Kinase inhibitors and particles comprising MYC modulators

Abstract

The present disclosure relates to combination therapies comprising a kinase inhibitor and a MYC expression repressor formulated as an LNP. The therapies can be used, for example, to treat cancers such as HCC.

Description

[0001] KINASE INHIBITORS AND PARTICLES COMPRISING MYC MODULATORS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application 63 / 615,073 filed on December 27, 2023, the entire contents of which is hereby incorporated by reference.

[0004] SEQUENCE LISTING

[0005] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on December 20, 2024, is named O2057-7037WO_SL.xml and is 264,077 bytes in size.

[0006] BACKGROUND

[0007] Mis-regulation of gene expression is the underlying cause of many diseases (e.g., in mammals, e.g., humans) e.g., neoplasia, neurological disorders, metabolic disorders and obesity. The mis-regulation of the transcription factor MYC plays a central role in a variety of human tumors and chronic liver diseases. MYC protein is considered "undruggablc" due to various factors, e.g., lack of a defined ligand binding site, physiological function essential to the maintenance of normal tissues. Techniques geared towards modulating the MYC gene expression provides a viable alternative approach in treating these diseases. There is a need for novel tools, systems, and methods to stably alter, e.g., decrease, expression of disease associated genes such as MYC.

[0008] SUMMARY

[0009] The disclosure provides, for instance, combination therapies comprising an expression repressor formulated as an LNP and a kinase inhibitor.

[0010] The disclosure provides expression repressors and expression repressor systems that may be used to modulate, e.g., decrease, expression of a target gene, e.g., MYC, encapsulated in lipid nanoparticles (LNPs). In some embodiments, the LNP comprises one or more of (e.g., all of) an ionizable lipid, a PEGylated lipid, a phosphatidylcholine, and a sterol.

[0011] In some embodiments, tire system comprises a first expression repressor comprising a first targeting moiety and optionally a first effector moiety, wherein the first expression repressor binds to a transcription regulatory element (e.g., a promoter or transcription start site (TSS)) operably linked to a target gene, e.g., MYC or to a sequence proximal to the transcription regulatory element, and a second expression repressor comprising a second targeting moiety and optionally a second effector moiety , wherein the second expression repressor binds to an anchor sequence of an anchor sequence mediated conjunction (ASMC) comprising a target gene, e.g., MYC or to a sequence proximal to the anchor sequence.

[0012] In some embodiments, the expression repressor is delivered by providing a nucleic acid encoding the first expression repressor, second expression repressor, both, or a component thereof (e.g., a gRNA, a mRNA). In some embodiments, the nucleic acid encoding the expression repressor system is a multi- cistronic sequence. In some embodiments, the multi -cistronic sequence is a bi-cistronic sequence.

[0013] In some aspects, the combination therapies described herein are used in a method of treating a condition associated with over-expression of a target gene e.g., MYC, in a subject, the method comprising administering an expression repressor, or a system, nucleic acid, or vector described herein to the subject, thereby treating tire condition.

[0014] Additional features of any of the aforesaid methods or compositions include one or more of the following enumerated embodiments.

[0015] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein. Such equivalents are intended to be encompassed by the following enumerated embodiments.

[0016] All publications, patent applications, patents, and other references (e.g., sequence database reference numbers) mentioned herein are incorporated by reference in their entirety. For example, all GenBank. Unigene, and Entrez sequences referred to herein, e.g., in any Table herein, are incorporated by reference. Unless otherwise specified, the sequence accession numbers specified herein, including in any Table herein, refer to the database entries current as of December 15, 2020. When one gene or protein references a plurality of sequence accession numbers, all of the sequence variants are encompassed.

[0017] ENUMERATED EMBODIMENTS

[0018] 1. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[0019] (A) a composition comprising:

[0020] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety that binds to a MY C promoter, and optionally, an effector moiety, wherein the expression repressor is capable of decreasing expression of MYC; and

[0021] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of

[0022] (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0023] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0024] (i') a compound having a general structure of formula (I):

[0025] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0026] L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[0027] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0028] G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0029] Rais H or C1-C12 alkyl;

[0030] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0031] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[0032] R4is C1-C12 alkyl;

[0033] R5is H or C1-C6 alkyl;

[0034] R11and R12are each independently C1-C12 alkyl or -G4-OR5, or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;

[0035] G4is C1-C24 alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0036] (i") a compound having a general structure of Fonnula (IX):

[0037] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond; G1is C1-C2 alkylene, -(C=0)-, -0(C=0)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0038] G2is -C(=O)- , -(C=O)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0039] G3is C1-C6 alkylene;

[0040] Rais H or C1-C12 alkyl;

[0041] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0042] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0043] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0044] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0045] R5and R6are each independently H or methyl;

[0046] R7is C4-C20 alkyl;

[0047] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[0048] (i'") a compound having a general structure of Formula (XI):

[0049] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0050] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0051] R2and R3are each independently optionally substituted C1 -C36 alkyl; R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0052] L1, L2, and L3are each independently optionally substituted Ci-Cis alkylene;

[0053] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0054] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0055] (ii) a second compound having a general structure of formula (II):

[0056] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (II):

[0057] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0058] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0059] (iv) a steroid (e g., sterol, e g., cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0060] (B) a compound having the general structure of Formula (Al): wherein:

[0061] R1is alkyl, cycloalkyl, or aryl; R2is halo, alkyl, or H;

[0062] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[0063] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0064] 2. The composition of embodiment 1, wherein the targeting moiety binds a genomic locus that is within 1400, 1200, 1000, 800. 600, 400. or 200 nt upstream or downstream of SEQ ID NO: 199 or 201, of SEQ ID NO: 4 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or of genomic coordinates chr8: 128748014-128748036.

[0065] 3. Tire composition of embodiment 1, wherein the targeting moiety binds a genomic locus comprising at least 14, 15, 16. 17, 18, 19, or 20 nucleotides of the sequence of any one of SEQ ID NOs: 77, 82, 83, 85. 199, or 201, of SEQ ID NO: 4 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or of genomic coordinates chr8: 128748014-128748036.

[0066] 4. A method of treating a cancer in a subject in need thereof, tire method comprising administering to the subject:

[0067] (A) a composition comprising:

[0068] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety that binds a genomic locus comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of any one of SEQ ID NOs: 75, 76, 78, 79, 80, 81, 84, 85, 86, 190, 191, 192, 200, or 202, or of the sequence of any of SEQ ID NOs: 3, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106. 107, 109. or 110 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, and optionally, an effector moiety. wherein the expression repressor is capable of decreasing expression of MYC: and

[0069] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0070] (i) a first compound selected from the group consisting of (i'), (i") and (i'"): (i') a compound having a general structure of formula (I):

[0071] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0072] L1and L2are each independently -O(C=O)-, -(C=O)O-. -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-. -NRaC(=O)O-. or a direct bond;

[0073] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene:

[0074] G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0075] Rais H or C1-C12 alkyl;

[0076] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0077] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12. or -NR5C(=O)R4;

[0078] R4is C1-C12 alkyl:

[0079] R5is H or C1-C6 alkyl;

[0080] R11and R12are each independently C1-C12 alkyl or -G4-OR5, or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;

[0081] G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0082] (i") a compound having a general structure of Formula (IX):

[0083] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[0084] G1is C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0085] G2is -C(=O)- , -(C=O)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0086] G3is C1-C6 alkylene;

[0087] Rais H or C1-C12 alkyl;

[0088] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0089] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0090] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0091] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0092] R3and R6are each independently H or methyl;

[0093] R7is C4-C20 alkyl;

[0094] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and.

[0095] (i'") a compound having a general structure of Formula (XI):

[0096] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0097] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0098] R2and R3are each independently optionally substituted C1 -C36 alkyl; R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0099] L1, L2, and L3are each independently optionally substituted Ci-Cis alkylene;

[0100] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0101] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0102] (ii) a second compound having a general structure of formula (II):

[0103] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (II):

[0104] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0105] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0106] (iv) a steroid (e g., sterol, e g., cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0107] (B) a compound having the general structure of Formula (Al):

[0108] Formula (Al) wherein:

[0109] R1is alkyl, cycloalkyl, or aryl; R2is halo, alkyl, or H;

[0110] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[0111] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0112] 5. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[0113] (A) a composition comprising:

[0114] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety that binds a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 77, 82, 83, 199, or 201, or SEQ ID NO: 2 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, and optionally, an effector moiety, wherein the expression repressor is capable of decreasing expression of MYC; and

[0115] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0116] (i) a first compound selected from the group consisting of (i'j, (i") and (i'"):

[0117] (i'j a compound having a general structure of formula (I):

[0118] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0119] L1and L2are each independently O(C~O)-. -(OO)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -CtyOjS-.

[0120] SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-. -NRaC(=O)O-, or a direct bond;

[0121] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0122] G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0123] Rais H or C1-C12 alkyl;

[0124] R1and R2arc each independently C6-C24 alkyl or C6-C24 alkenyl;

[0125] R3is H, OR3, CN, -C(=O)OR4, -OC(=O)R4, -NR1' R1; or -NRX (-O)R4;

[0126] R4is C1-C12 alkyl:

[0127] R' is H or C1-C6 alkyl; R11and R12are each independently C1-C12 alkyl or -G4-OR5, or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;

[0128] G4is C1-C24 alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0129] (i") a compound having a general structure of Fonnula (IX):

[0130] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0131] L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[0132] G1is C1-C2 alkylene, -(C=O)-, -O(C=O)-_ -SC(=O)-, -NRaC(=O)- or a direct bond;

[0133] G2is -C(=O)- , -(C=O)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0134] G3is C1-C6 alkylene;

[0135] Rais H or C1-C12 alkyl;

[0136] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0137] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0138] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0139] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0140] R5and R6are each independently H or methyl; R7is C4-C20 alkyl:

[0141] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and.

[0142] (i'") a compound having a general structure of Formula (XI):

[0143] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0144] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl:

[0145] R2and R3are each independently optionally substituted C1 -C36 alkyl;

[0146] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with tire N to which they are attached, to form a heterocyclyl or heteroaryl;

[0147] L1, L2. and L3are each independently optionally substituted C1 -C18 alkylene;

[0148] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0149] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0150] (ii) a second compound having a general structure of formula (II):

[0151] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (II):

[0152] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60; (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0153] (iv) a steroid (e.g., sterol, e.g., cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0154] (B) a compound having the general structure of Formula (Al): wherein:

[0155] R1is alkyl, cycloalkyl, or aryl;

[0156] R2is halo, alkyl, or H;

[0157] R3, R4, R5, R . R7, are each independently H or alkyl; and

[0158] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0159] 6. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[0160] (A) a composition comprising:

[0161] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety that binds a MY C locus, and an effector moiety comprising MQ 1 or a fragment or variant thereof, wherein the expression repressor is capable of decreasing expression of MYC; and (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of

[0162] (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0163] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0164] (i') a compound having a general structure of formula (I):

[0165] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0166] L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[0167] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0168] G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0169] Rais H or C1-C12 alkyl;

[0170] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0171] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[0172] R4is C1-C12 alkyl;

[0173] R5is H or C1-C6 alkyl;

[0174] R11and R12are each independently C1-C12 alkyl or -G4-OR5, or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;

[0175] G4is C1-C24 alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0176] (i") a compound having a general structure of Fonnula (IX):

[0177] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond; G1is C1-C2 alkylene, -(C=0)-, -0(C=0)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0178] G2is -C(=O)- , -(C=O)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0179] G3is C1-C6 alkylene;

[0180] Rais H or C1-C12 alkyl;

[0181] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0182] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0183] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0184] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0185] R5and R6are each independently H or methyl;

[0186] R7is C4-C20 alkyl;

[0187] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[0188] (i'") a compound having a general structure of Formula (XI):

[0189] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0190] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0191] R2and R3are each independently optionally substituted C1 -C36 alkyl; R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0192] L1, L2, and L3are each independently optionally substituted Ci-Cis alkylene;

[0193] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0194] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0195] (ii) a second compound having a general structure of formula (II):

[0196] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (II):

[0197] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0198] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0199] (iv) a steroid (e g., sterol, e g., cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0200] (B) a compound having the general structure of Formula (Al): wherein:

[0201] R1is alkyl, cycloalkyl, or aryl; R2is halo, alkyl, or H;

[0202] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[0203] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0204] 7. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[0205] (A) a composition comprising:

[0206] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety that binds a locus in MY C super enhancer region, optionally an effector moiety, e.g., an effector moiety comprising a DNA methyltransferase, wherein optionally the effector moiety comprises MQ 1 or a fragment or variant thereof. wherein the expression repressor is capable of decreasing expression of MYC; and

[0207] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0208] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0209] (i') a compound having a general structure of formula (I):

[0210] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0211] L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[0212] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0213] G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0214] Rais H or C1 -C12 alkyl;

[0215] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0216] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[0217] R4is C1 -C12 alkyl;

[0218] R5is H or C1-C6 alkyl;

[0219] R11and R12are each independently C1-C12 alkyl or -G4-OR5. or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0220] (i") a compound having a general structure of Formula (IX):

[0221] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0222] L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-,

[0223] -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-,

[0224] -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[0225] G1is C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0226] G2is -C(=O)- , -(OO)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0227] G3is C1-C6 alkylene;

[0228] Rais H or C1 -C12 alkyl;

[0229] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0230] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0231] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0232] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0233] R5and R6are each independently H or methyl;

[0234] R7is C4-C20 alkyl; R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[0235] (i'") a compound having a general structure of Formula (XI):

[0236] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0237] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0238] R2and R3are each independently optionally substituted C1 -C36 alkyl;

[0239] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with tire N to which they are attached, to form a heterocyclyl or heteroaryl;

[0240] L1, L2. and L3are each independently optionally substituted Ci-Cis alkylene;

[0241] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0242] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0243] (ii) a second compound having a general structure of formula (II):

[0244] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (II):

[0245] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60; (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0246] (iv) a steroid (e.g., sterol, e.g., cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0247] (B) a compound having the general structure of Formula (Al): wherein:

[0248] R1is alkyl, cycloalkyl, or aryl;

[0249] R2is halo, alkyl, or H;

[0250] R3, R4, R5, R . R7, are each independently H or alkyl; and

[0251] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0252] 8. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[0253] (A) a composition comprising:

[0254] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety that binds a locus in MY C super enhancer region, an effector moiety comprising a transcription repressor, wherein optionally the effector moiety comprises KRAB or a fragment or variant thereof, wherein the expression repressor is capable of decreasing expression of MYC; and

[0255] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e g., comprising all of (i)-(iv)):

[0256] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0257] (i') a compound having a general structure of formula (I):

[0258] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0259] L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[0260] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0261] G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0262] Rais H or C1-C12 alkyl;

[0263] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0264] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[0265] R4is C1-C12 alkyl;

[0266] R5is H or C1-C6 alkyl;

[0267] R11and R12are each independently C1-C12 alkyl or -G4-OR5, or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;

[0268] G4is C1-C24 alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0269] (i") a compound having a general structure of Fonnula (IX):

[0270] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond; G1is C1-C2 alkylene, -(C=0)-, -0(C=0)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0271] G2is -C(=O)- , -(C=O)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0272] G3is C1-C6 alkylene;

[0273] Rais H or C1-C12 alkyl;

[0274] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0275] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0276] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0277] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0278] R5and R6are each independently H or methyl;

[0279] R7is C4-C20 alkyl;

[0280] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[0281] (i'") a compound having a general structure of Formula (XI):

[0282] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0283] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0284] R2and R3are each independently optionally substituted C1 -C36 alkyl; R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0285] L1, L2, and L3are each independently optionally substituted C1 -C18 alkylene;

[0286] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0287] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0288] (ii) a second compound having a general structure of formula (II):

[0289] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (II):

[0290] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0291] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0292] (iv) a steroid (e g., sterol, e g., cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0293] (B) a compound having the general structure of Formula (Al): wherein:

[0294] R1is alkyl, cycloalkyl, or aryl; R2is halo, alkyl, or H;

[0295] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[0296] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0297] 9. The method of embodiment 7 or 8, wherein the targeting moiety binds a genomic locus comprising at least 14, 15, 16. 17. 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs: 83, 199, or 201, or any of SEQ ID NOs: 96-110 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety.

[0298] 10. Tire method of any of embodiments 7-9, wherein the targeting moiety binds a genomic locus comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of GRCh37: chr8: 129162465-129212140, using the hgl9 reference genome.

[0299] 11. The method of any of embodiments 7-10, wherein the targeting moiety binds a genomic locus comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of GRCh37: GRCh37: chr8: 129188878-129188900 or GRCh37: chr8: 129189190-129189212 or SEQ ID NO: 96 or 108 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety.

[0300] 12. The method of any of embodiments 7-11, wherein the targeting moiety comprises a zinc finger domain or a TAL effector domain.

[0301] 13. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[0302] (A) a composition comprising:

[0303] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety that binds a locus, e.g., a MYC locus. a first effector moiety comprising EZH2 or a fragment or variant thereof, and a second effector moiety comprising KRAB or a fragment or variant thereof, wherein the expression repressor is capable of decreasing expression at the locus, e.g., decreasing expression of MYC; and

[0304] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0305] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0306] (i') a compound having a general structure of formula (I):

[0307] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0308] L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[0309] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0310] G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0311] Rais H or C1-C12 alkyl;

[0312] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0313] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[0314] R4is C1-C12 alkyl;

[0315] R5is H or C1-C6 alkyl;

[0316] R11and R12are each independently C1-C12 alkyl or -G4-OR5, or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;

[0317] G4is C1-C24 alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0318] (i") a compound having a general structure of Fonnula (IX):

[0319] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond; G1is C1-C2 alkylene, -(C=0)-, -0(C=0)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0320] G2is -C(=O)- , -(C=O)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0321] G3is C1-C6 alkylene;

[0322] Rais H or C1-C12 alkyl;

[0323] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0324] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0325] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0326] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0327] R5and R6are each independently H or methyl;

[0328] R7is C4-C20 alkyl;

[0329] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[0330] (i'") a compound having a general structure of Formula (XI):

[0331] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0332] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0333] R2and R3are each independently optionally substituted C1 -C36 alkyl; R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0334] L1, L2, and L3are each independently optionally substituted Ci-Cis alkylene;

[0335] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0336] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0337] (ii) a second compound having a general structure of formula (II):

[0338] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (II):

[0339] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0340] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0341] (iv) a steroid (e g., sterol, e g., cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0342] (B) a compound having the general structure of Formula (Al):

[0343] Formula (Al) wherein:

[0344] R1is alkyl, cycloalkyl, or aryl; R2is halo, alkyl, or H;

[0345] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[0346] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0347] 14. The method of embodiment 13, wherein the targeting moiety binds the MYC promoter, super enhancer region, or anchor sequence.

[0348] 15. The method of embodiment 13 or 14, wherein the targeting moiety comprises a TAL effector domain, a CRISPR / Cas domain, or a zinc finger domain.

[0349] 16. Tire method of any of embodiments 13-15, wherein the first effector moiety is N-terminal of the second effector, or wherein the first effector is C-tcnninal of the second effector moiety.

[0350] 17. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject:

[0351] (A) a composition comprising:

[0352] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety that binds a MY C locus, wherein the targeting moiety comprises a zinc finger domain, and optionally, an effector moiety. wherein the expression repressor is capable of decreasing expression of MYC; and

[0353] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0354] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0355] (i') a compound having a general structure of formula (I):

[0356] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0357] L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[0358] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0359] G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0360] Rais H or C1-C12 alkyl; R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0361] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[0362] R4is C1-C12 alkyl;

[0363] R5is H or C1-C6 alkyl;

[0364] R11and R12are each independently C1-C12 alkyl or -G4-OR5. or R11and R12, together with the nitrogen atom to which they are attached, form a 5. 6 or 7-membered heterocyclic ring;

[0365] G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0366] (i") a compound having a general structure of Formula (IX):

[0367] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[0368] G1is C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0369] G2is -C(=O)- , -(C=O)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0370] G3is C1-C6 alkylene;

[0371] Rais H or C1 -C12 alkyl;

[0372] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0373] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0374] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R’ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond; R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0375] R5and R6are each independently H or methyl;

[0376] R7is C4-C20 alkyl;

[0377] R8and R9are each independently C1-C12 alkyl; or R8and R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[0378] (i'") a compound having a general structure of Fonnula (XI):

[0379] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0380] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0381] R2and R3are each independently optionally substituted C1 -C36 alkyl;

[0382] R4and R5are each independently optionally substituted Ci-Cs alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0383] L1, L2, and L3are each independently optionally substituted Ci-Cis alkylene;

[0384] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0385] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0386] (ii) a second compound having a general structure of formula (II):

[0387] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (II): Rband R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0388] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0389] (iv) a steroid (e.g., sterol, e.g., cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0390] (B) a compound having the general structure of Formula (Al): wherein:

[0391] R1is alkyl, cycloalkyl, or and;

[0392] R2is halo, alkyl, or H;

[0393] R3, R4, R5. R6, R7, are each independently H or alkyl; and

[0394] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0395] 18. A method of treating a cancer in a subject in need thereof, tire method comprising administering to the subject:

[0396] (A) a composition comprising:

[0397] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety comprising a CRISPR / Cas domain, e.g., comprising a catalytically inactive CRISPR / Cas protein, that binds to a transcription regulatory element (e.g., a promoter, an enhancer, a super enhancer, or transcription start site (TSS)) operably linked to a MYC gene or a sequence proximal to said transcription regulatory element; and an effector moiety comprising MQ 1 or a functional variant or fragment thereof; and (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0398] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0399] (i') a compound having a general structure of formula (I):

[0400] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0401] L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[0402] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0403] G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0404] Rais H or C1-C12 alkyl;

[0405] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0406] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[0407] R4is C1-C12 alkyl;

[0408] R5is H or C1-C6 alkyl;

[0409] R11and R12are each independently C1-C12 alkyl or -G4-OR5. or R11and R12, together with the nitrogen atom to which they are attached, form a 5. 6 or 7-membered heterocyclic ring;

[0410] G4is C1-C24 alkylene, C2-C24 alkenylene, Cg-Cs cycloalkylene, Cg-Cs cycloalkenylene; and x is 0, 1 or 2;

[0411] (i") a compound having a general structure of Fonnula (IX):

[0412] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(OO)-, -(OO)O-, -C(=0)-, -0-, -S(0)x-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[0413] G1is C1-C2 alkylene, -(C=0)-, -0(00)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0414] G2is -C(=0)- , -(OO)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0415] G3is C1-C6 alkylene;

[0416] Rais H or C1-C12 alkyl;

[0417] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0418] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0419] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0420] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0421] R5and R6are each independently H or methyl;

[0422] R7is C4-C20 alkyl;

[0423] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[0424] (i'") a compound having a general structure of Formula (XI):

[0425] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0426] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0427] R2and R3are each independently optionally substituted C1-C36 alkyl;

[0428] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0429] L1, L2, and L3are each independently optionally substituted C1 -C18 alkylene;

[0430] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0431] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0432] (ii) a second compound having a general structure of formula (II):

[0433] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Fonnula (II):

[0434] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0435] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0436] (iv) a steroid (e.g.. sterol, e.g.. cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and (B) a compound having the general structure of Formula (Al) wherein: R1is alkyl, cycloalkyl, or aryl;

[0437] R2is halo, alkyl, or H;

[0438] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[0439] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. 19. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[0440] (A) a composition comprising:

[0441] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety comprising a CRISPR / Cas domain, e.g., comprising a catalytically inactive CRISPR / Cas protein, that binds to a transcription regulatory element (e.g., a promoter, an enhancer, or transcription start site (TSS)) operably linked to a MYC gene or a sequence proximal to said transcription regulatory element; and an effector moiety' comprising MQ 1 or a functional variant or fragment thereof; and

[0442] (2) a formulation comprising:

[0443] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0444] (i') a compound having a general structure of formula (I):

[0445] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0446] L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-. -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[0447] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0448] G1is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0449] Rais H or C1 -C12 alkyl;

[0450] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0451] R3is H, OR5, CN, -C(=0)0R4, -0C(=0)R4, -NRHR12, or -NR5C(=O)R4;

[0452] R4is C1-C12 alkyl;

[0453] R5is H or C1-C6 alkyl;

[0454] R11and R12are each independently C1-C12 alkyl or -G4-OR5. or R11and R12, together with the nitrogen atom to which they are attached, fonn a 5. 6 or 7-membered heterocyclic ring;

[0455] G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0456] (i") a compound having a general structure of Fonnula (IX):

[0457] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(OO)-, -(OO)O-, -C(=0)-, -0-, -S(0)x-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[0458] G1is C1-C2 alkylene, -(C=0)-, -0(00)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0459] G2is -C(=0)- , -(OO)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0460] G3is C1-C6 alkylene;

