Formulations for modulating MYC expression

Abstract

The present disclosure relates to compositions and methods for reducing MYC gene expression in a cell. In some embodiments, the expression repressor comprises a targeting moiety that binds to an MYC promoter, an anchor sequence, or a super enhancer. In some embodiments, the expression repressor comprises an effector moiety that inhibits transcription or methylates DNA. Also disclosed are systems comprising two expression repressors. These compositions are useful, for example, in the treatment of cancer, such as HCC.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 366,833, filed on June 22, 2022, and U.S. Provisional Application No. 63 / 377,148, filed on September 26, 2022, the entire contents of which are incorporated herein by reference.

[0003] Sequence Listing

[0004] This application contains a sequence listing, which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy was created on June 19, 2023, is named O2057-7033WO_SL.xml, and is 344,197 bytes in size. Background Art

[0005] Misregulation of gene expression is the root cause of many diseases (e.g., mammals, such as humans), and these diseases are, for example, tumors, diseases of the nervous system, metabolic disorders and obesity. Misregulation of the transcription factor MYC plays a central role in a variety of human tumors and chronic liver diseases. Due to various factors, such as lack of a clear ligand binding site, lack of physiological functions necessary to maintain normal tissue, MYC protein is considered to be "undruggable". The technology of regulating MYC gene expression provides a feasible alternative for treating these diseases. New tools, systems and methods are needed to stably change (e.g., reduce) the expression of disease-associated genes (e.g., MYC). Summary of the Invention

[0006] Present disclosure especially provides therapeutic compositions, and this therapeutic composition includes the expression repressor and expression repressor system that can be used for regulating (for example, reducing) target gene (for example, MYC) expression encapsulated in lipid nanoparticle (LNP).In certain embodiments, LNP comprises one or more (for example, all) of ionizable lipid, PEGylated lipid, phosphatidylcholine and sterol.

[0007] In some aspects, the disclosure provides an expression repressor comprising a targeting moiety that binds to a target gene promoter (e.g., MYC promoter), and optionally an effector moiety, wherein the expression repressor is capable of reducing expression of the target gene (e.g., MYC).

[0008] In some aspects, the disclosure provides an expression repressor comprising: a targeting portion that binds to a target gene locus (e.g., MYC) and an effector portion comprising MQ1 or a fragment or variant thereof, wherein the expression repressor is capable of reducing expression of the target gene (e.g., MYC).

[0009] In some aspects, the disclosure provides an expression repressor comprising: a targeting portion that binds to a regulatory element located in a super enhancer region of MYC, and optionally an effector portion, wherein the expression repressor is capable of reducing expression of MYC.

[0010] In some aspects, the present disclosure provides an expression repressor comprising: a targeting portion that binds to a regulatory element located in a super enhancer region of a target gene (e.g., MYC), and an effector portion (e.g., KRAB or MQ1, or a fragment or variant thereof), wherein the expression repressor is capable of reducing expression of the target gene (e.g., MYC).

[0011] In some aspects, the present disclosure provides an expression repressor comprising: a targeting moiety that binds to a regulatory element located in a super enhancer region of a target gene (e.g., MYC), wherein the targeting moiety comprises a zinc finger domain, wherein the expression repressor is capable of reducing expression of the target gene (e.g., MYC).

[0012] In some aspects, the present disclosure provides an expression repressor comprising: a targeting portion that binds to a regulatory element located in a super enhancer region of MYC and an effector portion, wherein the targeting portion comprises a zinc finger domain or a TAL effector domain, wherein the effector portion comprises a transcriptional repressor (e.g., KRAB or a fragment or variant thereof) or a DNA methyltransferase (e.g., MQ1 or a fragment or variant thereof); wherein the expression repressor is capable of reducing the expression of MYC.

[0013] In some aspects, the disclosure provides an expression repressor comprising: a targeting moiety that binds to a target gene locus (e.g., MYC), wherein the targeting moiety comprises a zinc finger domain, wherein the expression repressor is capable of reducing expression of the target gene (e.g., MYC).

[0014] In some aspects, the disclosure provides an expression repressor comprising: a targeting portion that binds a genomic locus comprising at least 14, 15, 16, 17, 18, 19 or 20 nucleotides of the sequence of SEQ ID NO: 1, 3, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 109, 110, or 75, 76, 78, 79, 80, 81, 84, 85, 86, wherein the expression repressor is capable of reducing expression of MYC.

[0015] In some aspects, the disclosure provides an expression repressor comprising: a targeting portion that binds to a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of a sequence of SEQ ID NO: 2 or 77, 82, or 83, and wherein the expression repressor is capable of reducing expression of a target gene (e.g., MYC). In some embodiments, the expression repressor comprises an effector portion.

[0016] In some aspects, the disclosure provides an expression repressor comprising a targeting moiety, wherein the targeting moiety binds to a genomic locus within 1400 nt upstream or downstream of SEQ ID NO:4.

[0017] In some aspects, the disclosure provides an expression repressor comprising a targeting moiety, wherein the targeting moiety binds to a genomic locus comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 4, 77, 82, or 83.

[0018] In some aspects, the disclosure provides an expression repressor comprising a targeting moiety, wherein the targeting moiety binds to a genomic locus comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 83, 96, or 108.

[0019] In some aspects, the disclosure provides a system comprising a first expression repressor comprising a first targeting moiety and optionally a first effector moiety, wherein the first expression repressor binds to a transcriptional regulatory element (e.g., a promoter or transcription start site (TSS)) operably linked to a target gene (e.g., MYC) or a sequence proximal to the transcriptional 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 comprising anchor sequence-mediated conjugation (ASMC) of the target gene (e.g., MYC), or a sequence proximal to the anchor sequence.

[0020] In some aspects, the disclosure provides a system comprising a first expression repressor comprising a first targeting moiety and optionally a first effector moiety, wherein the first expression repressor binds to a transcriptional regulatory element (e.g., a promoter or transcription start site (TSS)) operably linked to a target gene (e.g., MYC) or a sequence proximal to the transcriptional 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 a genomic locus located in a super enhancer region of the target gene (e.g., MYC).

[0021] In some embodiments, the first targeting moiety specifically binds a first DNA sequence and the second targeting moiety specifically binds a second DNA sequence different from the first DNA sequence.In some embodiments, the first effector moiety is different from the second effector moiety.

[0022] In some aspects, the present disclosure provides an expression repressor comprising: a targeting portion comprising a CRISPR / Cas molecule (e.g., comprising a catalytically inactive CRISPR / Cas protein) that binds to a transcriptional regulatory element (e.g., a promoter or transcription start site (TSS)) operably linked to a target gene (e.g., MYC), or a sequence proximal to the transcriptional regulatory element; and an effector portion comprising MQ1 or a functional variant or fragment thereof.

[0023] In some aspects, the disclosure provides an expression repressor comprising: a targeting portion comprising a CRISPR / Cas molecule (e.g., comprising a catalytically inactive CRISPR / Cas protein) and an effector portion, wherein the targeting portion binds to a genomic locus located in a super enhancer region of a target gene (e.g., MYC), the effector portion comprising KRAB, MQ1, or a functional variant or fragment thereof, wherein the expression repressor is capable of reducing the expression of the target gene (e.g., MYC).

[0024] In some aspects, the disclosure provides an expression repressor comprising: a targeting portion comprising a CRISPR / Cas molecule (e.g., comprising a catalytically inactive CRISPR / Cas protein) that binds to an anchor sequence comprising anchor sequence-mediated conjugation (ASMC) of a target gene (e.g., MYC), or binds to a sequence proximal to the anchor sequence; and an effector portion comprising KRAB or a functional variant or fragment thereof.

[0025] In some aspects, the present disclosure provides an expression repressor comprising: a targeting portion comprising a zinc finger molecule that binds to a transcriptional regulatory element (e.g., a promoter or transcription start site (TSS)) operably linked to a target gene (e.g., MYC), or a sequence proximal to the transcriptional regulatory element; and an effector portion comprising MQ1 or a functional variant or fragment thereof.

[0026] In some aspects, the present disclosure provides an expression repressor comprising: a targeting portion comprising a zinc finger molecule that binds to an anchor sequence comprising anchor sequence-mediated conjugation (ASMC) of a target gene (e.g., MYC), or to a sequence proximal to the anchor sequence; and an effector portion comprising KRAB or a functional variant or fragment thereof.

[0027] In some aspects, the present disclosure provides an expression repressor comprising: a targeting portion comprising a zinc finger molecule and an effector portion comprising KRAB or a functional variant or fragment thereof, the targeting portion binding to a genomic locus located in a super enhancer region of a target gene (e.g., MYC).

[0028] In some aspects, the disclosure relates to nucleic acids encoding a first expression repressor, a second expression repressor, both or components thereof (e.g., gRNA, mRNA). In some embodiments, the nucleic acid encoding the expression repressor system is a polycistronic sequence. In some embodiments, the polycistronic sequence is a bicistronic sequence.

[0029] In some aspects, the present disclosure relates to vectors comprising a nucleic acid, system, or expression repressor described herein. In another aspect, the present disclosure relates to lipid nanoparticles comprising a nucleic acid, system, or expression repressor described herein. In another aspect, the present disclosure relates to reaction mixtures comprising an expression repressor, system, nucleic acid, vector, or lipid nanoparticle described herein. In another aspect, the present disclosure relates to pharmaceutical compositions comprising an expression repressor, system, nucleic acid, vector, lipid nanoparticle, or reaction mixture described herein.

[0030] In some aspects, the present disclosure relates to a method of reducing the expression of a target gene, the method comprising providing an expression repressor or an expression repression system as described herein, and contacting the target gene and / or one or more operably linked transcriptional control elements with the expression repressor or the expression repression system, thereby reducing the expression of the target gene.

[0031] In some aspects, the disclosure relates to a method of treating a disorder associated with overexpression of a target gene (e.g., MYC) in a subject, comprising administering to the subject an expression repressor or system, nucleic acid, or vector described herein, thereby treating the disorder.

[0032] In some aspects, the disclosure relates to a method of treating a disorder associated with misregulation of a target gene (e.g., MYC) in a subject, comprising administering to the subject an expression repressor, system, nucleic acid, or vector described herein, thereby treating the disorder.

[0033] In some aspects, the present disclosure provides a method of reducing the expression of a target gene (e.g., MYC) in a cell, the method comprising: contacting the cell with a system, the system comprising: a first expression repressor and a second expression repressor, the first expression repressor comprising a first targeting portion and optionally a first effector portion, wherein the first expression repressor binds to a transcriptional regulatory element (e.g., a promoter or transcription start site (TSS)) operably linked to the target gene (e.g., MYC), the second expression repressor comprising a second targeting portion and optionally a second effector portion, wherein the second expression repressor binds to an anchor sequence comprising anchor sequence-mediated conjugation (ASMC) of the target gene (e.g., MYC), or binds to a sequence proximal to the anchor sequence, thereby reducing the expression of the target gene (e.g., MYC) in the cell.

[0034] In some aspects, the present disclosure provides a method of reducing expression of a target gene (e.g., MYC) in a cell, the method comprising: contacting the cell with a system comprising: a first expression repressor and a second expression repressor, the first expression repressor comprising a first targeting moiety and optionally a first effector moiety, wherein the first expression repressor binds to a transcriptional regulatory element (e.g., a promoter or transcription start site (TSS)) operably linked to a target gene (e.g., MYC), the second expression repressor comprising a second targeting moiety and optionally a second effector moiety, wherein the second expression repressor binds to a genomic locus located in a super enhancer region of the target gene (e.g., MYC), thereby reducing expression of the target gene (e.g., MYC) in the cell.

[0035] The present disclosure further provides, in part, a kit comprising: a) a container comprising a composition comprising an expression repressor comprising a targeting portion that binds to a target gene (e.g., MYC) promoter and an effector portion that is capable of regulating, e.g., reducing, expression of the target gene (e.g., MYC), and b) a set of instructions comprising at least one method for using the composition to regulate expression of the target gene (e.g., MYC) in a cell.

[0036] The present disclosure further provides, in part, a kit comprising: a) a container comprising a composition comprising an expression repressor comprising a targeting portion that binds to a locus located in a super enhancer region of a target gene (e.g., MYC) and an effector portion capable of modulating, e.g., reducing, expression of the target gene (e.g., MYC), and b) a set of instructions comprising at least one method for using the composition to modulate expression of the target gene (e.g., MYC) in a cell.

