O)OR0, -C(O)R0, -C(O)N(R0)2, -N(R0)C(O)R0, -OC(O)OR0, or -OC(O)R0, wherein each R0is independently hydrogen or C1-6alkyl; each Rais independently hydrogen or C1-6alkyl; and each Rbis independently hydrogen, C1-6alkyl, or a nitrogen protecting group. In some embodiments, each R group is independently selected from the group consisting of R’, 30 C1-6alkyl, C3-6cycloalkyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and benzyl, each of which, other than R’, is optionally substituted with 1, 2, or 3 R’ groups, wherein each R’ is independently halogen, cyano, azido, nitro, -N(Rb)2, -O(Ra), -S(R0), -C(O)OR0, - C(O)R0, -C(O)N(R0)2, -N(R0)C(O)R0, -OC(O)OR0, or -OC(O)R0, wherein each R0is independently hydrogen or C1-6alkyl; each Rais independently hydrogen or C1-6alkyl; and each Rbis independently 35 hydrogen, C1-6alkyl, or a nitrogen protecting group. 122 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In certain embodiments, the compound of formula ( In certain embodiments, the compound of formula ( In certain embodiments, the compound of formula ( In certain embodiments, the compound of formula ( 5 A Embodiments, Formula (X) In some embodiments Formula (X), A is selected from an optionally substituted N- or a C-linked pyrazole, an optionally substituted N- or a C-linked triazole, and an optionally substituted N- or C-linked imidazole, wherein the optionally substituted N- or a C-linked pyrazole, the optionally substituted N- or a 10 C-linked triazole, and the optionally substituted N- or C-linked imidazole is optionally substituted by 1 or 2 substituents independently selected from methyl, ethyl, fluoro, hydroxymethyl, 2-hydroxypropan-2-yl, trifluoromethyl, difluoromethyl, and fluoromethyl. In some embodiments , wherein R1is hydrogen, methyl, or ethyl; R2is hydrogen or fluoro; and R3 is hydrogen, methyl, or ethyl. 15 In some embodiments . some embodiments A is . In some embodiments A is selected from: 123 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO RYEmbodiments, Formula (X) In some embodiments of any one of Formula (X), in RY, each R2is independently R as defined in Formula (X). 5 In some embodiments,R In some embodiments,R .In some embodiments, in RY, two R2groups on adjacent carbon atoms taken together with the atoms to which they are bound form a fused 4 – 8 membered ring that is optionally substituted with 1, 2, 3 or 4 groups independently selected from group consisting of R and a nitrogen protecting group, wherein R is 10 as defined in Formula (IV). In some embodiments, RYisNH wherein p is 0, 1, 2, 3 or 4; and each R21is independently selected from group consisting of R and a nitrogen protecting group, wherein R is as defined in Formula (IV). In some embodiments, RYis , wherein p is 0, 1, 2, 3 or 4; and each R21is 15 independently selected from the group consisting of R and a nitrogen protecting group, wherein R is as defined in Formula (IV). 124 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO , wherein RPis a nitrogen protecting group. In some embodiments, 5 group. In some embodiments of any embodiment of RYwherein RPis present, then RPis 10 , wherein r is 0, 1, 2, or 3; each RP2is independently halogen, nitro, cyano, C1- 4alkoxy, C1-4alkyl, C1-4haloalkyl; and each RP3is independently hydrogen, methyl, or ethyl. In some embodiments, when present, RPis methoxyacetyl (mac), phenoxyacetyl (pac), 2- chlorophenoxyacetyl, 3-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2,4-dichlorophenoxyacetyl, 2- 125 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO methylphenoxyacetyl, 3-methylphenoxyacetyl, 4-methylphenoxyacetyl, 4-chloro-2- methylphenoxyacetyl, 2-nitrophenoxyacetyl, 3-nitrophenoxyacetyl, 4-nitrophenoxyacetyl, 2- isopropylphenoxyacetyl, 3-isopropylphenoxyacetyl, 4-isopropylphenoxyacetyl, 2-(t-butyl)phenoxyacetyl, 3-(t-butyl)phenoxyacetyl, 4-(t-butyl)phenoxyacetyl, 2-fluorophenoxyacetyl, 3-fluorophenoxyacetyl, 4- 5 fluorophenoxyacetyl, 2,4-difluorophenoxyacetyl, 4-(trifluoromethoxy)phenoxyacetyl, 2- phenoxypropanoyl, 2-(4-chloro-2-methylphenoxy)propanoyl, or 2-(4-chlorophenoxy)propanoyl. In some embodiments, when present, RPis methoxyacetyl (mac), phenoxyacetyl (pac), 2- chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2-methylphenoxyacetyl, 4-methylphenoxyacetyl, or 4- isopropylphenoxyacetyl. 10 In some embodiments, when present, RPis methoxyacetyl (mac). In some embodiments, when present, RPis phenoxyacetyl (pac). In some embodiments, when present, R1is C1-6alkyl , wherein r is 0, 1, 2, or 3; each RP2is independently halogen, nitro, cyano, C1-4alkoxy, C1-4alkyl, C1-4haloalkyl; and each RP3is independently hydrogen, methyl, or ethyl. 15 In some embodiments or Formula (X), when present, R1is C1-6alkyl and RPis methoxyacetyl (mac), phenoxyacetyl (pac), 2-chlorophenoxyacetyl, 3-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2,4- dichlorophenoxyacetyl, 2-methylphenoxyacetyl, 3-methylphenoxyacetyl, 4-methylphenoxyacetyl, 4- chloro-2-methylphenoxyacetyl, 2-nitrophenoxyacetyl, 3-nitrophenoxyacetyl, 4-nitrophenoxyacetyl, 2- isopropylphenoxyacetyl, 3-isopropylphenoxyacetyl, 4-isopropylphenoxyacetyl, 2-(t-butyl)phenoxyacetyl,20 3-(t-butyl)phenoxyacetyl, 4-(t-butyl)phenoxyacetyl, 2-fluorophenoxyacetyl, 3-fluorophenoxyacetyl, 4- fluorophenoxyacetyl, 2,4-difluorophenoxyacetyl, 4-(trifluoromethoxy)phenoxyacetyl, 2- phenoxypropanoyl, 2-(4-chloro-2-methylphenoxy)propanoyl, or 2-(4-chlorophenoxy)propanoyl. In some embodiments, when present, R1is C1-6alkyl and RPis methoxyacetyl (mac), phenoxyacetyl (pac), 2-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2-methylphenoxyacetyl, 4- 25 methylphenoxyacetyl, or 4-isopropylphenoxyacetyl. In some embodiments, when present, R1is C1-6alkyl and RPis methoxyacetyl (mac). In some embodiments, when present, R1is C1-6alkyl and RPis phenoxyacetyl (pac). In some embodiments, when present, R1is methyl 1, 2, or 3; each RP2is independently halogen, nitro, cyano, C1-4alkoxy, C1-4alkyl, C1-4haloalkyl; and each 30 RP3is independently hydrogen, methyl, or ethyl. 126 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments, when present, R1is methyl and RPis methoxyacetyl (mac), phenoxyacetyl (pac), 2-chlorophenoxyacetyl, 3-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2,4- dichlorophenoxyacetyl, 2-methylphenoxyacetyl, 3-methylphenoxyacetyl, 4-methylphenoxyacetyl, 4- chloro-2-methylphenoxyacetyl, 2-nitrophenoxyacetyl, 3-nitrophenoxyacetyl, 4-nitrophenoxyacetyl, 2- 5 isopropylphenoxyacetyl, 3-isopropylphenoxyacetyl, 4-isopropylphenoxyacetyl, 2-(t-butyl)phenoxyacetyl, 3-(t-butyl)phenoxyacetyl, 4-(t-butyl)phenoxyacetyl, 2-fluorophenoxyacetyl, 3-fluorophenoxyacetyl, 4- fluorophenoxyacetyl, 2,4-difluorophenoxyacetyl, 4-(trifluoromethoxy)phenoxyacetyl, 2- phenoxypropanoyl, 2-(4-chloro-2-methylphenoxy)propanoyl, or 2-(4-chlorophenoxy)propanoyl. In some embodiments, when present, R1is methyl and RPis methoxyacetyl (mac), phenoxyacetyl 10 (pac), 2-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2-methylphenoxyacetyl, 4-methylphenoxyacetyl, or 4-isopropylphenoxyacetyl. In some embodiments, when present, R1is methyl and RPis methoxyacetyl (mac). In some embodiments, when present, R1is methyl and RPis phenoxyacetyl (pac). In some embodiments, when present, R1is hydrogen wherein r is 15 0, 1, 2, or 3; each RP2is independently halogen, nitro, cyano, C1-4alkoxy, C1-4alkyl, C1-4haloalkyl; and each RP3is independently hydrogen, methyl, or ethyl. In some embodiments, when present, R1is hydrogen and RPis methoxyacetyl (mac), phenoxyacetyl (pac), 2-chlorophenoxyacetyl, 3-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2,4- dichlorophenoxyacetyl, 2-methylphenoxyacetyl, 3-methylphenoxyacetyl, 4-methylphenoxyacetyl, 4-20 chloro-2-methylphenoxyacetyl, 2-nitrophenoxyacetyl, 3-nitrophenoxyacetyl, 4-nitrophenoxyacetyl, 2- isopropylphenoxyacetyl, 3-isopropylphenoxyacetyl, 4-isopropylphenoxyacetyl, 2-(t-butyl)phenoxyacetyl, 3-(t-butyl)phenoxyacetyl, 4-(t-butyl)phenoxyacetyl, 2-fluorophenoxyacetyl, 3-fluorophenoxyacetyl, 4- fluorophenoxyacetyl, 2,4-difluorophenoxyacetyl, 4-(trifluoromethoxy)phenoxyacetyl, 2- phenoxypropanoyl, 2-(4-chloro-2-methylphenoxy)propanoyl, or 2-(4-chlorophenoxy)propanoyl. 25 In some embodiments, when present, R1is hydrogen and RPis methoxyacetyl (mac), phenoxyacetyl (pac), 2-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2-methylphenoxyacetyl, 4- methylphenoxyacetyl, or 4-isopropylphenoxyacetyl. In some embodiments, when present, R1is hydrogen and RPis methoxyacetyl (mac). In some embodiments, when present, R1is hydrogen and RPis phenoxyacetyl (pac). 30 RTEmbodiments, Formula (X) In some embodiments of Formula (X), RTis RT1. 127 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments of Formula (X), RTis -G0-ORT1, wherein RT1is as defined for Formula (X) and G0is selected from: (a) G0 is absent or -D0-E0-F0-, wherein D0, E0, and F0 are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of 5 which is optionally substituted with 1, 2, 3, or 4 R groups; (b) G0 is -D0-E0-F0-, whereinD0and F0are independently a bond or C1-10alkyl optionally substituted with 1, 2, 3, or 4 R groups; and E0is C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is 10 optionally substituted with 1, 2, 3, or 4 R groups; (c) G0 is -D0-E0-F0-, whereinD0and F0are independently a bond or C1-10alkyl optionally substituted with 1, 2, 3, or 4 R groups; and E0is 3-10 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 R groups; and15 (d) G0 is 3-10 membered heterocyclyl optionally substituted with 1 or 2 R groups; examples include , s tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with 1 or 2 R groups; examples include: 20 (e) G0 is 3-10 membered-heterocyclyl-C1-10alkyl, optionally substituted with 1, 2, 3, or 4 R groups;examples include, 128 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (f) G0 is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with 1, 2, 3, or4 R groups (e.g., 1 or 2 R groups); (g) G0 is C1-10alkyl or C2-10alkenyl, each of which is optionally substituted with 1 or 2 R groups;5 (h) G0 is C1-10alkyl optionally substituted with 1 or 2 R groups;(i) G0 is C1-10alkyl, optionally substituted with -O(Ra), wherein Ra is independently hydrogen or C1-6alkyl; (j) G0 is C1-10alkyl, and10 (k) G0 is absent (a bond);wherein * represents the bond to L’, the broken bond represents the bond to ORT1, and R is -C1-6alkyl- ORaor -ORa, wherein Rais independently hydrogen or C1-6alkyl. -L’- Embodiments, Formula (X)15 In some embodiments of Formula (X), -L’- is *-G-L1-, wherein * is the bond to ZZ; and(a) L1 is a bond or -B-A-, whereinA is a bond, -O-, -S-, or -N(RN)-; B is a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RNis independently hydrogen or C1-6alkyl; and 20 G is -D-E-F-, wherein D, E, and F are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; (b) L1 is a bond or -B-A-, whereinA is a bond, -O-, -S-, or -N(RN)-; 25 B is a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RNis independently hydrogen or C1-6alkyl; and G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; (c) L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and30 G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; (d) L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and129 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; or (e) L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and G is C1-10alkyl.5 In some embodiments of Formula (X), -L’- is *-G-[L2-G]q-L1-, wherein * is the bond to ZZ; q is1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer selected from 1 to 8, an integer selected from 1 to 5, or an integer selected from 1 to 3); and (a) L1 is a bond or -B-A-; each L2 is independently -A-B-A-; each A is independently abond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), 10 S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RNis independently hydrogen or C1-6alkyl; each G is independently -D-E-F-, wherein