[0461] Rais H or C1-C12 alkyl;

[0462] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0463] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0464] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0465] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0466] R5and R6are each independently H or methyl;

[0467] R7is C4-C20 alkyl;

[0468] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[0469] (i'") a compound having a general structure of Formula (XI):

[0470] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0471] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0472] R2and R3are each independently optionally substituted C1-C36 alkyl;

[0473] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0474] L1, L2, and L3are each independently optionally substituted C1 -C18 alkylene;

[0475] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0476] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0477] (ii) a second compound having a general structure of formula (II):

[0478] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Fonnula (II):

[0479] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0480] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0481] (iv) a steroid (e.g.. sterol, e.g.. cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and (B) a compound having the general structure of Formula (Al): wherein:

[0482] R1is alkyl, cycloalkyl, or aryl;

[0483] R2is halo, alkyl, or H;

[0484] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[0485] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0486] 20. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[0487] (A) a composition comprising:

[0488] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety comprising a CRISPR / Cas domain, e.g., comprising a catalytically inactive CRISPR / Cas protein, that binds to a transcription regulatory element (e.g., a promoter, an enhancer, or transcription start site (TSS)) operably linked to a MYC gene or a sequence proximal to said transcription regulatory element; and an effector moiety comprising KRAB or a functional variant or fragment thereof; and

[0489] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0490] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0491] (i'j a compound having a general structure of formula (I):

[0492] Formula (1); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0493] L1and I? are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[0494] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0495] G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0496] Rais H or C1-C12 alkyl;

[0497] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0498] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[0499] R4is C1-C12 alkyl;

[0500] R5is H or C1-C6 alkyl;

[0501] R11and R12are each independently C1-C12 alkyl or -G4-OR5. or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;

[0502] G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0503] (i") a compound having a general structure of Formula (IX):

[0504] Fonnula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[0505] G1is C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0506] G2is -C(=O)- , -(C=O)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0507] G3is C1-C6 alkylene;

[0508] Rais H or C1 -C12 alkyl; Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0509] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0510] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0511] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0512] R5and Rbare each independently H or methyl;

[0513] R7is C4-C20 alkyl;

[0514] R8and R9are each independently C1-C12 alkyl; or R8and R9, together with the nitrogen atom to which they are attached, fomi a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0. 1 or 2; and,

[0515] (i'") a compound having a general structure of Formula (XI):

[0516] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0517] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0518] R2and R3are each independently optionally substituted C1 -C36 alkyl;

[0519] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0520] L1, L2, and L3are each independently optionally substituted C1 -C18 alkylene;

[0521] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0522] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0523] (ii) a second compound having a general structure of formula (II):

[0524] Formula (11): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (II):

[0525] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0526] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0527] (iv) a steroid (e.g., sterol, e.g., cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0528] (B) a compound having the general structure of Formula (Al): wherein:

[0529] R1is alkyl, cycloalkyl, or aryl;

[0530] R2is halo, alkyl, or H;

[0531] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[0532] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. 21. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[0533] (A) a composition comprising:

[0534] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety comprising a CRISPR / Cas domain, e g., comprising a catalytically inactive CRISPR / Cas protein, that binds to an anchor sequence of an anchor sequence mediated conjunction (ASMC) comprising a MYC gene or to a sequence proximal to the anchor sequence; and an effector moiety comprising KRAB or a functional variant or fragment thereof; and

[0535] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0536] (i) a first compound selected from the group consisting of (i'j, (i") and (i'"):

[0537] (i') a compound having a general structure of formula (I):

[0538] R3

[0539] 733

[0540] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0541] L1and L2are each independently -O(C=O)-, -(C=O)O-. -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-. -NRaC(=O)O-_ or a direct bond;

[0542] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0543] G’ is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0544] Rais H or C1-C12 alkyl;

[0545] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0546] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12. or -NR5C(=O)R4;

[0547] R4is C1-C12 alkyl;

[0548] R5is H or C1-C6 alkyl;

[0549] R11and R12are each independently C1-C12 alkyl or -G4-OR5, or R11and R12, together with the nitrogen atom to which they arc attached, form a 5, 6 or 7-mcmbcrcd heterocyclic ring;

[0550] G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2; (i") a compound having a general structure of Fonnula (IX):

[0551] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(OO)-, -(OO)O-, -C(=0)-, -0-, -S(0)x-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[0552] G1is C1-C2 alkylene, -(C=0)-, -0(00)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0553] G2is -C(=0)- , -(OO)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0554] G3is C1-C6 alkylene;

[0555] Rais H or C1-C12 alkyl;

[0556] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0557] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0558] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0559] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0560] R5and R6are each independently H or methyl;

[0561] R7is C4-C20 alkyl;

[0562] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[0563] (i'") a compound having a general structure of Formula (XI):

[0564] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0565] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0566] R2and R3are each independently optionally substituted C1-C36 alkyl;

[0567] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0568] L1, L2, and L3are each independently optionally substituted C1 -C18 alkylene;

[0569] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0570] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0571] (ii) a second compound having a general structure of formula (II):

[0572] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Fonnula (II):

[0573] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0574] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0575] (iv) a steroid (e.g.. sterol, e.g.. cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and (B) a compound having the general structure of Formula (Al): wherein:

[0576] R1is alkyl, cycloalkyl, or aryl;

[0577] R2is halo, alkyl, or H;

[0578] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[0579] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0580] 22. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[0581] (A) a composition comprising:

[0582] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety comprising a zinc finger domain that binds to a transcription regulatory element (e.g., a promoter, an enhancer, or transcription start site (TSS)) operably linked to a MYC gene or a sequence proximal to said transcription regulatory element; and an effector moiety comprising MQ 1 or a functional variant or fragment thereof; and

[0583] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0584] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0585] (i') a compound having a general structure of formula (1): ^R2

[0586] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0587] L1and I? are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[0588] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0589] G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0590] Rais H or C1-C12 alkyl;

[0591] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0592] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[0593] R4is C1-C12 alkyl;

[0594] R5is H or C1-C6 alkyl;

[0595] R11and R12are each independently C1-C12 alkyl or -G4-OR5. or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;

[0596] G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0597] (i") a compound having a general structure of Formula (IX):

[0598] Fonnula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[0599] G1is C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0600] G2is -C(=O)- , -(C=O)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0601] G3is C1-C6 alkylene;

[0602] Rais H or C1 -C12 alkyl; Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0603] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0604] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0605] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0606] R5and Rbare each independently H or methyl;

[0607] R7is C4-C20 alkyl;

[0608] R8and R9are each independently C1-C12 alkyl; or R8and R9, together with the nitrogen atom to which they are attached, fomi a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0. 1 or 2; and,

[0609] (i'") a compound having a general structure of Formula (XI):

[0610] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0611] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0612] R2and R3are each independently optionally substituted C1 -C36 alkyl;

[0613] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0614] L1, L2, and L3are each independently optionally substituted C1 -C18 alkylene;

[0615] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0616] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0617] (ii) a second compound having a general structure of formula (II):

[0618] Formula (11): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (II):

[0619] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0620] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0621] (iv) a steroid (e.g., sterol, e.g., cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0622] (B) a compound having the general structure of Formula (Al): wherein:

[0623] R1is alkyl, cycloalkyl, or aryl;

[0624] R2is halo, alkyl, or H;

[0625] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[0626] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. 23. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[0627] (A) a composition comprising:

[0628] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety comprising a zinc finger domain that binds to a transcription regulatory element (e.g., a promoter, an enhancer, or transcription start site (TSS)) operably linked to a MYC gene or a sequence proximal to said transcription regulatory' element; and an effector moiety comprising KRAB or a functional variant or fragment thereof; and

[0629] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0630] (i) a first compound selected from the group consisting of (i'j, (i") and (i'"):

[0631] (i'j a compound having a general structure of formula (I):

[0632] R3

[0633] X33

[0634] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0635] L1and L2are each independently O(C~O)-. -(C~O)O-. -C(=O)-, -O-, -S(O)X-, -S-S-, -C(~O)S-. SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[0636] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0637] G' is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0638] Rais H or C1 -C12 alkyl;

[0639] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0640] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[0641] R4is C1-C12 alkyl;

[0642] R3is H or C1-C6 alkyl;

[0643] R11and R12are each independently C1-C12 alkyl or -G4-OR5, or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;

[0644] G4is C1-C24 alkylene, C2-C 24 alkcnylcnc, C3-C8 cycloalkylcnc, C3-C8 cycloalkcnylcnc; and x is 0, 1 or 2; (i") a compound having a general structure of Fonnula (IX):

[0645] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(OO)-, -(OO)O-, -C(=0)-, -0-, -S(0)x-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[0646] G1is C1-C2 alkylene, -(C=0)-, -0(00)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0647] G2is -C(=0)- , -(OO)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0648] G3is C1-C6 alkylene;

[0649] Rais H or C1-C12 alkyl;

[0650] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0651] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0652] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0653] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0654] R5and R6are each independently H or methyl;

[0655] R7is C4-C20 alkyl;

[0656] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[0657] (i'") a compound having a general structure of Formula (XI):

[0658] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0659] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0660] R2and R3are each independently optionally substituted C1-C36 alkyl;

[0661] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0662] L1, L2, and L3are each independently optionally substituted C1 -C18 alkylene;

[0663] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0664] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0665] (ii) a second compound having a general structure of formula (II):

[0666] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Fonnula (II):

[0667] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0668] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0669] (iv) a steroid (e.g.. sterol, e.g.. cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and (B) a compound having the general structure of Formula (Al): wherein:

[0670] R1is alkyl, cycloalkyl, or aryl;

[0671] R2is halo, alkyl, or H;

[0672] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[0673] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0674] 24. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[0675] (A) a composition comprising:

[0676] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety that binds a mouse genomic locus comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs: 190-192, and optionally, an effector moiety. wherein the expression repressor is capable of decreasing expression of MYC; and

[0677] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0678] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0679] (i') a compound having a general structure of formula (I): ^R2

[0680] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0681] L1and I? are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[0682] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0683] G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0684] Rais H or C1-C12 alkyl;

[0685] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0686] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[0687] R4is C1-C12 alkyl;

[0688] R5is H or C1-C6 alkyl;

[0689] R11and R12are each independently C1-C12 alkyl or -G4-OR5. or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;

[0690] G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0691] (i") a compound having a general structure of Formula (IX):

[0692] Fonnula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[0693] G1is C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0694] G2is -C(=O)- , -(C=O)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0695] G3is C1-C6 alkylene;

[0696] Rais H or C1 -C12 alkyl; Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0697] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0698] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0699] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0700] R5and Rbare each independently H or methyl;

[0701] R7is C4-C20 alkyl;

[0702] R8and R9are each independently C1-C12 alkyl; or R8and R9, together with the nitrogen atom to which they are attached, fomi a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0. 1 or 2; and,

[0703] (i'") a compound having a general structure of Formula (XI):

[0704] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0705] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0706] R2and R3are each independently optionally substituted C1 -C36 alkyl;

[0707] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0708] L1, L2, and L3are each independently optionally substituted C1 -C18 alkylene;

[0709] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0710] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0711] (ii) a second compound having a general structure of formula (II):

[0712] Formula (11): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (II):

[0713] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0714] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0715] (iv) a steroid (e.g., sterol, e.g., cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0716] (B) a compound having the general structure of Formula (Al): wherein:

[0717] R1is alkyl, cycloalkyl, or aryl;

[0718] R2is halo, alkyl, or H;

[0719] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[0720] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. The method of embodiment 24, wherein the effector moiety comprises a DNA methyltransferase, e.g., MQ1 or a fragment or variant thereof. Tire method of embodiments 24 or 25, wherein the targeting moiety comprises a TAL effector domain, a CRISPR / Cas domain, a zinc finger domain, a tetR domain, a meganuclease domain, or an oligonucleotide. The method of any of embodiments 24-26, wherein the targeting moiety comprises a zinc finger domain or a TAL effector domain. The method of any of embodiments 24-27, wherein the expression repressor comprises an amino acid sequence chosen from any of SEQ ID NOs: 160-165, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8. 7, 6, 5, 4. 3, 2, or 1 positions of difference thereto. The method of any of embodiments 24-28, wherein the expression repressor is encoded by a nucleotide sequence chosen from any of SEQ ID NOs: 166-168, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto. The method of any of embodiments 24-29, wherein the targeting moiety comprises an amino acid sequence according to any of SEQ ID NOs: 154-156, or a sequence with at least 80. 85. 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18. 17. 16. 15, 14, 13, 12, 11, 10. 9,

[0721] 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto. The method of any of embodiments 24-30, wherein the targeting moiety is encoded by a nucleic acid sequence according to any of SEQ ID NOs: 157-159, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10,

[0722] 9, 8. 7, 6, 5, 4. 3, 2, or 1 positions of difference thereto. The method of any of embodiments 24-31, wherein the effector moiety is a durable effector moiety. The method of any of embodiments 24-32, wherein the effector moiety is a transient effector moiety. The method of any of embodiments 24-33, wherein the expression repressor is a fusion molecule. The method of any of embodiments 24-34, wherein the targeting moiety comprises a zinc finger domain, and the effector moiety comprises an epigenetic modifying moiety, e.g., a DNA methyltransferase, e.g., MQ1 or a fragment or variant thereof. The method of any of embodiments 18-20, 22, or 23, wherein the regulatory element is part of a cluster of regulatory elements. 37. The method of any embodiments 18-20, 22, or 23, wherein the regulatory element is located in a non-coding region.

[0723] 38. Tire method of any embodiments 18-20, 22, or 23, wherein the regulatory element is a distal enhancer e.g., located at least 1,000 nt away from a target gene promoter, e.g., MYC.

[0724] 39. The method of any embodiments 18-20. 22, 23or 36-38, wherein the regulatory element increases the expression of a target gene, e.g.. MYC.

[0725] 40. The method of any embodiments 18-20, 22, 23, or 36-39, wherein the regulatory element contains one or more mutations.

[0726] 41. Tire method of any embodiments 18-20, 22, 23, or 36-40, wherein the regulatory element contains at least one disease-associated single nucleotide polymorphism (SNP).

[0727] 42. The method of any of embodiments 18-20, 22, 23, or 36-41, wherein the transcription regulatory element interacts with the promoter of target gene, e.g., MYC through an enhancer docking site.

[0728] 43. The method of embodiment 42, wherein the enhancer docking site comprises a nucleotide sequence of according to any of SEQ ID NOs: 71, 72, or a nucleic acid sequence of CCGCCATNTT or AANATGGCGG, where N is any nucleotide.

[0729] 44. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[0730] (A) a composition comprising:

[0731] (1) a first nucleic acid encoding an expression repressor comprising: a targeting moiety comprising a zinc finger domain that binds to an anchor sequence of an anchor sequence mediated conjunction (ASMC) comprising a MYC gene or to a sequence proximal to the anchor sequence; and an effector moiety comprising KRAB or a functional variant or fragment thereof; and

[0732] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0733] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0734] (i') a compound having a general structure of fonnula (I):

[0735] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0736] L1and I? are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[0737] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0738] G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0739] Rais H or C1-C12 alkyl;

[0740] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0741] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[0742] R4is C1-C12 alkyl;

[0743] R5is H or C1-C6 alkyl;

[0744] R11and R12are each independently C1-C12 alkyl or -G4-OR5. or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;

[0745] G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0746] (i") a compound having a general structure of Formula (IX):

[0747] Fonnula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[0748] G1is C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0749] G2is -C(=O)- , -(C=O)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0750] G3is C1-C6 alkylene;

[0751] Rais H or C1 -C12 alkyl; Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0752] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0753] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0754] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0755] R5and Rbare each independently H or methyl;

[0756] R7is C4-C20 alkyl;

[0757] R8and R9are each independently C1-C12 alkyl; or R8and R9, together with the nitrogen atom to which they are attached, fomi a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0. 1 or 2; and,

[0758] (i'") a compound having a general structure of Formula (XI):

[0759] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0760] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0761] R2and R3are each independently optionally substituted C1 -C36 alkyl;

[0762] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0763] L1, L2, and L3are each independently optionally substituted C1 -C18 alkylene;

[0764] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0765] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0766] (ii) a second compound having a general structure of formula (II):

[0767] Formula (11): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (II):

[0768] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0769] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0770] (iv) a steroid (e.g., sterol, e.g., cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0771] (B) a compound having the general structure of Formula (Al): wherein:

[0772] R1is alkyl, cycloalkyl, or aryl;

[0773] R2is halo, alkyl, or H;

[0774] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[0775] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. The method of any of embodiments 1-44, wherein the first nucleic acid comprises an RNA, e.g., an mRNA. Tire method of any of embodiments 1-23 or 36-43, wherein the expression repressor comprises an amino acid sequence chosen from any of SEQ ID NOs: 22-33, 129, 133, 134, 139-149, or 177- 186. or of any of SEQ ID NOs: 34-37 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto. Tire method of any of embodiments 1-23 or 36-46, wherein the expression repressor is encoded by a nucleotide sequence chosen from any of SEQ ID NOs: 55-66, 130, 189, or 193-197, or of any of SEQ ID NOs: 67-70 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto. Tire method of any of embodiments 1-23 or 36-47, wherein the targeting moiety comprises an amino acid sequence according to any of SEQ ID NOs: 5-16, or 169-172, or a sequence with at least 80. 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17. 16, 15, 14, 13, 12, 11. 10. 9, 8, 7, 6. 5, 4, 3, 2. or 1 positions of difference thereto. The method of any of the preceding embodiments, wherein the effector moiety comprises an amino acid sequence according to any of SEQ ID NOs: 18, 19, or 87, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto Tire method of any of embodiments 1-12, 17-19, 22, 36-42. or 44-48. wherein the effector moiety is a durable effector moiety. The method of any of embodiments 1 -23, or 36-49, wherein the effector moiety is a transient effector moiety. Tire method of any of embodiments 1-12, 17-19, 22, 36-42, or 44-49, wherein the effector moiety comprises a DNA methyltransferase, e.g., MQ 1 or a fragment or variant thereof. The method of any of embodiments 1-23, 36-48, or 50, wherein the effector moiety comprises a transcription repressor, e.g.. comprises KRAB or a fragment or variant thereof. The method of any of the preceding embodiments, wherein the targeting moiety comprises a TAL effector domain, a CRISPR / Cas domain, a zinc finger domain, a tetR domain, a meganuclease domain, or an oligonucleotide. The method of embodiment 54, wherein the CRISPR / Cas domain binds a gRNA, e.g., a gRNA that binds a genomic locus comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs: 1-4 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, e.g., wherein the gRNA comprises a sequence that comprises at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs: 1-4 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety. The method of embodiment 54, wherein the CRISPR / Cas domain binds a gRNA, e.g., a gRNA that binds a genomic locus comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs: 96-110 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, e.g., wherein the gRNA comprises a sequence that comprises at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs: 96-110 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety. Tire method of any of embodiments 54-56, wherein the CRISPR / Cas domain comprises a Cas protein or Cpfl protein chosen from Table 1 as described in International Application WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or a variant (e.g., mutant) of any thereof. The method of any of embodiments 54-57, wherein the CRISPR / Cas domain comprises a catalytically inactive CRISPR / Cas protein, e.g., dCas9. Tire method of embodiment 54, wherein tire zinc finger domain binds a genomic locus comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs: 96-110 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, e.g.. wherein the gRNA comprises a sequence that comprises at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs: 96-110 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety. The method of any of embodiments 17, 22, 26-54, or 58, wherein the zinc finger domain comprises 1, 2, 3, 4. 5, 6, 7, 8. 9, or 10 zinc fingers (and optionally no more than 11, 10. 9, 8, 7, 6, or 5 zinc fingers). The method of any of embodiments 17, 22, 26-54, 58, or 59, wherein the zinc finger domain comprises 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6- 7, 7-10, 7-9. 7-8, 8-10, 8-9, or 9-10 zinc fingers. 62. The method of any of embodiments 17, 22, 26-54, or 58-60, wherein the zinc finger domain comprises 3 or 9 zinc fingers.

[0776] 63. Tire method of any of the preceding embodiments, wherein the expression repressor is a fusion molecule.

[0777] 64. The method of any of the preceding embodiments, wherein the expression repressor comprises a linker situated between the targeting domain and the effector domain, optionally wherein the linker comprises an amino sequence according to SEQ ID NO: 137 or SEQ ID NO: 138.

[0778] 65. The method of any of embodiments 1-17, 20, 21, 23, 44-49, 51, or 53-58, wherein the targeting moiety comprises a catalytically inactive CRISPR / Cas domain (e.g., dCas9) and the effector moiety comprises a transcription repressor, e.g., KRAB or a fragment or variant thereof.

[0779] 66. The method of any of embodiments 1-17, 20, 21, 23, 44-49. 51, 53, or 54-65, wherein the targeting moiety comprises a zinc finger domain, and the effector moiety comprises a transcription repressor, e.g., KRAB or a fragment or variant thereof.

[0780] 67. The method of any of embodiments 17, 36-43, 46-48, 54, or 59-64, wherein the targeting moiety comprises a zinc finger domain, and the expression repressor does not comprise an effector moiety.

[0781] 68. The method of any of embodiments 1-12, 18-19, 22, 36-43, 46-50, 52, or 54-58, wherein the targeting moiety comprises a catalytically inactive CRISPR / Cas domain (e.g.. dCas9) and the effector moiety comprises an epigenetic modifying moiety, e g., a DNA methyltransferase, e.g., MQ 1 or a fragment or variant thereof.

[0782] 69. Tire method of any of embodiments 1-12, 17-19, 22, 36-43, 46-50, 52, 54, or 59-64, wherein the targeting moiety comprises a zinc finger domain, and the effector moiety comprises an epigenetic modifying moiety, e.g., a DNA methyltransferase, e.g., MQ1 or a fragment or variant thereof.

[0783] 70. The method of any of the preceding embodiments, wherein the expression repressor comprises an amino acid sequence of any of SEQ ID NOS: 22-33, 129, 133, 134, 139-149, or 177-186, or any of SEQ ID NOs: 34-37 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity thereto.

[0784] 71. The method of any of the preceding embodiments, wherein the expression repressor: (i) comprises one or more nuclear localization signal sequences (NLS). or (ii) does not comprise an NLS.

[0785] 72. The method of any of the preceding embodiments, wherein the expression repressor comprises a first NLS at the N tenninus, e.g., wherein the first NLS has a sequence of SEQ ID NO: 88. 73. The method of any of the preceding embodiments, wherein the expression repressor comprises an NLS, e.g., a second NLS, at the C terminus, e.g., having a sequence of SEQ ID NO: 89.

[0786] 74. Tire method of any of the preceding embodiments, wherein the first and tire second NLS have tire same sequence.

[0787] 75. The method of any of embodiments 72-74, wherein the first and the second NLS have different sequences.

[0788] 76. The method of any of the preceding embodiments, wherein the expression repressor comprises an epitope tag.

[0789] 77. Tire method of embodiment 76, wherein tire epitope tag is an HA tag.

[0790] 78. Tire method of any of preceding embodiments, wherein the anchor sequence comprises the sequence of SEQ ID NO: 71 or 72, or a sequence with no more than 8, 7, 6, 5, 4, 3, 2, or 1 alterations relative thereto.

[0791] 79. The method of any of embodiments 1-78, wherein tire anchor sequence comprises a sequence according to a nucleic acid sequence of CCGCCATNTT or AANATGGCGG, where N is any nucleotide, or a sequence with no more than 8, 7, 6, 5, 4, 3, 2, or 1 alterations relative thereto.

[0792] 80. The method of any of preceding embodiments, wherein the anchor sequence is on the same chromosome as the MYC gene.

[0793] 81. The method of any of preceding embodiments, wherein the anchor sequence is upstream of the MYC gene (e.g., upstream of the TSS or upstream of the promoter).

[0794] 82. The method of any of preceding embodiments, wherein the anchor sequence is at least 1, 5, 10, 50, 100, or 1000 kilobases away from tire MYC gene (e.g., from the TSS or promoter of the MYC gene).

[0795] 83. The method of any of preceding embodiments, wherein the anchor sequence is 0.1-0.5, 0.1-1, 0 1- 5. 0.1-10, 0.1-50, 0.1-100. 0.1-500, 0.1-1000, 0.5-1. 0.5-5, 0.5-10. 0.5-50. 0.5-100, 0.5-500. 0.5- 1000, 1-5, 1-10, 1-50, 1-100, 1-500, 1-1000, 5-10, 5-50, 5-100, 5-500, 5-1000, 10-50, 10-100, 10- 500, 10-1000, 50-100, 50-500, 50-1000, 100-500, 100-1000, or 500-1000 kilobases away from the MYC gene (e.g., from the TSS or promoter of tire MYC gene).