[0037] In some aspects, the kit comprises a) a container comprising a composition comprising a system comprising two expression repressors comprising a first expression repressor comprising a first targeting moiety and optionally a first effector moiety, wherein the first expression repressor binds to a transcriptional regulatory element (e.g., a promoter or transcription start site (TSS)) operably linked to a target gene (e.g., MYC) or a sequence proximal to the transcriptional regulatory element, and the second expression repressor comprising a second targeting moiety and optionally a second effector moiety, wherein the second expression repressor binds to an anchor sequence comprising anchor sequence-mediated conjugation (ASMC) of the target gene (e.g., MYC), or a sequence proximal to the anchor sequence.

[0038] In some aspects, the kit comprises a) a container comprising a composition comprising a system comprising two expression repressors comprising a first expression repressor comprising a first targeting moiety and optionally a first effector moiety, wherein the first expression repressor binds to a transcriptional regulatory element (e.g., a promoter or transcription start site (TSS)) operably linked to a target gene (e.g., MYC) or a sequence proximal to the transcriptional 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 a genomic locus located in a super enhancer region of the target gene (e.g., MYC).

[0039] In some embodiments, the kit further includes b) a set of instructions, which includes at least one method of treating a disease with the composition or regulating (e.g., reducing) the expression of a target gene (e.g., MYC) in a cell. In some embodiments, the kit may optionally include a delivery vehicle (e.g., lipid nanoparticles) for the composition. The reagent may be provided suspended in an excipient and / or a delivery vehicle, or may be provided as a separate component that can then be combined with an excipient and / or a delivery vehicle. In some embodiments, the kit may optionally include another therapeutic agent to affect the desired target gene expression, such as MYC gene expression regulation, together with the composition. Although explanatory materials typically include written or printed materials, they are not limited thereto. Any medium capable of storing such instructions and transmitting them to end users is contemplated by the present invention. Such media include, but are not limited to, electronic storage media (e.g., disks, tapes, cassettes, chips), optical media (e.g., CD ROMs), etc. Such media may include the address of an Internet site that provides such explanatory materials.

[0040] Additional features of any of the foregoing methods or compositions include one or more of the embodiments listed below.

[0041] 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 embodiments listed below.

[0042] 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 mentioned herein (e.g., in any of the tables herein) are incorporated by reference. Unless otherwise indicated, sequence accession numbers specified herein (including in any of the tables herein) refer to database entries as of December 15, 2020. When a gene or protein references multiple sequence accession numbers, all sequence variants are encompassed.

[0043] Examples

[0044] 1. A composition comprising:

[0045] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0046] a targeting moiety that binds to the MYC promoter, and

[0047] Optionally, an effector moiety,

[0048] wherein the expression repressor is capable of reducing the expression of MYC; and

[0049] (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)):

[0050] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0051] (i') compounds having the general structure of formula (I)

[0052]

[0053] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[0054] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[0055] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0056] G 3 It is C1-C 24 Alkylene, C2-C24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0057] R a Is H or C1-C 12 alkyl;

[0058] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0059] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0060] R 4 It is C1-C 12 alkyl;

[0061] R 5 is H or C1-C6 alkyl;

[0062] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0063] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[0064] x is 0, 1, or 2;

[0065] (i") compounds having the general structure of Formula (IX):

[0066]

[0067] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0068] L 1 and L 2are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0069] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0070] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0071] G 3 is C1-C6 alkylene;

[0072] R a Is H or C1-C 12 alkyl;

[0073] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0074] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0075] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0076] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0077] R 5 and R 6 are each independently H or methyl;

[0078] R 7 It is C4-C 20 alkyl;

[0079] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0080] a, b, c, and d are each independently an integer from 1 to 24; and

[0081] x is 0, 1, or 2;

[0082] as well as,

[0083] (i'") compounds having the general structure of formula (XI):

[0084]

[0085] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[0086] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0087] R 2 and R 3 are each independently an optionally substituted C1-C36 alkyl;

[0088] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0089] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0090] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0091] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[0092] n is an integer greater than 0;

[0093] (ii) a second compound having the general structure of formula (II):

[0094]

[0095] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[0096] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0097] The mean value of y ranges from 30 to 60;

[0098] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0099] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0100] 2. The composition of embodiment 1, wherein the targeting moiety binds to a genomic locus within 1400, 1200, 1000, 800, 600, 400, or 200 nt upstream or downstream of SEQ ID NO: 4, 199, or 201.

[0101] 3. The composition of embodiment 1, wherein the targeting moiety binds to a genomic locus comprising at least 14, 15, 16, 17, 18, 19 or 20 nucleotides of a sequence of SEQ ID NO: 4, 77, 82, 83, 85, 199 or 201.

[0102] 4. A composition comprising:

[0103] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0104] Incorporates a targeting portion of a genomic locus comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 3, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 109, 110, 75, 76, 78, 79, 80, 81, 84, 85, 86, 190, 191, 192, 200, or 202 and

[0105] Optionally, an effector moiety,

[0106] wherein the expression repressor is capable of reducing the expression of MYC; and

[0107] (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)):

[0108] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0109] (i') compounds having the general structure of formula (I)

[0110]

[0111] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[0112] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x-, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[0113] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0114] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0115] R a Is H or C1-C 12 alkyl;

[0116] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0117] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0118] R 4 It is C1-C 12 alkyl;

[0119] R 5 is H or C1-C6 alkyl;

[0120] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0121] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[0122] x is 0, 1, or 2;

[0123] (i") compounds having the general structure of Formula (IX):

[0124]

[0125] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0126] L 1 and L 2 are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0127] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0128] G 2 is –C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0129] G 3 is C1-C6 alkylene;

[0130] R a Is H or C1-C 12 alkyl;

[0131] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0132] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0133] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0134] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0135] R 5 and R 6 are each independently H or methyl;

[0136] R 7 It is C4-C 20 alkyl;

[0137] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0138] a, b, c, and d are each independently an integer from 1 to 24; and

[0139] x is 0, 1, or 2;

[0140] as well as,

[0141] (i'") compounds having the general structure of formula (XI):

[0142]

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

[0144] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0145] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[0146] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0147] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0148] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0149] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[0150] n is an integer greater than 0;

[0151] (ii) a second compound having the general structure of formula (II):

[0152]

[0153] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[0154] R 6and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0155] The mean value of y ranges from 30 to 60;

[0156] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0157] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0158] 5. A composition comprising:

[0159] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0160] a targeting moiety that binds to a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of a sequence of SEQ ID NO: 2, 77, 82, 83, 199, or 201, and

[0161] Optionally, an effector moiety,

[0162] wherein the expression repressor is capable of reducing the expression of MYC; and

[0163] (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)):

[0164] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0165] (i') compounds having the general structure of formula (I)

[0166]

[0167] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[0168] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NRa -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[0169] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0170] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0171] R a Is H or C1-C 12 alkyl;

[0172] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0173] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0174] R 4 It is C1-C 12 alkyl;

[0175] R 5 is H or C1-C6 alkyl;

[0176] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0177] G 4 It is C1-C 24 Alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[0178] x is 0, 1, or 2;

[0179] (i") compounds having the general structure of Formula (IX):

[0180]

[0181] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0182] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0183] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0184] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0185] G 3 is C1-C6 alkylene;

[0186] R a Is H or C1-C 12 alkyl;

[0187] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0188] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0189] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0190] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0191] R 5 and R 6 are each independently H or methyl;

[0192] R 7 It is C4-C 20 alkyl;

[0193] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0194] a, b, c, and d are each independently an integer from 1 to 24; and

[0195] x is 0, 1, or 2;

[0196] as well as,

[0197] (i'") compounds having the general structure of formula (XI):

[0198]

[0199] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[0200] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0201] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[0202] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0203] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0204] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0205] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[0206] n is an integer greater than 0;

[0207] (ii) a second compound having the general structure of formula (II):

[0208]

[0209] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[0210] R 6 and R 7each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0211] The mean value of y ranges from 30 to 60;

[0212] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0213] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0214] 6. A composition comprising:

[0215] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0216] a targeting moiety that binds to the MYC locus, and

[0217] comprising an effector portion of MQ1 or a fragment or variant thereof,

[0218] wherein the expression repressor is capable of reducing the expression of MYC; and

[0219] (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)):

[0220] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0221] (i') compounds having the general structure of formula (I)

[0222]

[0223] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[0224] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NRa -、-NR a C(=O)O-, or a direct bond;

[0225] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0226] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0227] R a Is H or C1-C 12 alkyl;

[0228] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0229] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0230] R 4 It is C1-C 12 alkyl;

[0231] R 5 is H or C1-C6 alkyl;

[0232] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0233] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[0234] x is 0, 1, or 2;

[0235] (i") compounds having the general structure of Formula (IX):

[0236]

[0237] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0238] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0239] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0240] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0241] G 3 is C1-C6 alkylene;

[0242] R a Is H or C1-C 12 alkyl;

[0243] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0244] R 2a and R 2bis independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0245] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0246] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0247] R 5 and R 6 are each independently H or methyl;

[0248] R 7 It is C4-C 20 alkyl;

[0249] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0250] a, b, c, and d are each independently an integer from 1 to 24; and

[0251] x is 0, 1, or 2;

[0252] as well as,

[0253] (i'") compounds having the general structure of formula (XI):

[0254]

[0255] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[0256] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0257] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[0258] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0259] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0260] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0261] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[0262] n is an integer greater than 0;

[0263] (ii) a second compound having the general structure of formula (II):

[0264]

[0265] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[0266] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0267] The mean value of y ranges from 30 to 60;

[0268] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0269] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0270] 7. A composition comprising:

[0271] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0272] Binds to the targeted portion of the locus in the MYC super enhancer region,

[0273] Optionally an effector moiety, e.g., an effector moiety comprising a DNA methyltransferase, wherein optionally the effector moiety comprises MQ1 or a fragment or variant thereof,

[0274] wherein the expression repressor is capable of reducing the expression of MYC; and

[0275] (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)):

[0276] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0277] (i') compounds having the general structure of formula (I)

[0278]

[0279] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[0280] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[0281] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0282] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0283] R a Is H or C1-C 12 alkyl;

[0284] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0285] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0286] R 4 It is C1-C 12 alkyl;

[0287] R 5 is H or C1-C6 alkyl;

[0288] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0289] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1 or 2;

[0290] (i") compounds having the general structure of Formula (IX):

[0291]

[0292] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0293] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0294] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0295] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0296] G 3 is C1-C6 alkylene;

[0297] R a Is H or C1-C 12 alkyl;

[0298] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0299] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2bTogether with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0300] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0301] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0302] R 5 and R 6 are each independently H or methyl;

[0303] R 7 It is C4-C 20 alkyl;

[0304] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0305] a, b, c, and d are each independently an integer from 1 to 24; and

[0306] x is 0, 1, or 2;

[0307] as well as,

[0308] (i'") compounds having the general structure of formula (XI):

[0309]

[0310] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[0311] R1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0312] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[0313] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0314] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0315] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0316] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[0317] n is an integer greater than 0;

[0318] (ii) a second compound having the general structure of formula (II):

[0319]

[0320] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[0321] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0322] The mean value of y ranges from 30 to 60;

[0323] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0324] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0325] 8. A composition comprising:

[0326] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0327] Binds to the targeted portion of the locus in the MYC super enhancer region,

[0328] comprising an effector portion of a transcriptional repressor, wherein optionally the effector portion comprises KRAB or a fragment or variant thereof,

[0329] wherein the expression repressor is capable of reducing the expression of MYC; and

[0330] (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)):

[0331] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0332] (i') compounds having the general structure of formula (I)

[0333]

[0334] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[0335] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[0336] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0337] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0338] R a Is H or C1-C 12 alkyl;

[0339] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0340] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0341] R 4 It is C1-C 12 alkyl;

[0342] R 5 is H or C1-C6 alkyl;

[0343] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0344] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[0345] x is 0, 1, or 2;

[0346] (i") compounds having the general structure of Formula (IX):

[0347]

[0348] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0349] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0350] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0351] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0352] G 3 is C1-C6 alkylene;

[0353] R a Is H or C1-C 12 alkyl;

[0354] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0355] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0356] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0357] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0358] R 5 and R 6 are each independently H or methyl;

[0359] R 7 It is C4-C 20 alkyl;

[0360] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0361] a, b, c, and d are each independently an integer from 1 to 24; and

[0362] x is 0, 1, or 2;

[0363] as well as,

[0364] (i'") compounds having the general structure of formula (XI):

[0365]

[0366] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[0367] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0368] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[0369] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0370] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0371] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0372] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[0373] n is an integer greater than 0;

[0374] (ii) a second compound having the general structure of formula (II):

[0375]

[0376] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[0377] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0378] The mean value of y ranges from 30 to 60;

[0379] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0380] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0381] 9. The composition of embodiment 7 or 8, wherein the targeting moiety binds to a genomic locus comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of a sequence of any one of SEQ ID NOs: 96-110, 83, 199, or 201.