D, E, and F are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; (b) L1 is a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH);15 each L2is independently -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RNis independently hydrogen or C1-6alkyl, and each G is independently a bond, C1-10alkyl, optionally substituted with 1, 2, 3, or 4 R groups. (c) L1 is a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH);20 each L2is independently -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein RNis hydrogen or C1-6alkyl each B is independently a bond, CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); each G is independently C1-10alkyl, optionally substituted with 1, 2, 3, or 4 R groups; (d) L1 is a bond, CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); each L2 is independently -25 A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein RNis hydrogen or C1-6alkyl; each B is independently a bond, CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); each G is independently C1-10alkyl, optionally substituted with 1, 2, 3, or 4 R groups; or30 (e) L1 is a bond, CH2, C(O), S(O)2, P(O)(OH), or P(S)(OH); each L2 is independently -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein RNis hydrogen or C1-6alkyl; each B is independently a bond, CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); each G is independently C1-10alkyl.35 In some embodiments of Formula (X), -L’- is -[G-L2]q-G-L3-*, wherein * is the bond to ZZ; and130 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (i) q is 0, 1, 2, 3, 4, or 5; each L2 is independently -A-B-A-; L3 is a bond or -A-B-A-; each Ais independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RNis independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each 5 of which is optionally substituted with 1, 2, 3, or 4 R groups; (ii) q is 0, 1, 2, or 3; each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O),SO2N(RN), N(RN)SO2, OP(O)(OH), OP(S)(OH), P(O)(OH)O, P(S)(OH)O, OP(O)(OH)O, or OP(S)(OH)O, wherein each RNis independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted 10 with 1 or 2 R groups; (iii) q is 0, 1, 2, or 3; each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O),OP(O)(OH)O, or OP(S)(OH)O, wherein each RNis independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl or C2-10alkenyl, each of which is optionally substituted with 1 or 2 R groups;15 (iv) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independentlyC(O)O or OC(O); each G is independently C1-10alkyl, each of which is optionally substituted with 1 or 2 R groups; (v) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independentlyC(O)(NRN) or N(RN)C(O), wherein each RNis independently hydrogen or C1-6alkyl; each 20 G is independently C1-10alkyl, each of which is optionally substituted with 1 or 2 R groups; (vi) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independentlyOP(O)(OH)O, or OP(S)(OH)O (e.g., each is OP(O)(OH)O); each G is independently C1- 10alkyl, each of which is optionally substituted with 1 or 2 R groups; or25 (vii) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is a bond; each Gis independently C1-10alkyl, each of which is optionally substituted with 1 or 2 R groups. In some embodiments, -L’- is *-L3-G-L1-, wherein * is the bond to ZZ; and (a) L1 and L3 are independently -A-B-A-; each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is30 optionally substituted with 1, 2, or 3 R groups; each A is independently a bond, -O-, -S-, or - N(RN)-, wherein RNis hydrogen or C1-6alkyl; and each B is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); (b) L3 is -C(O)O- or C(O)N(RN)-, wherein RN is hydrogen or C1-6alkyl; L1 is -OP(O)(OH)O- or -OP(S)(OH)O-; and each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-3510cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, or 3 R groups; 131 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (c) L3 is -C(O)O- or C(O)N(RN)-, wherein RN is hydrogen or C1-6alkyl; L1 is -OP(O)(OH)O- or -OP(S)(OH)O-; and each G is independently C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one R group; (d) L3 is -C(O)O- or C(O)N(RN)-, wherein RN is hydrogen or C1-6alkyl; L1 is -OP(O)(OH)O- or -5 OP(S)(OH)O-; and each G is independently C3-10cycloalkyl or 3-10 membered heterocyclyl; or (e) L3 is -C(O)O- or C(O)N(RN)-, wherein RN is hydrogen or C1-6alkyl; L1 is -OP(O)(OH)O- or -OP(S)(OH)O-; and each G1is independently C3-10cycloalkyl or 3-10 membered heterocyclyl. In some embodiments, - wherein X is O or S (e.g., S). 10 In some embodiments, -L’- is *-G-, wherein * is the bond to ZZ; and G is C1-10alkyl is optionally substituted with 1 or 2 R groups. In embodiments, -L’- is --L1-[G-L2]q-G-L3-*, wherein * is the bond to ZZ. In some embodiments, -L’- is -L1-G-L3-*, wherein * is the bond to ZZ. In some embodiments, -L’- is -L1-[G-L2]q-G-L3-*, wherein * is the bond to ZZ; q is 0, 1, 2, 3, 4, 15 or 5; L1is a bond or -B-A-; each L2is independently -A-B-A-; L3is a bond or -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RNis independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with 1, 2, 3, or 4 R groups. 20 In some embodiments, -L’- is -L1-[G-L2]q-G-*, wherein * is the bond to ZZ; q is 0, 1, 2, or 3; L1is a bond or -B-A-; each L2is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), SO2N(RN), N(RN)SO2, OP(O)(OH), OP(S)(OH), P(O)(OH)O, P(S)(OH)O, OP(O)(OH)O, or OP(S)(OH)O, wherein each RNis independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with 1 or 2 R groups. 25 In some embodiments, -L’- is -L1-[G-L2]q-G-*, wherein * is the bond to ZZ; q is 0, 1, 2, or 3; L1is a bond or -B-A-; each L2is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O, wherein each RNis independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl or C2-10alkenyl, each of which is optionally substituted with 1 or 2 R groups. In some embodiments, -L’- is -[G-L2]q-G-*, wherein * is the bond to ZZ; and30 (a) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independentlyC(O)O or OC(O); each G is independently C1-10alkyl, each of which is optionally substituted with 1 or 2 R groups; (b) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independentlyC(O)(NRN) or N(RN)C(O), wherein each RNis independently hydrogen or C1-6alkyl; and 132 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO each G is independently C1-10alkyl, each of which is optionally substituted with 1 or 2 R groups; (c) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independentlyOP(O)(OH)O, or OP(S)(OH)O (e.g., each is OP(O)(OH)O); and each G is independently 5 C1-10alkyl, each of which is optionally substituted with 1 or 2 R groups; (d) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is a bond; and eachG is independently C1-10alkyl, each of which is optionally substituted with 1 or 2 R groups. In some embodiments, -L’- is -C2-30alkyl-*, wherein * is the bond to ZZ, such as -C5-20alkyl-* or -10 C10-20alkyl-*. In some embodiments, -L’- is -C(O)-C2-30alkyl-*, wherein * is the bond to ZZ, such as -C(O)- C5-20alkyl-* or -C(O)-C10-20alkyl-*. L’-RTEmbodiments In some embodiments, - , wherein * is the 15 bond to ZZ; L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and RT1is as defined for Formula (X). In some embodiments, - wherein * is the bond to ZZ; L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and RT1is as defined for Formula (X). In some embodiments, - , wherein * is the 20 bond to ZZ; L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); R is -OH or -C1-6alkyl-OH; and RT1is as defined for Formula (X). 133 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments, - , wherein * is the bond to ZZ; L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); R is -OH or -C1-6alkyl-OH; and RT1is as defined for Formula (X). In some embodiments, -L’-RTis 5 wherein* is the bond to ZZ; L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); R is -OH or -C1-6alkyl-OH; and RT1is as defined for Form In some embodiments, -L’-RTis , wherein * is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 10 1 to 5, or an integer from 1 to 3); each L2is (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O- ,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RNis independently 15 hydrogen or C1-6alkyl; or (ii) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (iii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -20 OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or 134 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-,and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O),wherein each RNis independently hydrogen or C1-6alkyl; 5 L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and RT1is as defined for Formula (X). In some embodiments, - , wherein * is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); each L2is10 (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O- ,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (ii) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -15 N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (iii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or20 (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-,and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl;25 (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O),wherein each RNis independently hydrogen or C1-6alkyl; L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and RT1is as defined for Formula (X). 135 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments, -L’-RT is wherein * is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); each L2is 5(i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O- ,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (ii) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -10 N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (iii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or15 (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-,and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or20 (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O),wherein each RNis independently hydrogen or C1-6alkyl; L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and RT1is as defined for Formula (X). In some embodiments, -L’-RTis wherein * is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-8; or 1-5; or 1-3); 25 each L2is (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O- ,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or 136 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (ii) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (iii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -5 OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or10 (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-,and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O),wherein each RNis independently hydrogen or C1-6alkyl; L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); R is -OH or -C1-6alkyl-OH; and RT1is as 15 defined for Formula (X). , wherein * is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); each L2is20 (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O- ,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (ii) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -25 N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (iii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or 137 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-,and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or 5(vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O),wherein each RNis independently hydrogen or C1-6alkyl; L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); R is -OH or -C1-6alkyl-OH; and RT1is as defined for Formula (X). In some embodiments, -L’-RTis 10 wherein* is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); each L2is (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -15 N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O- ,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (ii) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, 20 wherein each RNis independently hydrogen or C1-6alkyl; or (iii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -25 N(RN)C(O)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-,and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O),30 wherein each RNis independently hydrogen or C1-6alkyl; L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); R is -O(Ra) or -C1-6alkyl-O(Ra), wherein Rais hydrogen or a hydroxyl protecting group; and RT1is as defined for Formula (X). 