[0796] 84. The method of any of embodiments 1-80, 82, or 82, wherein the target sequence is downstream of the MYC gene (e.g., downstream of the TSS or downstream of the promoter).

[0797] 85. The method of any of preceding embodiments, wherein the targeting moiety binds to a sequence at chromosome coordinates 128746342-128746364, 128746321-128746343, 128746525- 128746547, 128748014-128748036, 129188878-129188900, 129188958-129188980, 129188960-129188982, 129189067-129189089, 129189457-129189479, 129189554-129189576, 129189679-129189701, 129209511-129209533, 129209643-129209665, 129209658-129209680, 129209856-129209878, 129189452-129189474, 129189190-129189212, 129189274-129189296, 129189421-129189443, 128746405-128746425, 128748069-128748089, 129188825-129188845, or 129188822-129188842 or a sequence proximal thereto. Tire method of any of the preceding embodiments, wherein binding of the expression repressor to the target gene locus, e.g.. MYC, increases methylation at a site in tire target gene locus, e.g., MYC. by 10, 20, 30, 40, 50. 60. 70, 80, 90, or 100% compared to methylation in the absence of the expression repressor, e.g., as measured by ELISA or as described in any of Examples 7 or 28 as described in International Application WO / 2022 / 132195, which is herein incorporated by reference in its entirety, wherein optionally the site assayed for methylation is chr8: 129188693- 129189048 according to hgl9 reference genome, e.g., comprises a sequence according to SEQ ID NO: 123. The method of any of the preceding embodiments, wherein binding of the expression repressor to the target gene locus, e.g., MYC increases methylation at a site in the target gene locus, e.g., MYC for a time period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 days, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cell divisions, e.g., as described in Example 28 as described in International Application WO / 2022 / 132195, which is herein incorporated by reference in its entirety. The method of any of the preceding embodiments, wherein binding of the expression repressor to the MYC locus decreases expression of MYC in a cell by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% compared to expression in the absence of the expression repressor, e.g., as measured by ELISA or as described in any of Examples 2-7 or 9 as described in International Application WO / 2022 / 132195, which is herein incorporated by reference in its entirety. The method of any of the preceding embodiments, wherein binding of the expression repressor to the MYC locus appreciably decreases expression of MYC for a time period of at least 1, 2, 3. 4. 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 days, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cell divisions, e.g., as measured by ELISA or as described in any of Examples 2-7 or 9 as described in International Application WO / 2022 / 132195, which is herein incorporated by reference in its entirety. The method of any of the preceding embodiments, wherein binding of the expression repressor to the MYC locus appreciably decreases expression of MYC at 1, 2. 3. 4, 5, 6. 7. 8, 10, 12. 16. 20. 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, or 96 hours post-transfection. The method of any of embodiments 1-23 or 36-90, wherein the targeting moiety binds to a human genomic locus. 92. The method of any of embodiments 24-43, 50, 52, 54, 57, 58, 60-63, 67-69, or 71-90, wherein the targeting moiety binds to a mouse genomic locus.

[0798] 93. Tire method of any of the preceding embodiments, wherein binding of the expression repressor to the MYC locus decreases the viability of a cell comprising the MYC locus (e.g., cancer cells).

[0799] 94. The method of any of the preceding embodiments, wherein contacting a plurality of cells with the composition decreases tire viability of the plurality of cells.

[0800] 95. The method of any of the preceding embodiments, wherein viability is decreased by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% compared to viability in the absence of the first expression repressor, e.g., as measured by CellTiter Gio or as described in any of Examples 2-7 as described in International Application WO / 2022 / 132195, which is herein incorporated by reference in its entirety.

[0801] 96. The method of any of the preceding embodiments, wherein administration of the composition results in apoptosis of at least 5%, 6%, 7%, 8%, 9% 10%, 12%, 15%, 17% 20%, 25% 30%, 40%, 45%, 50%, 55%, 60%, 65%, 75% of target cells (e.g., cancer cells).

[0802] 97. Tire method of any of the preceding embodiments, wherein administration of the composition results in cell death of at least 5%, 6%, 7%, 8%, 9% 10%, 12%, 15%, 17% 20%, 25% 30%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, or 80% of target cells (e.g., cancer cells).

[0803] 98. The method of any of the preceding embodiments, wherein administration of the composition results in reduction of MYC mRNA levels in target cells (e.g., cancer cells) to less than 70%, 605, 50%, or 40% of levels prior to administration.

[0804] 99. Tire method of any preceding embodiments, wherein the plurality of cells comprises a plurality of cancer cells and a plurality of non-cancer cells and / or a plurality of infected cells and a plurality of uninfected cells.

[0805] 100. The method of any of the preceding embodiments, wherein contacting tire plurality of cells with the composition decreases the viability of the plurality of cancer cells more than it decreases the viability of the plurality of non-cancer cells.

[0806] 101. Tire method of any of the preceding embodiments, wherein contacting the plurality of cells with the composition decreases the viability of the plurality of cancer cells 1.05x (i.e ., 1.05 times), l. lx, 1.15x, 1.2x, 1.25x, 1.3x. 1.35x, 1.4x, 1.45x, 1.5x, 1.6x, 1.7x, 1.8x. 1.9x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, 20x, 5 Ox. or lOOx more than it decreases the viability of tire plurality of non- cancer cells.

[0807] 102. The method of any of the preceding embodiments, wherein the cancer cells are gastric cancer cells, gastrointestinal cancer cells, colorectal cancer cells, pancreatic cancer cells, or hepatic cancer cells. 103. The method of any of the preceding embodiments, wherein the cancer is hepatocellular carcinoma (HCC), fibrolamellar hepatocellular carcinoma (FHCC), cholangiocarcinoma, angiosarcoma, secondary liver cancer, adenocarcinoma, large cell (undifferentiated) carcinoma, triple negative breast cancer, gastric adenocarcinoma, endometrial carcinoma, or pancreatic carcinoma.

[0808] 104. The method of any of the preceding embodiments, wherein when the composition is contacted with a plurality of infected cells and a plurality of uninfected cells, decreases the viability of tire plurality of infected cells more than it decreases the viability of the plurality of uninfected cells.

[0809] 105. The method of any of preceding embodiments, wherein the infection is viral.

[0810] 106. Tire method of embodiment 105, wherein the viral infection is hepatitis, e.g., hepatitis B.

[0811] 107. The method of any of embodiments 93-106, wherein the infected cells are human hepatocytes.

[0812] 108. The method of any of the preceding embodiments, wherein the composition has an EC50 of 0.04

[0813] - 0.4, 0.04 - 0.1, 0.1 - 0.2, 0.2 - 0.3, or 0.3 - 0.4 pg / mL when tested in an assay for viability of cancer cells (e.g., HCC cells), e.g., in an assay according to Example 12 as described in International Application WO / 2022 / 132195, which is herein incorporated by reference in its entirety.

[0814] 109. The method of any of embodiments 1-107, which has an EC50 of 0.1- 2.5, 0.5-2.2, 1.0-1.5, 1.2-2 pg / mL when tested in an assay for viability of cancer cells .

[0815] 110. The method of any of the preceding embodiments, wherein the composition has an EC50 of 0.004

[0816] - 0.08, 0.004 - 0.01, 0.01 - 0.02, 0.02 - 0.04, or 0.04 - 0.08 pg / mL when tested in an assay for reducing MYC mRNA levels in cancer cells (e.g., HCC cells), e.g., in an assay according to Example 12 as described in International Application WO / 2022 / 132195, which is herein incorporated by reference in its entirety.

[0817] 111. Tire method of any of the preceding embodiments, wherein the composition has an EC50 of 0.04

[0818] - 0.1, 0.04 - 0.09. 0.05 - 0.09, or 0.06 - 0.8 pg / mL when tested in an assay for reducing MYC mRNA levels in cancer cells.

[0819] 112. The method of any of the preceding embodiments, wherein the composition reduces the level of a protein encoded by atarget gene, e.g., MYC in a cell by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%. at least 60%, at least 70%, at least 80%, or at least 90% compared to the protein level in an untreated cell.

[0820] 113. The method of any of the preceding embodiments, wherein the tumor volume is reduced, e.g.. in a human subject or in a mammalian model.

[0821] 114. The method of any of preceding embodiments, wherein tumor volume is reduced to a similar or greater degree compared to a chemotherapeutic agent, e.g., in a mammalian model, e.g., when measured at day 20 after initiation of treatment, e.g., wherein the composition is administered every 5 days at a dose of 3mg / kg.

[0822] 115. Tire method of any of preceding embodiments, wherein the expression repressor is capable of reducing tumor volume compared to a PBS control, e.g., in a mammalian model, e.g., when measured at day 20 after initiation of treatment e.g., wherein the composition is administered every 5 days for 4 doses followed by every 3 days for 3 doses at Img / kg, 1.5 mg / kg, or 3mg / kg.

[0823] 116. The method of any of preceding embodiments, wherein the tumor volume is reduced by at least about 10%, 20%, 30%, or 40% compared to a control treated with PBS, e.g., at day 20 after start of treatment.

[0824] 117. Tire method of any of embodiment 114-116, wherein the chemotherapeutic agent is sorafenib or cisplatin.

[0825] 118. The method of any of preceding embodiments, wherein the composition is capable of reducing tumor volume to a similar or greater degree compared to a small molecule MY C inhibitor.

[0826] 119. The method of embodiment 118, wherein the small molecule MYC inhibitor is MYCi975 wherein optionally tumor volume is reduced by at least about 10%, 20%, 30%, or 40% compared to a control treated with the MYCi975, e.g., at day 20 after start of treatment.

[0827] 120. The method of any of preceding embodiments, which does not cause a decrease in body weight compared to at the start of treatment, or which causes a decrease in body weight of less than 3%, 2%, or 1%.

[0828] 121. The method of any of the preceding embodiments, wherein the composition further comprises a second nucleic acid encoding a second expression repressor, e.g., a second expression repressor described herein, e.g., a second expression repressor of any of the preceding embodiments.

[0829] 122. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[0830] (A) a composition comprising:

[0831] (1) a first nucleic acid encoding a first expression repressor comprising a first targeting moiety and optionally a first effector moiety, wherein the first expression repressor binds to a transcription regulatory element (e.g., a promoter, enhancer, or transcription start site (TSS)) operably linked to a MYC gene or to a sequence proximal to the transcription regulatory element.

[0832] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0833] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0834] (i'j a compound having a general structure of formula (I):

[0835] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0836] L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[0837] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0838] G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0839] Rais H or C1-C12 alkyl;

[0840] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0841] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[0842] R4is C1-C12 alkyl;

[0843] R5is H or C1-C6 alkyl;

[0844] R11and R12are each independently C1-C12 alkyl or -G4-OR5, or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;

[0845] G4is C1-C24 alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0846] (i") a compound having a general structure of Fonnula (IX):

[0847] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond; G1is C1-C2 alkylene, -(C=0)-, -0(C=0)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0848] G2is -C(=O)- , -(C=O)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0849] G3is C1-C6 alkylene;

[0850] Rais H or C1-C12 alkyl;

[0851] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0852] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0853] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0854] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0855] R5and R6are each independently H or methyl;

[0856] R7is C4-C20 alkyl;

[0857] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[0858] (i'") a compound having a general structure of Formula (XI):

[0859] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0860] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0861] R2and R3are each independently optionally substituted C1 -C36 alkyl; R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0862] L1, L2, and L3are each independently optionally substituted Ci-Cis alkylene;

[0863] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0864] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0865] (ii) a second compound having a general structure of formula (II):

[0866] Fonnula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (II):

[0867] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0868] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0869] (iv) a steroid (e g., sterol, e g., cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and

[0870] (3) a second nucleic acid encoding a second expression repressor comprising a second targeting moiety and optionally a second effector moiety, wherein the second expression repressor binds to an anchor sequence of an anchor sequence mediated conjunction (ASMC) comprising a MYC gene or to a sequence proximal to the anchor sequence; and

[0871] (B) a compound having the general structure of Formula (Al) wherein:

[0872] R1is alkyl, cycloalkyl, or aryl;

[0873] R2is halo, alkyl, or H;

[0874] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[0875] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0876] 123. The method of embodiment 121 or 122, wherein the transcription regulatory element comprises a promoter, and wherein the anchor sequence comprises a CTCF binding motif.

[0877] 124. The method of any of embodiments 121-123, wherein tire second expression repressor binds to a downstream region adjacent to the CTCF binding motif.

[0878] 125. The method of any of embodiments 121-123, wherein the second expression repressor binds to an upstream region adjacent to the CTCF binding motif.

[0879] 126. The method of any of embodiments 121-125, wherein the first expression repressor comprises a targeting moiety that binds a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 71, 72, 75-86, or 200- 206, or a nucleic acid sequence of CCGCCATNTT or AANATGGCGG, where N is any nucleotide; and the second expression repressor comprises a targeting moiety that binds a genomic locus comprising at least 16, 17, 18. 19. or 20 nucleotides of the sequence of SEQ ID NO: 71. 72. 75- 86, or 200-206, or a nucleic acid sequence of CCGCCATNTT or AANATGGCGG, where N is any nucleotide.

[0880] 127. Tire method of any of embodiments 121-126, wherein: the first expression repressor comprises a targeting moiety that binds a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NO: 96-110 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety.

[0881] 128. The method of any of embodiments 121-127, wherein, the first expression repressor comprises a targeting moiety that binds a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 71, SEQ ID NO: 72, or SEQ ID NO: 83; and the second expression repressor comprises a targeting moiety that binds a genomic locus comprising at least 16, 17. 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 77.

[0882] 129. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[0883] (A) a composition comprising:

[0884] (1) a first nucleic acid encoding a first expression repressor comprising a first targeting moiety and optionally a first effector moiety, wherein the first expression repressor binds to a promoter operably linked to a MY C gene or to a sequence proximal to the promoter,

[0885] (2) a fonnulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g.. comprising all of (i)-(iv)):

[0886] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0887] (i') a compound having a general structure of formula (I):

[0888] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0889] L1and L2are each independently -O(C=O)-, -(C=O)O-. -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-. -NRaC(=O)O-. or a direct bond;

[0890] G1and G2are each independently unsubstituted Ci-Ci? alkylene, or C2-C12 alkenylene;

[0891] G3is C1-C24 alkylene, C2-C 24 alkcnylcnc, C3-C8 cycloalkylcnc, or C3-C8 cycloalkcnylcnc;

[0892] Rais H or C1-C12 alkyl;

[0893] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0894] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NR"R12, or -NR5C(=O)R4; R4is C1-C12 alkyl:

[0895] R5is H or C1-C6 alkyl;

[0896] R11and R12are each independently C1-C12 alkyl or -G4-OR5, or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;

[0897] G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0898] (i") a compound having a general structure of Fonnula (IX):

[0899] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(OO)-, -(OO)O-, -C(=0)-, -0-, -S(0)x-, -S-S-, -C(=O)S-, -SC(=O)-. -NRaC(=O)-, -C(=O)NRa-, -NR“C(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[0900] G1is C1-C2 alkylene, -(C=0)-, -0(00)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0901] G2is -C(=0)- , -(OO)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0902] G3is C1-C6 alkylene;

[0903] Rais H or C1-C12 alkyl;

[0904] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond:

[0905] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0906] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond; R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0907] R5and R6are each independently H or methyl;

[0908] R7is C4-C20 alkyl;

[0909] R8and R9are each independently C1-C12 alkyl; or R8and R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[0910] (i'") a compound having a general structure of Fonnula (XI):

[0911] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0912] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0913] R2and R3are each independently optionally substituted C1 -C36 alkyl;

[0914] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0915] L1, L2, and L3are each independently optionally substituted Ci-Cis alkylene;

[0916] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0917] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0918] (ii) a second compound having a general structure of formula (II):

[0919] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (II): Rband R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0920] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0921] (iv) a steroid (e.g., sterol, e.g., cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and

[0922] (3) a second nucleic acid encoding a second expression repressor comprising a second targeting moiety and optionally a second effector moiety, wherein the second expression repressor binds to an enhancer (e.g.. a super-enhancer) of the MY C gene; and

[0923] (B) a compound having the general structure of Formula (Al): wherein:

[0924] R1is alkyl, cycloalkyl, or aryl;

[0925] R2is halo, alkyl, or H;

[0926] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[0927] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0928] 130. The method of embodiment 129, wherein. the first expression repressor comprises a targeting moiety that binds a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 204, and the second expression repressor comprises a targeting moiety that binds a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs: 199 or 201.

[0929] 131. A method for reducing MY C expression, the method comprising contacting a cell with: (A) a composition comprising:

[0930] (1) a first nucleic acid encoding a first expression repressor comprising: i) a first targeting moiety having an amino acid sequence according to SEQ ID NO: 13 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15. 14, 13, 12, 11, 10, 9, 8. 7, 6, 5, 4. 3, 2, or 1 positions of difference thereto and ii) a first effector moiety having an amino acid sequence according to SEQ ID NO: 19 or 87 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto,

[0931] (2) formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0932] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0933] (i') a compound having a general structure of formula (I):

[0934] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0935] L1and L2are each independently O(C~O)-. -(C~O)O-. -C(=O)-, -O-, -S(O)X-, -S-S-, -C(~O)S-. SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[0936] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0937] G' is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0938] Rais H or C1 -C12 alkyl;

[0939] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0940] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[0941] R4is C1-C12 alkyl;

[0942] R3is H or C1-C6 alkyl;

[0943] R11and R12are each independently C1-C12 alkyl or -G4-OR5, or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;

[0944] G4is C1-C24 alkylene, C2-C 24 alkcnylcnc, C1-C7 cycloalkylcnc, C3-C8 cycloalkcnylcnc; and x is 0, 1 or 2; (i") a compound having a general structure of Fonnula (IX):

[0945] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(OO)-, -(OO)O-, -C(=0)-, -0-, -S(0)x-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[0946] G1is C1-C2 alkylene, -(C=0)-, -0(00)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0947] G2is -C(=0)- , -(OO)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0948] G3is C1-C6 alkylene;

[0949] Rais H or C1-C12 alkyl;

[0950] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[0951] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0952] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[0953] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[0954] R5and R6are each independently H or methyl;

[0955] R7is C4-C20 alkyl;

[0956] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[0957] (i'") a compound having a general structure of Formula (XI):

[0958] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[0959] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[0960] R2and R3are each independently optionally substituted C1-C36 alkyl;

[0961] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[0962] L1, L2, and L3are each independently optionally substituted C1 -C18 alkylene;

[0963] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[0964] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[0965] (ii) a second compound having a general structure of formula (II):

[0966] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Fonnula (II):

[0967] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[0968] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0969] (iv) a steroid (e.g.. sterol, e.g.. cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and (3) a second nucleic acid encoding a second expression repressor comprising: i) a second targeting moiety having an amino acid sequence according to SEQ ID NO: 7, 169, or 171 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto, and ii) a second effector moiety having an amino acid sequence according to SEQ ID NO: 18, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19. 18. 17. 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto; and

[0970] (B) a compound having the general structure of Formula (Al):

[0971] Formula (Al) wherein:

[0972] R1is alkyl, cycloalkyl, or aryl;

[0973] R2is halo, alkyl, or H;

[0974] R3, R4, R5. R6, R7, are each independently H or alkyl; and

[0975] R8and R9together fonn an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0976] 132. The method of embodiments 131, wherein the first expression repressor further comprises a first nuclear localization signal, e.g., an SV40 NLS, e.g., a sequence according to SEQ ID NO: 135 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, e.g., situated N-tcrminal of the first targeting moiety.

[0977] 133. The method of embodiment 131 or 132. wherein the first expression repressor further comprises a second nuclear localization signal, e.g., a nucleoplasmin NLS, e.g., a sequence according to SEQ ID NO: 136 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, e.g., situated C -terminal of the first effector moiety.

[0978] 134. Tire method of any of embodiments 131-133, wherein tire second expression repressor further comprises a first nuclear localization signal, e g., an SV40 NLS, e.g., a sequence according to SEQ ID NO: 135 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, e.g., situated N-tenuinal of the second targeting moiety. Tire method of any of embodiments 131-134, wherein tire second expression repressor further comprises a second nuclear localization signal, e.g., a nucleoplasmin NLS, e.g., a sequence according to SEQ ID NO: 136 or a sequence with at least 80, 85, 90, 95, 99. or 100% identity thereto, e.g.. situated C-terminal of the second effector moiety. The method of any of embodiments 131-135, wherein the first expression repressor further comprises a first linker situated between the first targeting moiety and the first effector moiety, wherein optionally the first linker has an amino acid sequence according to SEQ ID NO: 137 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto. The method of any of embodiments 131-136, wherein the second expression repressor further comprises a second linker situated between the second targeting moiety and the second effector moiety, wherein optionally the second linker has an amino acid sequence according to SEQ ID NO: 138 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto. Tire method of any of embodiments 131-137, wherein tire first expression repressor further comprises an amino acid sequence C-terminal of the first effector moiety, e g., a sequence of up to 30, 25, 20, or 18 amino acids, e.g., a sequence according to SEQ ID NO: 126 or a sequence with at least 80. 85, 90, 95, 99, or 100% identity thereto. The method of any of embodiments 131-135, wherein the second expression repressor further comprises an amino acid sequence N-terminal of the second targeting moiety, e.g., a sequence of up to 30, 25, 20, or 18 amino acids, or an amino acid P. The method of any of embodiments 131-139, wherein the first expression repressor has an amino acid sequence according to SEQ ID NO: 30 or 129, or a sequence with at least 80, 85. 90, 95, 99, or 100% identity thereto. The method of any of embodiments 131-140, wherein the second expression repressor has an amino acid sequence according to SEQ ID NO: 24, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto. The method of any of embodiments 131-140, wherein the second targeting moiety comprises an amino acid sequence according to SEQ ID NO: 169, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto. The method of any of embodiments 131-140, wherein the second targeting moiety comprises an amino acid sequence according to SEQ ID NO: 171, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity’ thereto. The method of any of embodiments 131-143, wherein the second expression repressor has an amino acid sequence according to SEQ ID NO: 177 or 183, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto. Tire method of any of embodiments 131-143, wherein tire second expression repressor has an amino acid sequence according to SEQ ID NO: 179 or 185, or a sequence with at least 80, 85, 90. 95, 99, or 100% identity thereto. The method of any of embodiments 121-145, wherein the first nucleic acid and the second nucleic acid are comprised within the same nucleic acid molecule. Tire method of any of embodiments 121-145, wherein tire first nucleic acid and the second nucleic acid are in different nucleic acid molecules. The method of any of embodiments 121-147, wherein the first nucleic acid and the second nucleic acid are comprised within the same LNP. The method of any of embodiments 121-145 or 147, wherein the first nucleic acid and the second nucleic acid are in different LNPs. A method for reducing MYC expression, the method comprising contacting a cell with:

[0979] (A) a composition comprising:

[0980] (1) a nucleic acid comprising: a) a first region encoding a first expression repressor, the first expression repressor comprising: i) a first targeting moiety having an amino acid sequence according to SEQ ID NO: 13 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto, and ii) a first effector moiety having an amino acid sequence according to SEQ ID NO: 19 or 87 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto, and b) a second region encoding a second expression repressor, the second expression repressor comprising: i) a second targeting moiety having an amino acid sequence according to SEQ ID NO: 7 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto, and ii) a second effector moiety having an amino acid sequence according to SEQ ID NO: 18, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto; and

[0981] (2) a fonnulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[0982] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0983] (i') a compound having a general structure of formula (I):

[0984] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[0985] L1and L2are each independently -O(C=O)-, -(C=O)O-. -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-. -NRaC(=O)O-. or a direct bond;

[0986] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[0987] G is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or Ci-Cg cycloalkenylene;

[0988] Rais H or C1 -C12 alkyl;

[0989] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[0990] R3is H, OR5, CN. -C(=O)OR4, -OC(=O)R4. -NRnR12. or -NR5C(=O)R4;

[0991] R4is C1-C12 alkyl;

[0992] R5is H or C1-C6 alkyl;

[0993] R11and R12are each independently C1-C12 alkyl or -G4-OR5, or R11and R12, together with the nitrogen atom to which they are attached, form a 5. 6 or 7-membered heterocyclic ring;

[0994] G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0. 1 or 2; (i") a compound having a general structure of Fonnula (IX):

[0995] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(OO)-, -(OO)O-, -C(=0)-, -0-, -S(0)x-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[0996] G1is C1-C2 alkylene, -(C=0)-, -0(00)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[0997] G2is -C(=0)- , -(OO)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[0998] G3is C1-C6 alkylene;

[0999] Rais H or C1-C12 alkyl;

[1000] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[1001] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[1002] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[1003] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[1004] R5and R6are each independently H or methyl;

[1005] R7is C4-C20 alkyl;

[1006] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[1007] (i'") a compound having a general structure of Formula (XI):

[1008] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[1009] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[1010] R2and R3are each independently optionally substituted C1-C36 alkyl;

[1011] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[1012] L1, L2, and L3are each independently optionally substituted C1 -C18 alkylene;

[1013] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[1014] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[1015] (ii) a second compound having a general structure of formula (II):

[1016] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Fonnula (II):

[1017] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[1018] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1019] (iv) a steroid (e.g.. sterol, e.g.. cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and (B) a compound having the general structure of Formula (Al) wherein:

[1020] R1is alkyl, cycloalkyl, or aryl;

[1021] R2is halo, alkyl, or H;

[1022] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[1023] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1024] 151. The method of embodiment 150, wherein the first region is 5’ of the second region.