[0382] 10. The composition of any of embodiments 7-9, wherein the targeting moiety binds to 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 hg19 reference genome.

[0383] 11. The composition of any one of embodiments 7-10, wherein the targeting moiety binds to a genomic locus comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 96 or 108.

[0384] 12. The composition of any one of embodiments 7-11, wherein the targeting moiety comprises a zinc finger domain or a TAL effector domain.

[0385] 13. A composition comprising:

[0386] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0387] a targeting moiety that binds to a locus (e.g., the MYC locus),

[0388] a first effector portion comprising EZH2 or a fragment or variant thereof, and

[0389] a second effector moiety comprising KRAB or a fragment or variant thereof,

[0390] wherein the expression repressor is capable of reducing expression at the locus, such as reducing expression of MYC; and

[0391] (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)):

[0392] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0393] (i') compounds having the general structure of formula (I)

[0394]

[0395] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[0396] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[0397] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0398] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0399] R a Is H or C1-C 12 alkyl;

[0400] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0401] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0402] R 4 It is C1-C 12 alkyl;

[0403] R 5 is H or C1-C6 alkyl;

[0404] R11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0405] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[0406] x is 0, 1, or 2;

[0407] (i") compounds having the general structure of Formula (IX):

[0408]

[0409] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0410] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0411] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0412] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0413] G 3 is C1-C6 alkylene;

[0414] R a Is H or C1-C 12alkyl;

[0415] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0416] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0417] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0418] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0419] R 5 and R 6 are each independently H or methyl;

[0420] R 7 It is C4-C 20 alkyl;

[0421] R 8 and R 9 Each independently is C1-C 12Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0422] a, b, c, and d are each independently an integer from 1 to 24; and

[0423] x is 0, 1, or 2;

[0424] as well as,

[0425] (i'") compounds having the general structure of formula (XI):

[0426]

[0427] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[0428] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0429] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[0430] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0431] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0432] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0433] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[0434] n is an integer greater than 0;

[0435] (ii) a second compound having the general structure of formula (II):

[0436]

[0437] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[0438] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0439] The mean value of y ranges from 30 to 60;

[0440] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0441] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0442] 14. The composition of embodiment 13, wherein the targeting moiety binds to the MYC promoter, super enhancer region, or anchor sequence.

[0443] 15. The composition of embodiment 13 or 14, wherein the targeting moiety comprises a TAL effector domain, a CRISPR / Cas domain, or a zinc finger domain.

[0444] 16. The composition of any one of embodiments 13-15, wherein the first effector moiety is N-terminal to the second effector moiety, or wherein the first effector is C-terminal to the second effector moiety.

[0445] 17. A composition comprising:

[0446] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0447] a targeting moiety that binds to the MYC locus, wherein the targeting moiety comprises a zinc finger domain, and

[0448] Optionally, an effector moiety,

[0449] wherein the expression repressor is capable of reducing the expression of MYC; and

[0450] (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)):

[0451] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0452] (i') compounds having the general structure of formula (I)

[0453]

[0454] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[0455] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[0456] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0457] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0458] R a Is H or C1-C 12 alkyl;

[0459] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0460] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0461] R 4 It is C1-C 12 alkyl;

[0462] R 5 is H or C1-C6 alkyl;

[0463] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0464] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[0465] x is 0, 1, or 2;

[0466] (i") compounds having the general structure of Formula (IX):

[0467]

[0468] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0469] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0470] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0471] G 2is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0472] G 3 is C1-C6 alkylene;

[0473] R a Is H or C1-C 12 alkyl;

[0474] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0475] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0476] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0477] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0478] R 5 and R6 are each independently H or methyl;

[0479] R 7 It is C4-C 20 alkyl;

[0480] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0481] a, b, c, and d are each independently an integer from 1 to 24; and

[0482] x is 0, 1, or 2;

[0483] as well as,

[0484] (i'") compounds having the general structure of formula (XI):

[0485]

[0486] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[0487] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0488] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[0489] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0490] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0491] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0492] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[0493] n is an integer greater than 0;

[0494] (ii) a second compound having the general structure of formula (II):

[0495]

[0496] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[0497] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0498] The mean value of y ranges from 30 to 60;

[0499] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0500] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0501] 18. A composition comprising:

[0502] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0503] A targeting moiety comprising a CRISPR / Cas domain (e.g., comprising a catalytically inactive CRISPR / Cas protein) that binds to a transcriptional regulatory element (e.g., a promoter, enhancer, super enhancer, or transcription start site (TSS)) operably linked to the MYC gene, or a sequence proximal to the transcriptional regulatory element; and

[0504] An effector portion comprising MQ1 or a functional variant or fragment thereof; and

[0505] (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)):

[0506] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0507] (i') compounds having the general structure of formula (I)

[0508]

[0509] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[0510] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[0511] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0512] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0513] R a Is H or C1-C 12 alkyl;

[0514] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0515] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0516] R 4It is C1-C 12 alkyl;

[0517] R 5 is H or C1-C6 alkyl;

[0518] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0519] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[0520] x is 0, 1, or 2;

[0521] (i") compounds having the general structure of Formula (IX):

[0522]

[0523] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0524] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0525] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0526] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0527] G 3 is C1-C6 alkylene;

[0528] R a Is H or C1-C 12 alkyl;

[0529] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0530] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0531] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0532] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0533] R 5 and R 6 are each independently H or methyl;

[0534] R7 It is C4-C 20 alkyl;

[0535] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0536] a, b, c, and d are each independently an integer from 1 to 24; and

[0537] x is 0, 1, or 2;

[0538] as well as,

[0539] (i'") compounds having the general structure of formula (XI):

[0540]

[0541] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[0542] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0543] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[0544] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0545] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0546] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0547] G 2 and G 3are each independently -(C=O)O- or -O(C=O)-; and

[0548] n is an integer greater than 0;

[0549] (ii) a second compound having the general structure of formula (II):

[0550]

[0551] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[0552] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0553] The mean value of y ranges from 30 to 60;

[0554] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0555] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0556] 19. A composition comprising:

[0557] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0558] A targeting moiety comprising a CRISPR / Cas domain (e.g., comprising a catalytically inactive CRISPR / Cas protein) that binds to a transcriptional regulatory element (e.g., a promoter, enhancer, or transcription start site (TSS)) operably linked to the MYC gene, or a sequence proximal to the transcriptional regulatory element; and

[0559] An effector portion comprising MQ1 or a functional variant or fragment thereof; and

[0560] (2) A preparation comprising:

[0561] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0562] (i') compounds having the general structure of formula (I)

[0563]

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

[0565] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[0566] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0567] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0568] R a Is H or C1-C 12 alkyl;

[0569] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0570] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0571] R 4 It is C1-C 12 alkyl;

[0572] R 5 is H or C1-C6 alkyl;

[0573] R11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0574] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[0575] x is 0, 1, or 2;

[0576] (i") compounds having the general structure of Formula (IX):

[0577]

[0578] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0579] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0580] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0581] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0582] G 3 is C1-C6 alkylene;

[0583] R a Is H or C1-C 12alkyl;

[0584] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0585] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0586] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0587] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0588] R 5 and R 6 are each independently H or methyl;

[0589] R 7 It is C4-C 20 alkyl;

[0590] R 8 and R 9 Each independently is C1-C 12Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0591] a, b, c, and d are each independently an integer from 1 to 24; and

[0592] x is 0, 1, or 2;

[0593] as well as,

[0594] (i'") compounds having the general structure of formula (XI):

[0595]

[0596]

[0597] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[0598] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0599] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[0600] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0601] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0602] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0603] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[0604] n is an integer greater than 0;

[0605] (ii) a second compound having the general structure of formula (II):

[0606]

[0607] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[0608] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0609] The mean value of y ranges from 30 to 60;

[0610] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0611] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0612] 20. A composition comprising:

[0613] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0614] A targeting moiety comprising a CRISPR / Cas domain (e.g., comprising a catalytically inactive CRISPR / Cas protein) that binds to a transcriptional regulatory element (e.g., a promoter, enhancer, or transcription start site (TSS)) operably linked to the MYC gene, or a sequence proximal to the transcriptional regulatory element; and

[0615] An effector portion comprising KRAB or a functional variant or fragment thereof; and

[0616] (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)):

[0617] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0618] (i') compounds having the general structure of formula (I)

[0619]

[0620] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[0621] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[0622] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0623] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0624] R a Is H or C1-C 12 alkyl;

[0625] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0626] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0627] R 4 It is C1-C 12 alkyl;

[0628] R 5 is H or C1-C6 alkyl;

[0629] R11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0630] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[0631] x is 0, 1, or 2;

[0632] (i") compounds having the general structure of Formula (IX):

[0633]

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

[0635] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0636] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0637] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0638] G 3 is C1-C6 alkylene;

[0639] R a Is H or C1-C 12alkyl;

[0640] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0641] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0642] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0643] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0644] R 5 and R 6 are each independently H or methyl;

[0645] R 7 It is C4-C 20 alkyl;

[0646] R 8 and R 9 Each independently is C1-C 12Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0647] a, b, c, and d are each independently an integer from 1 to 24; and

[0648] x is 0, 1, or 2;

[0649] as well as,

[0650] (i'") compounds having the general structure of formula (XI):

[0651]

[0652] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[0653] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0654] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[0655] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0656] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0657] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0658] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[0659] n is an integer greater than 0;

[0660] (ii) a second compound having the general structure of formula (II):

[0661]

[0662] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[0663] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0664] The mean value of y ranges from 30 to 60;

[0665] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0666] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0667] 21. A composition comprising:

[0668] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0669] a targeting moiety comprising a CRISPR / Cas domain (e.g., comprising a catalytically inactive CRISPR / Cas protein) that binds to an anchor sequence comprising anchor sequence-mediated conjugation (ASMC) of the MYC gene, or to a sequence proximal to the anchor sequence; and

[0670] An effector portion comprising KRAB or a functional variant or fragment thereof; and

[0671] (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)):

[0672] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0673] (i') compounds having the general structure of formula (I)

[0674]

[0675] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[0676] L 1 and L2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[0677] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0678] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0679] R a Is H or C1-C 12 alkyl;

[0680] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0681] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0682] R 4 It is C1-C 12 alkyl;

[0683] R 5 is H or C1-C6 alkyl;

[0684] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5, or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0685] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[0686] x is 0, 1, or 2;

[0687] (i") compounds having the general structure of Formula (IX):

[0688]

[0689] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0690] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0691] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0692] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0693] G 3 is C1-C6 alkylene;

[0694] R a Is H or C1-C 12 alkyl;

[0695] R 1a and R 1bis independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0696] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0697] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0698] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0699] R 5 and R 6 are each independently H or methyl;

[0700] R 7 It is C4-C 20 alkyl;

[0701] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0702] a, b, c, and d are each independently an integer from 1 to 24; and

[0703] x is 0, 1, or 2;

[0704] as well as,

[0705] (i'") compounds having the general structure of formula (XI):

[0706]

[0707] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[0708] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0709] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[0710] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0711] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0712] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0713] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[0714] n is an integer greater than 0;

[0715] (ii) a second compound having the general structure of formula (II):

[0716]

[0717] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[0718] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0719] The mean value of y ranges from 30 to 60;

[0720] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0721] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0722] 22. A composition comprising:

[0723] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0724] a targeting moiety comprising a zinc finger domain that binds to a transcriptional regulatory element (e.g., a promoter, enhancer, or transcription start site (TSS)) operably linked to a MYC gene, or a sequence proximal to the transcriptional regulatory element; and

[0725] An effector portion comprising MQ1 or a functional variant or fragment thereof; and

[0726] (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)):

[0727] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0728] (i') compounds having the general structure of formula (I)