138 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); each L2is 5(i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O- ,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (ii) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -10 N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (iii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or15 (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-,and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl;20 (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O),wherein each RNis independently hydrogen or C1-6alkyl; L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); R is -OH or -C1-6alkyl-OH; and RT1is as defined for Formula (X). In some embodiments, -L’-RTis 25 wherein* is the bond to ZZ; L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); R is -O(Ra) or -C1-6alkyl-O(Ra), wherein Rais hydrogen; and RT1is as defined for Formula (X). 139 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO RLEmbodiments, Formula (X) In one embodiment the Formula (X), or a salt thereof, RLis -N(R3)(R4), -O(R5), -S(R5), or -R5, wherein R5is according to one Formulae (x-a) through (x-ab): 140 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (x-ab) wherein RP3is hydrogen and L, ZZ, L’ and RT1are as defined for Formula (X) or any embodiment herein. In another embodiment, RLis according to one of Formulae (xi-a) through (xi-m): 141 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (xi-m) wherein RP3is hydrogen, and L, ZZ, L’ and RT1are as defined for Formula (X) or any embodiment herein. In another embodiment, RLis according to one of Formulae (xi-n) through (xi-z): 142 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO wherein RP3is hydrogen, and L, ZZ, L’ and RT1are as defined for Formula (X) or any embodiment herein. In some embodiments, RLis -N(R3)(R4), wherein R3is hydrogen or C1-6alkyl and R4is R5. In some embodiments, RLis -N(R3)(R4), wherein R3is hydrogen and R4is R5. In some embodiments, RLis -N(R3)(R4), wherein R3is C1-3alkyl and R4is R5. 5 In some embodiments, RLis -N(R3)(R4), wherein R3is methyl and R4is R5. In some embodiments, RLis --N(R3)(R4), wherein R3and R4taken together with the nitrogen atom to which they are attached form a 4 – 8 membered monocyclic heterocyclyl group that is substituted with R5. In some embodiments, RLis --N(R3)(R4), wherein R3and R4taken together with the nitrogen 10 atom to which they are attached form a 4 – 8 membered monocyclic heterocyclyl group that is substituted with R5, provided that R3and R4taken together with the nitrogen atom to which they are attached do not form a morpholino group. In some embodiments, RLis --N(R3)(R4), wherein R3and R4taken together with the nitrogen atom to which they are attached form a group that is piperidinyl, piperazinyl, pyrrolidinyl, 15 imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, azetidinyl, pyrrolinyl, imidazolinyl, or pyrazolinyl, each substituted with R5. 143 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments, . In one embodiment the Formula (X), or a salt thereof, RLis -N(R3)(R4). In one embodiment the Formula (X), or a salt thereof, RLis -N(R3)(R4), wherein R3and R4taken together with the nitrogen atom to which they are attached form a 4 – 8 membered monocyclic heterocyclyl 5 group that is substituted with R5. In some embodiments, RLis -O(R5). In some embodiments, RLis -R5. In some embodiments, RL is , wherein * is a bond to a ZZ group; s is 1 – 24(e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an 10 integer from 4 to 6). In some embodiments, RL is , wherein * is a bond to a ZZ group; t is0 to 10 (e.g., 1-5; or 1-3; or 1; or 2; or 3). L Embodiments, Formula (X) 15 In some embodiments of any one of Formula (X) and any embodiments thereof, L is -L1-[G-L2]q- G-L3-*, wherein * is the bond to ZZ. In another embodiment, wherein L is -L1-[G-L2]q-G-L3-*, wherein q is 0, 1, 2, 3, 4, or 5. In another embodiment , L is -L1-[G-L2]q-G-L3-*, wherein q is 0, 1, 2, 3, or 4 In another embodiment , L is -L1-[G-L2]q-G-L3-*, wherein q is 0, 1, 2, or 3. 20 In another embodiment , L is -L1-[G-L2]q-G-L3-*, wherein q is 0, 1, or 2. In another embodiment , L is -L1-[G-L2]q-G-L3-*, wherein q is 1, 2, 3, 4, or 5. In another embodiment , L is -L1-[G-L2]q-G-L3-*, wherein q is 1, 2, 3, or 4. In another embodiment , L is -L1-[G-L2]q-G-L3-*, wherein q is 1, 2, or 3. In another embodiment , L is -L1-[G-L2]q-G-L3-*, wherein q is 1 or 2. 25 In another embodiment, L is -L1-[G-L2]q-G-L3-*, wherein q is 4. In another embodiment , L is - L1-[G-L2]q-G-L3-*, wherein q is 3. In another embodiment, L is -L1-[G-L2]q-G-L3-*, wherein q is 2. In another embodiment, L is -L1-G-L2-G-L3-*. In another embodiment, L is -L1-G-L3-*. In another embodiment, L is -G-L3-*. In another embodiment , L is -L1-G-*. In another embodiment, L is - G-*. 30 In another embodiment, wherein L is -[G-L2]q-G-*, wherein q is 1, 2, 3, 4, or 5 (e.g., q is 2; or q is 3; or q is 4; or q is 5). In some embodiments, each instance of A-B-A- is independently selected fromthe group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, - 144 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -OP(O)(OH)O- ,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl. In some embodiments, each instance of A-B-A- is independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,- 5 N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl. In some embodiments, each instance of A-B-A- is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and - N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl. In some embodiments, each instance of A-B-A- is independently selected from the group 10 consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl. In some embodiments, each instance of A-B-A- is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl. 15 In some embodiments, D and F are each independently a bond, C1-10alkyl, C2-10alkenyl, or C2- 10alkynyl, each optionally substituted with 1, 2, 3, or 4 R groups; and E is C1-10alkyl, C2-10alkenyl, C2- 10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups. In some embodiments, D and F are each independently a bond or C1-10alkyl optionally 20 substituted with 1, 2, 3, or 4 R groups; and E is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3- 10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups. In some embodiments, each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3- 10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted 25 with 1, 2, 3, or 4 R groups. In some embodiments, each G is independently C1-10alkyl, optionally substituted with 1, 2, or 3 R groups. In some embodiments , each G is independently C1-10alkyl, optionally substituted with 1 or 2 R groups. In some embodiments, each G is independently C1-10alkyl, optionally substituted with one R group . In some embodiments, each G is independently C1-10alkyl. 30 In some embodiments, L is -L1-G-L3-*, wherein * is the bond to ZZ ; G is -D-E-F-, wherein D, E, and F are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; L1is -B-A-; 35 L3is a bond or -A-B-A-; 145 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO each A is independently a bond, -O-, -S-, or -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl. each B is independently a bond, CH2, C(O), S(O)2, P(O)(OH), or P(S)(OH); and In some embodiments, L is -L1-G-L3-*, wherein * is the bond to ZZ; 5 G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; L1is -B-; L3is a bond or -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein each RNis independently hydrogen 10 or C1-6alkyl; and each B is independently a bond, CH2, C(O), S(O)2, P(O)(OH), or P(S)(OH; and In some embodiments, L is -L1-G-*, wherein * is the bond to ZZ; G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; 15 L1is -B-A-, wherein, A is a bond, -O-, -S-, or -N(RN)-, wherein each RNis independently hydrogen or C1- 6alkyl; and B is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH). In some embodiments, L is -L1-G-*, wherein * is the bond to ZZ; 20 G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with 1 or 2 R groups; L1is -B-A-, wherein A is a bond, -O-, -S-, or -N(RN)-, each RNis independently hydrogen or C1-6alkyl; and B is a bond, C(O), S(O)2, P(O)(OH), or P(S)(OH). 25 In some embodiments L is -L1-G-*, wherein * is the bond to ZZ; G is C1-10alkyl or C2-10alkenyl, each of which is optionally substituted with 1 or 2 R groups; L1is bond, C(O), S(O)2, P(O)(OH), or P(S)(OH); and RNis hydrogen or C1-6alkyl. In some embodiments, L is -L1-G-*, wherein * is the bond to ZZ , G is C1-10alkyl or C2-10alkenyl, 30 and L1is -B-A-, wherein, A is a bond, -O-, -S-, or -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; and B is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH). In some embodiments, L is -L1-G-*, wherein * is the bond to ZZ , G is C1-10alkyl or C2-10alkenyl, L1is -O-, -S-, or -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl. In some embodiments, L is -L1-G-*, wherein * is the bond to ZZ , G is C2-10alkyl, L1is -O-, -S-, 35 or -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl. 146 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments, L is -L1-G-*, wherein * is the bond to ZZ , G is C2-10alkyl, L1is -O- (e.g., G is C3-10alkyl or C4-10alkyl or C5-10alkyl or C6-10alkyl or C2-8alkyl or C4-8alkyl or C4-8alkyl or C4alkyl or C5alkyl or C6alkyl). In some embodiments, L is wherein * is the bond to ZZ; k is an integerfrom 1 to 10; L1is bond, C(O), C(S), C(NRN), S(O)2, P(O)(OH), or P(S)(OH); and RNis hydrogen or C1-56alkyl. In some embodiments, L is wherein * is the bond to ZZ; k is an integer from 1 to 10; L1is bond, C(O), P(O)(OH), or P(S)(OH). In some embodiments, L is , wherein * is the bond to ZZ; k is an integer from 1 to 10; or an integer from 2 to 10; or an integer from 3 to 10; or an integer from 4 to 10; or an integer from 5 10 to 10; or an integer from 5 to 9; or an integer from 5 to 8; or an integer from 5 to 7. In some embodiments, L is L wherein * is the bond to ZZ; L1is bond; and k is an integer from 1 to 10; or an integer from 2 to 10; or an integer from 3 to 10; or an integer from 4 to 10; or an integer from 5 to 10; or an integer from 5 to 9; or an integer from 5 to 8; or an integer from 5 to 7. In another embodiment, wherein L is -[G-L2]q-G-*, wherein q is 1, 2, 3, 4, or 5 (e.g., q is 2; or q 15 is 3; or q is 4; or q is 5), each G is indepdently C1-10alkyl and L2is O, S, or N(H). In another embodiment, wherein L is -[G-L2]q-G-*, wherein q is 1, 2, 3, 4, or 5 (e.g., q is 2; or q is 3; or q is 4; or q is 5), each G is indepdently C1-10alkyl and L2is O. In another embodiment, wherein L is -[CH2CH2O]q-G-*, wherein q is 1, 2, 3, 4, or 5 (e.g., q is 2; or q is 3; or q is 4; or q is 5), G is indepdently C1-10alkyl.20 In some embodiments, L is , wherein * is the bond to ZZ; t is aninteger from 0 to 10 (e.g., an integer from 1 to 5; or 1; or 2; or 3). In some embodiments, L is , wherein * is the bond to ZZ.In some embodiments, L is , wherein * is the bond to ZZ; t is 1 to 10 (e.g., 1-5;or 1-3; or 1; or 2; or 3); and z is 1-10 (e.g., 1-6; or 1-4; or 1; or 2; or 3 or 4 or 5 or 6).25 In some embodiments, L is , wherein * is the bond to ZZ, and t is an integerfrom 1 to 5 (e.g., 1; or 2; or 3). 