[1025] 152. The method of embodiment 150, wherein the first region is 3’ of the second region.

[1026] 153. The method of embodiment 151 or 152, wherein the first region further comprises a nucleotide sequence encoding a first nuclear localization signal, e.g., an SV40 NLS, e.g., a sequence according to SEQ ID NO: 135 or a sequence with at least 80, 85, 90, 95, 99. or 100% identity thereto, e.g.. situated N-terminal of the first targeting moiety.

[1027] 154. The method of any of embodiments 151-153, wherein the first region further comprises a nucleotide sequence encoding a second nuclear localization signal, e.g., a nucleoplasmin NLS, e.g., a sequence according to SEQ ID NO: 136 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, e.g ., situated C-tcrminal of the first effector moiety .

[1028] 155. The method of any of embodiments 151-154, wherein the second region further comprises a nucleotide sequence encoding a first nuclear localization signal, e.g., an SV40 NLS, e.g., a sequence according to SEQ ID NO: 135 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, e.g., situated N-terminal of the second targeting moiety.

[1029] 156. The method of any of embodiments 151-155, wherein tire second region further comprises a nucleotide sequence encoding a second nuclear localization signal, e.g., a nuclcoplasmin NLS, e.g., a sequence according to SEQ ID NO: 136 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, e.g., situated C -terminal of the second effector moiety. 157. The method of any of embodiments 151-156, wherein the first region further comprises a nucleotide sequence encoding a first linker situated between the first targeting moiety and the first effector moiety, wherein optionally the first linker has an amino acid sequence according to SEQ ID NO: 137 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto.

[1030] 158. The method of any of embodiments 151-157, wherein the second region further comprises a nucleotide sequence encoding a second linker situated between the second targeting moiety and the second effector moiety, wherein optionally the second linker has an amino acid sequence according to SEQ ID NO: 138 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto.

[1031] 159. Tire method of any of embodiments 151-158, wherein the first region further comprises a nucleotide sequence encoding an amino acid sequence C-terminal of the first effector moiety, e.g.. a sequence of up to 30. 25, 20, or 18 amino acids, e.g., a sequence according to SEQ ID NO: 126 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto.

[1032] 160. The method of any of embodiments 151-159, wherein tire second region further comprises a nucleotide sequence encoding an amino acid sequence N-terminal of the second targeting moiety, e.g., a sequence of up to 30, 25, 20, or 18 amino acids, or an amino acid P.

[1033] 161. The method of any of embodiments 151-160, wherein the first expression repressor has an amino acid sequence according SEQ ID NO: 30 or 129, or a sequence with at least 80. 85, 90, 95, 99, or 100% identity thereto.

[1034] 162. The method of any of embodiments 151-161, wherein tire second expression repressor has an amino acid sequence according to SEQ ID NO: 24, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto.

[1035] 163. The method of any of embodiments 151-162, wherein the first region comprises a nucleotide sequence encoding the first targeting moiety, wherein the nucleotide sequence encoding the first targeting moiety comprises a sequence according to SEQ ID NO: 46 or 131 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

[1036] 164. The method of any of embodiments 151-163, wherein the first region comprises a nucleotide sequence encoding the first effector moiety, wherein the nucleotide sequence encoding the first effector moiety comprises a sequence according to SEQ ID NO: 52 or 132, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

[1037] 165. Tire method of any of embodiments 151-164, wherein tire second region comprises a nucleotide sequence encoding the second targeting moiety, wherein the nucleotide sequence encoding the second targeting moiety comprises a sequence according to SEQ ID NO: 40 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto. Tire method of any of embodiments 151-165, wherein tire first region comprises a nucleotide sequence encoding the first effector moiety, wherein the nucleotide sequence encoding the first effector moiety comprises a sequence according to SEQ ID NO: 51. or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto. Tire method of any of embodiments 151-166, wherein tire first region comprises a nucleotide sequence according to SEQ ID NO: 63 or 130, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20. 19, 18, 17, 16, 15, 14, 13, 12. 11. 10, 9, 8, 7, 6, 5, 4. 3, 2, or 1 positions of difference thereto, wherein apoly-A sequence is optional. The method of any of embodiments 151-167, wherein the second region comprises a nucleotide sequence according to SEQ ID NO: 57, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2. or 1 positions of difference thereto, wherein a poly-A sequence is optional. A method for reducing MYC expression, the method comprising contacting a cell with:

[1038] (A) a composition comprising:

[1039] (1) a nucleic acid comprising: a) a first region encoding a first expression repressor, the first expression repressor comprising: i) a first targeting moiety having an amino acid sequence according to SEQ ID NO: 13 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20. 19, 18, 17, 16, 15, 14, 13. 12. 11. 10, 9. 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto, and ii) a first effector moiety having an amino acid sequence according to SEQ ID NO: 19 or 87 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12. 11, 10, 9. 8, 7, 6, 5. 4, 3, 2, or 1 positions of difference thereto, and b) a second region encoding a second expression repressor, the second expression repressor comprising: i) a second targeting moiety having an amino acid sequence according to SEQ ID NO: 169 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto, and ii) a second effector moiety having an amino acid sequence according to SEQ ID NO: 18, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13. 12, 11, 10, 9, 8, 7, 6. 5, 4, 3, 2. or 1 positions of difference thereto; and

[1040] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[1041] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[1042] (i') a compound having a general structure of formula (I):

[1043] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[1044] L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(-O)-. -NR 'C(-O)-. -C(-O)NR '-. -NRaC(=O)NRa-, -OC(=O)NRa-, NR3C(~0)0-. or a direct bond;

[1045] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[1046] G3is C1-C24 alkylene. C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[1047] Rais H or C1-C12 alkyl;

[1048] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[1049] R3is H, OR5, CN, -C(~O)OR4. -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[1050] R4is C1-C12 alkyl;

[1051] R5is H or C1-C6 alkyl;

[1052] R11and R12are each independently C1-C12 alkyl or -G4-OR5. or R11and R12. together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring:

[1053] G4is C1-C24 alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2; (i") a compound having a general structure of Fonnula (IX):

[1054] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(OO)-, -(OO)O-, -C(=0)-, -0-, -S(0)x-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[1055] G1is C1-C2 alkylene, -(C=0)-, -0(00)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[1056] G2is -C(=0)- , -(OO)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[1057] G3is C1-C6 alkylene;

[1058] Rais H or C1-C12 alkyl;

[1059] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[1060] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[1061] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[1062] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[1063] R5and R6are each independently H or methyl;

[1064] R7is C4-C20 alkyl;

[1065] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[1066] (i'") a compound having a general structure of Formula (XI):

[1067] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[1068] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[1069] R2and R3are each independently optionally substituted C1-C36 alkyl;

[1070] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[1071] L1, L2, and L3are each independently optionally substituted C1 -C18 alkylene;

[1072] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[1073] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[1074] (ii) a second compound having a general structure of formula (II):

[1075] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Fonnula (II):

[1076] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[1077] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1078] (iv) a steroid (e.g.. sterol, e.g.. cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and (B) a compound having the general structure of Formula (Al): wherein:

[1079] R1is alkyl, cycloalkyl, or aryl;

[1080] R2is halo, alkyl, or H;

[1081] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[1082] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1083] 170. A method for reducing MYC expression, the method comprising contacting a cell with:

[1084] (A) a composition comprising:

[1085] (1) a nucleic acid comprising: a) a first region encoding a first expression repressor, tire first expression repressor comprising: i) a first targeting moiety having an amino acid sequence according to SEQ ID NO: 13 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto, and ii) a first effector moiety having an amino acid sequence according to SEQ ID NO: 19 or 87 or a sequence with at least 80, 85, 90, 95, 99. or 100% identity thereto, or having no more than 20. 19, 18, 17, 16, 15, 14, 13, 12. 11. 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto, and b) a second region encoding a second expression repressor, the second expression repressor comprising: i) a second targeting moiety having an amino acid sequence according to SEQ ID NO: 171 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto, and ii) a second effector moiety having an amino acid sequence according to SEQ ID NO: 18, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13. 12, 11, 10, 9, 8, 7, 6. 5, 4, 3, 2. or 1 positions of difference thereto; and

[1086] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[1087] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[1088] (i') a compound having a general structure of formula (I):

[1089] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[1090] L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[1091] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[1092] G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[1093] Rais H or C1-C12 alkyl;

[1094] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[1095] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[1096] R4is C1-C12 alkyl;

[1097] R5is H or C1-C6 alkyl;

[1098] R11and R12are each independently C1-C12 alkyl or -G4-OR5. or R11and R12, together with the nitrogen atom to which they are attached, form a 5. 6 or 7-membered heterocyclic ring;

[1099] G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2; (i") a compound having a general structure of Fonnula (IX):

[1100] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(OO)-, -(OO)O-, -C(=0)-, -0-, -S(0)x-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[1101] G1is C1-C2 alkylene, -(C=0)-, -0(00)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[1102] G2is -C(=0)- , -(OO)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[1103] G3is C1-C6 alkylene;

[1104] Rais H or C1-C12 alkyl;

[1105] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[1106] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[1107] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[1108] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[1109] R5and R6are each independently H or methyl;

[1110] R7is C4-C20 alkyl;

[1111] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[1112] (i'") a compound having a general structure of Formula (XI):

[1113] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[1114] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[1115] R2and R3are each independently optionally substituted C1-C36 alkyl;

[1116] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[1117] L1, L2, and L3are each independently optionally substituted C1 -C18 alkylene;

[1118] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[1119] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[1120] (ii) a second compound having a general structure of formula (II):

[1121] Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Fonnula (II):

[1122] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[1123] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1124] (iv) a steroid (e.g.. sterol, e.g.. cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and (B) a compound having the general structure of Formula (Al) wherein:

[1125] R1is alkyl, cycloalkyl, or aryl;

[1126] R2is halo, alkyl, or H;

[1127] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[1128] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1129] 171. The method of embodiment 169 or 170. wherein the first region is 5’ of the second region.

[1130] 172. The method of embodiment 169 or 170, wherein the first region is 3’ of the second region.

[1131] 173. The method of any of embodiments 169-172, wherein the first region further comprises a nucleotide sequence encoding a first nuclear localization signal, e.g., an SV40 NTS, e.g., a sequence according to SEQ ID NO: 135 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, e.g., situated N-terminal of the first targeting moiety.

[1132] 174. The method of any of embodiments 169-173, wherein the first region further comprises a nucleotide sequence encoding a second nuclear localization signal, e.g., a nucleoplasmin NLS, e.g., a sequence according to SEQ ID NO: 136 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, e.g ., situated C-tcrminal of the first effector moiety .

[1133] 175. The method of any of embodiments 169-174, wherein the second region further comprises a nucleotide sequence encoding a first nuclear localization signal, e.g., an SV40 NLS, e.g., a sequence according to SEQ ID NO: 135 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, e.g., situated N-terminal of the second targeting moiety.

[1134] 176. Tire method of any of embodiments 169-175, wherein tire second region further comprises a nucleotide sequence encoding a second nuclear localization signal, e.g., a nuclcoplasmin NLS, e.g., a sequence according to SEQ ID NO: 136 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, e.g., situated C -terminal of the second effector moiety. 177. The method of any of embodiments 169-176, wherein the first region further comprises a nucleotide sequence encoding a first linker situated between the first targeting moiety and the first effector moiety, wherein optionally the first linker has an amino acid sequence according to SEQ ID NO: 137 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto.

[1135] 178. The method of any of embodiments 169-177, wherein the second region further comprises a nucleotide sequence encoding a second linker situated between the second targeting moiety and the second effector moiety, wherein optionally the second linker has an amino acid sequence according to SEQ ID NO: 138 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto.

[1136] 179. Tire method of any of embodiments 169-177, wherein the first region further comprises a nucleotide sequence encoding an amino acid sequence C-terminal of the first effector moiety, e.g.. a sequence of up to 30. 25, 20, or 18 amino acids, e.g., a sequence according to SEQ ID NO: 126 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto.

[1137] 180. The method of any of embodiments 169-179, wherein tire second region further comprises a nucleotide sequence encoding an amino acid sequence N-terminal of the second targeting moiety, e.g., a sequence of up to 30, 25, 20, or 18 amino acids, or an amino acid P.

[1138] 181. The method of any of embodiments 169- 180, wherein the first expression repressor has an amino acid sequence according SEQ ID NO: 30 or 129, or a sequence with at least 80. 85, 90, 95, 99, or 100% identity thereto.

[1139] 182. The method of any of embodiments 150-181, wherein tire second expression repressor has an amino acid sequence according to SEQ ID NO: 177 or 183 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto.

[1140] 183. The method of any of embodiments 150-182, wherein the second expression repressor has an amino acid sequence according to SEQ ID NO: 179 or 185. or a sequence with at least 80, 85. 90. 95, 99, or 100% identity thereto.

[1141] 184. The method of any of embodiments 150-183, wherein first expression repressor comprises an amino acid sequence according to SEQ ID NO: 30 or 129, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto and the second expression repressor has an amino acid sequence according to SEQ ID NO: 24, 141, 177, 179, 183, or 185, or a sequence with at least 80, 85. 90, 95, 99, or 100% identity thereto.

[1142] 185. The method of any of embodiments 150-184, wherein the first region comprises a nucleotide sequence encoding the first targeting moiety, wherein the nucleotide sequence encoding the first targeting moiety comprises a sequence according to SEQ ID NO: 46 or 131, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto. Tire method of any of embodiments 150-185, wherein tire first region comprises a nucleotide sequence encoding the first effector moiety, wherein the nucleotide sequence encoding the first effector moiety comprises a sequence according to SEQ ID NO: 52 or 132, or a sequence with at least 80. 85. 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17. 16. 15. 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto. The method of any of embodiments 150-186, wherein the second region comprises a nucleotide sequence according to SEQ ID NO: 173, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2. or 1 positions of difference thereto, wherein a poly-A sequence is optional. The method of any of embodiments 150-187, wherein the second region comprises a nucleotide sequence according to SEQ ID NO: 175, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto, wherein a poly-A sequence is optional. The method of any of embodiments 150-188, wherein the second region comprises a nucleotide sequence encoding the second effector moiety, wherein the nucleotide sequence encoding the second effector moiety comprises a sequence according to SEQ ID NO: 51. or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto. Tire method of any of embodiments 150-189, wherein tire first region comprises a nucleotide sequence according to SEQ ID NO: 63 or 130, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20. 19, 18, 17, 16, 15, 14, 13, 12. 11. 10, 9, 8, 7, 6, 5. 4. 3, 2, or 1 positions of difference thereto, wherein apoly-A sequence is optional. The method of any of embodiments 150-190, wherein the second region comprises a nucleotide sequence according to SEQ ID NO: 189, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2. or 1 positions of difference thereto, wherein a poly-A sequence is optional. The method of any of embodiments 150-191, wherein the second region comprises a nucleotide sequence according to SEQ ID NO: 194, or a sequence with at least 80. 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto, wherein a poly-A sequence is optional. Tire method of any of embodiments 150-192, wherein tire first region comprises a nucleotide sequence encoding the first effector moiety, wherein the nucleotide sequence encoding tire first effector moiety comprises a sequence according to SEQ ID NO: 52 or 132, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

[1143] 194. Tire method of any of embodiments 150-193, wherein tire first region comprises a nucleotide sequence encoding the first targeting moiety, wherein the nucleotide sequence encoding the first targeting moiety comprises a sequence according to SEQ ID NO: 46 or 131, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

[1144] 195. Tire method of any of embodiments 150-194, wherein tire second region comprises a nucleotide sequence encoding the second effector moiety, wherein tire nucleotide sequence encoding the second effector moiety comprises a sequence according to SEQ ID NO: 51, or a sequence with at least 80. 85. 90. 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17. 16. 15. 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

[1145] 196. The method of any of embodiments 150-195, wherein tire second region comprises a nucleotide sequence according to SEQ ID NO: 189, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14. 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2. or 1 positions of difference thereto.

[1146] 197. The method of any of embodiments 150-196, wherein the second region comprises a nucleotide sequence according to SEQ ID NO: 194, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

[1147] 198. The method of any of embodiments 150-197, which has a nucleotide sequence according to SEQ ID NO: 93 or 112, or a sequence with at least 80, 85, 90, 95, 99. or 100% identity thereto, or having no more than 20, 19. 18. 17. 16, 15, 14, 13, 12, 11. 10. 9, 8, 7, 6. 5, 4, 3. 2. or 1 positions of difference thereto.

[1148] 199. The method of any of embodiments 150-198, which has a nucleotide sequence according to SEQ ID NO: 196 or 197, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11. 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

[1149] 200. The method of any of embodiments 121-199, wherein the first expression repressor comprises the first effector moiety.

[1150] 201. The method of any of embodiments 121-200, wherein tire second expression repressor comprises the second effector moiety. 202. The method of any of embodiments 121-201, wherein the first effector moiety has a different amino acid sequence from the second effector moiety.

[1151] 203. Tire method of any of embodiments 121-202, wherein the first effector moiety is a durable effector moiety.

[1152] 204. The method of any of embodiments 121-128 or 150-203, wherein the first effector moiety is a transient effector moiety.

[1153] 205. The method of any of embodiments 121-204, wherein the first effector moiety is an epigenetic modifying moiety.

[1154] 206. Tire method of any of embodiments 121-149, 169-203, or 205, wherein the first effector moiety comprises a histone methyltransferase.

[1155] 207. The method of embodiment 206, wherein the first effector moiety comprises a protein chosen from SETDB1, SETDB2, EHMT2 (i.e.. G9A), EHMT1 (i.e., GLP). SUV39H1. EZH2, EZH1, SUV39H2, SETD8, SUV420H1, SUV420H2, or a functional variant or fragment of any thereof, e.g., a SET domain of any thereof.

[1156] 208. Tire method of any of embodiments 121-149, 169-203, or 205, wherein the first effector moiety comprises a histone demethylase (e.g., a lysine demethylase).

[1157] 209. The method of embodiment 208, wherein the first effector moiety comprises a protein chosen from KDM1A (i.e., LSD1), KDM1B (i.e.. LSD2). KDM2A, KDM2B, KDM5A, KDM5B, KDM5C, KDM5D, KDM4B, NO66 (or a functional variant or fragment of any thereof).

[1158] 210. The method of any of embodiments 121-149, 169-203, or 205, wherein the first effector moiety comprises a histone deacetylase.

[1159] 211. The method of embodiment 210, wherein the first effector moiety comprises a protein chosen from HDAC1, HDAC2. HDAC3, HDAC4, HDAC5, HDAC6, HDAC7. HDAC8, HDAC9, HDAC10. HDAC11, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7, SIRT8, SIRT9, or a functional variant or fragment of any thereof.

[1160] 212. The method of any of embodiments 121-203 or 206, wherein the first effector moiety comprises a DNA methyltransferase.

[1161] 213. The method of embodiment 212, wherein the first effector moiety comprises a protein chosen from MQ1, DNMT1, DNMT3A1. DNMT3A2, DNMT3B1. DNMT3B2, DNMT3B3, DNMT3B4. DNMT3B5, DNMT3B6. DNMT3L, or a functional variant or fragment of any thereof.

[1162] 214. The method of any of embodiments 121-149, 166-202, or 204, wherein the first effector moiety is a transcription repressor moiety, e.g., comprising a transcription repressor. The method of embodiment 204 or 205, wherein the first effector moiety comprises a protein chosen from KRAB, MeCP2, HP1, RBBP4, REST, FOG1, SUZ12, or a functional variant or fragment of any thereof. Tire method of any of embodiments 121-215, wherein tire first effector moiety promotes epigenetic modification of the transcription regulatory element or a sequence proximal thereto. The method of any of embodiments 121-216, wherein the first effector moiety catalyzes epigenetic modification of the transcription regulatory element or a sequence proximal thereto. The method of any of embodiments 121-128, 200, or 203-217, wherein the second expression repressor does not comprise an effector moiety. Tire method of any of embodiments 121-218, wherein the second effector moiety is a transient effector moiety. The method of any of embodiments 121-128 or 200-217, wherein the second effector moiety is a durable effector moiety. The method of any of embodiments 121-217 or 220, wherein the second effector moiety is an epigenetic modifying moiety. The method of any of embodiments 121-128, 200-217, 220, or 221, wherein the second effector moiety comprises a histone methyltransferase. The method of embodiment 222, wherein the second effector moiety comprises a protein chosen from SETDB1, SETDB2, EHMT2 (i.e., G9A), EHMT1 (i.e., GLP), SUV39H1, EZH2, EZH1, SUV39H2, SETD8, SUV420H1, SUV420H2, or a functional variant or fragment of any thereof, e.g., a SET domain of any thereof. The method of any of embodiments 121-128, 200-217, 220, or 221, wherein the second effector moiety comprises a histone demethylase (e.g.. a lysine demethylase). The method of embodiment 224, wherein the second effector moiety comprises a protein chosen from KDM1A (i.e., LSD1), KDM1B (i.e., LSD2), KDM2A, KDM2B, KDM5A, KDM5B, KDM5C, KDM5D, KDM4B, NO66 (or a functional variant or fragment of any thereof. Tire method of any of embodiments 121-128, 200-217, 220, or 221, wherein the second effector moiety comprises a histone deacetylase. The method of embodiment 226, wherein the second effector moiety comprises a protein chosen from HDAC1. HDAC2. HDAC3. HDAC4, HDAC5, HDAC6, HDAC7. HDAC8. HDAC9, HDAC10, HDAC11, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7, SIRT8, SIRT9, or a functional variant or fragment of any thereof. Tire method of any of embodiments 121-128, 200-217, 220, or 221, wherein the second effector moiety comprises a DNA methyltransferase. 229. The method of embodiment 228, wherein the second effector moiety comprises a protein chosen from MQ1, DNMT1, DNMT3A1, DNMT3A2, DNMT3B1, DNMT3B2, DNMT3B3, DNMT3B4, DNMT3B5, DNMT3B6, DNMT3L, or a functional variant or fragment of any thereof.

[1163] 230. The method of any of embodiments 121-217 or 219, wherein the second effector moiety is a transcription repressor moiety.

[1164] 231. The method of embodiment 230, wherein the second effector moiety promotes epigenetic modification of the anchor sequence or a sequence proximal thereto.

[1165] 232. Tire method of embodiment 229 or 230, wherein the second effector moiety binds to one or more endogenous epigenetic modifying proteins or one or more endogenous transcription modifying proteins.

[1166] 233. The method of any of embodiments 229-232, wherein the second effector moiety comprises KRAB, MeCP2, HP1, RBBP4, REST, FOG1, SUZ12, or a functional variant or fragment of any thereof.

[1167] 234. Tire method of any of embodiments 121-203, 205-213, 216, 217, 219, or 230-233, wherein: the first effector moiety is a durable effector moiety, and the second effector moiety is a transient effector moiety.

[1168] 235. The method of embodiment 234, wherein the first effector moiety is an epigenetic modifying moiety.

[1169] 236. The method of embodiment 233 or 234, wherein the second effector moiety is a transcription repressor moiety.

[1170] 237. The method of any of embodiments 233-236, wherein: the first effector moiety comprises a histone methyltransferase, histone demethylase, histone deacetylase. DNA methyltransferase, a functional variant or fragment of any thereof, or a combination of any thereof, and the second effector moiety comprises a transcription repressor or a functional variant or fragment of any thereof.