[0729]

[0730] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[0731] L 1 and L 2are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[0732] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0733] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0734] R a Is H or C1-C 12 alkyl;

[0735] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0736] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0737] R 4 It is C1-C 12 alkyl;

[0738] R 5 is H or C1-C6 alkyl;

[0739] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0740] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[0741] x is 0, 1, or 2;

[0742] (i") compounds having the general structure of Formula (IX):

[0743]

[0744] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0745] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0746] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0747] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0748] G 3 is C1-C6 alkylene;

[0749] R a Is H or C1-C 12 alkyl;

[0750] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0751] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0752] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0753] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0754] R 5 and R 6 are each independently H or methyl;

[0755] R 7 It is C4-C 20 alkyl;

[0756] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0757] a, b, c, and d are each independently an integer from 1 to 24; and

[0758] x is 0, 1, or 2;

[0759] as well as,

[0760] (i'") compounds having the general structure of formula (XI):

[0761]

[0762] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[0763] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0764] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[0765] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0766] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0767] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0768] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[0769] n is an integer greater than 0;

[0770] (ii) a second compound having the general structure of formula (II):

[0771]

[0772] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[0773] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0774] The mean value of y ranges from 30 to 60;

[0775] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0776] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0777] 23. A composition comprising:

[0778] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0779] a targeting moiety comprising a zinc finger domain that binds to a transcriptional regulatory element (e.g., a promoter, enhancer, or transcription start site (TSS)) operably linked to a MYC gene, or a sequence proximal to the transcriptional regulatory element; and

[0780] An effector portion comprising KRAB or a functional variant or fragment thereof; and

[0781] (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)):

[0782] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0783] (i') compounds having the general structure of formula (I)

[0784]

[0785] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[0786] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x-, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[0787] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0788] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0789] R a Is H or C1-C 12 alkyl;

[0790] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0791] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0792] R 4 It is C1-C 12 alkyl;

[0793] R 5 is H or C1-C6 alkyl;

[0794] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0795] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[0796] x is 0, 1, or 2;

[0797] (i") compounds having the general structure of Formula (IX):

[0798]

[0799] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0800] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0801] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0802] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0803] G 3 is C1-C6 alkylene;

[0804] R a Is H or C1-C 12 alkyl;

[0805] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0806] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0807] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0808] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0809] R 5 and R 6 are each independently H or methyl;

[0810] R 7 It is C4-C 20 alkyl;

[0811] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0812] a, b, c, and d are each independently an integer from 1 to 24; and

[0813] x is 0, 1, or 2;

[0814] as well as,

[0815] (i'") compounds having the general structure of formula (XI):

[0816]

[0817] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[0818] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0819] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[0820] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0821] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0822] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0823] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[0824] n is an integer greater than 0;

[0825] (ii) a second compound having the general structure of formula (II):

[0826]

[0827] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[0828] R 6and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0829] The mean value of y ranges from 30 to 60;

[0830] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0831] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0832] 24. A composition comprising:

[0833] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0834] a targeting portion that binds to a mouse genomic locus, the targeting portion comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of any one of SEQ ID NOs: 190-192, and

[0835] Optionally, an effector moiety,

[0836] wherein the expression repressor is capable of reducing the expression of MYC; and

[0837] (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)):

[0838] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0839] (i') compounds having the general structure of formula (I)

[0840]

[0841] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[0842] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NRa -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[0843] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0844] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0845] R a Is H or C1-C 12 alkyl;

[0846] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0847] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0848] R 4 It is C1-C 12 alkyl;

[0849] R 5 is H or C1-C6 alkyl;

[0850] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0851] G 4 It is C1-C 24 Alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[0852] x is 0, 1, or 2;

[0853] (i") compounds having the general structure of Formula (IX):

[0854]

[0855] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0856] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0857] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0858] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0859] G 3 is C1-C6 alkylene;

[0860] R a Is H or C1-C 12 alkyl;

[0861] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0862] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0863] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0864] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0865] R 5 and R 6 are each independently H or methyl;

[0866] R 7 It is C4-C 20 alkyl;

[0867] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0868] a, b, c, and d are each independently an integer from 1 to 24; and

[0869] x is 0, 1, or 2;

[0870] as well as,

[0871] (i'") compounds having the general structure of formula (XI):

[0872]

[0873]

[0874] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[0875] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0876] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[0877] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0878] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0879] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0880] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[0881] n is an integer greater than 0;

[0882] (ii) a second compound having the general structure of formula (II):

[0883]

[0884] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[0885] R 6 and R 7each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0886] The mean value of y ranges from 30 to 60;

[0887] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0888] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0889] 25. The composition of embodiment 24, wherein the effector moiety comprises a DNA methyltransferase, such as MQ1 or a fragment or variant thereof.

[0890] 26. The composition of embodiment 24 or 25, wherein the targeting moiety comprises a TAL effector domain, a CRISPR / Cas domain, a zinc finger domain, a tetR domain, a large nuclease domain, or an oligonucleotide.

[0891] 27. The composition of any one of embodiments 24-26, wherein the targeting moiety comprises a zinc finger domain or a TAL effector domain.

[0892] 28. The composition of any of embodiments 24-27, wherein the expression repressor comprises an amino acid sequence selected from any one of SEQ ID NOs: 160-165, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[0893] 29. The composition of any of embodiments 24-28, wherein the expression repressor is encoded by a nucleotide sequence selected from any one of SEQ ID NOs: 166-168, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[0894] 30. The composition 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 that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

[0895] 31. The composition of any one 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 that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[0896] 32. The composition of any one of embodiments 24-31, wherein the effector moiety is a persistent effector moiety.

[0897] 33. The composition of any one of embodiments 24-32, wherein the effector moiety is a transient effector moiety.

[0898] 34. The composition of any one of embodiments 24-33, wherein the expression repressor is a fusion molecule.

[0899] 35. The composition of any one of embodiments 24-34, wherein the targeting moiety comprises a zinc finger domain and the effector moiety comprises an epigenetic modification moiety, e.g., a DNA methyltransferase, e.g., MQ1 or a fragment or variant thereof.

[0900] 36. The composition of any one of embodiments 18-20, 22, or 23, wherein the regulatory element is part of a regulatory element cluster.

[0901] 37. The composition of any one of embodiments 18-20, 22, or 23, wherein the regulatory element is located in a non-coding region.

[0902] 38. The composition of any one of embodiments 18-20, 22, or 23, wherein the regulatory element is a distal enhancer, eg, located at least 1,000 nt from the target gene (eg, MYC) promoter.

[0903] 39. The composition of any one of embodiments 18-20, 22, 23, or 36-38, wherein the regulatory element increases expression of a target gene (e.g., MYC).

[0904] 40. The composition of any one of embodiments 18-20, 22, 23, or 36-39, wherein the regulatory element comprises one or more mutations.

[0905] 41. The composition of any one of embodiments 18-20, 22, 23, or 36-40, wherein the regulatory element comprises at least one disease-associated single nucleotide polymorphism (SNP).

[0906] 42. The composition of any one of embodiments 18-20, 22, 23, or 36-41, wherein the transcriptional regulatory element interacts with the promoter of a target gene (e.g., MYC) through an enhancer docking site.

[0907] 43. The composition of embodiment 42, wherein the enhancer docking site comprises a nucleotide sequence according to any one of SEQ ID NOs: 71, 72, or a nucleic acid sequence of CCGCCATNTT or AANATGGCGG, wherein N is any nucleotide.

[0908] 44. A composition comprising:

[0909] (1) A first nucleic acid encoding an expression repressor, the expression repressor comprising:

[0910] a targeting moiety comprising a zinc finger domain that binds to an anchor sequence comprising anchor sequence-mediated conjugation (ASMC) of the MYC gene, or to a sequence proximal to the anchor sequence; and

[0911] An effector portion comprising KRAB or a functional variant or fragment thereof; and

[0912] (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)):

[0913] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[0914] (i') compounds having the general structure of formula (I)

[0915]

[0916] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[0917] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x-, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[0918] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[0919] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[0920] R a Is H or C1-C 12 alkyl;

[0921] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0922] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[0923] R 4 It is C1-C 12 alkyl;

[0924] R 5 is H or C1-C6 alkyl;

[0925] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[0926] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[0927] x is 0, 1, or 2;

[0928] (i") compounds having the general structure of Formula (IX):

[0929]

[0930] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[0931] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[0932] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[0933] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[0934] G 3 is C1-C6 alkylene;

[0935] R a Is H or C1-C 12 alkyl;

[0936] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0937] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0938] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0939] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[0940] R 5 and R 6 are each independently H or methyl;

[0941] R 7 It is C4-C 20 alkyl;

[0942] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[0943] a, b, c, and d are each independently an integer from 1 to 24; and

[0944] x is 0, 1, or 2;

[0945] as well as,

[0946] (i'") compounds having the general structure of formula (XI):

[0947]

[0948] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[0949] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[0950] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[0951] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[0952] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[0953] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[0954] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[0955] n is an integer greater than 0;

[0956] (ii) a second compound having the general structure of formula (II):

[0957]

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

[0959] R 6and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[0960] The mean value of y ranges from 30 to 60;

[0961] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[0962] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0963] 45. The composition of any one of embodiments 1-44, wherein the first nucleic acid comprises RNA, e.g., mRNA.

[0964] 46. ​​The composition of any one of embodiments 1-23 or 36-43, wherein the expression repressor comprises an amino acid sequence selected from any one of SEQ ID NOs: 22-37, 129, 133, 134, 139-149, or 177-186, or a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[0965] 47. The composition of any one of embodiments 1-23 or 36-46, wherein the expression repressor is encoded by a nucleotide sequence selected from any one of SEQ ID NOs: 55-70, 130, 189, or 193-197, or a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[0966] 48. The composition of any one of embodiments 1-23 or 36-47, wherein the targeting moiety comprises an amino acid sequence according to any one of SEQ ID NOs: 5-16 or 169-172, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

[0967] 49. The composition of any preceding embodiment, wherein the effector portion comprises an amino acid sequence according to SEQ ID NO: 18, 19, or 87, or a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[0968] 50. The composition of any of embodiments 1-12, 17-19, 22, 36-42, or 44-48, wherein the effector moiety is a persistent effector moiety.

[0969] 51. The composition of any of embodiments 1-23 or 36-49, wherein the effector moiety is a transient effector moiety.

[0970] 52. The composition of any one of embodiments 1-12, 17-19, 22, 36-42, or 44-49, wherein the effector portion comprises a DNA methyltransferase, eg, MQ1, or a fragment or variant thereof.

[0971] 53. The composition of any one of embodiments 1-23, 36-48, or 50, wherein the effector portion comprises a transcriptional repressor, eg, comprises KRAB or a fragment or variant thereof.

[0972] 54. The composition 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 large nuclease domain, or an oligonucleotide.

[0973] 55. The composition of embodiment 54, wherein the CRISPR / Cas domain binds a gRNA, e.g., a gRNA that binds to 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: 1-4, e.g., wherein the gRNA comprises a sequence comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of any one of SEQ ID NOs: 1-4.

[0974] 56. The composition of embodiment 54, wherein the CRISPR / Cas domain binds a gRNA, e.g., a gRNA that binds to a genomic locus comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of a sequence of any one of SEQ ID NOs: 96-110, e.g., wherein the gRNA comprises a sequence comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of a sequence of any one of SEQ ID NOs: 96-110.

[0975] 57. The composition of any one of embodiments 54-56, wherein the CRISPR / Cas domain comprises a Cas protein or a Cpf1 protein selected from Table 1 or a variant (e.g., mutant) of any one thereof.

[0976] 58. The composition of any one of embodiments 54-57, wherein the CRISPR / Cas domain comprises a catalytically inactive CRISPR / Cas protein, e.g., dCas9.

[0977] 59. The composition of embodiment 54, wherein the zinc finger domain binds to 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: 96-110, e.g., wherein the gRNA comprises a sequence comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of any one of SEQ ID NOs: 96-110.

[0978] 60. The composition of any one 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).

[0979] 61. The composition of any one 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.

[0980] 62. The composition of any one of embodiments 17, 22, 26-54, or 58-60, wherein the zinc finger domain comprises 3 or 9 zinc fingers.

[0981] 63. The composition of any one of the preceding embodiments, wherein the expression repressor is a fusion molecule.