147 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments, L is , wherein * is the bond to ZZ. In someembodiments, L is wherein * is the bond to ZZ, t is an integer from 0 to 10 (e.g., aninteger from 1 to 5 or 1; or 2; or 3); a is an integer from 1 to 3; and s and s’ are each independently an integer from 1 to 24 (e.g., an integer from 1 to 16; an integer from 1 to 10; an integer from 3 to 10; an 5 integer from 3 to 7; or an integer from 4 to 6). In some embodiments, wherein * is the bond to ZZ; a is 1, 2 or 3; and each s, s’, and s” independently is an integer from 1 to 24 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7, or an integer from 4 to 6). In some embodiments, L is wherein * is the bond to ZZ; and s, s’, 10 and s’’ are independently is an integer from 1 to 24 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7, or an integer from 4 to 6). In some embodiments, L is , wherein * is the bond to ZZ and each s, s’, and s” independently is an integer from 1 to 24(e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7, or an integer from 4 to 6)15 In some embodiments, L is wherein * is the bond to ZZ; s and kare independently is an integer from 1 to 20 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an integer from 4 to 6); and w is an integer from 1 to 10 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an integer from 4 to 6).20 In some embodiments, L is wherein * is the bond to ZZ andw is an integer from 1 to 20 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an integer from 4 to 6). 148 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments, L is C1-20alkyl. In some embodiments, L is C2-20alkyl. In some embodiments, L is C6-20alkyl. In some embodiments, L is C8-12alkyl. In some embodiments, L is C10alkyl. In some embodiments, L is -G-L2-G-*, wherein L2is -A-B-A-; each A is independently a bond, 5 -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RNis independently hydrogen or C1-6alkyl, or two RNwithin an -A-B-A- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; and each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups. 10 In some embodiments, L is -G10-L2-G20-*, wherein L2is -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RNis independently hydrogen or C1-6alkyl, or two RNwithin an - A-B-A- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; G10is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, 15 aryl, or heteroaryl; and G20is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups. In some embodiments, L is -G10-L2-G20-*, wherein L2is a bond, -O-, -S-, or -N(RN)-; RNis independently hydrogen or C1-6alkyl, G10is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl; and G20is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3- 20 10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups. In some embodiments, L is -G10-L2-G20-*, wherein L2is a bond, -O-, -S-, or -N(RN)-; RNis independently hydrogen or C1-6alkyl, G10is aryl or heteroaryl; and G20is C1-10alkyl or C2-10alkenyl. In some embodiments, L is -G10-L2-G20-*, wherein L2is a bond, -O-, G10is aryl (e.g., phenyl);25 and G20is C1-10alkyl. In embodiments of Formula (X), including embodiments of Formulae (x-a) through (x-s) and (xi- a) throught (xi-z), RP3, when present, is hydrogen.In another embodiment, the compound of Formula (X) is according to one of Formulae (X-b) through (X-e) and (X-x) through (X-ab): 149 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (X-x) 150 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (X-aa) (X-ab) or a salt thereof, wherein RPis hydrogen or a nitrogen protecting group (e.g., a nitrogen protecting group), wheren R and the remaining variables are as defined in Formula (X). In one embodiment of Formulae (X- b) through (X-e) and (X-x) through (X-ab), R1is hydrogen. In another embodiment of Formulae (X-b) through (X-e) and (X-x) through (X-ab), R1is C1-6alkyl (e.g., methyl or t-butyl). In another embodiment 5 of Formulae (X-b) through (X-e) and (X-x) through (X-ab), R1is hydrogen and RPis hydrogen. In another embodiment of Formulae (X-b) through (X-e) and (X-x) through (X-ab), R1is hydrogen and a nitrogen protecting group. In another embodiment of Formulae (X-b) through (X-e) and (X-x) through (X-ab), R1is C1-6alkyl (e.g., methyl or t-butyl) and RPis hydrogen. In another embodiment of Formulae (X-b) through (X-e) and (X-x) through (X-ab), R1is C1-6alkyl (e.g., methyl or t-butyl) and a nitrogen protecting group. 10 -L-ZZ-L’-RTEmbodiments In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis 151 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis (x-b). In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis (x-c). 5 In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) 10 through (X-ab), -L-ZZ-L’-RTis (x-f). In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis 152 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (x-g). In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis (x-h). In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis (x-i). 5 In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis (x-j). In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis (x-k). In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) 10 through (X-ab), -L-ZZ-L’-RTis 153 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis (x-m). In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis (x-n). 5 In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis (x-o). In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis (x-p). In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through 10 (X-ab), -L-ZZ-L’-RTis 154 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (x-q). In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis (x-r) In an embodiment, of any one of Formula (X) and Formulae (X-a) through (X-e) and (X-x) through (X-ab), -L-ZZ-L’-RTis (x-s). 5 RT1Embodiments, Formula (X) Nucleotide Conjugates In embodiments of any embodiments of RLof Formula (X), Formula (X-a) through (X-e) and (X- x) through (X-ab), Formula (x-a) through (x-s), and Formula (xi-a) through (xi-z), 10 RT1is -LL-oligonucleotide, wherein LLis a divalent linker that connects to the 3’-end of the oligonucleotide, the 5’-end of the oligonucleotide, or an internal 2’- or 3’ position on a internal nucleotide (i.e., a nucleotide that is not the 5’-terminal or 3’-terminal nucleoside). In some embodiments. LLis a bond. In some embodiments, RT1is -LL-oligonucleotide, wherein LLis a divalent linker that connects to 15 the 3’-end of the oligonucleotide, such as one of : directly to the 3’-carbon of the 3’-terminal nucleoside; directly to the 3’-O of the 3’-terminal nucleoside; directly to the 4’-carbon of the 3’-terminal nucleoside; directly to the 2’-carbon of the 3’-terminal nucleoside; or 20 directly to the 2’-O of the 3’-terminal nucleoside. 155 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments, RT1is -LL-oligonucleotide, wherein LLis a divalent linker that connects to the 5'-end of the oligonucleotide, such as one of: directly to the 5’-carbon of the 5’-terminal nucleoside; directly to the 5’-O of the 5’-terminal nucleoside; 5 directly to the 4’-carbon of the 5’-terminal nucleoside; directly to the 2’-carbon of the 5’-terminal nucleoside; or directly to the 2’-O of the 5’-terminal nucleoside. In some embodiments, RT1is -LL-oligonucleotide, wherein LLis a divalent linker that connects to an internal 2’- or 3’ position on an internal nucleotide. 10 In some embodiments, RT1is -LL-oligonucleotide, wherein LLis a divalent linker that connects to an internal 2’- position on a internal nucleotide. In some embodiments, RTis RT1, wherein RT1is -LL-oligonucleotide, wherein LLis a divalent linker that connects to an internucleotide linkage (i.e., to an oxygen atom in a phosphodiester linkage to form a phosphotriester; or to a nitrogen when the internucleotide linkage is a phosphoroamidate). 15 In another embodiment of any of the preceding embodiments of RT1, when LLconnects to a carbon atom on a nucleoside, then LLis -B3-A3-, wherein B3is -P(O)(OH)-, -P(S)(OH)-, or -P(S)(SH)-; and A3is -O-, -S-, or -N(H)-. In another embodiment, when LLconnects to a carbon atom on a nucleoside, then LLis -B3-A3-, wherein B3is -P(O)(OH)- or-P(S)(OH)-; and A3is -O-. 20 In another embodiment, when LLconnects to a oxygen atom on a nucleoside, then LLis - P(O)(OH)-, -P(S)(OH)-, or -P(S)(SH). In another embodiment, when LLconnects to a oxygen atom on a nucleoside, then LLis -P(O)(OH)- or -P(S)(OH)-. In another embodiment, when LLconnects to a oxygen atom on a nucleoside, then LLis -P(O)(OH)-. In another embodiment, when LLconnects to a oxygen atom on a nucleoside, then LLis -P(S)(OH)-.25 In another embodiment, when LL connects to an oxygen atom on a nucleoside, then LL is -B3-A3-LL1-A3-B3-, wherein B3is a bond, -C(O)-, C(S)-, C(NH), S(O), S(O)2, -P(O)(OH)-, -P(S)(OH)-, or - P(S)(SH); A3is a bond, -O-, -S-, or -N(H)- ; and LL1is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3- 10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl. In another embodiment, when LL connects to a oxygen atom on a nucleoside, then LL is -B3-LL1-30 B3-, wherein B3is -C(O)-; and LL1is C1-10alkyl. In another embodiment, when LLconnects to a oxygen atom on a nucleoside, then LLis-a bond. In certain embodiments, RTis RT1wherein RT1is is -LL-oligonucleotide, when LLconnects to a oxygen atom on a nucleoside, and LLis a bond, the nucleoside is of Formula (X-f), 156 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO (X-f) wherein B is an optionally modified nucleobase (e.g., adenine, cytosine, uracil, guanine, 5- methylcytosine, or-5-methyluracil); L’ is according any of the preceding embodiments; and * represent the bond to ZZ. In some embodiments of Formula (X-f), -L’- is -L1-G-L3-*, wherein * is the bond to ZZ. 5 In some embodiments, -L’- is -C2-30alkyl-*, wherein the alkyl is optionally substituted with one or two R groups, and * is the bond to ZZ. In some embodiments, -L’- is -C2-30alkyl-*, wherein the alkyl is optionally substituted with one or two groups selected from the group consisting of halogen, hydroxy, C1-6alkoxy, amino, Cl-6alkylamino, di(C1-6alkylamino), cyano, carboxy , and * is the bond to ZZ. In some embodiments, -L’- is -C2-30alkyl-*, wherein the alkyl is optionally substituted with one group selected from 10 the group consisting of halogen, hydroxy, C1-6alkoxy, amino, Cl-6alkylamino, di(C1-6alkylamino), cyano, carboxy , and * is the bond to ZZ. In some embodiments, -L’- is -C2-30alkyl-*, wherein the alkyl is optionally substituted with one group selected from the group consisting of hydroxy, amino, and carboxy , and * is the bond to ZZ. In some embodiments, -L’- is -C2-30alkyl-*, wherein the alkyl is optionally substituted with hydroxy, and * is the bond to ZZ. 15 In some embodiments, -L’- is -C2-30alkyl-*, wherein * is the bond to ZZ. In some embodiments, - L’- is -C2-16alkyl-*, wherein * is the bond to ZZ. In some embodiments, -L’- is -C4-12alkyl-*, wherein * is the bond to ZZ. In some embodiments, -L’- is -C4-10alkyl-*, wherein * is the bond to ZZ. In some embodiments, -L’- is -C5-10alkyl-*, wherein * is the bond to ZZ. In some embodiments, -L’- is -C6alkyl-*, wherein * is the bond to ZZ. In some embodiments, -L’- is -C8alkyl-*, wherein * is the bond to ZZ. In 20 some embodiments, -L’- is -C10alkyl-*, wherein * is the bond to ZZ. In some embodiments of Formula (X-f), -L’- is -L1-[G-L2]q-G-L3-*, wherein * is the bond to ZZ; q is 0, 1, 2, 3, 4, or 5; L1is a bond or -B-A-; each L2is independently -A-B-A-; 25 L3is a bond or -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O)2, P(O)(OH), or P(S)(OH); each RNis independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally 30 substituted with 1, 2, 3, or 4 R groups. 157 ME1\53466565.v1 Atty. Docket No.121301-23820 / ALN-523-WO In some embodiments, -L’- is -L1-[G-L2]q-G-*, wherein * is the bond to ZZ, q is 0, 1, 2, or 3; L1is a bond or -B-A-; and (a) each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), SO2N(R...