[1171] 238. The method of any of embodiments 212-128, 196, 200, 203, 205-213, or 216-218, wherein: the first effector moiety comprises a histone methyltransferase, histone demethylase, histone deacetylase. DNA methyltransferase, a functional variant or fragment of any thereof, or a combination of any thereof, and the second expression repressor does not comprise a second effector moiety. The method of any of embodiments 121-128, 203-213, 216, 217, 219, 220, or 230-236, wherein: the first effector moiety comprises a SETDB1, SETDB2, EHMT2 (i.e., G9A), EHMT1 (i.e., GLP), SUV39H1, EZH2, EZH1, SUV39H2, SETD8, SUV420H1, SUV420H2, KDM1A (i.e., LSD1), KDM1B (i.e., LSD2), KDM2A, KDM2B, KDM5A, KDM5B, KDM5C, KDM5D, KDM4B, NO66, HDAC1. HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7. HDAC8, HDAC9, HDAC10, HDAC11, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7, SIRT8, SIRT9, MQ1, DNMT1, DNMT3A1, DNMT3A2, DNMT3B1, DNMT3B2, DNMT3B3, DNMT3B4, DNMT3B5, DNMT3B6, DNMT3L, a functional variant or fragment of any thereof, or a combination of any thereof, and the second effector moiety comprises KRAB, MeCP2, EIP1, RBBP4, REST, FOG1, SUZ12, a functional variant or fragment of any thereof, or a combination of any thereof. The method of any of embodiments 121-203, 205, 212, 213, 216, 217, 219, 221, 230-237. or 239. wherein: the first effector moiety comprises a DNA methyltransferase, and the second effector moiety comprises a transcription repressor. The method of any of embodiments 121-128, 200, 203, 206, 212, 213, 216-218, or 238, wherein: the first effector moiety comprises a DNA methyltransferase, and the second expression repressor does not comprise a second effector moiety. The method of any of embodiments 121-128, 206, 212, 213, or 216-241, wherein the first effector moiety comprises MQ1, DNMT1, DNMT3A1, DNMT3A2, DNMT3B1, DNMT3B2, DNMT3B3, DNMT3B4, DNMT3B5, DNMT3B6, DNMT3L, or a functional variant or fragment of any thereof. The method of any of embodiments 121-217, 220, 230-240. or 242, wherein the second effector moiety comprises KRAB. MeCP2, HP1, RBBP4, REST, FOG1, SUZ12, or a functional variant or fragment of any thereof. The method of any of embodiments 121-217, 212, 213, 219, 230-240, 242, or 243, wherein: the first effector moiety comprises MQ 1 or a functional variant or fragment of any thereof, and the second effector comprises KRAB or a functional variant or fragment of any thereof. The method of any of embodiments 121-128, 200, 203, 205-213, 216-218, 235, 238, 241, or 242, wherein: the first effector moiety comprises MQ1 or a functional variant or fragment of any thereof, and the second expression repressor does not comprise a second effector moiety. The method of any of embodiments 121-206, wherein the first expression repressor comprises an amino acid sequence chosen from any of SEQ ID NOs: 22-33, 129, 133, 134, 139-149, 177-180, or 183-186, or any of SEQ ID NOs: 34-37 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

[1172] 247. The method of any of embodiments 121-204, 206, 212, 213, 219-222. 228-229, 242, 243, or 246, wherein the second expression repressor comprises an amino acid sequence chosen from any of SEQ ID NOs: 22-33, 129, 133, 134, 139-149, 177-180, or 183-186, or any of SEQ ID NOs: 34-37 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5. 4, 3, 2, or 1 positions of difference thereto.

[1173] 248. The method of any of embodiments 121-204, 206, 212, 213, 219-222. 228-229. 242, 243. 246, or

[1174] 247, wherein the first expression repressor comprises an amino acid sequence of SEQ ID NO: 30, 129, 133, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto, and the second expression repressor comprises an amino acid sequence of SEQ ID NO: 24, 134. 141, 177. 179, 183, or 185. or a sequence with at least 80, 85, 90, 95. or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17. 16. 15. 14, 13, 12, 11, 10, 9, 8, 7. 6, 5, 4, 3, 2, or 1 positions of difference thereto.

[1175] 249. The method of any of embodiments 121-204, 206, 212, 213, 219-222, 228-229, 242, 243, or 246-

[1176] 248, wherein the first expression repressor is encoded by a first nucleotide sequence of SEQ ID NO: 63 or 130, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20. 19, 18, 17, 16, 15, 14, 13, 12. 11, 10, 9. 8, 7, 6, 5. 4, 3, 2, or 1 positions of difference thereto, and the second expression repressor are encoded by a second nucleotide sequence of SEQ ID NO: 57, 189, or 194, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

[1177] 250. The method of any of embodiments 121-204, 206, 212, 213, 219-222, 228-229, 242, 243, or 246-

[1178] 249, wherein the first and the second repressor are encoded by a nucleic acid sequence of SEQ ID NO: 93. 94. 112, 113. 196, or 197, or a sequence with at least 80. 85. 90. 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

[1179] 251. Tire method of embodiment 250, wherein the expression repressor comprises an amino acid sequence of SEQ ID NO: 91, 92, 121, 122, 181, 182, 187, or 188, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto. Tire method of any of embodiments 121-203, 205, 212, 213, 216, 217, 219, 221, 230-237, 239, 240, 242, 243, or 246-250, wherein: the first expression repressor comprises from N-terminus to C-terminus:

[1180] (i) a first nuclear localization signal, e.g., a SV40 NLS; e.g.. a sequence according to SEQ ID NO:

[1181] 135;

[1182] (ii) a first targeting moiety, e.g., a zinc finger binding domain, e.g., ZF9; e.g., a sequence according to SEQ ID NO: 13;

[1183] (iii) a first effector moiety, e.g., a DNA methyltransferase, e.g., MQ1; e g., a sequence according to SEQ ID NO: 19 or 87; and

[1184] (iv) a second nuclear localization signal, e.g., a nucleoplasmin NLS; e.g., a sequence according to

[1185] SEQ ID NO: 136; and the second expression repressor comprises, from N-terminus to C-terminus:

[1186] (v) a third nuclear localization signal, e.g., a SV40NLS; e.g., a sequence according to SEQ ID

[1187] NO: 135;

[1188] (vi) a second targeting moiety, e.g., a zinc finger binding domain, e.g., ZF3; e.g., a sequence according to SEQ ID NO: 7;

[1189] (vii) a second effector moiety, e.g., KRAB, e g., a sequence according to SEQ ID NO: 18; and

[1190] (viii) a fourth nuclear localization signal, e.g., a nucleoplasmin NLS, e.g., a sequence according to SEQ ID NO: 136. The method of any of embodiments 121-203, 205, 212, 213, 216, 217, 219, 221, 230-237. 239, 240. 242, 243. or 246-250, wherein: the first expression repressor comprises from N-terminus to C-terminus:

[1191] (i) a first nuclear localization signal, e.g., a SV40 NLS; e g., a sequence according to SEQ ID NO:

[1192] 135;

[1193] (ii) a first targeting moiety, e.g., a zinc finger binding domain, e.g., ZF9; e.g., a sequence according to SEQ ID NO: 13;

[1194] (iii) a first effector moiety, e.g., a DNA methyltransferase, e.g., MQ1; e.g., a sequence according to SEQ ID NO: 19 or 87; and

[1195] (iv) a second nuclear localization signal, e.g., a nucleoplasmin NLS: e.g., a sequence according to

[1196] SEQ ID NO: 136; and the second expression repressor comprises, from N-tcrminus to C-tcrminus: (v) a third nuclear localization signal, e.g., a SV40NLS; e.g., a sequence according to SEQ ID

[1197] NO: 135;

[1198] (vi) a second targeting moiety, e.g., a zinc finger binding domain, e.g., ZF54; e.g., a sequence according to SEQ ID NO: 169;

[1199] (vii) a second effector moiety, e.g., KRAB, e.g.. a sequence according to SEQ ID NO: 18; and

[1200] (viii) a fourth nuclear localization signal, e.g.. a nucleoplasmin NLS, e.g.. a sequence according to SEQ ID NO: 136.

[1201] 254. The method of any of embodiments 121-203, 205, 212, 213, 216, 217, 219, 221, 230-237, 239, 240, 242, 243, or 246-250, wherein: the first expression repressor comprises from N-tenninus to C-terminus:

[1202] (i) a first nuclear localization signal, e.g., a SV40 NLS; e.g.. a sequence according to SEQ ID NO:

[1203] 135;

[1204] (ii) a first targeting moiety, e.g., a zinc finger binding domain, e.g., ZF9; e.g., a sequence according to SEQ ID NO: 13;

[1205] (iii) a first effector moiety, e.g., a DNA methyltransferase, e.g., MQ1; e.g., a sequence according to SEQ ID NO: 19 or 87; and

[1206] (iv) a second nuclear localization signal, e.g., a nucleoplasmin NLS; e.g., a sequence according to

[1207] SEQ ID NO: 136; and the second expression repressor comprises, from N-terminus to C-terminus:

[1208] (v) a third nuclear localization signal, e.g., a SV40NLS; e.g., a sequence according to SEQ ID

[1209] NO: 135;

[1210] (vi) a second targeting moiety, e.g., a zinc finger binding domain, e.g., ZF67; e.g., a sequence according to SEQ ID NO: 171;

[1211] (vii) a second effector moiety, e.g., KRAB, e.g.. a sequence according to SEQ ID NO: 18; and

[1212] (viii) a fourth nuclear localization signal, e g., a nucleoplasmin NLS, e.g., a sequence according to

[1213] SEQ ID NO: 136.

[1214] 255. Tire method of any of embodiments 121-254, wherein tire composition is capable of the decreasing expression of MY C to a greater degree compared to the first expression repressor alone or the second expression repressor alone.

[1215] 256. The method of any of embodiments 131-200 or 248-255, wherein the composition is capable of decreasing expression of MY C to a greater degree compared to any of the expression repressors of SEQ ID: 22, 23, 25-29, 31-37 alone or in combination.

[1216] 257. Tire method of any of embodiments 121-256, which is capable of reducing tumor volume, e.g., in a human subject or in a mammalian model. The method of any of embodiments 131-199 or 248-255, wherein the composition is capable of reducing tumor volume to a similar or greater degree compared to a chemotherapeutic agent, e.g., in a mammalian model, e.g., when measured at day 20 after initiation of treatment, e.g., wherein the expression repressor is administered every 5 days at a dose of 3 mg / kg, e.g., in a model composition as described in Example 15 as described in International Application WO / 2022 / 132195, which is herein incorporated by reference in its entirety. The method of any of embodiments 131-199 or 248-258, wherein the composition is capable of reducing tumor volume to a greater degree compared to a chemotherapeutic agent, e.g., in a mammalian model, e.g., when measured at day 15 after initiation of treatment, e.g., wherein the composition is administered every 5 days at a dose of 6 mg / kg, e.g., in a model composition as described in Example 14 as described in International Application WO / 2022 / 132195, which is herein incorporated by reference in its entirety. The method of any of embodiments 131-199 or 248-259, wherein the tumor volume is reduced by at least about 10%, 20%, 30%, 40%, 50%, or 60% compared to a control treated with PBS, e.g., at day 20 after start of treatment. The method of embodiment 260, wherein the chemotherapeutic agent is sorafenib or cisplatin. The method of any of embodiments 131-199 or 248-259, wherein the method is capable of reducing tumor volume to a similar or greater degree compared to a small molecule MYC inhibitor. The method of embodiment 262, wherein the small molecule MYC inhibitor is MYCi975 wherein optionally tumor volume is reduced by at least about 10%, 20%, 30%, or 40% compared to a control treated with the MYCi975, e.g., at day 20 after start of treatment. The method of any of embodiments 121-263, which does not cause a decrease in body weight compared to at the start of treatment, or which causes a decrease in body weight of less than 3%, 2%, or 1%. The method of any of embodiments 121-264, wherein the first targeting moiety is selected from a TAL effector domain, a CRISPR / Cas domain, a zinc finger domain, a tetR domain, a meganuclease, or an oligonucleotide. The method of any of embodiments 121-265, wherein the second targeting moiety is selected from a TAL effector domain, a CRISPR / Cas domain, a zinc finger domain, a tetR domain, a meganuclease, or an oligonucleotide. The method of any of embodiments 121-266, wherein tire first targeting moiety comprises a CRISPR / Cas domain (e.g., a first CRISPR / Cas domain). 268. The method of any of embodiments 121-267, wherein the second targeting moiety comprises a second CRISPR / Cas domain (e.g., a second CRISPR / Cas domain).

[1217] 269. The method of embodiment 268, wherein: i) the first CRISPR / Cas domain binds a first guide RNA, ii) the second CRISPR / Cas domain binds a second guide RNA, or iii) both (i) and (ii).

[1218] 270. The method of embodiment 268 or 269, wherein the first CRISPR / Cas domain does not bind the second guide RNA or binds with a KD of at least 10, 20. 50. 100, 1000, or 10,000 nM. and the second CRISPR / Cas domain does not bind the first guide RNA, or binds with a KD of at least 10, 20, 50, 100, 1000, or 10,000 nM.

[1219] 271. Tire method of any of embodiments 266-270, wherein the first CRISPR / Cas domain comprises a different amino acid sequence than the second CRISPR / Cas domain.

[1220] 272. The method of any of embodiments 266-271, wherein the first or second CRISPR / Cas domain comprises an amino acid sequence of a Cas protein or Cpfl protein chosen from Table 1 as described in International Application WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or a variant (e.g., mutant) of any thereof.

[1221] 273. Tire method of any of embodiments 266-272, wherein the first CRISPR / Cas domain comprises an amino acid sequence of a Cas protein or Cpfl protein chosen from Table 1 as described in International Application WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or a variant (e.g.. mutant) of any thereof, and the second CRISPR / Cas domain comprises an amino acid sequence of a different Cas protein or Cpfl protein chosen from Table 1 as described in International Application WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or a variant (e.g., mutant) of any thereof.

[1222] 274. The method of any of embodiments 121-266, wherein the first targeting moiety comprises a zinc finger domain (e.g., a first zinc finger domain).

[1223] 275. The method of any of embodiments 121-266 or 274, wherein the second targeting moiety comprises a zinc finger domain (e.g., a second zinc finger domain).

[1224] 276. The method of any of embodiments 121-267, 274, or 275, wherein the first targeting moiety comprises a first zinc finger domain and the second targeting moiety comprises a second zinc finger domain.

[1225] 277. The method of any of embodiments 274-276, wherein the first zinc finger domain and tire second zinc finger domain bind the same genomic locus, e.g.. have the same amino acid sequence.

[1226] 278. The method of any of embodiments 274-277, wherein the first zinc finger domain and the second zinc finger domain have different amino acid sequences or bind different genomic loci. 279. The method of any of embodiments 121-267 or 273-278, wherein the first zinc finger molecule comprises at least 1, 2, 3, 4, 5, 7, 8, 9, or 10 zinc fingers (and optionally no more than 11, 10, 9, 8, 7, 6, or 5 zinc fingers).

[1227] 280. Tire method of any of embodiments 273-279, wherein the first zinc finger molecule comprises 1- 10, 1-9, 1-8. 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-10, 2-9, 2-8, 2-7, 2-6. 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3-7, 3-6. 3-5, 3-4, 4-10, 4-9, 4-8. 4-7, 4-6, 4-5. 5-10. 5-9, 5-8, 5-7, 5-6. 6-10. 6-9, 6-8, 6-7. 7-10. 7-9, 7-8, 8-10, 8-9, or 9-10 zinc fingers.

[1228] 281. The method of any of embodiments 274-280, wherein the first zinc finger domain comprises 3 or 9 zinc fingers.

[1229] 282. Tire method of any of embodiments 274-281, wherein the second zinc finger domain comprises at least 1, 2, 3, 4, 5, 7, 8, 9, or 10 zinc fingers (and optionally no more than 11, 10. 9, 8, 7, 6. or 5 zinc fingers).

[1230] 283. The method of any of embodiments 274-282, wherein the second zinc finger domain comprises

[1231] 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3- 7, 3-6, 3-5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7- 9, 7-8, 8-10, 8-9, or 9-10 zinc fingers.

[1232] 284. The method of any of embodiments 274-283, wherein the second zinc finger domain comprises 3 or 9 zinc fingers.

[1233] 285. The method of any of embodiments 121-284, wherein the first targeting moiety comprises a TAL effector domain (e.g., a first TAL effector domain).

[1234] 286. The method of any of embodiments 121-266 or 285 wherein the second targeting moiety comprises a

[1235] TAL effector domain (e.g., a second TAL effector domain).

[1236] 287. The method of any of embodiments 285 or 286, wherein the first TAL effector domain comprises at least 2, 4. 6, 8, 10, 12, 14. 16. 18. 20, 22, 24, 26, 28, 30, 32. 34. 36. 38. or 40 central repeats (and optionally, no more than 45, 40, 35, 30, 25, 20, 15, or 10 central repeats).

[1237] 288. The method of any of embodiments 285-287, wherein tire first TAL effector domain comprises 2- 40, 5-40, 10-40, 15-40, 20-40, 25-40, 30-40, 35-40, 2-35, 5-35, 10-35, 15-35, 20-35, 25-35, 30- 35, 2-30, 5-30, 10-30, 15-30, 20-30, 25-30, 2-25, 5-25, 10-25, 15-25, 20-25, 2-20, 5-20, 10-20, 15-20, 2-15. 5-15. 10-15, 2-10, 5-10, or 2-5 central repeats.

[1238] 289. The method of any of embodiments 285-288, wherein the second TAL effector domain comprises at least 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 central repeats (and optionally, no more than 45, 40, 35, 30, 25, 20, 15, or 10 central repeats).

[1239] 290. Tire method of any of embodiments 285-289, wherein tire second TAL effector domain comprises

[1240] 2-40, 5-40, 10-40, 15-40, 20-40, 25-40, 30-40, 35-40, 2-35, 5-35, 10-35, 15-35, 20-35, 25-35, 30- Ill

[1241] 35, 2-30, 5-30, 10-30, 15-30, 20-30, 25-30, 2-25, 5-25, 10-25, 15-25, 20-25, 2-20, 5-20, 10-20, 15-20, 2-15, 5-15, 10-15, 2-10, 5-10, or 2-5 central repeats.

[1242] 291. Tire method of any of embodiments 121-290, wherein tire first targeting moiety comprises a nucleic acid (e.g., a first nucleic acid).

[1243] 292. The method of any of embodiments 131-291, wherein the second targeting moiety comprises a nucleic acid (e.g., a second nucleic acid).

[1244] 293. The method of any of embodiments 131-292, wherein the first targeting moiety comprises a polypeptide (e.g., a first polypeptide).

[1245] 294. Tire method of any of embodiments 131-293, wherein tire second targeting moiety comprises a polypeptide (e.g., a second polypeptide).

[1246] 295. The method of embodiment 293 or 294, wherein the nucleic acid is covalently attached to the polypeptide.

[1247] 296. The method of embodiment 294 or 295, wherein the nucleic acid is non-covalently associated with the polypeptide.

[1248] 297. Tire method of any of embodiments 281-296, wherein the nucleic acid comprises a sequence that is complementary to the transcriptional regulatory element or a sequence proximal thereto, or comprises no more than 10, 9. 8, 7, 6, 5. 4, 3, 2, or 1 mismatches relative to the transcriptional regulatory element or a sequence proximal thereto.

[1249] 298. The method of any of embodiments 281-297, wherein the nucleic acid comprises a sequence that is complementary to tire anchor sequence or a sequence proximal thereto, or comprises no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mismatches relative to the anchor sequence or a sequence proximal thereto.

[1250] 299. The method of any of embodiments 281-298, wherein the nucleic acid comprises DNA. a peptide nucleic acid (PNA). a peptide-oligonucleotide conjugate, a locked nucleic acid (LNA), a bridged nucleic acid (BNA), a polyamide, a triplex-forming oligonucleotide, an antisense oligonucleotide, tRNA, mRNA, rRNA, miRNA, gRNA, siRNA, or other RNAi molecule.

[1251] 300. Tire method of any of embodiments 281-299, wherein the nucleic acid comprises a gRNA.

[1252] 301. The method of any of embodiments 281-300, wherein the nucleic acid comprises a sequence with at least 80, 85, 90. 95. 99, or 100% identity to any of SEQ ID NOs: 1-4 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 positions of difference thereto.

[1253] 302. Tire method of any of embodiments 281-301, wherein tire first nucleic acid comprises a sequence with at least 80, 85, 90, 95, 99, or 100% identity to any of SEQ ID NOs: 1-4 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 positions of difference thereto, and the second nucleic acid 4comprises a sequence with at least 80, 85, 90, 95, 99, or 100% identity to any of SEQ ID NOs: 1-4 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or has no more than 1, 2. 3, 4, 5, 6. 7, 8, 9. or 10 positions of difference thereto. The method of any of embodiments 281-301, wherein the first nucleic acid comprises a sequence with at least 80, 85, 90, 95, 99, or 100% identity to any of SEQ ID NOs: 96-110 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 positions of difference thereto, and the second nucleic acid comprises a sequence with at least 80, 85, 90. 95, 99, or 100% identity to any of SEQ ID NOs: 96-110 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 positions of difference thereto. Tire method of any of embodiments 121-303, wherein tire transcriptional regulatory element comprises a promoter. The method of any of embodiments 121-304, wherein the transcriptional regulatory element comprises an enhancer; e.g.. a super enhancer. The method of any of embodiments 121-305, wherein the anchor sequence comprises a CTCF binding motif. Tire method of any of embodiments 121-306, wherein the anchor sequence comprises a YY1 binding motif. The method of any of embodiments 121-307, wherein the anchor sequence comprises the sequence of SEQ ID NO: 71 or 72, or a sequence with no more than 8, 7, 6. 5, 4, 3, 2. or 1 alterations relative thereto. The method of any of embodiments 121-308, wherein tire anchor sequence comprises a sequence according to a nucleic acid sequence of CCGCCATNTT or AANATGGCGG, where N is any nucleotide, or a sequence with no more than 8, 7, 6, 5. 4, 3, 2, or 1 alterations relative thereto. The method of any of embodiments 121-309, wherein the anchor sequence is on tire same chromosome as the MYC gene. The method of any of embodiments 121-310, wherein the anchor sequence is upstream of the MYC gene (e.g., upstream of the TSS or upstream of the promoter). The method of any of embodiments 121-311, wherein the anchor sequence is at least 1, 5, 10, 50, 100, or 1000 kilobases away from the MYC gene (e.g., from the TSS or promoter of the MYC gene). Tire method of any of embodiments 121-312, wherein the anchor sequence is O.1-0.5, 0.1-1, 0.1- 5, 0.1-10, 0.1-50, 0.1-100. 0.1-500, 0.1-1000, 0.5-1, 0.5-5, 0.5-10. 0.5-50, 0.5-100, 0.5-500, 0.5- 1000, 1-5. 1-10. 1-50. 1-100, 1-500. 1-1000, 5-10, 5-50. 5-100, 5-500, 5-1000, 10-50. 10-100, 10- 500, 10-1000, 50-100, 50-500, 50-1000, 100-500, 100-1000, or 500-1000 kilobases away from the MYC gene (e.g., from the TSS or promoter of the MYC gene). Tire method of any of embodiments 121-309, or 311-313, wherein the anchor sequence is on a different chromosome than the MYC gene. The method of any of embodiments 121-314, wherein the second targeting moiety binds to the anchor sequence or a sequence proxim7al to tire anchor sequence with affinity sufficient to compete for binding with an endogenous polypeptide (e.g., CTCF or YY1). The method of any of embodiments 121-315, wherein tire first targeting moiety binds to a sequence at chromosome coordinates 128746342-128746364, 128746321-128746343, or 128746525-128746547, or a sequence proximal thereto. The method of any of embodiments 121-315, wherein the first targeting moiety binds to a sequence at chromosome coordinates 128746405-128746425. 128748069-128748089, 129188825-129188845, or 129188822-129188842 or a sequence proximal thereto. The method of any of embodiments 121-317, wherein tire second targeting moiety binds to a sequence at chromosome coordinates 128748014-128748036, or a sequence proximal thereto. The method of any of embodiments 121-317, wherein the second targeting moiety binds to a sequence at chromosome coordinates 128746405-128746425. 128748069-128748089, 129188825-129188845. or 129188822-129188842, or a sequence proximal thereto. The method of any of embodiments 121-319, wherein the first expression repressor is a fusion molecule. Tire method of any of embodiments 121-319, wherein tire second expression repressor is a fusion molecule. The method of any of embodiments 121-321, wherein the first expression repressor comprises a linker. The method of any of embodiments 121-322, wherein the second expression repressor comprises a linker. Tire method of any of embodiments 121-173 or 291-323, wherein: the first expression repressor comprises a targeting moiety comprising a first CRISPR / Cas molecule, e.g., comprising a first catalytically inactive CRISPR / Cas protein, and an effector moiety comprising an epigenetic modifying moiety; and the second expression repressor comprises a targeting moiety comprising a second CRISPR / Cas molecule, e.g., comprising a second catalytically inactive CRISPR / Cas protein, and an optionally an effector moiety comprising a transcription repressor. The method of any of embodiments 121-166, 274-184, or 281-323 wherein: the first expression repressor comprises a targeting moiety comprising a first zinc finger domain, and an effector moiety comprising an epigenetic modifying moiety; and the second expression repressor comprises a targeting moiety comprising a second zinc finger domain, and optionally an effector moiety comprising a transcription repressor. The method of any of embodiments 121-123, 268, 274, or 181-324. wherein: the first expression repressor comprises a targeting moiety comprising a CRISPR / Cas molecule, e.g., comprising a catalytically inactive CRISPR / Cas protein, and an effector moiety comprising an epigenetic modifying moiety; and the second expression repressor comprises a targeting moiety comprising a zinc finger domain, and optionally an effector moiety comprising a transcription repressor. The method of any of embodiments 121-266, 274, or 281-324, wherein: the first expression repressor comprises a targeting moiety comprising a zinc finger domain, and an effector moiety comprising an epigenetic modifying moiety; and the second expression repressor comprises a targeting moiety comprising a CRISPR / Cas domain, e.g., comprising a catalytically inactive CRISPR / Cas protein, and optionally an effector moiety comprising a transcription repressor. The method of any of embodiments 266 or 274-324, wherein the zinc finger domain (e.g.. the first or second zinc finger domain) comprises 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-10, 2- 9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, or 9-10 zinc fingers, e.g., 3 or 9 zinc fingers. The method of any of embodiments 328, wherein the epigenetic modifying moiety comprises a DNA methyltransferase. The method of any of embodiments 121-328, wherein the epigenetic modifying moiety comprises MQ 1 or a functional variant or fragment thereof. method of any of embodiments 121-330, wherein the second expression repressor comprises an effector moiety comprising a transcription repressor. The method of any of embodiments 121-329, wherein the transcription repressor comprises KRAB or a functional variant or fragment thereof. Tire method of any of embodiments 121-332, wherein tire first expression repressor comprises an amino acid sequence of any of SEQ ID NOS: 28-33, 145-149, 151, 152, or any of SEQ ID NOs: 35-37 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or a sequence with at least 80, 85, 90, 95, 99. or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto. Tire method of any of embodiments 121-333, wherein tire second expression repressor comprises an amino acid sequence of any of SEQ ID NOS: 22-27, 139-144, 150. 177-180, 183-186, or SEQ ID NO: 34 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, or a sequence with at least 80. 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto. Tire method of any of embodiments 121-334, wherein binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto decreases expression of MY C in a cell. The method of embodiment 333, wherein expression is decreased by 10, 20, 30. 40. 50. 60, 70, 80, 90, or 100% compared to expression in the absence of the first expression repressor, e.g., as measured by QPCR or ELISA. Tire method of embodiment 332 or 333, wherein binding of the first expression repressor to the transcription regulatory element appreciably decreases expression of MY C for a time period of at least 1, 2, 3. 4, 5, 6, 7. 8, 9, 10, 11, 12, 13. 14, 15, 16, 17, 18, 19, 20, 21. 22. 23, 24, or 25 days, or at least 1, 2. 3, 4, 5, 6. 7, 8, 9, or 10 cell divisions, e.g., as measured by QPCR or ELISA. The method of any of embodiments 335-338, wherein binding of the first expression repressor to the transcription regulatory element appreciably decreases expression of MYC at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, or 96 hours posttransfection. The method of any of embodiments 334-338, wherein binding of the second expression repressor to the anchor sequence or a sequence proximal thereto decreases expression of MY C in a cell. The method of embodiment 339, wherein expression is decreased by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% compared to expression in the absence of the second expression repressor, e.g., as measured by QPCR or ELISA. The method of embodiment 339 or 340, wherein binding of the second expression repressor to the anchor sequence or a sequence proximal thereto appreciably decreases expression of MYC for a time period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 days, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cell divisions, e.g., as measured by QPCR or ELISA. The method of embodiment 340 or 341. wherein binding of the second expression repressorto the anchor sequence or a sequence proximal thereto appreciably decreases expression of MYC at 1,