[0982] 64. The composition of any preceding embodiment, wherein the expression repressor comprises a linker located between the targeting domain and the effector domain, optionally wherein the linker comprises an amino acid sequence according to SEQ ID NO: 137 or SEQ ID NO: 138.

[0983] 65. The composition of any one 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 transcriptional repressor, e.g., KRAB, or a fragment or variant thereof.

[0984] 66. The composition of any one 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 transcriptional repressor, e.g., KRAB, or a fragment or variant thereof.

[0985] 67. The composition of any one 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.

[0986] 68. The composition of any one 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 modification moiety, e.g., a DNA methyltransferase, e.g., MQ1, or a fragment or variant thereof.

[0987] 69. The composition 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 modification moiety, e.g., a DNA methyltransferase, e.g., MQ1, or a fragment or variant thereof.

[0988] 70. The expression repressor of any one of the preceding embodiments, wherein the expression repressor comprises the amino acid sequence of any one of SEQ ID NOs: 22-37, 129, 133, 134, 139-149, or 177-186, or a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.

[0989] 71. The composition of any one 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.

[0990] 72. The composition of any one of the preceding embodiments, wherein the expression repressor comprises a first NLS at the N-terminus, eg, wherein the first NLS has the sequence of SEQ ID NO: 88.

[0991] 73. The composition of any one of the preceding embodiments, wherein the expression repressor comprises an NLS (eg, a second NLS) at the C-terminus, eg, having the sequence of SEQ ID NO: 89.

[0992] 74. The composition of any preceding embodiment, wherein the first and the second NLS have the same sequence.

[0993] 75. The composition of any one of embodiments 72-74, wherein the first and second NLS have different sequences.

[0994] 76. The composition of any preceding embodiment, wherein the expression repressor comprises an epitope tag.

[0995] 77. The composition of embodiment 76, wherein the epitope tag is an HA tag.

[0996] 78. The composition of any preceding embodiment, wherein the anchor sequence comprises the sequence of SEQ ID NO: 71 or 72, or a sequence having no more than 8, 7, 6, 5, 4, 3, 2, or 1 alterations thereto.

[0997] 79. The composition of any one of embodiments 1-78, wherein the anchor sequence comprises a sequence according to the nucleic acid sequence of CCGCCATNTT or AANATGGCGG, or a sequence having no more than 8, 7, 6, 5, 4, 3, 2, or 1 alterations thereto, wherein N is any nucleotide.

[0998] 80. The composition of any preceding embodiment, wherein the anchor sequence is located on the same chromosome as the MYC gene.

[0999] 81. The composition of any preceding embodiment, wherein the anchor sequence is upstream of the MYC gene (eg, upstream of the TSS or upstream of the promoter).

[1000] 82. The composition of any preceding embodiment, wherein the anchor sequence is at least 1, 5, 10, 50, 100, or 1000 kilobases from the MYC gene (eg, from the TSS or promoter of the MYC gene).

[1001] 83. The composition of any preceding embodiment, 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, 0.5-50 or 500-1000 kilobases.

[1002] 84. The composition of any one of embodiments 1-80, 82, or 82, wherein the target sequence is located downstream of the MYC gene (e.g., downstream of the TSS or downstream of the promoter).

[1003] 85. The composition of any preceding embodiment, wherein the targeting moiety binds to 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、12918 9274-129189296, 129189421-129189443, 128746405-128746425, 128748069-128748089, 129188825-129188845, or 129188822-129188842, or sequences proximal thereto.

[1004] 86. The composition of any preceding embodiment, 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) 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 17, wherein optionally the site at which methylation is determined is chr8:129188693-129189048 according to the hg19 reference genome, e.g., comprising a sequence according to SEQ ID NO: 123.

[1005] 87. The compositions of any of the preceding embodiments, wherein the binding of the expression repressor to the target gene locus (e.g., MYC) increases methylation at sites in the target gene locus (e.g., MYC) for a 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 for a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cell divisions, e.g., as described in Example 17.

[1006] 88. The composition of any of the preceding embodiments, wherein binding of the expression repressor to the MYC locus reduces expression of MYC in the 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.

[1007] 89. The composition of any of the preceding embodiments, wherein binding of the expression repressor to the MYC locus results in a significant reduction in expression of MYC for a 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 for a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cell divisions, as measured by ELISA or as described in any of examples 2-7 or 9.

[1008] 90. The composition of any of the preceding embodiments, wherein binding of the expression repressor to the MYC locus results in a significant decrease in MYC expression 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.

[1009] 91. The composition of any one of embodiments 1-23 or 36-90, wherein the targeting moiety binds to a human genomic locus.

[1010] 92. The composition of any one of embodiments 24-43, 50, 52, 54, 57, 58, 60-63, 67-69, or 71-90, wherein the targeting portion binds to a mouse genomic locus.

[1011] 93. The composition of any one of the preceding embodiments, wherein binding of the expression repressor to the MYC locus reduces the viability of cells (e.g., cancer cells) comprising the MYC locus.

[1012] 94. The composition of any one of the preceding embodiments, wherein contacting a plurality of cells with the composition reduces the viability of the plurality of cells.

[1013] 95. The composition of any of the preceding embodiments, wherein the viability is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% compared to the viability in the absence of the first expression repressor, e.g., as measured by CellTiter Glo or as described in any of Examples 2-7.

[1014] 96. The composition of any of the preceding embodiments, wherein administration of the composition results in apoptosis in 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).

[1015] 97. The composition 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).

[1016] 98. The composition of any one of the preceding embodiments, wherein administration of the composition results in a reduction in MYC mRNA levels in target cells (eg, cancer cells) to less than 70%, 605%, 50%, or 40% of pre-administration levels.

[1017] 99. The composition of any preceding embodiment, wherein the plurality of cells comprises a plurality of cancer cells and a plurality of non-cancerous cells and / or a plurality of infected cells and a plurality of uninfected cells.

[1018] 100. The composition of any preceding embodiment, wherein contacting the plurality of cells with the composition reduces the viability of the plurality of cancer cells more than the composition reduces the viability of the plurality of non-cancerous cells.

[1019] 101. The composition of any preceding embodiment, wherein contacting the plurality of cells with the composition reduces the viability of the plurality of cancer cells by 1.05x (i.e., 1.05-fold), 1.1x, 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, 10x, 20x, 50x, or 100x more than the reduction in viability of the plurality of non-cancerous cells.

[1020] 102. The composition of any one of embodiments 93-100, wherein the cancer cells are gastric cancer cells, gastrointestinal cancer cells, colorectal cancer cells, pancreatic cancer cells, or liver cancer cells.

[1021] 103. The composition of any one of embodiments 93-102, 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 cancer, or pancreatic cancer.

[1022] 104. The composition of any preceding embodiment, which, when contacted with a plurality of infected cells and a plurality of uninfected cells, reduces the viability of the plurality of infected cells more than it reduces the viability of the plurality of uninfected cells.

[1023] 105. The composition of any preceding embodiment, wherein the infection is a viral infection.

[1024] 106. The composition of embodiment 105, wherein the viral infection is hepatitis, such as hepatitis B.

[1025] 107. The composition of any of embodiments 93-106, wherein the infected cells are human hepatocytes.

[1026] 108. The composition of any preceding embodiment, wherein the expression suppressor has an EC50 of 0.04-0.4, 0.04-0.1, 0.1-0.2, 0.2-0.3, or 0.3-0.4 μg / mL when tested in a cancer cell (e.g., HCC cell) viability assay using LNPs delivering mRNA encoding the expression suppressor (e.g., in an assay according to Example 12).

[1027] 109. The composition of any one of embodiments 1-107, which has an EC50 of 0.1-2.5, 0.5-2.2, 1.0-1.5, 1.2-2 μg / mL when tested in a cancer cell viability assay.

[1028] 110. The composition of any preceding embodiment, wherein the expression suppressor has an EC50 of 0.004-0.08, 0.004-0.01, 0.01-0.02, 0.02-0.04, or 0.04-0.08 μg / mL when tested in an assay using LNPs delivering mRNA encoding the expression suppressor for reducing MYC mRNA levels in cancer cells (e.g., HCC cells), e.g., in an assay according to Example 12.

[1029] 111. The composition of any preceding embodiment, having an EC50 of 0.04-0.1, 0.04-0.09, 0.05-0.09, or 0.06-0.8 μg / mL when tested in an assay for reducing MYC mRNA levels in cancer cells.

[1030] 112. The composition of any of the preceding embodiments, which reduces the level of protein encoded by a target 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 untreated cells.

[1031] 113. The composition of any preceding embodiment, which is capable of reducing tumor volume, eg, in a human subject or a mammalian model.

[1032] 114. The composition of any of the preceding embodiments, which is capable of reducing tumor volume to a similar or greater extent than 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 at a dose of 3 mg / kg every 5 days.

[1033] 115. The expression suppressor of any of the preceding embodiments, wherein the composition 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 at 1 mg / kg, 1.5 mg / kg, or 3 mg / kg every 5 days for 4 doses, followed by every 3 days for 3 doses.

[1034] 116. The composition of any preceding embodiment, wherein tumor volume is reduced by at least about 10%, 20%, 30% or 40% compared to a control treated with PBS, eg, at day 20 after initiation of treatment.

[1035] 117. The composition of any one of embodiments 114-116, wherein the chemotherapeutic agent is sorafenib or cisplatin.

[1036] 118. The composition of any preceding embodiment, wherein the composition is capable of reducing tumor volume to a similar or greater extent than a small molecule MYC inhibitor.

[1037] 119. The composition 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 MYCi975, e.g., at day 20 after initiation of treatment.

[1038] 120. The composition of any preceding embodiment, which causes no weight loss, or causes less than 3%, 2% or 1% weight loss compared to the start of treatment.

[1039] 121. The composition of any preceding embodiment, further comprising a second nucleic acid encoding a second expression repressor, eg, a second expression repressor described herein, eg, a second expression repressor of any preceding embodiment.

[1040] 122. A composition comprising:

[1041] (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 transcriptional regulatory element (e.g., a promoter, enhancer, or transcription start site (TSS)) operably linked to a MYC gene or a sequence proximal to the transcriptional regulatory element,

[1042] (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)):

[1043] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[1044] (i') compounds having the general structure of formula (I)

[1045]

[1046] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[1047] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[1048] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[1049] G 3 It is C1-C 24Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[1050] R a Is H or C1-C 12 alkyl;

[1051] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[1052] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[1053] R 4 It is C1-C 12 alkyl;

[1054] R 5 is H or C1-C6 alkyl;

[1055] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[1056] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[1057] x is 0, 1, or 2;

[1058] (i") compounds having the general structure of Formula (IX):

[1059]

[1060] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[1061] L 1 and L2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[1062] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[1063] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[1064] G 3 is C1-C6 alkylene;

[1065] R a Is H or C1-C 12 alkyl;

[1066] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1067] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1068] R 3a and R 3bis independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1069] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1070] R 5 and R 6 are each independently H or methyl;

[1071] R 7 It is C4-C 20 alkyl;

[1072] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[1073] a, b, c, and d are each independently an integer from 1 to 24; and

[1074] x is 0, 1, or 2;

[1075] as well as,

[1076] (i'") compounds having the general structure of formula (XI):

[1077]

[1078] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[1079] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[1080] R 2 and R3 are each independently an optionally substituted C1-C 36 alkyl;

[1081] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[1082] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[1083] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[1084] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[1085] n is an integer greater than 0;

[1086] (ii) a second compound having the general structure of formula (II):

[1087]

[1088] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[1089] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[1090] The mean value of y ranges from 30 to 60;

[1091] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1092] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and

[1093] (3) a second nucleic acid encoding a second expression repressor comprising a second targeting portion and optionally a second effector portion, wherein the second expression repressor binds to an anchor sequence comprising anchor sequence-mediated conjugation (ASMC) of the MYC gene, or to a sequence proximal to the anchor sequence.

[1094] 123. The composition of embodiment 121 or 122,

[1095] wherein the transcriptional regulatory element comprises a promoter, and

[1096] The anchor sequence comprises a CTCF binding motif.

[1097] 124. The composition of any of embodiments 121-123, wherein the second expression repressor binds to a downstream region adjacent to the CTCF binding motif.

[1098] 125. The composition of any of embodiments 121-123, wherein the second expression repressor binds to an upstream region adjacent to the CTCF binding motif.