Claims

Atty. Docket No.121301-23820 / ALN-523-WO CLAIMS What is claimed is:

1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of a target gene, comprising: an antisense strand which is complementary to the target gene; a sense strand which is complementary to the antisense strand and forms a double stranded region with the antisense strand; at least one alpha-v-beta-6 (αvβ6) integrin targeting ligand that mediates delivery to muscle tissue conjugated to at least one strand; and at least one in vivo delivery enhancing moiety conjugated to one or more positions on at least one strand.

2. The dsRNA agent of claim 1, wherein the in vivo delivery enhancing moiety comprises at least one C10-C26 hydrocarbon chain.

3. The dsRNA agent of claim 2, wherein the in vivo delivery enhancing moiety comprises at least one C22 hydrocarbon chain.

4. The dsRNA agent of claim 2, wherein the in vivo delivery enhancing moiety comprises at least one C17 hydrocarbon chain. 5 The dsRNA agent of claim 2, wherein the in vivo delivery enhancing moiety comprises at least one C11 hydrocarbon chain.

6. The dsRNA agent of any one of claims 2-5, wherein the at least one C10-C26 hydrocarbon chain is unsubstituted or substituted with at least one functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne.

7. The dsRNA agent of claim 6, wherein the at least one C10-C26 hydrocarbon chains is substituted with a carboxylic acid group.

8. The dsRNA of any one of claims 2-5, wherein the at least one C10-C26 hydrocarbon chain is covalently attached to the following moiety:456 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO, wherein is a bond connecting the moiety to the at least one C10-C26 hydrocarbon chain.

9. The dsRNA agent of any one of claims 1-8, wherein the in vivo delivery enhancing moiety is attached to the dsRNA agent via a linker or via a carrier or via an internucleotide phosphate linkage.

10. The dsRNA agent of claim 9, wherein the in vivo delivery enhancing moiety is attached to the dsRNA agent via a linker.

11. The dsRNA agent of claim 10, wherein the linker comprises an ether, a thioether, a urea, a carbonate, an amine, an amide, a maleimide-thioether, a disulfide, a phosphodiester, a sulfonamide linkage, a product of a click reaction, or carbamate.

12. The dsRNA agent of claim 10, wherein the linker is selected from the group consisting of - (CH2)nNH-; -C(O)(CH2)nNH-; -NR’’’’(CH2)nNH-, -C(O)-(CH2)n-C(O)-; -C(O)-(CH2)n-C(O)O-; -C(O)-O- ; -C(O)-(CH2)n-NH-C(O)-; -C(O)-(CH2)n-; -C(O)-NH-; -C(O)-; -(CH2)n-C(O)-; -(CH2)n-C(O)O-; -(CH2)n- ; and -(CH2)n-NH-C(O)-; wherein n is a number from 1 to 20; and R’’’’ is C1-C6alkyl.

13. The dsRNA agent of claim 10, wherein the linker comprises –(CH2)n-NH-C(O)- or –(CH2)n-NH- C(O)-(CH2)2-C(COOH)-NH-C(O)-, wherein n is a number from 1 to 20.

14. The dsRNA agent of claim any one of claims 10-13, wherein the linker comprises –(CH)2-O- (CH2CH2)-(O)-(CH2CH2)-NH-C(O)-.

15. The dsRNA agent of any one of claims 1-14, wherein the in vivo delivery enhancing moiety is represented by the following structure: , ,, 457 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO ,. wherein a broken bond represents a bond to the remainder of the dsRNA agent.

16. The dsRNA agent of any one of claims 1-14, wherein the in vivo delivery enhancing moiety is represented by the following structure:, wherein m is selected from 1-6, n is selected from 7-23, RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2; and E is -C(O)N(H)-(CH2)p-*, -N(H)C(O)-(CH2)p-*, -C(O)O-(CH2)p-*, -OC(O)-(CH2)p-*, - OP(Y)(OH)O-(CH2)p-*, -O-(CH2)p-, -N(H)-(CH2)p, -S-(CH2)p-, -N(H)-O-(CH2)p-, -O-N(H)-(CH2)p-, N(H)N(H)-(CH2)p-, or -S-S-(CH2)p-*, -Ph-(CH2)p-, -OPh-(CH2)p-, or -ZZ1-(CH2)p-; wherein * is the bond to the alpha-amino acid carbon, Ph is phenyl, Y is =O or =S, p is selected from 1 – 6; and 458 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO ZZ1is a group formed by reaction of a reactive pair.

17. The dsRNA agent of claim 16, wherein the in vivo delivery enhancing moiety is represented by the following structure:, wherein m is selected from 1-6 and n is selected from 7-23.

18. The dsRNA agent of any one of claims 1-17, wherein the in vivo delivery enhancing moiety is conjugated to the 5’-end of the at least one strand.

19. The dsRNA agent of claim 18, wherein the in vivo delivery enhancing moiety is conjugated to the 5’-oxygen of the 5’-terminal nucleotide of the at least one strand.

20. The dsRNA agent of any one of claims 1-17, wherein the in vivo delivery enhancing moiety is conjugated to the 3’-end of the at least one strand.

21. The dsRNA agent of any one of claims 1-17, wherein the in vivo delivery enhancing moiety is conjugated to the 3’-oxygen of the 3’-terminal nucleotide of the at least one strand.

22. The dsRNA agent of any one of claims 1-21, wherein the in vivo delivery enhancing moiety is attached to the remainder of the dsRNA agent at a 2’ position on an internal nucleotide.

23. The dsRNA agent of any one of claims 1-22, wherein the αvβ6 integrin targeting ligand comprises a structure represented by Formula (X):or a salt thereof, wherein: Y is O, N(H), S, or CH2;, wherein m is 0, 1, 2, 3, or 4; and 459 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO each R2is independently R, or two R2groups on adjacent carbon atoms taken together with the atoms to which they are bound form a fused 4 – 8 membered ring that is optionally substituted by 1, 2, 3 or 4 groups independently selected from group consisting of R and a nitrogen protecting group; A is an 5-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, fluoro, hydroxymethyl, 2-hydroxypropan-2-yl, trifluoromethyl, difluoromethyl, and fluoromethyl; Q is -COOR1or tetrazolyl, wherein R1is hydrogen or R1-6alkyl; and RLis -N(R3)(R4), -O(R5), -S(R5), or -R5, wherein R3and R4are either (i) R3 is hydrogen or C1-6alkyl and R4 is R5; or(ii) R3 and R4 taken together with the nitrogen atom to which they areattached form a 4 – 8 membered monocyclic heterocyclyl group that is substituted with R5; and R5is -L-ZZ-L’-RTwherein L and L’ are independently -L1-[G-L2]q-G-L3-*, wherein * is the bond to ZZ; q is 0 or an integer selected from 1 to 25; L1is a bond or -B-A-; each L2is independently -A-B-A-; L3is a bond or -A-B-A-; each G is independently -D-E-F-, wherein D, E, and F are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); 460 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO each RNis independently hydrogen or C1-6alkyl, or two RNwithin an -A- B-A- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; and ZZ is -A’-B’-A’- or a linking group formed by a reactive pair, wherein each A’ is independently a bond, -O-, -S-, or -N(RN3)-; each B’ is independently a bond, CH2, C(O), C(S), C(NRN3), -C=N-, S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RN3is independently hydrogen or C1-6alkyl, or two RN3within the -A’-B’- A’- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; RTis RT1or -G0-ORT1, wherein G0is absent or -D0-E0-F0-, wherein D0, E0, and F0are independently a bond, C1- 10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; RT1is LL-oligonucleotide, wherein LLis an oligonucleotide linking group connecting the αvβ6 integrin targeting ligand to oligonucleotide comprised in the dsRNA agent; and each R group is independently selected from the group consisting of R’, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkylC1-6alkyl, heterocyclylC1-6alkyl, aryl C1-6alkyl, heteroarylC1-6alkyl, each of which, other than R’, is optionally substituted with 1, 2, or 3 R’ groups, wherein each R’ is independently halogen, cyano, azido, nitro, -N(Rb)2, -O(Ra), -S(R0), - C(O)OR0, C(O)R0, -C(O)N(R0)2, -C(NR0)OR0, -C(NR0)R0, -C(NR0)N(R0)2, -C(S)OR0, -C(S)R0, -C( S)N(R0)2, -S(O)2R0, -S(O)2OR0, -S(O)2N(R0)2, -N(R0)C(O)OR0, -N(R0)C(O)R0, -N(R0)C( O)N(R0)2, -N(R0)S(O)2R0, -N(R0)S(O)2OR0, -N(R0)S(O)2N(R0)2, -OC(O)OR0, -OC(O)R0, -OC(O)N(R0)2, -OS(O)2R0, -OS(O)2OR0, -OS(O)2N(R0)2, or -SC(O)R0, wherein each R0is independently hydrogen or C1-6alkyl; each Rais independently hydrogen or C1-6alkyl; and each Rbis independently hydrogen, C1-6alkyl, or a nitrogen protecting group 461 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO provided that in each -D-E-F- group, at least one of D, E, and F is not a bond; and RLis not N- morpholinyl.

24. The dsRNA agent of claim 23, wherein RYis, wherein p is 0, 1, 2, 3 or 4; and each R21is independently selected from the group consisting of R and a nitrogen protecting group.

25. The dsRNA agent of claim 23, wherein, wherein RPis a nitrogen protecting group.

26. The dsRNA agent of any one of claims 23-25, wherein -L’-RTiswherein* is the bond to ZZ; L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and R is -OH or -C1-6alkyl-OH.