[1254] 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, or 96 hours post-transfection. Tire method of any of embodiments 335-342, wherein binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto and the second expression repressorto the anchor sequence or a sequence proximal thereto decreases expression of MYC in a cell. The method of any of embodiments 335-342, wherein binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto and binding of the second expression repressor to the anchor sequence or a sequence proximal thereto appreciably decreases expression of MYC at 1, 2, 3, 4. 5, 6, 7, 8. 10. 12, 16, 20, 24, 28, 32, 36, 40. 44, 48, 52, 56, 60, 64, 68, 72, 76. 80. or 96 hours post-transfection. The method of any of embodiments 343 or 344, wherein expression is decreased by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% compared to expression in tire absence of the first and second expression repressors, e.g., as measured by QPCR or ELISA. The method of any of embodiments 335-345, wherein binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto and the second expression repressor to the anchor sequence or a sequence proximal thereto appreciably decreases expression of MYC for a time period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 days, or at least 1, 2,

[1255] 3, 4, 5, 6, 7, 8, 9, or 10 cell divisions, e.g., as measured by QPCR or ELISA. The method of any of embodiments 335-346, wherein the decrease in expression resulting from the binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto and the second expression repressor to the anchor sequence or a sequence proximal thereto is greater than the decrease in expression resulting from the binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto or the binding of the second expression repressor to the anchor sequence or a sequence proximal thereto individually. The method of embodiment 347, wherein the binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto and the second expression repressor to the anchor sequence or a sequence proximal thereto decreases expression 1.05x (i.e., 1.05 times), l.lx, L15x, 1.2x, 1.25x, 1.3x, 1.35x, 1.4x, 1.45x, 1.5x, 1.6x, 1.7x, 1.8x, L9x, 2x, 3x, 4x, 5x, 6x, 7x. 8x, 9x, lOx, 20x, 50x, or lOOx more than either tire binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto or the binding of the second expression repressor to the anchor sequence or a sequence proximal thereto individually, e.g., as measured by QPCR or ELISA. Tire method of any of embodiments 335-348, wherein tire decrease in expression resulting from the binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto and the second expression repressor to the anchor sequence or a sequence proximal thereto persists for a longer time (e.g.. more hours, days, or cell divisions) than the decrease in expression resulting from the binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto or the binding of the second expression repressor to the anchor sequence or a sequence proximal thereto individually. The method of embodiment 349, wherein the binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto and the second expression repressor to the anchor sequence or a sequence proximal thereto decreases expression 1.05x (i.e.,

[1256] I.05 times), l .lx, 1.15x, 1.2x, 1.25x, 1.3x, 1.35x, 1.4x, 1.45x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, 20x, 50x, or lOOx longer (e.g., as measured in hours, days, or cell divisions) than either the binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto or the binding of the second expression repressor to the anchor sequence or a sequence proximal thereto individually, e.g., as measured by QPCR or ELISA. The method of any of embodiments 335-350, wherein binding of the first expression repressor to the promoter or a sequence proximal thereto and the second expression repressor to the superenhancer or a sequence proximal thereto appreciably decreases expression of MY C for a time period of at least 1, 2, 3. 4, 5, 6, 7. 8, 9, 10, 11, or 12 hours, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,

[1257] I I, 12, 13, 14. 15. 16, 17, 18, 19, 20, 21, 22, 23. 24. or 25 days, or at least 1, 2, 3, 4. 5, 6, 7, 8. 9, or 10 cell divisions, e.g., as measured by QPCR or ELISA. The method of any of embodiments 335-351, wherein the decrease in expression resulting from the binding of the first expression repressor to the promoter or a sequence proximal thereto and the second expression repressor to the supcr-cnhanccr or a sequence proximal thereto is greater than the decrease in expression resulting from the binding of the first expression repressor to the promoter or a sequence proximal thereto or the binding of the second expression repressor to the super-enhancer or a sequence proximal thereto individually. Tire method of embodiment 352, wherein the binding of the first expression repressor to the promoter or a sequence proximal thereto and the second expression repressor to the superenhancer or a sequence proximal thereto decreases expression 1.05x (i.e., 1.05 times), l.lx, 1.15x. 1.2x, 1.25x, 1.3x, 1.35x, 1.4x, 1.45x. 1.5x, 1.6x, 1.7x, 1.8x, 1.9x. 2x. 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, 20x, 50x, or lOOx more than either the binding of the first expression repressor to the promoter or a sequence proximal thereto or the binding of the second expression repressor to the super-enhancer or a sequence proximal thereto individually, e.g., as measured by QPCR or ELISA. The method of any of embodiments 335-353, wherein the decrease in expression resulting from the binding of the first expression repressor to the promoter or a sequence proximal thereto and the second expression repressor to the super-enhancer or a sequence proximal thereto persists for a longer time (e.g., more hours, days, or cell divisions) than the decrease in expression resulting from the binding of the first expression repressor to the promoter or a sequence proximal thereto or the binding of the second expression repressor to the super-enhancer or a sequence proximal thereto individually. The method of embodiment 354, wherein the binding of the first expression repressor to the promoter or a sequence proximal thereto and the second expression repressor to the superenhancer or a sequence proximal thereto decreases expression 1.05x (i.e., 1.05 times), l.lx, 1.15x, 1.2x, 1.25x, 1.3x, 1.35x, 1.4x, 1.45x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, 20x, 50x, or lOOx longer (e.g., as measured in hours, days, or cell divisions) than either the binding of the first expression repressor to the promoter or a sequence proximal thereto or the binding of the second expression repressor to the super-enhancer or a sequence proximal thereto individually, e.g., as measured by QPCR or ELISA. The method of any of embodiments 335-355, wherein expression is appreciably decreased indefinitely (e.g., for a time period greater than can be experimentally measured). The method of any of embodiments 335-356, wherein binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto decreases the viability of a cell comprising the transcription regulatory element or a sequence proximal thereto. The method of any of embodiments 335-357, wherein contacting a plurality of cells with the first expression repressor or a nucleic acid encoding the first expression repressor decreases the viability of the plurality of cells, optionally wherein the plurality of cells comprise cancerous and non-cancerous cells and / or infected cells and uninfected cells. 359. The method of embodiment 358, wherein viability is decreased by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% compared to viability in the absence of the first expression repressor, e.g., as measured by CellTiter Gio.

[1258] 360. Tire method of any of embodiments 335-359, wherein, administration of the first expression repressor results in apoptosis of at least 5%, 6%, 7%, 8%, 9% 10%, 12%, 15%, 17% 20%, 25% 30%, 40%, 45%, 50%, 55%, 60%, 65%. 75% of target cells (e.g., cancer cells).

[1259] 361. The method of any of embodiments 335-360, wherein binding of the second expression repressor to the anchor sequence or a sequence proximal thereto decreases the viability of a cell comprising the anchor sequence or a sequence proximal thereto.

[1260] 362. Tire method of any of embodiments 335-361, wherein contacting a plurality of cells with the second expression repressor or a nucleic acid encoding the second expression repressor decreases the viability of the plurality of cells.

[1261] 363. The method of any of embodiments 335-362, wherein binding of the second expression repressor to the super-enhancer or a sequence proximal thereto decreases the viability of a cell comprising the transcription regulatory element or a sequence proximal thereto.

[1262] 364. The method of any of embodiments 335-363, wherein contacting a plurality of cells with tire second expression repressor or a nucleic acid encoding the first expression repressor decreases the viability of the plurality of cells, optionally wherein the plurality of cells comprise cancerous and non-cancerous cells and / or infected cells and uninfected cells.

[1263] 365. The method of embodiment 364, wherein viability is decreased by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% compared to viability in the absence of the second expression repressor, e.g., as measured by CellTiter Gio.

[1264] 366. The method of any of embodiments 335-365, wherein, administration of the second expression repressor results in apoptosis of at least 5%. 6%, 7%, 8%. 9% 10%. 12%, 15%, 17% 20%, 25% 30%, 40%, 45%, 50%, 55%, 60%, 65%, 75% of target cells (e.g., cancer cells).

[1265] 367. The method of any of embodiments 335-366, wherein binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto and the second expression repressor to the anchor sequence or a sequence proximal thereto decreases the viability of a cell comprising the anchor sequence or a sequence proximal thereto.

[1266] 368. The method of any of embodiments 335-367, wherein binding of the first expression repressor to the promoter or a sequence proximal thereto and the second expression repressor to the superenhancer or a sequence proximal thereto decreases the viability of a cell

[1267] 369. Tire method of any of embodiments 335-368, wherein contacting a plurality of cells with the composition decreases the viability of the plurality of cells. The method of embodiments 335-369, wherein viability is decreased by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% compared to viability in the absence of the composition, e.g., as measured by CellTiter Gio. Tire method of any of embodiments 335-370, wherein the decrease in viability resulting from the binding of the first expression repressor to tire transcription regulatory element or a sequence proximal thereto and the second expression repressor to the anchor sequence or a sequence proximal thereto is greater than the decrease in viability resulting from the binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto or the binding of the second expression repressor to the anchor sequence or a sequence proximal thereto individually. The method of any of embodiments 335-371, wherein the decrease in viability resulting from the binding of the first expression repressor to tire promoter or a sequence proximal thereto and the second expression repressor to the super-enhancer or a sequence proximal thereto is greater than the decrease in viability resulting from the binding of the first expression repressor to the promoter or a sequence proximal thereto or the binding of the second expression repressor to the super-enhancer or a sequence proximal thereto individually. The method of embodiment 372, wherein the binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto and the second expression repressor to the anchor sequence or a sequence proximal thereto decreases viability 1.05x (i.e., 1.05 times), l.lx, 1.15x, 1.2x, 1.25x, 1.3x, 1.35x, 1.4x, 1.45x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, 20x, 5 Ox, or lOOx more than either the binding of the first expression repressor to the transcription regulatory element or a sequence proximal thereto or the binding of the second expression repressor to the anchor sequence or a sequence proximal thereto individually, e.g., as measured by CellTiter Gio. The method of embodiment 372 or 373, wherein the binding of the first expression repressor to the promoter or a sequence proximal thereto and the second expression repressor to the superenhancer or a sequence proximal thereto decreases viability 1.05x (i.e., 1.05 times), l.lx, 1.15x, 1.2x, 1.25x, 1.3x, 1.35x, 1.4x, 1.45x, 1.5x, 1.6x. 1.7x, 1.8x, 1.9x, 2x, 3x, 4x, 5x. 6x, 7x, 8x, 9x, lOx. 20x, 5 Ox. or lOOx more than either the binding of tire first expression repressor to the promoter or a sequence proximal thereto or the binding of the second expression repressor to the super-enhancer or a sequence proximal thereto individually, e.g., as measured by CellTiter Gio. The method of any of embodiments 335-374, wherein, administration of the first expression repressor and the second expression repressor result in apoptosis of at least 5%, 6%, 7%, 8%, 9% 10%, 12%, 15%, 17% 20%, 25% 30%, 40%, 45%, 50%, 55%, 60%, 65%, 75% of target cells (e.g., cancer cells).

[1268] 376. Tire method of embodiments 335-375, wherein the plurality of cells comprises a plurality of cancer cells and a plurality’ of non-cancer cells.

[1269] 377. The method of embodiment 376, wherein contacting the plurality of cells with the composition decreases the viability of the plurality of cancer cells more than it decreases the viability of the plurality' of non-cancer cells.

[1270] 378. The method of embodiment 376 or 377, wherein contacting the plurality of cells yvith the composition decreases the viability of the plurality' of cancer cells 1 ,05x (i.e., 1.05 times), 1. lx, 1.15x, 1.2x, 1.25x, 1.3x, 1.35x, 1.4x, 1.45x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, 20x, 5 Ox. or lOOx more than it decreases the viability of tire plurality of non-cancer cells.

[1271] 379. The method of any preceding embodiments, which does not reduce viability- of non-cancer cells (e.g., primary hepatocytes) by more than 5, 10, 15, or 20%, e.g., when assayed according to Example 29 as described in International Application WO / 2022 / 132195, which is herein incorporated by reference in its entirety.

[1272] 380. The method of embodiment 379, yvherein viability is assayed 72 hours after contacting the cells with the composition.

[1273] 381. The method of embodiment 380, wherein the assay comprises contacting the non-cancer cells with 2.5, 2, 1.25, 1, 0.6, or 0.5 pg / ml of the composition.

[1274] 382. The method of any of embodiments 358-381, which, when contacted with a plurality of infected cells and a plurality of uninfected cells, decreases the viability of the plurality of infected cells more than it decreases the viability of the plurality of uninfected cells and / or decreases the viability of the plurality of cancerous cells more than it decreases the viability of the plurality of non-cancerous cells.

[1275] 383. The method of any of embodiments 358-382, wherein the cancer is hepatocellular carcinoma (HCC), Fibrolamellar Hepatocellular Carcinoma (FHCC), Cholangiocarcinoma, Angiosarcoma, secondary liver cancer, Adenocarcinoma, Large cell (undifferentiated) carcinoma, triple negative breast cancer, gastric adenocarcinoma, endometrial carcinoma, or pancreatic carcinoma.

[1276] 384. The method of any of embodiments 358-383, wherein the cancer cells are gastric cancer cells, gastrointestinal cancer cells, colorectal cancer cells, pancreatic cancer cells, or hepatic cancer cells.

[1277] 385. The method of any of embodiments 358-384, yvherein tire infection is a viral infection.

[1278] 386. Tire method of embodiment 385, yvherein the viral infection is hepatitis, e.g., hepatitis B.

[1279] 387. The method of any of embodiments 384-386, wherein the infected cells are human hepatocytes. 388. The method of any of embodiments 358-387, wherein the viral infection is a chronic infection.

[1280] 389. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:

[1281] (A) a composition comprising:

[1282] (1) a nucleic acid, the nucleic acid encoding a fusion protein comprising: a first amino acid region comprising a sequence encoding the first expression repressor of a composition of any of embodiments 121-388; and a second amino acid region comprising a sequence encoding the second expression repressor of a composition of any of embodiments 121-388; and

[1283] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[1284] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[1285] (i') a compound having a general structure of formula (I):

[1286] R3

[1287] X33

[1288] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[1289] L1and L2are each independently -O(C=O)-, -(C=O)O-. -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-_ -NRaC(=O)O-_ or a direct bond;

[1290] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[1291] G’ is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[1292] Rais H or C1-C12 alkyl;

[1293] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[1294] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12. or -NR5C(=O)R4;

[1295] R4is C1-C12 alkyl;

[1296] R5is H or C1-C6 alkyl;

[1297] R11and R12are each independently C1-C12 alkyl or -G4-OR5, or R11and R12, together with the nitrogen atom to which they arc attached, form a 5, 6 or 7-mcmbcrcd heterocyclic ring;

[1298] G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2; (i") a compound having a general structure of Fonnula (IX):

[1299] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(OO)-, -(OO)O-, -C(=0)-, -0-, -S(0)x-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[1300] G1is C1-C2 alkylene, -(C=0)-, -0(00)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[1301] G2is -C(=0)- , -(OO)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[1302] G3is C1-C6 alkylene;

[1303] Rais H or C1-C12 alkyl;

[1304] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[1305] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[1306] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[1307] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[1308] R5and R6are each independently H or methyl;

[1309] R7is C4-C20 alkyl;

[1310] R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and,

[1311] (i'") a compound having a general structure of Formula (XI):

[1312] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[1313] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[1314] R2and R3are each independently optionally substituted C-Cv, alkyl;

[1315] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[1316] L1, L2, and L3are each independently optionally substituted C1 -C18 alkylene;

[1317] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[1318] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[1319] (ii) a second compound having a general structure of formula (II):

[1320] Fonnula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Fonnula (II):

[1321] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[1322] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmacally acceptable salt, tautomer or stereoisomer thereof; and

[1323] (iv) a steroid (e.g.. sterol, e.g.. cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and (B) a compound having the general structure of Formula (Al) wherein:

[1324] R1is alkyl, cycloalkyl, or aryl;

[1325] R2is halo, alkyl, or H;

[1326] R3, R4, R5, R6, R7, are each independently H or alkyl; and

[1327] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1328] 390. The method of embodiment 389, wherein the fusion protein comprises a third amino acid region, wherein the third amino acid region is situated between the first amino acid region and the second amino acid region.

[1329] 391. Tire method of embodiment 390, wherein the third amino acid region comprises a protease cleavage peptide sequence, e.g., a self-cleaving peptide sequence, e.g., a T2A self-cleaving peptide sequence, e.g., a sequence according to SEQ ID NO: 120.

[1330] 392. The method of embodiment 391, wherein the third amino acid region comprises a protease cleavage peptide sequence, e g., a self-cleaving peptide sequence, e.g., a tandem 2A peptide sequence, e.g., a tPT2A sequence, e.g., a sequence according to SEQ ID NO: 124.

[1331] 393. Tire method of embodiment 390, wherein the peptide sequence comprises a T2A peptide sequence and a P2A peptide sequence.

[1332] 394. The method of any of embodiments 389-393, wherein: the first expression repressor comprises an amino acid sequence according to SEQ ID NO: 30 or 129, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto; and the second expression repressor comprises an amino acid sequence according to SEQ ID NO: 24 or 142, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto. 395. The method of any of embodiments 389-393, wherein: the first expression repressor comprises an amino acid sequence according to SEQ ID NO: 30 or 129, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto; and the second expression repressor comprises an amino acid sequence according to SEQ ID NO: 177 or 183, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto.

[1333] 396. The method of any of embodiments 389-393, wherein: the first expression repressor comprises an amino acid sequence according to SEQ ID NO: 30 or 129, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto; and the second expression repressor comprises an amino acid sequence according to SEQ ID NO: 179 or 185, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto.

[1334] 397. The method of any of embodiments 389-396, wherein the fusion protein comprises an amino acid sequence of SEQ ID NO: 91, 92, 121. or 122, or a sequence with at least 80, 85, 90. 95. or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

[1335] 398. Tire method of any of embodiments 389-397, wherein tire fusion protein comprises an amino acid sequence of SEQ ID NO: 181, 182, 187, or 188. or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17. 16, 15, 14, 13, 12, 11, 10, 9, 8, 7. 6. 5. 4, 3, 2. or 1 positions of difference thereto.

[1336] 399. A method of any one of embodiments 121-398, wherein the composition comprises a nucleic acid comprising: a first region comprising a sequence encoding the first expression repressor of a composition of any of embodiments 121-398; and a second region comprising a sequence encoding the second expression repressor of a composition of any of embodiments 121-398.

[1337] 400. The method of embodiment 399, wherein the nucleic acid comprises a third region, wherein the third region is situated between the first region and the second region.

[1338] 401. Tire method of embodiment 399 or 400, wherein the third region encodes a ribosome-skipping sequence.

[1339] 402. The method of embodiment 400 or 401. wherein the third region encodes a tPT2A peptide sequence, e.g., a sequence according to SEQ ID NO: 124.

[1340] 403. The method of any of embodiments 400-402, wherein the third region encodes a protease cleavage peptide sequence, e.g., a self-cleaving peptide sequence, e.g., a T2A self-cleaving peptide sequence, e.g., a sequence according to SEQ ID NO: 95. 404. The method of any of embodiments 400-403, wherein the third region encodes a protease cleavage peptide sequence, e.g., a self-cleaving peptide sequence, e.g., a tandem 2A peptide sequence, e.g., a tPT2A peptide sequence, e.g., a sequence according to SEQ ID NO: 124.

[1341] 405. Tire method of any of embodiments 399-404, wherein the first expression repressor comprises an amino acid sequence according to SEQ ID NO: 30, 129 or a sequence with at least 80, 85. 90. 95. or 99% identity thereto: and the second expression repressor comprises an amino acid sequence according to SEQ ID NO: 24, 142, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto.

[1342] 406. Tire method of any of embodiments 399-404, wherein the first expression repressor comprises an amino acid sequence according to SEQ ID NO: 30 or 129. or a sequence with at least 80, 85, 90, 95, or 99% identity thereto; and the second expression repressor comprises an amino acid sequence according to any of SEQ ID NOs: 177, 179, 183, or 185, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto.

[1343] 407. The method of any of embodiments 399-406, wherein tire nucleic acid encodes an amino acid sequence of any of SEQ ID NOs: 91, 92, 121, 122, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17, 16, 15, 14, 13, 12. 11, 10, 9. 8, 7. 6, 5, 4, 3. 2, or 1 positions of difference thereto.