[1099] 126. A composition as described in any of embodiments 121-125, wherein

[1100] The first expression repressor comprises a targeting moiety that binds to a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 2, 3, 4, 71, 72, 75-86, or 200-206, or a nucleic acid sequence of CCGCCATNTT or AANATGGCGG, wherein N is any nucleotide; and

[1101] The second expression repressor comprises a targeting portion that binds to a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 2, 3, 4, 71, 72, 74-86, or 200-206, or a nucleic acid sequence of CCGCCATNTT or AANATGGCGG, wherein N is any nucleotide.

[1102] 127. A composition as described in any of embodiments 121-126, wherein

[1103] The first expression repressor binds to a targeting portion of a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of any one of SEQ ID NOs: 96-110.

[1104] 128. The composition of any one of embodiments 121-127, wherein

[1105] The first expression repressor binds to a targeting portion of 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

[1106] The second expression repressor binds to a targeting portion of a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO:77.

[1107] 129. A composition comprising:

[1108] (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 MYC gene or a sequence proximal to the promoter,

[1109] (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)):

[1110] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[1111] (i') compounds having the general structure of formula (I)

[1112]

[1113] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[1114] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[1115] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[1116] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[1117] R a Is H or C1-C 12 alkyl;

[1118] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[1119] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[1120] R 4 It is C1-C 12 alkyl;

[1121] R 5 is H or C1-C6 alkyl;

[1122] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[1123] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[1124] x is 0, 1, or 2;

[1125] (i") compounds having the general structure of Formula (IX):

[1126]

[1127] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[1128] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[1129] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[1130] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[1131] G 3 is C1-C6 alkylene;

[1132] R a Is H or C1-C 12 alkyl;

[1133] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1134] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2bTogether with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1135] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1136] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1137] R 5 and R 6 are each independently H or methyl;

[1138] R 7 It is C4-C 20 alkyl;

[1139] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[1140] a, b, c, and d are each independently an integer from 1 to 24; and

[1141] x is 0, 1, or 2;

[1142] as well as,

[1143] (i'") compounds having the general structure of formula (XI):

[1144]

[1145] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[1146] R 1 is an optionally substituted C1-C 24Alkyl or optionally substituted C2-C 24 alkenyl;

[1147] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[1148] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[1149] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[1150] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[1151] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[1152] n is an integer greater than 0;

[1153] (ii) a second compound having the general structure of formula (II):

[1154]

[1155] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[1156] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[1157] The mean value of y ranges from 30 to 60;

[1158] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1159] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and

[1160] (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 (eg, a super enhancer) of the MYC gene.

[1161] 130. The composition of embodiment 129, wherein

[1162] The first expression repressor binds to a targeting portion of a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 204, and

[1163] The second expression repressor binds to a targeting portion of a genomic locus comprising at least 16, 17, 18, 19 or 20 nucleotides of the sequence of any one of SEQ ID NO: 199 or 201.

[1164] 131. A composition for reducing MYC expression, the composition comprising:

[1165] (1) A first nucleic acid encoding a first expression repressor, the first expression repressor comprising:

[1166] i) a first targeting moiety having an amino acid sequence according to SEQ ID NO: 13, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position, and

[1167] ii) a first effector moiety having an amino acid sequence according to SEQ ID NO: 19 or 87, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position,

[1168] (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)):

[1169] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[1170] (i') compounds having the general structure of formula (I)

[1171]

[1172] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[1173] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[1174] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[1175] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[1176] R a Is H or C1-C 12 alkyl;

[1177] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[1178] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[1179] R 4 It is C1-C 12 alkyl;

[1180] R 5 is H or C1-C6 alkyl;

[1181] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[1182] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[1183] x is 0, 1, or 2;

[1184] (i") compounds having the general structure of Formula (IX):

[1185]

[1186] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[1187] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[1188] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[1189] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[1190] G3 is C1-C6 alkylene;

[1191] R a Is H or C1-C 12 alkyl;

[1192] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1193] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1194] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1195] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1196] R 5 and R 6 are each independently H or methyl;

[1197] R 7 It is C4-C 20alkyl;

[1198] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[1199] a, b, c, and d are each independently an integer from 1 to 24; and

[1200] x is 0, 1, or 2;

[1201] as well as,

[1202] (i'") compounds having the general structure of formula (XI):

[1203]

[1204]

[1205] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[1206] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[1207] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[1208] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[1209] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[1210] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[1211] G 2 and G3 are each independently -(C=O)O- or -O(C=O)-; and

[1212] n is an integer greater than 0;

[1213] (ii) a second compound having the general structure of formula (II):

[1214]

[1215] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[1216] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[1217] The mean value of y ranges from 30 to 60;

[1218] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1219] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and

[1220] (3) a second nucleic acid encoding a second expression repressor, the second expression repressor comprising:

[1221] i) a second targeting moiety having an amino acid sequence according to SEQ ID NO: 7 169 or 171, or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position, and

[1222] ii) a second effector moiety having an amino acid sequence according to SEQ ID NO: 18, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

[1223] 132. The composition of embodiment 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 at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, e.g., located at the N-terminus of the first targeting moiety.

[1224] 133. The composition of embodiment 131 or 132, wherein the first expression repressor further comprises a second nuclear localization signal, e.g., a nucleoprotein NLS, e.g., a sequence according to SEQ ID NO: 136 or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, e.g., located at the C-terminus of the first effector portion.

[1225] 134. The composition of any of embodiments 131-133, wherein the 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 at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, e.g., located at the N-terminus of the second targeting moiety.

[1226] 135. The composition of any of embodiments 131-134, wherein the second expression repressor further comprises a second nuclear localization signal, e.g., a nucleoplasmic protein NLS, e.g., a sequence according to SEQ ID NO: 136 or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, e.g., located at the C-terminus of the second targeting moiety.

[1227] 136. The composition of any of embodiments 131-135, wherein the first expression repressor further comprises a first linker 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 at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1228] 137. The composition of any of embodiments 131-136, wherein the second expression repressor further comprises a second linker 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 at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1229] 138. The composition of any one of embodiments 131-137, wherein the first expression repressor further comprises an amino acid sequence at the C-terminus of the first effector portion, such as a sequence of up to 30, 25, 20 or 18 amino acids, such as a sequence according to SEQ ID NO: 126 or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1230] 139. The composition of any one of embodiments 131-135, wherein the second expression repressor further comprises an amino acid sequence at the N-terminus of the second targeting portion, such as a sequence of up to 30, 25, 20 or 18 amino acids, or amino acid P.

[1231] 140. The composition of any one 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 at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1232] 141. The composition 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 at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1233] 142. The composition 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 at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1234] 143. The composition 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 at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1235] 144. The composition of any one 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 at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1236] 145. The composition of any one of embodiments 131-143, wherein the second expression repressor has an amino acid sequence according to SEQ ID NO: 179, 185, or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1237] 146. The composition of any one of embodiments 121-145, wherein the first nucleic acid and the second nucleic acid are contained within the same nucleic acid molecule.

[1238] 147. The composition of any one of embodiments 121-145, wherein the first nucleic acid and the second nucleic acid are in different nucleic acid molecules.

[1239] 148. The composition of any one of embodiments 121-147, wherein the first nucleic acid and the second nucleic acid are contained within the same LNP.

[1240] 149. The composition of any one of embodiments 121-145 or 147, wherein the first nucleic acid and the second nucleic acid are in different LNPs.

[1241] 150. A composition for reducing MYC expression, the composition comprising:

[1242] (1) A nucleic acid comprising:

[1243] a) a first region encoding a first expression repressor, the first expression repressor comprising:

[1244] i) a first targeting moiety having an amino acid sequence according to SEQ ID NO: 13, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position, and

[1245] ii) a first effector moiety having an amino acid sequence according to SEQ ID NO: 19 or 87, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position, and

[1246] b) a second region encoding a second expression repressor, the second expression repressor comprising:

[1247] i) a second targeting moiety having an amino acid sequence according to SEQ ID NO: 7, or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position, and

[1248] ii) a second effector moiety having an amino acid sequence according to SEQ ID NO: 18, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position; and

[1249] (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)):

[1250] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[1251] (i') compounds having the general structure of formula (I)

[1252]

[1253] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[1254] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[1255] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[1256] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[1257] R a Is H or C1-C 12 alkyl;

[1258] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[1259] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[1260] R 4 It is C1-C 12 alkyl;

[1261] R 5 is H or C1-C6 alkyl;

[1262] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[1263] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[1264] x is 0, 1, or 2;

[1265] (i") compounds having the general structure of Formula (IX):

[1266]

[1267] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[1268] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[1269] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[1270] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[1271] G 3 is C1-C6 alkylene;

[1272] R a Is H or C1-C 12 alkyl;

[1273] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1274] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1275] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1276] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1277] R 5 and R 6 are each independently H or methyl;

[1278] R 7 It is C4-C 20 alkyl;

[1279] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[1280] a, b, c, and d are each independently an integer from 1 to 24; and

[1281] x is 0, 1, or 2;

[1282] as well as,

[1283] (i'") compounds having the general structure of formula (XI):

[1284]

[1285] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[1286] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[1287] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[1288] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[1289] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[1290] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[1291] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[1292] n is an integer greater than 0;

[1293] (ii) a second compound having the general structure of formula (II):

[1294]

[1295] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[1296] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[1297] The mean value of y ranges from 30 to 60;

[1298] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1299] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1300] 151. The composition of embodiment 150, wherein the first region is 5' to the second region.

[1301] 152. The composition of embodiment 150, wherein the first region is 3' to the second region.

[1302] 153. The composition 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 at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, e.g., located at the N-terminus of the first targeting moiety.

[1303] 154. The composition of any of embodiments 151-153, wherein the first region further comprises a nucleotide sequence encoding a second nuclear localization signal, e.g., a nucleoplasmic protein NLS, e.g., a sequence according to SEQ ID NO: 136 or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, e.g., located at the C-terminus of the first effector portion.

[1304] 155. A composition as described in any of embodiments 151-154, wherein the second region further comprises a nucleotide sequence encoding a first nuclear localization signal, which is, for example, SV40NLS, for example, a sequence according to SEQ ID NO: 135 or a sequence having at least 80%, 85%, 90%, 95%, 99% or 100% identity thereto, for example, located at the N-terminus of the second targeting portion.

[1305] 156. The composition of any of embodiments 151-155, wherein the second region further comprises a nucleotide sequence encoding a second nuclear localization signal, e.g., a nucleoplasmic protein NLS, e.g., a sequence according to SEQ ID NO: 136 or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, e.g., located at the C-terminus of the second effector portion.

[1306] 157. The composition of any of embodiments 151-156, wherein the first region further comprises a nucleotide sequence encoding a first linker positioned between the first targeting portion and the first effector portion, wherein optionally the first linker has an amino acid sequence according to SEQ ID NO: 137 or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1307] 158. The composition of any of embodiments 151-157, wherein the second region further comprises a nucleotide sequence encoding a second linker positioned between the second targeting portion and the second effector portion, wherein optionally the second linker has an amino acid sequence according to SEQ ID NO: 138 or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1308] 159. The composition of any of embodiments 151-158, wherein the first region further comprises a nucleotide sequence encoding an amino acid sequence at the C-terminus of the first effector portion, which amino acid sequence is, for example, a sequence of up to 30, 25, 20 or 18 amino acids, such as a sequence according to SEQ ID NO: 126, or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1309] 160. A composition as described in any of embodiments 151-159, wherein the second region further comprises a nucleotide sequence encoding an amino acid sequence at the N-terminus of the second targeting portion, for example, a sequence of up to 30, 25, 20 or 18 amino acids, or amino acid P.

[1310] 161. The composition of any of embodiments 151-160, wherein the first expression repressor has an amino acid sequence according to SEQ ID NO: 30 or 129, or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1311] 162. The composition of any one of embodiments 151-161, wherein the second expression repressor has an amino acid sequence according to SEQ ID NO: 24, or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1312] 163. The composition 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 that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs from it in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1313] 164. The composition of any of embodiments 151-163, wherein the first region comprises a nucleotide sequence encoding the first effector portion, wherein the nucleotide sequence encoding the first effector portion comprises a sequence according to SEQ ID NO: 52 or 132, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1314] 165. The composition of any of embodiments 151-164, wherein the 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 that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs from it in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

[1315] 166. The composition of any of embodiments 151-165, wherein the first region comprises a nucleotide sequence encoding the first effector portion, wherein the nucleotide sequence encoding the first effector portion comprises a sequence according to SEQ ID NO: 51, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1316] 167. The composition of any of embodiments 151-166, wherein the first region comprises a nucleotide sequence according to SEQ ID NO: 63 or 130, or a sequence that is at least 80, 85, 90, 95, 99, or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position, wherein a poly A sequence is optional.