27. The dsRNA agent of any one of claims 23-26, wherein -L’- is -L1-G-L3-*, wherein * is the bond to ZZ.

28. The dsRNA agent of any one of claims 23-27, wherein the αvβ6 integrin targeting ligand comprises the following structure:462 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO (X-b), (X-c),463 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO(X-aa), or (X-ab).

29. The dsRNA agent of any one of claims 23-28, wherein L is -L1-[G-L2]q-G-L3-*, wherein q is 0, 1, 2, 3, 4, or 5.

30. The dsRNA agent of any one of claims 23-28, wherein L is -L1-G-*, wherein * is the bond to ZZ; G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; L1is -B-A-, wherein, A is a bond, -O-, -S-, or -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; and B is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

31. The dsRNA agent of any one of claims 23-28, wherein L iswherein * is the bond toZZ; k is an integer from 1 to 10; L1is bond, C(O), C(S), C(NRN), S(O)2, P(O)(OH), or P(S)(OH); and RNis hydrogen or C1-6alkyl.

32. The dsRNA agent of any one of claims 23-28, wherein L is a group selected from:n integer from 1 to 3; and s and s’ are each independently an integer from 1 to 24; (c)wherein * is the bond to ZZ; a is 1, 2 or 3; and each s, s’, and s” independently is an integer from 1 to 24; 464 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WOwherein * is the bond to ZZ; and s, s’, and s’’ are independently is an integer from 1 to 24;wherein * is the bond to ZZ and each s, s’, and s” independently is an integer from 1 to 24; and (f)wherein * is the bond to ZZ; s and k are independently is an integer from 1 to 20; and w is an integer from 1 to 10.

33. The dsRNA agent of any one of claims 23-28, wherein L iswherein * is the bond to ZZ and w is an integer from 1 to 20.

34. The dsRNA agent of any one of claims 23-28, wherein L is , wherein * is the bond to ZZ; k is an integer from 1 to 10.

35. The dsRNA agent of any one of claims 23-28, wherein L is L is -L1-G-*, wherein * is the bond to ZZ , G is C1-10alkyl or C2-10alkenyl, and L1is -B-A-, wherein, A is a bond, -O-, -S-, or -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; and B is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

36. The dsRNA agent of any one of claims 23-28, wherein L is -[G-L2]q-G-*, wherein q is an integer from 1 to 5, each G is independently C1-10alkyl and L2is O, S, or N(H).

37. The dsRNA agent of any one of claims 23-28, wherein L is -G-L2-G-*, wherein L2is -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RNis independently hydrogen or C1-6alkyl, or two RNwithin an -A-B-A- group taken together with the atoms to which they are connected form a 4-8 membered heterocyclyl; and each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3- 10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; 465 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO wherein each R group is independently selected from the group consisting of R’, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkylC1-6alkyl, heterocyclylC1-6alkyl, aryl C1-6alkyl, heteroarylC1-6alkyl, each of which, other than R’, is optionally substituted with 1, 2, or 3 R’ groups, wherein each R’ is independently halogen, cyano, azido, nitro, -N(Rb)2, -O(Ra), -S(R0), -C(O)OR0, - C(O)R0, -C(O)N(R0)2, -C(NR0)OR0, -C(NR0)R0, -C(NR0)N(R0)2, -C(S)OR0, -C(S)R0, -C(S)N (R0)2, -S(O)2R0, -S(O)2OR0, -S(O)2N(R0)2, -N(R0)C(O)OR0, -N(R0)C(O)R0, -N(R0)C(O)N(R0)2, -N(R0)S(O)2R0, -N(R0)S(O)2OR0, -N(R0)S(O)2N(R0)2, -OC(O)OR0, -OC(O)R0, - OC(O)N(R0)2, -OS(O)2R0, -OS(O)2OR0, -OS(O)2N(R0)2, or -SC(O)R0, wherein each R0is independently hydrogen or C1-6alkyl; and each Rais independently hydrogen or C1- 38. The dsRNA agent of any one of claims 23-37, wherein ZZ comprises a group selected from the group consisting of:Group(466 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WOGroupGroup39. The dsRNA agent of any one of claims 23-38, wherein LLis a divalent linker that connects to the 3’-end of the oligonucleotide , the 5’-end of the oligonucleotide, a 2’ position on an internal nucleotide or a 3’ position on an internal nucleotide.

40. The dsRNA agent of claim 39, wherein LLconnects to an oxygen atom on a nucleotide of the oligonucleotide, and is -P(O)(OH)-, -P(S)(OH)-, or -P(S)(SH)-.

41. The dsRNA agent of any one of claims 23-40, wherein RTis RT1, wherein RT1is -LL- oligonucleotide, wherein LLconnects to an oxygen atom on a nucleotide of the oligonucleotide, LLis a bond, and the nucleoside is represented by Formula (X-f):(X-f) wherein B is an optionally modified nucleobase and * represents the bond to ZZ.

42. The dsRNA agent of claim 41, wherein -L’- is -C4-10alkyl-*, wherein * is the bond to ZZ.

43. The dsRNA agent of claim 41, wherein the nucleoside is of a formula selected from the group consisting of,(X-g) (X-h) 467 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WOB is an optionally modified nucleobase; each n is independently 0 or an integer selected from 1-10; and each m is independently integer selected from 1-20. 468 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO 44. The dsRNA agent of any one of claims 1-43, wherein the αvβ6 integrin targeting ligand is conjugated at the 5’-end of the sense strand or at the 5’-end of the antisense strand.

45. The dsRNA agent of claim 44, wherein the sense strand or the antisense strand conjugated to the αvβ6 integrin targeting ligand comprised in the dsRNA agent is represented by the following formula:wherein Y’ is O or S; andrepresents the remainder for the sense strand or the antisense strand.

46. The dsRNA agent of any one of claims 1-43, wherein the αvβ6 integrin targeting ligand is conjugated at the 3’-end of the sense strand or the 3’ end of the antisense strand.

47. The dsRNA agent of claim 46, wherein sense strand or the antisense strand conjugated to the αvβ6 integrin targeting ligand comprised in the dsRNA agent is represented by the formula selected from the group consisting of:, 469 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO , ,, 470 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WOwherein Y’ is O or S, R1is hydrogen or C1-6alkyl, RPis hydrogen or a nitrogen protecting group andrepresents the remainder for the sense strand or the antisense strand.

48. The dsRNA agent of claim 47, wherein RPis hydrogen and R1is hydrogen.

49. The compound of claim 47 or 48, wherein Y’ is O.

50. The compound of claim 47 or 48, wherein Y’ is S.

51. The dsRNA agent of any one of claims 1-22, wherein the αvβ6 integrin targeting ligand comprises a compound represented by Formula (XV): (Φ-ZZ-)xΔ-T-RT(XV) or a salt thereof, wherein 471 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO x is 2, 3, 4, 5, 6, 7, or 8; T is a divalent linking group; Δ is a branching group; each ZZ is independently -A’-B’-A’- or a linking group formed by a first reactive pair, wherein each A’ is independently a bond, -O-, -S-, or -N(RN3)-; each B’ is independently a bond, CH2, C(O), C(S), C(NRN3), -C=N-, S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RN3is independently hydrogen or C1-6alkyl, or two RN3within the -A’-B’-A’- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; RTis -G0-ORT1, wherein G0is -D0-E0-F0-, wherein D0, E0, and F0are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3- 10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; and RT1is LL-oligonucleotide, wherein LLis an oligonucleotide linking group connecting the αvβ6 integrin targeting ligand to the oligonucleotide comprised in the dsRNA agent; and each Φ is a compound of the Formula (XII),wherein: Y is O, N(H), S, or CH2; R1is hydrogen or C1-6alkyl;, wherein m is 0, 1, 2, 3, or 4; and 472 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO each R2is independently R, or two R2groups on adjacent carbon atoms taken together with the atoms to which they are bound form a fused 4 – 8 membered ring that is optionally substituted by 1, 2, 3 or 4 groups independently selected from group consisting of R and a nitrogen protecting group; A is an 5-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, fluoro, hydroxymethyl, 2-hydroxypropan-2-yl, trifluoromethyl, difluoromethyl, and fluoromethyl; Q is -COOR1or tetrazolyl (e.g., 1,2,3,4-tetrazol-5-yl);and RLis -N(R3)(R4), -O(R5), -S(R5), or -R5, wherein R3and R4are either (i) R3is hydrogen or C1-6alkyl and R4is R5; or (ii) R3and R4taken together with the nitrogen atom to which they are attached form a 4 – 8 membered monocyclic heterocyclyl group that is substituted with R5; and R5is -L-* wherein L is -L1-[G-L2]q-G-L3-*, * is the bond to a ZZ; and q is 0 or an integer selected from 1 – 25; (e.g., 1-20, or 1-15); L1is a bond or -B-A-; each L2is independently -A-B-A-; L3is a bond or -A-B-A-; each G is independently -D-E-F-, wherein D, E, and F are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3- 10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RNis independently hydrogen or C1-6alkyl, or two RNwithin an -A-B-A- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl.

52. The dsRNA agent of claim 51, wherein the αvβ6 integrin targeting ligand is selected from the group consisting of, 473 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO(XVa) (XVb) and (XVc).

53. The dsRNA agent of claim 51 or 52, wherein RYis, wherein p is 0, 1, 2, 3 or 4; and each R21is independently selected from the group consisting of R and a nitrogen protecting group.

54. The dsRNA agent of any one of claims 51-53, wherein RYis, wherein RPis a nitrogen protecting group.

55. The dsRNA agent of any one of claims 51-54, wherein RTis -G0-ORT1, wherein G0is -D0-E0-F0-, wherein D0and F0are independently a bond or C1-10alkyl optionally substituted with 1, 2, 3, or 4 R groups; and E0is C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups.

56. The dsRNA agent of claim 55, wherein G0is 3-10 membered heterocyclyl optionally substituted with 1 or 2 R groups.

57. The dsRNA agent of claim 56, whereinwherein * represents the bond to T, the broken bond represents the bond to ORT1, and R is -C1-6alkyl-ORaor -ORa, wherein Rais independently hydrogen or C1-6alkyl; 474 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO 58. The dsRNA agent of claim 56, whereinwherein * represents the bond to T, the broken bond represents the bond to ORT1, and R is -C1-6alkyl-ORaor -ORa, wherein Rais independently hydrogen or C1-6alkyl.

59. The dsRNA agent of any one of claims 51-58, wherein T is a bond or **-L6-G1-[L5-G1]q1-L4-, wherein ** is the bond to RT; q1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each L4, L5, and L6are independently a bond or -A1-B1-A1-, or ZZ1; ZZ1is a group formed by reaction of a reactive pair; each G1is independently -D1-E1-F1-, wherein D1, E1, and F1are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, or 3 R groups; each A1is independently a bond, -O-, -S-, or -N(RN1)-; each B1is independently a bond, C(O), C(S), C(NRN1), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN1is independently hydrogen or C1-6alkyl, or two RN1within an -A1-B1-A1- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl.