[1344] 408. The method of any of embodiments 399-407, wherein the nucleic acid encodes an amino acid sequence of any of SEQ ID NOs: 181, 182, 187, 188, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

[1345] 409. The method of any of embodiments 399-408, wherein the nucleic acid comprises a nucleotide sequence of any of SEQ ID NOs: 93, 94, 112, or 113 or a sequence with at least 80. 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20. 19. 18. 17, 16, 15, 14, 13, 12. 11. 10. 9. 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

[1346] 410. The method of any of embodiments 399-409, wherein tire nucleic acid comprises a nucleotide sequence of SEQ ID NO: 196 or 197, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10. 9, 8, 7, 6, 5, 4, 3, 2. or 1 positions of difference thereto.

[1347] 411. The method of any one of embodiments 46-410, wherein the nucleic acid comprises an RNA. e.g., an mRNA.

[1348] 412. The method of any of embodiments 399-411, wherein tire nucleic acid comprises an N7- mcthylatcd guanosine, e.g., linked to the 5’ end of the RNA, e.g., via a reverse 5' to 5' triphosphate linkage. The method of any of embodiments 399-412, wherein the nucleic acid comprises a 5’ UTR. The method of any of embodiments 399-413, wherein the nucleic acid comprises a Kozak sequence, e.g., between the 5’ UTR and the sequence encoding the expression repressor. Tire method of any one of embodiments 121-398, wherein the first nucleic acid has a nucleotide sequence of SEQ ID NO: 63 or 130. or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18. 17. 16, 15, 14, 13, 12, 11, 10. 9, 8, 7. 6, 5, 4, 3, 2, or 1 positions of difference thereto, and the second nucleic acid having a nucleotide sequence of SEQ ID NO: 57, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto. The method of embodiment 414, wherein the first nucleic acid has a nucleotide sequence of SEQ ID NO: 63 or 130, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto, and the second nucleic acid having a nucleotide sequence of SEQ ID NO: 189 or 194, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto. The method of embodiment 416, wherein the first nucleic acid has a nucleotide sequence of SEQ ID NO: 189 or 194, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto, and the second nucleic acid having a nucleotide sequence of SEQ ID NO: 63 or 130, or a sequence with at least 80, 85, 90, 95, or 99% identity thereto, or a sequence with no more than 20, 19, 18, 17, 16, 15, 14, 13. 12. 11, 10, 9. 8, 7, 6, 5. 4, 3, 2, or 1 positions of difference thereto. The method of any of embodiments 399-417, wherein the nucleic acid comprises mRNA. The method of any of the preceding embodiments, which comprises a lipid nanoparticle.

[1349] 420. The lipid nanoparticle or method of any of the preceding embodiments, wherein the first compound has a general structure of formula (III):

[1350] Formula (III): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein L1and L2are each independently -(C=O)O- or -O(C=O)-;

[1351] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[1352] R3occurs once and is H, OR5, CN, -C(=O)OR4, -OC(=O)R4or -NR5C(=O)R4;

[1353] R4is C1 -C12 alkyl;

[1354] R5is H or C1-C6 alkyl;

[1355] R8occurs n times and is, at each occurrence, independently H, OH or Ci-C24 alkyl; n is an integer ranging from 1 to 15; and m and 1 are each independently integers ranging from 1 to 12.

[1356] 421. Tire lipid nanoparticlc or method of any of the preceding embodiments, wherein the first compound has a general structure of formula (IV):

[1357] Formula (IV): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1and R2are each independently Cg-C24 alkyl or C6-C24 alkenyl;

[1358] R3is H, OR5, CN, -C(~O)OR4. -OC(=O)R4or -NR5C(=O)R4;

[1359] R4is C1 -C12 alkyl;

[1360] R5is H or C1-C6 alkyl;

[1361] R8is H, OH or C1-C24 alkyl: n is an integer ranging from 1 to 15; and m and 1 are each independently integers ranging from 1 to 12.

[1362] 422. The lipid nanoparticle or method of any of the preceding embodiments, wherein the first compound comprises any of the following:

[1363] 

[1364] 

[1365] 423. The lipid nanoparticle or method of any of the preceding embodiments, wherein the first compound comprises: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1366] 424. The method of any one of embodiments 1-419, wherein the first compound comprises a compound having a general structure of Formula (IX):

[1367] Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[1368] L1and L2are each independently -O(C=O)-, -(C=O)O-_ -C(=O)-, -O-. -S(O)X-, -S-S-, -C(=O)S-,

[1369] -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-,

[1370] -OC(=O)NRa-, -NRaC(=O)O- or a direct bond:

[1371] G1is Ci-C2alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[1372] G2is -C(=O)- , -(C=O)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[1373] G1is C1-C6 alkylene;

[1374] Rais H or C1-C12 alkyl;

[1375] Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[1376] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[1377] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[1378] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;

[1379] R5and R6are each independently H or methyl:

[1380] R7is C4-C20 alkyl;

[1381] R8and R9are each independently C1-C12 alkyl; or R8and R9, together with the nitrogen atom to which they are attached, fonn a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2.

[1382] 425. Tire method of any one of embodiments 1-419, wherein the first compound comprises a compound having a general structure of Formula (XI):

[1383] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[1384] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[1385] R2and R3are each independently optionally substituted C1-C36 alkyl;

[1386] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[1387] L1, L2, and L3are each independently optionally substituted Ci-Cis alkylene;

[1388] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or -(C=O)-;

[1389] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0.

[1390] 426. The lipid nanoparticle or composition of any of the preceding embodiments, wherein the second compound comprises any of the following: , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein n has mean value ranging from 30 to 60. 427. The lipid nanoparticle or composition of any of the preceding embodiments, wherein the second compound comprises

[1391] , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. 428. The lipid nanoparticle or composition of any of the preceding embodiments, wherein stereoisomer thereof; and the second compound comprises: , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1392] 429. Tire lipid nanoparticle or composition of the disclosure, wherein the first compound comprises: , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and the second compound comprises:

[1393] , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. 430. The lipid nanoparticle or composition of the disclosure, wherein the first compound comprises: pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and the second compound comprises:

[1394] , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1395] 431. The lipid nanoparticle or composition of the disclosure, which comprises (e.g., as the ionizable lipid): , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and the second compound comprises:

[1396] , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1397] 432. The lipid nanoparticle or composition of tire disclosure, which comprises (e.g., as the ionizable lipid): , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and the second compound comprises:

[1398] , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1399] 433. Tire lipid nanoparticlc or composition of any of the preceding embodiments, wherein the neutral lipid (e.g.. phosphatidylcholine) comprises Distearoylphosphatidylcholine (DSPC) (Fonnula V):

[1400] Formula V; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1401] 434. The lipid nanoparticle or composition of any of the preceding embodiments, wherein the steroid (e.g., sterol, e.g., cholesterol) comprises cholesterol (Formula VI):

[1402] Formula VI; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1403] 435. Tire lipid nanoparticle or composition of any of the preceding embodiments, wherein: stereoisomer thereof; and the second compound comprises:

[1404] , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; the neutral lipid (c.g., phosphatidylcholine) comprises Distcaroylphosphatidylcholinc (DSPC) (Fonnula V):

[1405] Formula V; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and the steroid (e.g., sterol, e.g., cholesterol) comprises a cholesterol (Formula VI):

[1406] Formula VI; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1407] 436. The lipid nanoparticle or composition of any of the preceding embodiments, wherein: the first compound comprises: pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and the second compound comprises:

[1408] , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; the neutral lipid (e.g., phosphatidylcholine) comprises Distcaroylphosphatidylcholinc (DSPC) (Fonnula V):

[1409] Formula V; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and the steroid (e.g., sterol, e.g., cholesterol) comprises cholesterol (Formula VI):

[1410] Formula VI; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1411] 437. The lipid nanoparticle or composition of any of the preceding embodiments, wherein: the first compound comprises: pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and the second compound comprises:

[1412] , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; the neutral lipid (e.g., phosphatidylcholine) comprises Distearoylphosphatidylcholme (DSPC) (Formula V):

[1413] Formula V: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and the steroid (e.g., sterol, e.g., cholesterol) comprises cholesterol (Formula VI):

[1414] Formula VI; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1415] 438. The lipid nanoparticle or composition of any of the preceding embodiments, which: comprises (e.g., as the ionizable lipid): pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and the second compound comprises:

[1416] . or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; the neutral lipid (e.g., phosphatidylcholine) comprises Distearoylphosphatidylcholine (DSPC) (Formula V):

[1417] Formula V; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and the steroid (e.g., sterol, e.g., cholesterol) comprises cholesterol (Formula VI):

[1418] Formula VI; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1419] 439. Tire lipid nanoparticle or composition of any of the preceding embodiments, which comprises (e.g., as the ionizable lipid): , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and the second compound comprises:

[1420] , or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; the neutral lipid (e.g., phosphatidylcholine) comprises Di stearoylphosphatidylcholine (DSPC) (Formula V):

[1421] Formula V; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and the steroid (e.g., sterol, e.g., cholesterol) comprises cholesterol (Formula VI):

[1422] Formula VI; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1423] 440. The lipid nanoparticle or composition of any of the preceding embodiments, wherein the molar ratio of (i) : (ii) : (iii) : (iv) is (47.5 ± 20%) : (2.5 ± 20%) : (10 ± 20%) : (40 ± 20%).

[1424] 441. The lipid nanoparticle or composition of any of the preceding embodiments, wherein the molar ratio of (i) : (ii) : (iii) : (iv) is (47.5 ± 10%) : (2.5 ± 10%) : (10 ± 10%) : (40 ± 10%).

[1425] 442. The lipid nanoparticle or composition of any of the preceding embodiments, wherein the molar ratio of (i) : (ii) : (iii) : (iv) is (47.5 ± 5%) : (2.5 ± 5%) : (10 ± 5%) : (40 ± 5%).

[1426] 443. The lipid nanoparticle or composition of any of the preceding embodiments, wherein the molar ratio of (i) : (ii) : (iii) : (iv) is any of the following:

[1427] (38-57) : (2-3) : (8-12) : (32-48);

[1428] (42.75-52.25) : (2.25-2.75) : (9-11) : (36-44);

[1429] (45.125-49.875) : (2.375-2.625) : (9.5-10.5) : (38-42): or

[1430] 47.5 : 2.5 : 10 : 40.

[1431] 444. The lipid nanoparticle or composition of any of the preceding embodiments, wherein the molar ratio of (i) : (ii) : (iii) : (iv) is about 47.5 : 2.5 : 10 : 40.

[1432] 445. The lipid nanoparticle or composition of any of the preceding embodiments, wherein one or more of: the first compound comprises about 47.5 molar % of the sum of (i), (ii), (iii), and (iv); the second compound comprises about 2.5 molar % of the sum of (i), (ii), (iii), and (iv); the neutral lipid, such as phosphatidylcholine, or pharmaceutically acceptable salt, tautomer or stereoisomer thereof comprises about 10 molar % of the sum of (i), (ii), (iii), and (iv); and the steroid (e.g., sterol, e.g., cholesterol) or pharmaceutically acceptable salt, tautomer or stereoisomer thereof comprises about 40 molar % of the sum of (i). (ii). (iii), and (iv), wherein the first compound, the second compound, the neutral lipid, such as phosphatidylcholine, or pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and the steroid (e.g., sterol, e.g., cholesterol) or pharmaceutically acceptable salt, tautomer or stereoisomer thereof comprise 100 molar % of the sum of (i), (ii), (iii), and (iv). 446. The lipid nanoparticle of any of the preceding embodiments, wherein the nucleic acid is encapsulated within the LNP.

[1433] 447. Tire method of any of the preceding embodiments, which comprises reducing tumor growth.

[1434] 448. Tire method of embodiment447, w herein the reduction in tumor growth comprises reduction of tumor volume compared to tumor volume at the start of treatment.

[1435] 449. The method of embodiment 448, wherein the reduction in tumor growth in the subject is greater compared to an untreated subject.

[1436] 450. The method of any of the preceding embodiments, which comprises delivering the expression repressor expression repressor to the liver of a subject.

[1437] 451. Tire method of embodiment 450, wherein the expression repressor is administered parenterally, e.g.. by intravenous administration.

[1438] 452. The method of any of the preceding embodiments, wherein the cancer is stage I, stage II, stage III, or stage IV cancer.

[1439] 453. The method of any of preceding embodiments, wherein the subject’s body weight remains about the same before treatment and post-treatment.

[1440] 454. The method of any of preceding embodiments, wherein the subject does not experience a decrease in body weight, or wherein the subject experiences a decrease in body weight of less than 3%, 2%, or 1% compared to at the start of treatment.

[1441] 455. The method of any of the preceding embodiments, wherein the subject does not experience a reduction or gain in body weight post-treatment compared to the subject’s body weight before the treatment.

[1442] 456. A method of treating a liver disease in a subject in need thereof, the method comprising: administering to the subject:

[1443] (A) a composition comprising:

[1444] (1) a first nucleic acid encoding an expression repressor: and

[1445] (2) a formulation comprising one or both of (i) and (ii) and optionally further comprising one or both of (iii) and (iv) (e.g., comprising all of (i)-(iv)):

[1446] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[1447] (i'j a compound having a general structure of formula (I):

[1448] Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (I):

[1449] L1and I? are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;

[1450] G1and G2are each independently unsubstituted C1-C12 alkylene, or C2-C12 alkenylene;

[1451] G3is C1-C24 alkylene, C2-C24 alkenylene, Ci-Cs cycloalkylene, or C3-C8 cycloalkenylene;

[1452] Rais H or C1-C12 alkyl;

[1453] R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;

[1454] R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;

[1455] R4is C1-C12 alkyl;

[1456] R5is H or C1-C6 alkyl;

[1457] R11and R12are each independently C1-C12 alkyl or -G4-OR5. or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;

[1458] G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[1459] (i") a compound having a general structure of Formula (IX):

[1460] Fonnula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX): L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O- or a direct bond;

[1461] G1is C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NRaC(=O)- or a direct bond;

[1462] G2is -C(=O)- , -(C=O)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;

[1463] G3is C1-C6 alkylene;

[1464] Rais H or C1 -C12 alkyl; Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;

[1465] R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to fonn a carbon-carbon double bond;

[1466] R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;

[1467] R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;

[1468] R5and Rbare each independently H or methyl;

[1469] R7is C4-C20 alkyl;

[1470] R8and R9are each independently C1-C12 alkyl; or R8and R9, together with the nitrogen atom to which they are attached, fomi a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0. 1 or 2; and,

[1471] (i'") a compound having a general structure of Formula (XI):

[1472] Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein for Formula (XI):

[1473] R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;

[1474] R2and R3are each independently optionally substituted C1 -C36 alkyl;

[1475] R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;

[1476] L1, L2, and L3are each independently optionally substituted C1 -C18 alkylene;

[1477] G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or-(C=O)-;

[1478] G2and G3are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0;

[1479] (ii) a second compound having a general structure of formula (II):

[1480] Formula (II): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (II):

[1481] R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms (e.g., from 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60;

[1482] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1483] (iv) a steroid (e.g., sterol, e.g., cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and wherein the expression repressor comprises targeting moiety that binds a MYC locus (e.g., a transcribed region of MYC, a MYC promoter, or an anchor sequence of an anchor sequence mediated conjunction (ASMC) comprising a MYC gene or to a sequence proximal to the anchor sequence), and optionally , an effector moiety, e.g., an effector moiety described herein; and

[1484] (B) a compound having the general structure of Formula (Al): wherein:

[1485] R1is alkyl, cycloalkyl, or aryl;

[1486] R2is halo, alkyl, or H; R3, R4, R5, R6, R7, are each independently H or alkyl; and

[1487] R8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; thereby treating the liver disease in the subject.

[1488] 457. The method of embodiment 456, which further comprises administering to tire subject a second nucleic acid encoding a second expression repressor, the second expression repressor comprising a targeting moiety that binds to an anchor sequence of an anchor sequence mediated conjunction (ASMC) comprising a target gene, e.g., MYC, and optionally, a second effector moiety, e.g., an effector moiety described herein; e.g., KRAB; thereby treating the liver disease in the subject.

[1489] 458. The method of embodiment 456 or 457, wherein the first nucleic acid and the second nucleic acid are located within the same nucleic acid molecule.

[1490] 459. The method of any of embodiment 456-458, wherein the liver disease is a chronic liver disease.

[1491] 460. The method of any of embodiments 456-459, wherein the liver disease is viral or alcohol related.

[1492] 461. Tire method of any of embodiments 456-460, wherein the liver disease is hepatitis or hepatocellular carcinoma.

[1493] 462. The method of any of the preceding embodiments, wherein the cancer is a hepatocellular carcinoma selected from HCC subtype SI, HCC subtype S2, or HCC subtype S3.

[1494] 463. The method of any of the preceding embodiments, wherein the hepatocellular carcinoma is HCC

[1495] 51.

[1496] 464. Tire method of any of the preceding embodiments, wherein the hepatocellular carcinoma is HCC

[1497] 52.

[1498] 465. The method of any of embodiments 456-464, wherein the liver disease is caused by a hepatitis B virus or hepatitis C virus.

[1499] 466. The method of any of the preceding embodiments, wherein contacting or administering comprises intravenous administration to a subject.

[1500] 467. Tire method of any of the preceding embodiments, wherein contacting or administering comprises intra-tumoral delivery (e.g., injection).

[1501] 468. The method of any of the preceding embodiments, wherein the cancer is characterized by increased MYC expression relative to a reference level (e.g., relative to a reference cell’s MYC expression, e g., an otherwise similar non-cancerous cell of the subject).

[1502] 469. The method of any of the preceding embodiments, wherein the cancer is characterized by duplication of a portion of or all of a MYC gene. The method of any of the preceding embodiments, wherein the cancer is selected from colorectal cancer, breast cancer, AML, prostate cancer, neuroblastoma, endometrial cancer, liver cancer, a lymphoma (e.g., Burkitt lymphoma), carcinoma of the cervix, or stomach cancer. Tire method of any of the preceding embodiments, wherein the cancer is a human chorionic gonadotropin (hCG) secreting cancer. The method of any of the preceding embodiments, wherein the cancer is hepatocarcinoma. The method of any of the preceding embodiments, wherein the cancer is a non-responsive cancer, e.g., a non-responsive hepatocarcinoma. Tire method of any of the preceding embodiments, wherein the cancer over-expresses alphafetoprotein (AFP) (e.g., relative to a reference cell’s AFP expression, e.g., an otherwise similar non-cancerous cell of the subject). The method of any of the preceding embodiments, wherein cells of the cancer are characterized by the presence of a super enhancer, e.g., comprising the MYC gene or comprising the anchorsequence mediated conjunction comprising the MYC gene, wherein optionally the cancer is selected from liver cancer, colorectal cancer, breast cancer, AML, prostate cancer, neuroblastoma, or endometrial cancer. The method of embodiment 474, wherein the expression repressor (e.g.. the second expression repressor) binds to an anchor sequence of an anchor sequence mediated conjunction (ASMC) comprising a MYC gene or to a sequence proximal to the anchor sequence. The method of any of the preceding embodiments, wherein cells of the cancer are characterized by the absence of a super enhancer comprising the MY C gene or comprising the anchor-sequence mediated conjunction comprising the MYC gene. The method of embodiment 477, wherein the expression repressor (e.g.. the first expression repressor) binds the MYC promoter. The method of any of the preceding embodiments, wherein the cancer comprises cells comprising a super enhancer comprising the MY C gene or comprising the anchor-sequence mediated conjunction comprising the MYC gene, and cells not comprising a super enhancer comprising the MYC gene or comprising the anchor-sequence mediated conjunction comprising tire MYC gene. The method of any of the preceding embodiments, wherein the cancer comprises cells characterized by increased MYC expression relative to a reference level (e.g.. relative to a reference cell’s MYC expression, e.g., an otherwise similar non-cancerous cell of the subject), and cells not characterized by increased MYC expression relative to a reference level (e.g., relative to a reference cell’s MYC expression, e.g., an otherwise similar non-canccrous cell of the subject), e.g., having normal MYC expression. 481. The method of any of the preceding embodiments, which comprises administering a plurality of doses of the composition, lipid nanoparticle, or a pharmaceutical composition to the subject, e.g., at least 2, 3, 4, 5, or 6 doses.

[1503] 482. Tire method of any of the preceding embodiments, which comprises administering a plurality of doses of the composition, lipid nanoparticle, or a pharmacal composition to the subject in 5 day intervals.

[1504] 483. The method of any of the preceding embodiments, comprising: a) first, administering to the subject a first plurality of doses of a composition described herein (e.g., of any of embodiments 1-446), wherein optionally each subsequent dose in the first plurality is administered 5 days after the previous dose in the first plurality; b) second, withdrawing the composition for a period of time (a “‘drug holiday"), e g., for about 2 weeks), and c) third, administering to the subject a second plurality of doses of the composition, wherein optionally a subsequent dose of the second plurality is administered 5 days after the previous dose in the second plurality.

[1505] 484. The method of embodiment 483, wherein the first plurality of doses comprises 4 doses.

[1506] 485. The method of embodiment 482 or 483, wherein the second plurality of doses comprises 2 doses.

[1507] 485. The method of any of embodiments 483-485, wherein the subject receives no therapeutic at all during the drug holiday.

[1508] 486. The method of any of embodiments 483-485, wherein tire subject receives a second therapeutic agent during the drug holiday.

[1509] 487. The method of any of embodiments 483-486, wherein the drug holiday is at least twice as long as the time between administration of doses in the first plurality of doses.

[1510] 488. The method of any of embodiments 483-487, wherein the drug holiday is at least twice as long as the time between administration of doses in the second plurality of doses.

[1511] 489. The method of any of the preceding embodiments, wherein volume of tire cancer’s tumor declines to undetectable levels following treatment with the composition.

[1512] 490. The method of any of the preceding embodiments, wherein the cancer’s tumor volume declines (e.g., to undetectable levels) after cessation of treatment with the composition.

[1513] 491. The method of any of the preceding embodiments, wherein the cancer does not become resistant to the composition, or does not become resistant to the composition within a period of 10, 20, 30, 40, 50, or 60 days.

[1514] 492. Tire method of any of the preceding embodiments, wherein the cancer cells have a functional apop to tic pathway. 493. The method of any of the preceding embodiments, wherein the cancer cells have functional Caspase 3.

[1515] 494. Tire method of embodiment 493, wherein Caspase 3 is upregulated in cancer cells upon administration of the composition to the subject.

[1516] 495. The method of any of the preceding embodiments, wherein Ki67 is downregulated in the cancer cells upon administration of the composition to the subject.

[1517] 496. The method of any of the preceding embodiments, wherein cancer cell proliferation declines upon administration of the composition to the subject.

[1518] 497. Tire method of any of embodiments 1-496, wherein the composition and the compound of (B) are administered concurrently.

[1519] 498. The method of any of embodiments 1-496, wherein the composition and the compound of (B) are administered sequentially.

[1520] 499. The method of any of embodiments 1-496, wherein compound (B) is administered concurrently.

[1521] 500. The method of any of embodiments 1-496, wherein compound (B) is administered sequentially.

[1522] 501. Tire method of any of the preceding embodiments, wherein compound (B) is administered simultaneously with the composition.

[1523] 502. The method of any of the preceding embodiments, wherein compound (B) is administered consecutively with the composition.

[1524] 503. The method of any of the preceding embodiments, wherein the composition is administered intravenously, and compound (B) is administered orally.

[1525] 504. Tire method of any of the preceding embodiments, wherein the cancer is a resistant or refractor}' cancer.

[1526] 505. The method of any of the preceding embodiments, wherein the cancer is resistant or refractory to a kinase inhibitor, e.g., a kinase inhibitor that inhibits one or more of VEGFR, PDGFR. or RAF kinase, e g., sorafenib.

[1527] 506. The method of any of the preceding embodiments, wherein the subject has an amplification in the MY C super-enhancer.

[1528] 507. The method of any preceding embodiments, wherein Formula (Al) R1is alkyl or cycloalkyl.

[1529] 508. The method of any preceding embodiments, wherein Formula (Al) R1= cyclopropane.

[1530] 509. The method of any of embodiments 1-507, wherein Fonnula (Al) R1= and.

[1531] 510. The method of any preceding embodiments, wherein Formula (Al) R2is halo.

[1532] 511. The method of any preceding embodiments, wherein Formula (Al) R2= Cl.

[1533] 512. Tire method of any of embodiments 1-509, wherein Formula (Al) R2= H.

[1534] 513. The method of any preceding embodiments, wherein Formula (Al) R\ R4, R5, R6, R7, are each H. The method of any preceding embodiments, wherein R8is CH3NHCO- and R9is H. The method of any of embodiments 1-513, wherein Rsand R9together form an optionally substituted aromatic ring. Tire method of any of embodiments 1-513, wherein the Fonnula (Al) substituted aromatic ring is a substituted phenyl ring. The method of any of embodiments 1-516, wherein the compound of Formula (Al) comprises: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. The method of any of embodiments 1-517, wherein Formula (Al) R1is optionally substituted aryl.