[1317] 168. The composition of any of embodiments 151-167, wherein the second region comprises a nucleotide sequence according to SEQ ID NO: 57, or a sequence that is at least 80, 85, 90, 95, 99, or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position, wherein a poly A sequence is optional.

[1318] 169. A composition for reducing MYC expression, the composition comprising:

[1319] (1) A nucleic acid comprising:

[1320] a) a first region encoding a first expression repressor, the first expression repressor comprising:

[1321] i) a first targeting moiety having an amino acid sequence according to SEQ ID NO: 13, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position, and

[1322] ii) a first effector moiety having an amino acid sequence according to SEQ ID NO: 19 or 87, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position, and

[1323] b) a second region encoding a second expression repressor, the second expression repressor comprising:

[1324] i) a second targeting moiety having an amino acid sequence according to SEQ ID NO: 169, or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position, and

[1325] ii) a second effector moiety having an amino acid sequence according to SEQ ID NO: 18, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position; and

[1326] (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)):

[1327] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[1328] (i') compounds having the general structure of formula (I)

[1329]

[1330] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[1331] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[1332] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[1333] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[1334] R a Is H or C1-C 12 alkyl;

[1335] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[1336] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[1337] R 4 It is C1-C 12 alkyl;

[1338] R 5 is H or C1-C6 alkyl;

[1339] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[1340] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[1341] x is 0, 1, or 2;

[1342] (i") compounds having the general structure of Formula (IX):

[1343]

[1344] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[1345] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[1346] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[1347] G 2is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[1348] G 3 is C1-C6 alkylene;

[1349] R a Is H or C1-C 12 alkyl;

[1350] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1351] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1352] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1353] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1354] R 5 and R6 are each independently H or methyl;

[1355] R 7 It is C4-C 20 alkyl;

[1356] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[1357] a, b, c, and d are each independently an integer from 1 to 24; and

[1358] x is 0, 1, or 2;

[1359] as well as,

[1360] (i'") compounds having the general structure of formula (XI):

[1361]

[1362] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[1363] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[1364] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[1365] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[1366] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[1367] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[1368] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[1369] n is an integer greater than 0;

[1370] (ii) a second compound having the general structure of formula (II):

[1371]

[1372] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[1373] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[1374] The mean value of y ranges from 30 to 60;

[1375] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1376] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1377] 170. A composition for reducing MYC expression, the composition comprising:

[1378] (1) A nucleic acid comprising:

[1379] a) a first region encoding a first expression repressor, the first expression repressor comprising:

[1380] i) a first targeting moiety having an amino acid sequence according to SEQ ID NO: 13, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position, and

[1381] ii) a first effector moiety having an amino acid sequence according to SEQ ID NO: 19 or 87, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position, and

[1382] b) a second region encoding a second expression repressor, the second expression repressor comprising:

[1383] i) a second targeting moiety having an amino acid sequence according to SEQ ID NO: 171, or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position, and

[1384] ii) a second effector moiety having an amino acid sequence according to SEQ ID NO: 18, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs therefrom in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position; and

[1385] (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)):

[1386] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[1387] (i') compounds having the general structure of formula (I)

[1388]

[1389] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[1390] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NRa -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[1391] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[1392] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[1393] R a Is H or C1-C 12 alkyl;

[1394] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[1395] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[1396] R 4 It is C1-C 12 alkyl;

[1397] R 5 is H or C1-C6 alkyl;

[1398] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[1399] G 4 It is C1-C 24 Alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[1400] x is 0, 1, or 2;

[1401] (i") compounds having the general structure of Formula (IX):

[1402]

[1403] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[1404] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[1405] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[1406] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[1407] G 3 is C1-C6 alkylene;

[1408] R a Is H or C1-C 12 alkyl;

[1409] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1410] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1411] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1412] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1413] R 5 and R 6 are each independently H or methyl;

[1414] R 7 It is C4-C 20 alkyl;

[1415] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[1416] a, b, c, and d are each independently an integer from 1 to 24; and

[1417] x is 0, 1, or 2;

[1418] as well as,

[1419] (i'") compounds having the general structure of formula (XI):

[1420]

[1421] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[1422] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[1423] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[1424] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[1425] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[1426] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[1427] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[1428] n is an integer greater than 0;

[1429] (ii) a second compound having the general structure of formula (II):

[1430]

[1431] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[1432] R 6 and R 7each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[1433] The mean value of y ranges from 30 to 60;

[1434] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1435] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1436] 171. The composition of embodiment 169 or 170, wherein the first region is 5' to the second region.

[1437] 172. The composition of embodiment 169 or 170, wherein the first region is 3' to the second region.

[1438] 173. A composition as described in any of embodiments 169-172, wherein the first region further comprises a nucleotide sequence encoding a first nuclear localization signal, which is, for example, SV40NLS, for example, a sequence according to SEQ ID NO: 135 or a sequence having at least 80%, 85%, 90%, 95%, 99% or 100% identity thereto, for example, located at the N-terminus of the first targeting portion.

[1439] 174. The composition of any of embodiments 169-173, wherein the first region further comprises a nucleotide sequence encoding a second nuclear localization signal, e.g., a nucleoplasmic protein NLS, e.g., a sequence according to SEQ ID NO: 136 or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, e.g., located at the C-terminus of the first effector portion.

[1440] 175. A composition as described in any of embodiments 169-174, wherein the second region further comprises a nucleotide sequence encoding a first nuclear localization signal, which is, for example, SV40NLS, for example, a sequence according to SEQ ID NO: 135 or a sequence having at least 80%, 85%, 90%, 95%, 99% or 100% identity thereto, for example, located at the N-terminus of the second targeting portion.

[1441] 176. The composition of any of embodiments 169-175, wherein the second region further comprises a nucleotide sequence encoding a second nuclear localization signal, e.g., a nucleoplasmic protein NLS, e.g., a sequence according to SEQ ID NO: 136 or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, e.g., located at the C-terminus of the second effector portion.

[1442] 177. The composition of any of embodiments 169-176, wherein the first region further comprises a nucleotide sequence encoding a first linker positioned between the first targeting portion and the first effector portion, wherein optionally the first linker has an amino acid sequence according to SEQ ID NO: 137 or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1443] 178. The composition of any of embodiments 169-177, wherein the second region further comprises a nucleotide sequence encoding a second linker positioned between the second targeting portion and the second effector portion, wherein optionally the second linker has an amino acid sequence according to SEQ ID NO: 138 or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1444] 179. The composition of any of embodiments 169-177, wherein the first region further comprises a nucleotide sequence encoding an amino acid sequence at the C-terminus of the first effector portion, the amino acid sequence being, for example, a sequence of up to 30, 25, 20 or 18 amino acids, such as a sequence according to SEQ ID NO: 126, or a sequence having at least 80%, 85%, 90%, 95%, 99% or 100% identity thereto.

[1445] 180. The composition of any one of embodiments 169-179, wherein the second region further comprises a nucleotide sequence encoding an amino acid sequence at the N-terminus of the second targeting portion, e.g., a sequence of up to 30, 25, 20, or 18 amino acids, or amino acid P.

[1446] 181. The composition of any of embodiments 169-180, wherein the first expression repressor has an amino acid sequence according to SEQ ID NO: 30 or 129, or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1447] 182. The composition of any of embodiments 150-181, wherein the second expression repressor has an amino acid sequence according to SEQ ID NO: 177 or 183, or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1448] 183. The composition 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 at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1449] 184. The composition of any of embodiments 150-183, wherein the first expression repressor comprises an amino acid sequence according to SEQ ID NO: 30 or 129, or a sequence at least 80%, 85%, 90%, 95%, 99% or 100% identical 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 at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto.

[1450] 185. The composition 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 that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs from it in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1451] 186. The composition of any of embodiments 150-185, wherein the first region comprises a nucleotide sequence encoding the first effector portion, wherein the nucleotide sequence encoding the first effector portion comprises a sequence according to SEQ ID NO: 52 or 132, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1452] 187. The composition of any of embodiments 150-186, wherein the second region comprises a nucleotide sequence according to SEQ ID NO: 173, or a sequence that is at least 80, 85, 90, 95, 99, or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position, wherein a poly A sequence is optional.

[1453] 188. The composition of any of embodiments 150-187, wherein the second region comprises a nucleotide sequence according to SEQ ID NO: 175, or a sequence that is at least 80, 85, 90, 95, 99, or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position, wherein a poly A sequence is optional.

[1454] 189. The composition of any of embodiments 150-188, wherein the second region comprises a nucleotide sequence encoding the second effector portion, wherein the nucleotide sequence encoding the second effector portion comprises a sequence according to SEQ ID NO: 51, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1455] 190. The composition of any of embodiments 150-189, wherein the first region comprises a nucleotide sequence according to SEQ ID NO: 63 or 130, or a sequence that is at least 80, 85, 90, 95, 99, or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position, wherein a poly A sequence is optional.

[1456] 191. The composition of any of embodiments 150-190, wherein the second region comprises a nucleotide sequence according to SEQ ID NO: 189, or a sequence that is at least 80, 85, 90, 95, 99, or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position, wherein a poly A sequence is optional.

[1457] 192. The composition of any of embodiments 150-191, wherein the second region comprises a nucleotide sequence according to SEQ ID NO: 194, or a sequence that is at least 80, 85, 90, 95, 99, or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position, wherein a poly A sequence is optional.

[1458] 193. The composition of any of embodiments 150-192, wherein the first region comprises a nucleotide sequence encoding the first effector portion, wherein the nucleotide sequence encoding the first effector portion comprises a sequence according to SEQ ID NO: 52 or 132, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1459] 194. The composition of any of embodiments 150-193, 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 that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs from it in no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

[1460] 195. The composition of any of embodiments 150-194, wherein the second region comprises a nucleotide sequence encoding the second effector portion, wherein the nucleotide sequence encoding the second effector portion comprises a sequence according to SEQ ID NO: 51, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1461] 196. The composition of any of embodiments 150-195, wherein the second region comprises a nucleotide sequence according to SEQ ID NO: 189, or a sequence that is at least 80, 85, 90, 95, 99, or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1462] 197. The composition of any of embodiments 150-196, wherein the second region comprises a nucleotide sequence according to SEQ ID NO: 194, or a sequence that is at least 80, 85, 90, 95, 99, or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1463] 198. The composition of any of embodiments 150-197, wherein the nucleic acid has a nucleotide sequence according to SEQ ID NO: 93, 112, or a sequence that is at least 80, 85, 90, 95, 99, or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1464] 199. The composition of any of embodiments 150-198, wherein the nucleic acid has a nucleotide sequence according to SEQ ID NO: 196 or 197, or a sequence that is at least 80, 85, 90, 95, 99, or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1465] 200. The composition of any one of embodiments 121-199, wherein the first expression repressor comprises the first effector portion.

[1466] 201. The composition of any of embodiments 121-200, wherein the second expression repressor comprises the second effector portion.

[1467] 202. The composition of any of embodiments 121-201, wherein the first effector moiety has an amino acid sequence that is different from the second effector moiety.

[1468] 203. The composition of any one of embodiments 121-202, wherein the first effector moiety is a persistent effector moiety.

[1469] 204. The composition of any of embodiments 121-128 or 150-203, wherein the first effector moiety is a transient effector moiety.

[1470] 205. The composition of any of embodiments 121-204, wherein the first effector moiety is an epigenetic modification moiety.

[1471] 206. The composition of any one of embodiments 121-149, 169-203, or 205, wherein the first effector moiety comprises a histone methyltransferase.

[1472] 207. The composition of embodiment 206, wherein the first effector portion comprises a protein selected from the group consisting of 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 one thereof, e.g., a SET domain of any one thereof.

[1473] 208. The composition of any one of embodiments 121-149, 169-203, or 205, wherein the first effector moiety comprises a histone demethylase (eg, a lysine demethylase).

[1474] 209. The composition of embodiment 208, wherein the first effector portion comprises a protein selected from the group consisting of KDM1A (i.e., LSD1), KDM1B (i.e., LSD2), KDM2A, KDM2B, KDM5A, KDM5B, KDM5C, KDM5D, KDM4B, NO66 (or a functional variant or fragment of any one thereof).