60. The dsRNA agent of any one of claims 51-59, wherein T is **-L6-G1-[L5-G1]q1-L4-, wherein ** is the bond to RT; q1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each L4, L5, and L6are independently a bond or -A1-B1-A1-, or ZZ1; ZZ1is a group formed by reaction of an azide and alkyne or cycloalkyne; each G1is independently C1-10alkyl, each A1is independently a bond, -O-, -S-, or -N(RN1)-; each B1is independently a bond, C(O), C(S), C(NRN1), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN1is independently hydrogen or C1-6alkyl. 475 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO 61. The dsRNA agent of claim 60, wherein one L5is ZZ1.

62. The dsRNA agent of claim 61, wherein ZZ1comprises:.

63. The dsRNA agent of any one of claims 51-62, wherein T is **-C(O)-C2-20alkyl-C(O)N(H)- wherein ** is the bond to RT:

64. The dsRNA agent of any one of claims 51-62, wherein T is T is **-C(O)-[CH2CH2-O]q5-G5-L4-, wherein ** is the bond to RT; q5 is an integer selected from 1 to 20; L4is -A1-B1-A1-, wherein each A1is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1is hydrogen or C1- 6alkyl; each B1is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and G5is C1-10alkyl.

65. The dsRNA agent of any one of claims 51-64, wherein Δ is#–[G2-L7]q2-* or #–G3-([L7-G4]q3-*)y, wherein # is the bond to T; 476 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO y is 1, 2, 3, 4, or 5; q2 is 1, 2, 3, 4, 5, 6, 7, or 8; q3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; each G2, G3, and G4is independently -D2-E2-F2-, wherein D2, E2, and F2are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 RBgroups, and wherein each G2and G4optionally contains at least one bond to a ZZ; or G3is N and y is 2; each L7is independently -A2-B2-A2-; wherein each A2is independently a bond, -O-, -S-, or -N(RN2)-; each B2is independently a bond, C(O), C(S), C(NRN2), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RN2is independently hydrogen, C1-6alkyl, a bond to a ZZ, or two RN2within an -A2-B2-A2- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; and each RBis independently halogen, cyano, azido, nitro, -N(R10)2, -O(R10), -S(R10), -C(O)OR10, - C(O)R10, -C(O)N(R10)2, -C(NR10)OR10, -C(NR10)R10, -C(NR10)N(R10)2, -C(S)OR10, - C(S)R10, -C(S)N(R10)2, -S(O)2R10, -S(O)2OR10, -S(O)2N(R10)2, -N(R10)C(O)OR10, -N(R10)C(O)R10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2R10, -N(R10)S(O)2OR10, -N(R10)S(O)2N(R10)2, -OC(O)OR10, -OC(O)R10, - OC(O)N(R10)2, -OS(O)2R10, -OS(O)2OR10, -OS(O)2N(R10)2, or -SC(O)R10, wherein each R10is independently hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 memberedheterocyclyl, aryl, or heteroaryl.provided that Δ contains x bonds to ZZ.

66. The dsRNA agent of claim 65, wherein Δ is selected from the group consisting of,wherein each * is a bond to a ZZ; # is the bond to T, 477 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO each G2is independently C1-10alkyl, C2-10alkenyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 RBgroups; and each L7is independently -A2-B2-A2-, wherein each A2is independently a bond, -O-, -S-, or - N(RN2)-; each B2is independently a bond, C(O), S(O)2, P(O)(OH), or P(S)(OH).

67. The dsRNA agent of claim 66, wherein each G2is independently C1-10alkyl, each optionally substituted with 1 or 2 RBgroups.

68. The dsRNA agent of any one of claims 65-67, wherein Δ is selected from the group consistingof,wherein # is the bond to T and each * is a bond to a ZZ group. ; and each G2is independently C1-10alkyl.

69. The dsRNA agent of any one of claims 65-67, wherein Δ is selected from the group consistingof,478 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WOwherein # is the bond to T and each * is a bond to a ZZ group.

70. The dsRNA agent of claim 65, wherein Δ is -#–G3-([L7-G4]q3-*)y, wherein # is the bond to T and* is a bond to a ZZ group.

71. The dsRNA agent of claim 70, wherein Δ is selected from the group consisting of,wherein # is the bond to T, each * is a bond to a ZZ group, and each L7is selected from the group consisting of -O-, -S-, -N(H)-, -C(O)O-, -OC(O)-, -C(O)N(H)- , -OC(O)O-, -N(H)C(O)O-, -OC(O)N(H)-, -OP(O)(OH)O-, or -OP(S)(OH)O-; and each G4is independently -D2-E2-F2-, wherein each D2and F2are independently a bond or C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3- 10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 RBgroups, and each E2is independently bond, C1-10alkyl, C2-10alkenyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 RBgroups, provided that E2is not a bond with D2and F2are each bonds. 479 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO72. The dsRNA agent of claim 65, wherein Δ is selected from the group consisting of,wherein # is the bond to T and each * is a bond to a ZZ group.

73. The dsRNA agent of any one of claims 51-72, wherein ZZ is -A’-B’-A’-, wherein each A’ is independently a bond, -O-, -S-, or -N(RN3)-, wherein RN3is independently hydrogen or C1-6alkyl and each B’ is independently CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

74. The dsRNA agent of any one of claims 51-72, wherein ZZ is -CH2O-, -OCH2-, -S-S-, -C=N-, - C=N-O-, -C=N-N(RN3)-, -N=C-, -O-N=C-, -N(RN3)-N=C-, -C(O)N(RN3)-, -N(RN3)C(O)-, -C(O)O-, - OC(O)-, -OC(O)N(RN3)-, -N(RN3)C(O)O-, -N(RN3)C(O)N(RN3)-, -S(O)2N(RN3)-, -N(RN3)S(O)2-, - OP(O)(OH)O-, -OP(S)(OH)O-, -OP(O)(OH)-, -OP(S)(OH)-, -P(O)(OH)O-, or -P(S)(OH)O-. wherein RN3is independently hydrogen or C1-6alkyl.

75. The dsRNA agent of any one of claims 51-74, wherein Formula (XII) is selected from the group consisting of: 480 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO(XII-r) (XII-s) 481 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO(XII-t) wherein p is 0, 1, 2 or 3; each R21is independently selected from group consisting of R and a nitrogen protecting group, and RPis a nitrogen protecting group.

76. The dsRNA agent of any one of claims 51-75, wherein L is -L1-[G-L2]q-G-L3-*, wherein q is 0, 1, 2, 3, 4, or 5.

77. The dsRNA agent of any one of claims 51-75, wherein L is -L1-G-*, wherein * is the bond to ZZ; G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; L1is -B-A-, wherein, A is a bond, -O-, -S-, or -N(RN)-, wherein each RNis independently hydrogen or C1- 6alkyl; and B is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

78. The dsRNA agent of any one of claims 51-75, wherein L iswherein * is the bond toZZ; k is an integer from 1 to 10; L1is bond, C(O), C(S), C(NRN), S(O)2, P(O)(OH), or P(S)(OH); and RNis hydrogen or C1-6alkyl.

79. The dsRNA agent of any one of claims 51-75, wherein L is a group selected from: (a) , wherein * is the bond to ZZ; t is an integer from 0 to 10; (b) L iswherein * is the bond to ZZ, t is an integer from 0 to 10; a is an integer from 1 to 3; and s and s’ are each independently an integer from 1 to 24; 482 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO (c)wherein * is the bond to ZZ; a is 1, 2 or 3; and each s, s’, and s” independently is an integer from 1 to 24;an integer from 1 to 24; and (f)wherein * is the bond to ZZ; s and k are independently is an integer from 1 to 20; and w is an integer from 1 to 10.

80. The dsRNA agent of any one of claims 51-75, wherein L iswherein * is the bond to ZZ and w is an integer from 1 to 20.

81. The dsRNA agent of any one of claims 51-75, wherein L is, wherein * is the bond to ZZ; k is an integer from 1 to 10.

82. The dsRNA agent of any one of claims 51-75, wherein L is L is -L1-G-*, wherein * is the bond to ZZ , G is C1-10alkyl or C2-10alkenyl, and L1is -B-A-, wherein, A is a bond, -O-, -S-, or -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; and B is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

83. The dsRNA agent of any one of claims 51-75, wherein L is -[G-L2]q-G-*, wherein q is an integer from 1 to 5, each G is independently C1-10alkyl and L2is O, S, or N(H).

84. The dsRNA agent of any one of claims 51-75, wherein L is -G-L2-G-*, wherein L2is -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RNis independently hydrogen or C1-6alkyl, or two RNwithin an -A-B-A- group taken together with the atoms to which they are connected form a 4-8 483 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO membered heterocyclyl; and each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups.; wherein each R group is independently selected from the group consisting of R’, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkylC1-6alkyl, heterocyclylC1-6alkyl, aryl C1-6alkyl, heteroarylC1-6alkyl, each of which, other than R’, is optionally substituted with 1, 2, or 3 R’ groups, wherein each R’ is independently halogen, cyano, azido, nitro, -N(Rb)2, -O(Ra), -S(R0), -C(O)OR0, - C(O)R0, -C(O)N(R0)2, -C(NR0)OR0, -C(NR0)R0, -C(NR0)N(R0)2, -C(S)OR0, -C(S)R0, -C(S)N (R0)2, -S(O)2R0, -S(O)2OR0, -S(O)2N(R0)2, -N(R0)C(O)OR0, -N(R0)C(O)R0, -N(R0)C(O)N(R0)2, -N(R0)S(O)2R0, -N(R0)S(O)2OR0, -N(R0)S(O)2N(R0)2, -OC(O)OR0, -OC(O)R0, - OC(O)N(R0)2, -OS(O)2R0, -OS(O)2OR0, -OS(O)2N(R0)2, or -SC(O)R0, wherein each R0is independently hydrogen or C1-6alkyl; and each Rais independently hydrogen or C1- 6alkyl; and each Rbis independently hydrogen, C1-6alkyl, or a nitrogen protecting group.

85. The dsRNA agent of any one of claims 51-84, wherein LLis a divalent linker that connects to the 3’-end of the oligonucleotide, the 5’-end of the oligonucleotide, a 2’position on an internal nucleotide, a 3’ position on an internal nucleotide, or a internucleotide linkage.

86. The dsRNA agent of claim 85, wherein LLconnects to an oxygen atom on a nucleotide, and is P(O)(OH)-, -P(S)(OH)-, or -P(S)(SH).

87. The dsRNA agent of any one of claims 51-86, wherein RTis RT1wherein RT1is -LL- oligonucleotide, wherein LLconnects to an oxygen atom on a nucleoside of the oligonucleotide, LLis a bond, and the nucleoside is represented by Formula (XV-f):(XV-f) wherein B is an optionally modified nucleobase and * represents the bond to Δ.