[1535] H. The method of any of embodiments 1-506 or 518-520, wherein the compound of Formula (Al) compnses: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1536] 522. The method of any of embodiments 1-521, wherein the compound of Formula (Al) is administered orally.

[1537] 523. Tire method of any of embodiments 1-522, wherein the compound of Fonnula (Al) is administered at a dose of 6-10 (e.g., about 8), 10-14 (e.g., about 12), or about 8-26 (e.g., about 24) mg per day.

[1538] 524. The method of any of embodiments 2-522, wherein the compound of Formula (Al) is administered at a dose of 300-500 (e.g., about 400) mg per day.

[1539] 525. Tire method of any of embodiments 2-522, wherein the compound of Fonnula (Al) is administered at a dose of 300-500 (e.g., about 400) mg per day.

[1540] DEFINITIONS

[1541] A, an, the. As used herein, the singular forms '‘a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[1542] Agent: As used herein, the temi “agent”, may be used to refer to a compound or entity of any chemical class including, for example, a polypeptide, nucleic acid, saccharide, lipid, small molecule, metal, or combination or complex thereof. As will be clear from context to those skilled in the art, in some embodiments, the term may be utilized to refer to an entity that is or comprises a cell or organism, or a fraction, extract, or component thereof. Alternatively, or additionally, as those skilled in the art will understand in light of context, in some embodiments, the term may be used to refer to a natural product in that it is found in and / or is obtained from nature. In some embodiments, again as will be understood by those skilled in the art in light of context, the term may be used to refer to one or more entities that is man-made in that it is designed, engineered, and / or produced through action of the hand of man and / or is not found in nature. In some embodiments, an agent may be utilized in isolated or pure form: in some embodiments, an agent may be utilized in crude form. In some embodiments, potential agents may be provided as collections or libraries, for example that may be screened to identify or characterize active agents within them. In some embodiments, the term “agent” may refer to a compound or entity that is or comprises a polymer; in some embodiments, the term may refer to a compound or entity that comprises one or more polymeric moieties. In some embodiments, the term “agent” may refer to a compound or entity that is not a polymer and / or is substantially free of any polymer and / or of one or more particular polymeric moieties. In some embodiments, the term may refer to a compound or entity that lacks or is substantially free of any polymeric moiety.

[1543] Anchor Sequence: The term “anchor sequence” as used herein, refers to a nucleic acid sequence recognized by a nucleating agent that binds sufficiently to form an anchor sequence -mediated conjunction, e.g., a complex. In some embodiments, an anchor sequence comprises one or more CTCF binding motifs. In some embodiments, an anchor sequence is not located within a gene coding region. In some embodiments, an anchor sequence is located within an intergenic region. In some embodiments, an anchor sequence is not located within either of an enhancer or a promoter. In some embodiments, an anchor sequence is located at least 400 bp, at least 450 bp. at least 500 bp. at least 550 bp, at least 600 bp, at least 650 bp, at least 700 bp, at least 750 bp, at least 800 bp, at least 850 bp. at least 900 bp. at least 950 bp, or at least Ikb away from any transcription start site. In some embodiments, an anchor sequence is located within a region that is not associated with genomic imprinting, monoallelic expression, and / or monoallelic epigenetic marks. In some embodiments, the anchor sequence has one or more functions selected from binding an endogenous nucleating polypeptide (e.g., CTCF), interacting with a second anchor sequence to form an anchor sequence mediated conjunction, or insulating against an enhancer that is outside the anchor sequence mediated conjunction. In some embodiments of the present disclosure, technologies are provided that may specifically target a particular anchor sequence or anchor sequences, without targeting other anchor sequences (e.g., sequences that may contain a nucleating agent (e.g., CTCF) binding motif in a different context); such targeted anchor sequences may be referred to as the "target anchor sequence". In some embodiments, sequence and / or activity of a target anchor sequence is modulated while sequence and / or activity of one or more other anchor sequences that may be present in the same system (e.g.. in the same cell and / or in some embodiments on the same nucleic acid molecule - e.g., the same chromosome) as the targeted anchor sequence is not modulated. In some embodiments, the anchor sequence comprises or is a nucleating polypeptide binding motif. In some embodiments, the anchor sequence is adjacent to a nucleating polypeptide binding motif.

[1544] Anchor Sequence-Mediated Conjunction: The term “anchor sequence-mediated conjunction” as used herein, refers to a DNA structure, in some cases, a complex, that occurs and / or is maintained via physical interaction or binding of at least two anchor sequences in the DNA by one or more polypeptides, such as nucleating polypeptides, or one or more proteins and / or a nucleic acid entity’ (such as RNA or DNA), that bind the anchor sequences to enable spatial proximity and functional linkage between the anchor sequences.

[1545] Associated with: Two events or entities are “associated” with one another, as that term is used herein, if presence, level, form and / or function of one is correlated with that of the other. For example, in some embodiments, a particular entity (e.g.. polypeptide, genetic signature, metabolite, microbe, etc.) is considered to be associated with a particular disease, disorder, or condition, if its presence, level, form and / or function correlates with incidence of and / or susceptibility to the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities arc physically “associated” with one another if they interact, directly or indirectly, so that they are and / or remain in physical proximity with one another. In some embodiments, two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another but are non-covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof. In some embodiments, a DNA sequence is "‘associated with" a target genomic or transcription complex when the nucleic acid is at least partially within the target genomic or transcription complex, and expression of a gene in the DNA sequence is affected by formation or disruption of the target genomic or transcription complex.

[1546] Biologically Active portion of an effector domain'. As used herein, a “biologically active portion of an effector domain” is a portion that maintains function (e.g., completely, partially, minimally) of an effector domain (e.g., a “minimal” or “core” domain).

[1547] Domain: As used herein, the term “domain” refers to a section or portion of an entity. In some embodiments, a “domain” is associated with a particular structural and / or functional feature of the entity so that, when the domain is physically separated from the rest of its parent entity, it substantially or entirely retains the particular structural and / or functional feature. Alternatively or additionally, in some embodiments, a domain may be or include a portion of an entity that, when separated from that (parent) entity and linked with a different (recipient) entity, substantially retains and / or imparts on the recipient entity one or more structural and / or functional features that characterized it in the parent entity. In some embodiments, a domain is or comprises a section or portion of a molecule (e.g., a small molecule, carbohydrate, lipid, nucleic acid, polypeptide, etc.). In some embodiments, a domain is or comprises a section of a polypeptide. In some such embodiments, a domain is characterized by a particular structural element (e.g., a particular amino acid sequence or sequence motif, alpha-helix character, beta-sheet character, coiled-coil character, random coil character, etc.), and / or by a particular functional feature (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.).

[1548] Effector moiety: As used herein, the term “effector moiety” refers to a domain that is capable of altering the expression of a target gene when localized to an appropriate site in the nucleus of a cell. In some embodiments, an effector moiety recruits components of the transcription machinery'. In some embodiments, an effector moiety inhibits recruitment of components of transcription factors or expression repressing factors. In some embodiments, an effector moiety comprises an epigenetic modifying moiety (e.g., epigenetically modifies a target DNA sequence).

[1549] Epigenetic modifying moiety: As used herein, “epigenetic modifying moiety” refers to a domain that alters: i) the structure, e.g., two dimensional structure, of chromatin; and / or ii) an epigenetic marker (e.g., one or more of DNA methylation, histone methylation, histone acetylation, histone sumoylation, histone phosphorylation, and RNA-associated silencing), when the epigenetic modifying moiety is appropriately localized to a nucleic acid (e.g., by a targeting moiety). In some embodiments, an epigenetic modifying moiety comprises an enzyme, or a functional fragment or variant thereof, that affects (e.g., increases or decreases the level of) one or more epigenetic markers. In some embodiments, an epigenetic modifying moiety comprises a DNA methyltransferase, a histone methyltransferase, CREB-binding protein (CBP). or a functional fragment of any thereof.

[1550] Expression control sequence: As used herein, the term “expression control sequence'’ refers to a nucleic acid sequence that increases or decreases transcription of a gene and includes (but is not limited to) a promoter and an enhancer. An “enhancing sequence” refers to a subtype of expression control sequence and increases the likelihood of gene transcription. A “silencing or repressor sequence” refers to a subtype of expression control sequence and decreases the likelihood of gene transcription.

[1551] Expression repressor: As used herein, tire term “expression repressor” refers to an agent or entity with one or more functionalities that decreases expression of a target gene in a cell and that specifically binds to a DNA sequence (e.g., a DNA sequence associated with a target gene or a transcription control element operably linked to a target gene). An expression repressor comprises at least one targeting moiety and optionally one effector moiety.

[1552] Expression repression system: As used herein, the term “expression repression system” refers to a plurality of expression represso...

Claims

CLAIMSWe claim:

1. A method of treating a cancer in a subject in need thereof, tire method comprising administering to the subject:(A) a composition comprising:(1) a nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein tire expression repressor comprises:(a) a targeting moiety that binds to a MYC promoter, and(b) optionally, an effector moiety, wherein the expression repressor is capable of decreasing expression of MYC; and(2) a fonnulation comprising one or both of:(i) a first compound having a general structure of formula (I):R3X33Formula (T); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein L1and L2arc each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, - C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;G1and G2are each independently unsubstituted C1-C12 alkylene or C2-C12 alkenylene;G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene;Rais H or C1-C12 alkyl;R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;R4is C1-C12 alkyl;R5is H or C1-C6 alkyl;R11and R12are each independently C1-C12 alkyl or -G4-OR5, or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2; and(ii) a second compound having a general structure of formula (II):Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60; and(B) a compound having the general structure of Formula (Al):R1is alkyl, cycloalkyl, or aryl;R2is halo, alkyl, or H;R3, R4, R5, Rb, R7, are each independently H or alkyl; andR8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

2. The method of claim 1, wherein the composition comprises (i).

3. The method of claim 1 or 2, wherein the composition comprises (ii).

4. The method of any of claims 1-3, wherein the composition comprises:(iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

5. The method of any of claims 1-4, wherein the composition comprises:(iv) a sterol, such as cholesterol or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

6. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(A) a composition comprising:(1) a nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein tire expression repressor comprises:(a) a first targeting moiety that binds a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs: 83, 75-86, 190-192, or 199-202, or SEQ ID NOs:

2. 3, 97-107, 109, or 110 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, and(b) optionally, a first effector moiety. wherein the expression repressor is capable of decreasing expression of MYC; and(2) a formulation comprising one or both of:(i) a first compound having a general structure of formula (I):R3X33.L1.R1731732Formula (I); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, - C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa-, -NRaC(=O)O-, or a direct bond;G1and G2are each independently unsubstituted C1-C12 alkylene or C2-C12 alkenylene;G3is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene;Rais H or C1 -C12 alkyl;R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4, -NRnR12, or -NR5C(=O)R4;R4is C1-C12 alkyl;R5is H or C1-C6 alkyl;R11and R12are each independently C1-C12 alkyl or -G4-OR5, or R11and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;G4is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2; and(ii) a second compound having a general structure of formula (II):Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60; and(B) a compound having the general structure of Formula (Al):R1is alkyl, cycloalkyl, or aryl;R2is halo, alkyl, or H;R3, R4, R5, R6, R7, are each independently H or alkyl; andR8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

7. The method of claim 6, wherein the composition comprises (i).

8. Tire method of claim 6 or 7, wherein the composition comprises (ii).

9. The method of any of claims 6-8, wherein the composition comprises:(iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

10. Tire method of any of claims 6-9, wherein the composition comprises:(iv) a sterol, such as cholesterol, or a pharmacally acceptable salt, tautomer or stereoisomer thereof.

11. The method of any of the preceding claims, wherein the first compound has a general structure of formula (III):Formula (III); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein L1and L2are each independently -(C=O)O- or -O(C=O)-;R1and R2arc each independently C6-C24 alkyl or C6-C24 alkenyl;R3occurs once and is H, OR5, CN, -C(=O)OR4, -OC(=O)R4or -NR5C(=O)R4;R4is C1-C12 alkyl;R is H or C1-C6 alkyl;R8occurs n times and is, at each occurrence, independently H, OH or C1-C24 alkyl; n is an integer ranging from 1 to 15; and m and 1 are each independently integers ranging from 1 to 12.

12. The method of any of claims 1-11, wherein the first compound has a general structure of formula (IV):Formula (IV); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1and R2are each independently C6-C24 alkyl or C6-C24 alkenyl;R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4or -NR5C(=O)R4;R4is C1-C12 alkyl;R5is H or C1-C6 alkyl;R8is H, OH or C1-C24 alkyl;11 is an integer ranging from 1 to 15; and m and 1 are each independently integers ranging from 1 to 12.

13. The method of any of claims 1-12, wherein the first compound comprises any of the following:or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

14. The method of any of claims 1-13, wherein the first compound comprises:

15. The method of any of claims 1-13, wherein the first compound comprises:

16. Tire method of any of claims 1-13, wherein the first compound comprisesor a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

17. The method of any of claims 1-16, wherein the second compound comprises any of the following:or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein n has mean value ranging from 30 to 60.

18. Tire method of any of claims 1-17, wherein the second compound comprises, or a pharmacally acceptable salt, tautomer or stereoisomer thereof.

19. The method of any of claims 1-18, wherein:stereoisomer thereof and the second compound comprises:, or a pharmacally acceptable salt, tautomer or stereoisomer thereof.

20. The method of any of claims 1-19, wherein the phosphatidylcholine comprises Distearoylphosphatidylcholine (DSPC) (Formula V):Formula V; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

21. The method of any of claims 1-20, wherein the sterol comprises cholesterol (Formula VI):Formula VI; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

22. Tire method of claims 1-21, the composition comprising: the first compound comprising:stereoisomer thereof; and the second compound comprising:, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; the neutral lipid (e g., phosphatidylcholine) comprising Distearoylphosphatidyl choline (DSPC) (Formula V):Formula V; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; andcholesterol (Formula VI):Formula VI; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

23. Tire method of any of claims 1-22, wherein the molar ratio of (i) : (ii) : (iii) : (iv) is any of the following:(38-57) : (2-3) : (8-12) : (32-48);(42.75-52.25) : (2.25-2.75) : (9-11) : (36-44);(45.125-49.875) : (2.375-2.625) : (9.5-10.5) : (38-42); or47.5 : 2.5 : 10 : 40.

24. The method of any of claims 1-22, wherein the molar ratio of (i) : (ii) : (iii) : (iv) is about 47.5 : 2.5 : 10 : 40.

25. The method of any of claims 1 -24, wherein one or more of: the first compound comprises about 47.5 molar % of the sum of (i), (ii), (iii), and (iv); the second compound comprises about 2.5 molar % of the sum of (i), (ii), (iii), and (iv); the phosphatidylcholine or pharmaceutically acceptable salt, tautomer or stereoisomer thereof comprises about 10 molar % of the sum of (i). (ii), (iii), and (iv); and the sterol or pharmaceutically acceptable salt, tautomer or stereoisomer thereof comprises about 40 molar % of the sum of (i), (ii), (iii), and (iv), wherein the first compound, the second compound, the phosphatidylcholine or pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and the sterol or phannaccutically acceptable salt, tautomer or stereoisomer thereof comprise 100 molar % of the sum of (i), (ii), (iii), and (iv).

26. The method of any of claims 1-25, wherein (1) and (2) form lipid nanoparticles (LNPs), wherein optionally the nucleic acid encapsulated within the LNPs.

27. The method of any of the preceding claims, wherein the fonnulation forms a lipid nanoparticle (LNP), and the nucleic acid is encapsulated within the LNP.

28. Tire method of any of claims 1-27, wherein the nucleic acid comprises an RNA, e.g., an mRNA.

29. The method of any of claims 1-28, which has an N:P ratio of between 3 and 22. between 4 and 12, between 4 and 8, between 5 and 9, between 5 and 7, between 5.5 and 6.5, between 6 and 9, between 7 and 9, between 6 and 8, about 5, about 6, about 7, or about 8.

30. Tire method of any of claims 6-29, wherein: the first targeting moiety binds a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 83, and the expression repressor comprises the first effector moiety, wherein the first effector moiety comprises a DNA methyltransferase.

31. The method of claim 30, wherein the first targeting moiety comprises a zinc finger domain.

32. The method of claim 30 or 31, wherein the first targeting moiety comprises an amino acid sequence according to SEQ ID NO: 13 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

33. The method of any of claims 30-32, wherein the first effector moiety comprises MQ1 or a functional variant or fragment thereof.

34. The method of any of claims 30-33, wherein the first effector moiety comprises a sequence of SEQ ID NO: 19 or 87, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

35. The method of any of claims 30-34, wherein the first effector moiety comprises a sequence of SEQ ID NO: 129, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

36. The method of any of claims 30-35, wherein the RNA comprises a nucleotide sequence encoding the first targeting moiety, wherein the nucleotide sequence encoding the first targeting moiety comprises a sequence according to SEQ ID NO: 131 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16. 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

37. The method of any of claims 30-36, wherein the RNA comprises a nucleotide sequence encoding the first effector moiety, wherein the nucleotide sequence encoding the first effector moiety' comprises a sequence according to SEQ ID NO: 132, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16. 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

38. The method of any of claims 30-37, wherein the RNA comprises a nucleotide sequence according to SEQ ID NO: 130, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4. 3, 2, or 1 positions of difference thereto.

39. The method of any of claims 30-38, wherein the RNA further encodes a second expression repressor, wherein the second expression repressor comprises: a second targeting moiety that binds a second genomic locus, and a second effector moiety.

40. The method of claim 39, wherein the second targeting moiety binds a second genomic locus comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 77.

41. Tire method of claim 39 or 40, wherein the second targeting moiety comprises a zinc finger domain.

42. The method of any of claims 39-41. wherein the second targeting moiety comprises an amino acid sequence according to SEQ ID NO: 7, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.

43. The method of any of claims 39-42, wherein the second effector moiety comprises KRAB or a functional variant or fragment thereof.

44. Tire method of any of claims 39-43, wherein the second effector moiety comprises an amino acid sequence according to SEQ ID NO: 18, or a sequence with at least 80. 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16.

15. 14, 13, 12, 11, 10, 9, 8. 7, 6, 5, 4. 3, 2, or 1 positions of difference thereto.

45. Tire method of any of claims 39-44, wherein the second expression repressor comprises an amino acid sequence according to SEQ ID NO: 24 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15. 14, 13, 12, 11, 10, 9, 8. 7, 6, 5, 4. 3, 2, or 1 positions of difference thereto.

46. The method of any of claims 39-45, wherein the RNA comprises a nucleotide sequence according to SEQ ID NO: 113.

47. The method of any of claims 39-46, wherein contacting a plurality of cells with the composition decreases the viability of the plurality of cells.

48. The method of any of the preceding claims, wherein the cancer is a hepatocellular carcinoma (HCC), Fibrolamellar Hepatocellular Carcinoma (FHCC), Cholangiocarcinoma, Angiosarcoma, or secondary liver cancer.

49. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(A) composition comprising:(1) a nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein the expression repressor comprises:(a) a targeting moiety that binds to a MYC promoter or a genomic locus comprising at least 16, 17, 18.

19. or 20 nucleotides of the sequence of any of SEQ ID NOs:

83. 75-82, 84-86, 190-192, or 199-202, or SEQ ID NOs: 2, 3, 97-107, 109, or 110 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, and(b) optionally, an effector moiety,wherein the expression repressor is capable of decreasing expression of MYC; and (2) a formulation comprising one or both of:(i) a first compound having a general structure of formula (IX)Formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:L1and L2are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-,-S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-,-OC(=O)NRa-, -NRaC(=O)O- or a direct bond;G1is C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NRaC(=O)- or a direct bond;G2is -C(=O)- , -(OO)O-, -C(=O)S-, -C(=O)NRa- or a direct bond;G3is C1-C6 alkylene;Rais H or C1 -C12 alkyl;Rlaand Rlbare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) Rlais H or C1-C12 alkyl, and Rlbtogether with the carbon atom to which it is bound is taken together with an adjacent Rlband the carbon atom to which it is bound to form a carbon-carbon double bond;R2aand R2bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R2ais H or C1-C12 alkyl, and R2btogether with the carbon atom to which it is bound is taken together with an adjacent R2band the carbon atom to which it is bound to form a carbon-carbon double bond;R3aand R3bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R3ais H or C1-C12 alkyl, and R3btogether with the carbon atom to which it is bound is taken together with an adjacent R3band the carbon atom to which it is bound to form a carbon-carbon double bond;R4aand R4bare, at each occurrence, independently either: (a) H or C1-C12 alkyl; or (b) R4ais H or C1-C12 alkyl, and R4btogether with the carbon atom to which it is bound is taken together with an adjacent R4band the carbon atom to which it is bound to form a carbon-carbon double bond;R5and R6are each independently H or methyl;R7is C4-C20 alkyl;R8and R9are each independently C1-C12 alkyl; or Rsand R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; a, b, c and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and(ii) a second compound having a general structure of formula (II):Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R6and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60; and(B) a compound having the general structure of Formula (Al):R1is alkyl, cycloalkyl, or aryl;R2is halo, alkyl, or H;R3, R4, R5, R6. R7, are each independently H or alkyl; andR8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

50. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(A) a composition comprising:(1) a nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein the expression repressor comprises:(a) a targeting moiety that binds to a MYC promoter or a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs: 83, 75-82, 84-86, 190-192, or 199-202, or SEQ ID NOs: 2, 3, 97-107, 109, or 110 as described in International Application Publication WO / 2022 / 132195, which is herein incorporated by reference in its entirety, and(b) optionally, an effector moiety, wherein the expression repressor is capable of decreasing expression of MYC; and(2) a formulation comprising one or both of:(i) a first compound having a general structure of formula (XI)Formula (XI) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:R1is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;R2and R3are each independently optionally substituted C-Cv, alkyl;R4and R5are each independently optionally substituted C1-C6 alkyl, or R4and R5join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;L1, L2, and L3are each independently optionally substituted Ci-Cis alkylene:G1is a direct bond, -(CH2)nO(C=O)-, -(CH2)n(C=O)O-, or -(C=O)-;G2and G3are each independently -(C=O)O- or -O(C=O)-; and11 is an integer greater than 0; and(ii) a second compound having a general structure of formula (II):Formula (II); or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R and R7are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and y has mean value ranging from 30 to 60; and(B) a compound having the general structure of Formula (Al):R1is alkyl, cycloalkyl, or aryl;R2is halo, alkyl, or H;R3, R4, R5, R6, R7, are each independently H or alkyl; andR8and R9together form an optionally substituted aromatic ring, or R8is CH3NHCO- and R9is H; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

51. The method of any of claims 1-50, wherein Formula (Al) R1is alkyl or cycloalkyl.

52. The method of any of claims 1-50, wherein Formula (Al) R1= cyclopropane.The method of any of claims 1-50, wherein Formula (Al) R1= aryl.

54. The method of any of claims 1-53, wherein Formula (Al) R2is halo.

55. Tire method of any of claims 1-53, wherein Formula (Al) R2= Cl.

56. The method of any of claims 1-53, wherein Formula (Al) R2= H.

57. The method of any of claims 1-56, wherein Formula (Al) R3, R4, R5, R6, R7, are each H.

58. Tire method of any of the preceding claims, wherein R8and R9together fonn an optionally substituted aromatic ring.

59. The method of any of the preceding claims, wherein the Formula (Al) substituted aromatic ring is a substituted phenyl ring.

60. The method of any of the preceding claims, wherein the compound of Formula (Al) comprises:or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

61. The method of any of claims 1-50, wherein R8is CH3NHCO- and R9is H.

62. The method of any of claims 1-50 or 58, wherein Formula (Al) R1is optionally substituted aryl.

63. The method of any of claims 1-50, 61, or 62, wherein Formula (64. Tire method of any of claims 1-50 or 61-63, wherein Formula (Al) R2, R3, R4, R5, R6, R7, are eachH.

65. The method of any of claims 1-50 or 61-64, wherein the compound of Formula (Al) comprises:or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

66. The method of any of the preceding claims, wherein the compound of Formula (Al) is administered orally.

67. The method of any of the preceding claims, wherein the compound of Formula (Al) is administered at a dose of 6-10 (e.g., about 8), 10-14 (e.g., about 12), or about 8-26 (e.g., about 24) mg per day.

68. The method of any of claims 1-66, wherein the compound of Formula (Al) is administered at a dose of 300-500 (e.g., about 400) mg twice per day.

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