88. The dsRNA agent of claim 87, wherein -T- is -C4-10alkyl-*, wherein * is the bond to Δ.

89. The dsRNA agent of claim 87, wherein the nucleoside is of a formula selected from the group consisting of, 484 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO(XV-q) wherein 485 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO B is an optionally modified nucleobase; each n is independently 0 or an integer selected from 1-10; and each m is independently integer selected from 1-20.

90. The dsRNA agent of any one of claims 51-84, wherein the αvβ6 integrin targeting ligand is conjugated at the 5’-end of the oligonucleotide.

91. The dsRNA agent of claim 90, wherein oligonucleotide conjugated to the αvβ6 integrin targeting ligand comprised in the dsRNA agent is represented by the following formula:wherein Y’ is O or S andrepresents the remainder for the oligonucleotide.

92. The dsRNA agent of any one of claims 51-84, wherein the αvβ6 integrin targeting ligand is conjugated at the 3’-end of the oligonucleotide.

93. The dsRNA agent of claim 92, wherein oligonucleotide conjugated to the αvβ6 integrin targeting ligand comprised in the dsRNA agent is represented by the formula:wherein Y' is O or S.

94. The dsRNA agent of claim 93, wherein oligonucleotide conjugated to the αvβ6 integrin targeting ligand comprised in the dsRNA agent is represented by Formula (XV-x): 486 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WOwherein Y’ is O or S; each ZZ is N(H)C(O) or C(O)N(H); eachwherein m is an integer selected from 1 – 10; L4and L6are independently -B1-A1- or -A1-B1-; each L5is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); each G1is independently C1-10alkyl or C2-10alkenyl; each A1is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1is independently hydrogen or C1-6alkyl; and each B1is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

95. The dsRNA agent of claim 94, wherein oligonucleotide conjugated to the αvβ6 integrin targeting ligand comprised in the dsRNA agent is represented by Formula (XV-x1):487 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO wherein Y’ is O or S; each ZZ is N(H)C(O) or C(O)N(H); eachwherein m is an integer selected from 1 – 10; L5is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); each G1is independently C1-10alkyl; each A1is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1is independently hydrogen or C1-6alkyl; and each B1is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

96. The dsRNA agent of claim 95, wherein each Φ is selected from the group consisting of:, 488 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO, wherein m is an integer selected from 1 – 10.

97. The dsRNA agent of claim 96, wherein RPis hydrogen and R1is hydrogen.

98. The dsRNA agent of claim 97, wherein Y’ is O.

99. The dsRNA agent of claim 97, wherein Y’ is S.

100. The dsRNA agent of any one of claims 1-22, wherein the αvβ6 integrin targeting ligand comprises the following structure: 489 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO ,, 490 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO, 491 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO ,, 492 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO, 493 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO, or any combination thereof, wherein * represents the bond to the remainder of the dsRNA agent.

101. The dsRNA agent of any one of claims 1-100, wherein the at least one αvβ6 integrin targeting ligand is conjugated to the sense strand.

102. The dsRNA agent of claim 101, wherein the at least one αvβ6 integrin targeting ligand is conjugated to the 3’-end of the sense strand.

103. The dsRNA agent of claim 101, wherein the at least one αvβ6 integrin targeting ligand is conjugated to the 5’-end of the sense strand.

104. The dsRNA agent of claim 101, wherein the at least one αvβ6 integrin targeting ligand is conjugated to both the 5’-end and the 3’-end of the sense strand.

105. The dsRNA agent of claim 101, wherein the at least one αvβ6 integrin targeting ligand is conjugated to an internal position of the sense strand. 494 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO 106. The dsRNA agent of any one of claims 1-100, wherein the at least one αvβ6 integrin targeting ligand is conjugated to the antisense strand.

107. The dsRNA agent of claim 106, wherein the at least one αvβ6 integrin targeting ligand is conjugated to the 3’ end antisense strand.

108. The dsRNA agent of claim 106, wherein the at least one αvβ6 integrin targeting ligand is conjugated to the 5’ end of the antisense strand.

109. The dsRNA agent of claim 106, wherein the at least one αvβ6 integrin targeting ligand is conjugated to both the 5’-end and the 3’-end of the antisense strand.

110. The dsRNA agent of claim 106, wherein the at least one αvβ6 integrin targeting ligand is conjugated to an internal position of the antisense strand.

111. The dsRNA agent of any one of claims 1-110, wherein the at least one in vivo delivery enhancing moiety is conjugated to an internal position or an external position of the sense strand.

112. The dsRNA agent of claim 111, wherein the at least one in vivo delivery enhancing moiety is conjugated to one or more of the following internal positions: positions 4-8 and 13-18 on the sense strand, counting from the 5’ end.

113. The dsRNA agent of claim 112, wherein the at least one in vivo delivery enhancing moiety is conjugated to one or more of the following internal positions: positions 5, 6, 7, 15, 16 and 17 on the sense strand, counting from the 5’-end.

114. The dsRNA agent of claim 113, wherein the at least one in vivo delivery enhancing moiety is conjugated to position 6 on the sense strand, counting from the 5’-end.

115. The dsRNA agent of any one of claims 1-110, wherein the at least one in vivo delivery enhancing moiety is conjugated to an internal position or external position of the antisense strand.

116. The dsRNA agent of claim 115, wherein the at least one in vivo delivery enhancing moiety is conjugated to one or more of the following internal positions: positions 6-10 and 15-18 on the antisense strand, counting from the 5’-end.

117. The dsRNA agent of claim 116, wherein the at least one in vivo delivery enhancing moiety is conjugated to one or more of the following internal positions: positions 15, 16 and 17 on the antisense strand, counting from the 5’-end.

118. The dsRNA agent of any one of claims 1-100, wherein the at least one αvβ6 integrin targeting ligand and the at least one in vivo delivery enhancing moiety are both conjugated to the sense strand.

119. The dsRNA agent of any one of claims 1-100, wherein the at least one αvβ6 integrin targeting ligand and the at least one in vivo delivery enhancing moiety are both conjugated to the antisense strand. 495 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO 120. The dsRNA agent of any one of claims 1-100, wherein the at least one αvβ6 integrin targeting ligand is conjugated to the sense strand and the at least one in vivo delivery enhancing moiety is conjugated to the antisense strand.

121. The dsRNA agent of any one of claims 1-100, wherein the at least one αvβ6 integrin targeting ligand is conjugated to the antisense strand and the at least one in vivo delivery enhancing moiety is conjugated to the sense strand.

122. The dsRNA agent of any one of claims 1-121, wherein the sense strand and the antisense strand are each independently 15-30 nucleotides in length; 19 to 25 nucleotides in length; or 21 to 23 nucleotides in length.

123. The dsRNA agent of any one of claims 1-122, wherein the target gene is selected from the group consisting of adrenoceptor beta 1 (ADRB1); calcium voltage-gated channel subunit alpha1 C (CACNA1C); calcium voltage-gated channel subunit alpha1 G (CACNA1G) (T type calcium channel); angiotensin II receptor type 1(AGTR1); Sodium Voltage-Gated Channel Alpha Subunit 2 (SCN2A); Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 1 (HCN1); Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4 (HCN4); Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 3 (HCN3); Potassium Voltage-Gated Channel Subfamily A Member 5 (KCNA5); Potassium Inwardly Rectifying Channel Subfamily J Member 3 (KCNJ3); Potassium Inwardly Rectifying Channel Subfamily J Member 4 (KCNJ4); phospholamban (PLN); calcium / calmodulin dependent protein kinase II delta (CAMK2D); and Phosphodiesterase 1 (PDE1); myostatin (MSTN); Cholinergic Receptor Nicotinic Alpha 1 Subunit (CHRNA1); Cholinergic Receptor Nicotinic Beta 1 Subunit (CHRNB1); Cholinergic Receptor Nicotinic Delta Subunit (CHRND); Cholinergic Receptor Nicotinic Epsilon Subunit (CHRNE); Cholinergic Receptor Nicotinic Gamma Subunit (CHRNG); Collagen Type XIII Alpha 1 Chain (COL13A1); Docking Protein 7 (DOK7); LDL Receptor Related Protein 4 (LRP4); Muscle Associated Receptor Tyrosine Kinase (MUSK); Receptor Associated Protein Of The Synapse (RAPSN); Sodium Voltage-Gated Channel Alpha Subunit 4 (SCN4A); Double Homeobox 4 (DUX4); dystrophy myotonic protein kinase (DMPK); glycogen synthase 1 (GYS1); survival of motor neuron 1 (SMN1), and alpha-glucosidase (GAA).

124. A cell containing the dsRNA agent of any one of claims 1-123.

125. A pharmaceutical composition for inhibiting expression of the target gene, comprising the dsRNA agent of any one of claims 1-123.

126. A method of inhibiting expression of a target gene in a muscle cell, said method comprising contacting the cell with the dsRNA agent of any one of claims 1-123 or the pharmaceutical composition of claim 124, thereby inhibiting expression of the target gene in the muscle cell. 496 ME1\53466565.v1Atty. Docket No.121301-23820 / ALN-523-WO 127. The method of claim 126, wherein the muscle cell is a skeletal muscle cell or a cardiac muscle cell.

128. The method of claim 126 or 127, wherein the cell is within a subject.

129. A method of treating a subject having a muscle disorder, said method comprising administering to the subject a therapeutically effective amount of the dsRNA agent of any one of claims 1-123 or the pharmaceutical composition of claim 125, thereby treating the subject.

130. The method of claim 129, wherein the muscle disorder is a skeletal muscle disorder or a cardiac muscle disorder.

131. The method of claim 130, wherein the skeletal muscle disorder or cardiac muscle disorder is selected from the group consisting of myostatin-related muscle hypertrophy, congenital myasthenic syndrome, facioscapulohumeral muscular dystrophy (FSHD), Spinal Muscular Atrophy (SMA), Myotonic Dystrophy Type 1 (DM1), Pompe disease, PLN cardiomyopathy, spasticity, obstructive hypertrophic cardiomyopathy (HOCM); familial hypertrophic cardiomyopathy (FHC); heart failure with preserved ejection fraction (HFPEF); atrial fibrillation (AFIB); ventricular fibrillation (VFIB); angina; myocardial infarction (MI); heart failure or heart failure with reduced ejection fraction (HFREF); supraventricular tachycardia (SVT); hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmia, and congestive heart failure (CHF).

132. The method of any one of claims 129-131, wherein the dsRNA agent is administered to the subject subcutaneously.

133. The method of any one of claims 129-131, wherein the dsRNA agent is administered to the subject intramuscularly.

134. The method of any one of claims 129-131, wherein the dsRNA agent is administered to the subject intravenously.

135. The method of any one of claims 128-134, wherein the subject is a human.

136. An RNA-induced silencing complex (RISC) comprising an antisense strand of any of the dsRNA agents of claims 1-123. 497 ME1\53466565.v1

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