[1475] 210. The composition of any one of embodiments 121-149, 169-203, or 205, wherein the first effector moiety comprises a histone deacetylase.

[1476] 211. The composition of embodiment 210, wherein the first effector portion comprises a protein selected from the group consisting of: 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 one thereof.

[1477] 212. The composition of any one of embodiments 121-203 or 206, wherein the first effector portion comprises a DNA methyltransferase.

[1478] 213. The composition of embodiment 212, wherein the first effector portion comprises a protein selected from the group consisting of: MQ1, DNMT1, DNMT3A1, DNMT3A2, DNMT3B1, DNMT3B2, DNMT3B3, DNMT3B4, DNMT3B5, DNMT3B6, DNMT3L, or a functional variant or fragment of any one thereof.

[1479] 214. The composition of any one of embodiments 121-149, 166-202, or 204, wherein the first effector moiety is a transcriptional repressor moiety, eg, comprises a transcriptional repressor.

[1480] 215. The composition of embodiment 204 or 205, wherein the first effector portion comprises a protein selected from the group consisting of KRAB, MeCP2, HP1, RBBP4, REST, FOG1, SUZ12, or a functional variant or fragment of any one thereof.

[1481] 216. The composition of any one of embodiments 121-215, wherein the first effector moiety promotes epigenetic modification of a transcriptional regulatory element or a sequence proximal thereto.

[1482] 217. The composition of any one of embodiments 121-216, wherein the first effector portion catalyzes epigenetic modification of a transcriptional regulatory element or a proximal sequence thereof.

[1483] 218. The composition of any one of embodiments 121-128, 200, or 203-217, wherein the second expression repressor does not comprise an effector portion.

[1484] 219. The composition of any of embodiments 121-218, wherein the second effector moiety is a transient effector moiety.

[1485] 220. The composition of any of embodiments 121-128 or 200-217, wherein the second effector moiety is a persistent effector moiety.

[1486] 221. The composition of any one of embodiments 121-217 or 220, wherein the second effector moiety is an epigenetic modification moiety.

[1487] 222. The composition of any one of embodiments 121-128, 200-217, 220, or 221, wherein the second effector moiety comprises a histone methyltransferase.

[1488] 223. The composition of embodiment 222, wherein the second effector portion comprises a protein selected from the group consisting of 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 one thereof, e.g., a SET domain of any one thereof.

[1489] 224. The composition of any one of embodiments 121-128, 200-217, 220, or 221, wherein the second effector moiety comprises a histone demethylase (eg, a lysine demethylase).

[1490] 225. The composition of embodiment 224, wherein the second effector portion comprises a protein selected from the group consisting of KDM1A (i.e., LSD1), KDM1B (i.e., LSD2), KDM2A, KDM2B, KDM5A, KDM5B, KDM5C, KDM5D, KDM4B, NO66 (or a functional variant or fragment of any one thereof).

[1491] 226. The composition of any one of embodiments 121-128, 200-217, 220, or 221, wherein the second effector moiety comprises a histone deacetylase.

[1492] 227. The composition of embodiment 226, wherein the second effector portion comprises a protein selected from the group consisting of: 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 one thereof.

[1493] 228. The composition of any one of embodiments 121-128, 200-217, 220, or 221, wherein the second effector moiety comprises a DNA methyltransferase.

[1494] 229. The composition of embodiment 228, wherein the second effector portion comprises a protein selected from the group consisting of: MQ1, DNMT1, DNMT3A1, DNMT3A2, DNMT3B1, DNMT3B2, DNMT3B3, DNMT3B4, DNMT3B5, DNMT3B6, DNMT3L, or a functional variant or fragment of any one thereof.

[1495] 230. The composition of any one of embodiments 121-217 or 219, wherein the second effector moiety is a transcriptional repressor moiety.

[1496] 231. The composition of embodiment 230, wherein the second effector moiety promotes epigenetic modification of the anchor sequence or a sequence proximal thereto.

[1497] 232. The composition of embodiment 229 or 230, wherein the second effector portion binds one or more endogenous epigenetic modifying proteins or one or more endogenous transcriptional modifying proteins.

[1498] 233. The composition of any one of embodiments 229-232, wherein the second effector portion comprises KRAB, MeCP2, HP1, RBBP4, REST, FOG1, SUZ12, or a functional variant or fragment of any one thereof.

[1499] 234. The composition of any one of embodiments 121-203, 205-213, 216, 217, 219, or 230-233, wherein:

[1500] The first effector moiety is a persistent effector moiety, and

[1501] The second effector moiety is a transient effector moiety.

[1502] 235. The composition of embodiment 234, wherein the first effector moiety is an epigenetic modification moiety.

[1503] 236. The composition of embodiment 233 or 234, wherein the second effector moiety is a transcriptional repressor moiety.

[1504] 237. The composition of any one of embodiments 233-236, wherein:

[1505] The first effector moiety comprises a histone methyltransferase, a histone demethylase, a histone deacetylase, a DNA methyltransferase, a functional variant or fragment of any one thereof, or any combination thereof, and

[1506] The second effector moiety comprises a transcriptional repressor or a functional variant or fragment of any thereof.

[1507] 238. The composition of any one of embodiments 212-128, 196, 200, 203, 205-213, or 216-218, wherein: the first effector portion comprises a histone methyltransferase, a histone demethylase, a histone deacetylase, a DNA methyltransferase, a functional variant or fragment of any one thereof, or any combination thereof, and

[1508] The second expression repressor does not comprise a second effector moiety.

[1509] 239. The composition of any one of embodiments 121-128, 203-213, 216, 217, 219, 220, or 230-236, wherein:

[1510] The first effector portion comprises 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, HDA C5, 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 one thereof, or any combination thereof, and

[1511] The second effector moiety comprises KRAB, MeCP2, HP1, RBBP4, REST, FOG1, SUZ12, a functional variant or fragment of any one thereof, or any combination thereof.

[1512] 240. The composition of any one of embodiments 121-203, 205, 212, 213, 216, 217, 219, 221, 230-237, or 239, wherein:

[1513] The first effector moiety comprises a DNA methyltransferase, and

[1514] The second effector moiety comprises a transcriptional repressor.

[1515] 241. The composition of any one of embodiments 121-128, 200, 203, 206, 212, 213, 216-218, or 238, wherein:

[1516] The first effector moiety comprises a DNA methyltransferase, and

[1517] The second expression repressor does not comprise a second effector moiety.

[1518] 242. The composition of any of embodiments 121-128, 206, 212, 213, or 216-241, wherein the first effector portion comprises MQ1, DNMT1, DNMT3A1, DNMT3A2, DNMT3B1, DNMT3B2, DNMT3B3, DNMT3B4, DNMT3B5, DNMT3B6, DNMT3L, or a functional variant or fragment of any one thereof.

[1519] 243. The composition of any one of embodiments 121-217, 220, 230-240, or 242, wherein the second effector portion comprises KRAB, MeCP2, HP1, RBBP4, REST, FOG1, SUZ12, or a functional variant or fragment of any one thereof.

[1520] 244. The composition of any one of embodiments 121-217, 212, 213, 219, 230-240, 242, or 243, wherein:

[1521] The first effector portion comprises MQ1 or a functional variant or fragment thereof, and

[1522] The second effector comprises KRAB or a functional variant or fragment of any one thereof.

[1523] 245. The composition of any one of embodiments 121-128, 200, 203, 205-213, 216-218, 235, 238, 241 or 242, wherein:

[1524] The first effector portion comprises MQ1 or a functional variant or fragment thereof, and

[1525] The second expression repressor does not comprise a second effector moiety.

[1526] 246. The composition of any of embodiments 121-206, wherein the first expression repressor comprises an amino acid sequence selected from any one of SEQ ID NOs: 22-37, 129, 133, 134, 139-149, 177-180, or 183-186, or a sequence at least 80%, 85%, 90%, 95%, or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1527] 247. The composition of any one 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 selected from any one of SEQ ID NOs: 22-37, 129, 133, 134, 139-149, 177-180, or 183-186, or a sequence at least 80%, 85%, 90%, 95%, or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1528] 248. The composition of any one of embodiments 121-204, 206, 212, 213, 219-222, 228-229, 242, 243, 246, or 247, wherein the first expression repressor comprises the amino acid sequence of SEQ ID NO: 30, 129, 133, or a sequence at least 80%, 85%, 90%, 95%, or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position, and the second expression repressor comprises SEQ ID NO: or an amino acid sequence of NO:24, 134, 141, 177, 179, 183 or 185, or a sequence that is at least 80%, 85%, 90%, 95% or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

[1529] 249. The composition of any one of embodiments 121-204, 206, 212, 213, 219-222, 228-229, 242, 243, or 246-248, wherein the first expression repressor is encoded by the first nucleotide sequence of SEQ ID NO: 63 or 130, or a sequence having at least 80%, 85%, 90%, 95%, or 99% identity thereto, or a sequence 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 position difference therefrom, and the second expression repressor is encoded by the first nucleotide sequence of SEQ ID NO: 63 or 130, or a sequence having at least 80%, 85%, 90%, 95%, or 99% identity thereto, or a sequence 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 position difference therefrom, or a second nucleotide sequence of NO:57, 189 or 194, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto, or encoding a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

[1530] 250. The composition of any one of embodiments 121-204, 206, 212, 213, 219-222, 228-229, 242, 243, or 246-249, wherein the first repressor 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 that is at least 80%, 85%, 90%, 95%, or 99% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1531] 251. The composition of embodiment 250, wherein the expression repressor comprises the amino acid sequence of SEQ ID NO: 91, 92, 121, 122, 181, 182, 187, or 188, or a sequence at least 80%, 85%, 90%, 95%, or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1532] 252. The composition of any one of embodiments 121-203, 205, 212, 213, 216, 217, 219, 221, 230-237, 239, 240, 242, 243, or 246-250, wherein:

[1533] The first expression repressor comprises, from N-terminus to C-terminus:

[1534] (i) a first nuclear localization signal, such as the SV40 NLS; for example, a sequence according to SEQ ID NO: 135;

[1535] (ii) a first targeting moiety, such as a zinc finger binding domain, such as ZF9; for example, a sequence according to SEQ ID NO: 13;

[1536] (iii) a first effector moiety, such as a DNA methyltransferase, such as MQ1; for example, a sequence according to SEQ ID NO: 19 or 87;

[1537] (iv) a second nuclear localization signal, such as a nucleoplasmin NLS; for example, a sequence according to SEQ ID NO: 136;

[1538] And the second expression repressor comprises from N-terminus to C-terminus:

[1539] (v) a third nuclear localization signal, such as SV40 NLS; for example, a sequence according to SEQ ID NO: 135;

[1540] (vi) a second targeting moiety, such as a zinc finger binding domain, such as ZF3; for example, a sequence according to SEQ ID NO: 7;

[1541] (vii) a second effector moiety, such as KRAB, such as a sequence according to SEQ ID NO: 18; and

[1542] (viii) a fourth nuclear localization signal, such as a nucleoplasmin NLS, such as a sequence according to SEQ ID NO: 136.

[1543] 253. The composition of any one of embodiments 121-203, 205, 212, 213, 216, 217, 219, 221, 230-237, 239, 240, 242, 243, or 246-250, wherein:

[1544] The first expression repressor comprises, from N-terminus to C-terminus:

[1545] (i) a first nuclear localization signal, such as the SV40 NLS; for example, a sequence according to SEQ ID NO: 135;

[1546] (ii) a first targeting moiety, such as a zinc finger binding domain, such as ZF9; for example, a sequence according to SEQ ID NO: 13;

[1547] (iii) a first effector moiety, such as a DNA methyltransferase, such as MQ1; for example, a sequence according to SEQ ID NO: 19 or 87;

[1548] (iv) a second nuclear localization signal, such as a nucleoplasmin NLS; for example, a sequence according to SEQ ID NO: 136;

[1549] And the second expression repressor comprises from N-terminus to C-terminus:

[1550] (v) a third nuclear localization signal, such as SV40 NLS; for example, a sequence according to SEQ ID NO: 135;

[1551] (vi) a second targeting moiety, such as a zinc finger binding domain, such as ZF54; for example, a sequence according to SEQ ID NO: 169;

[1552] (vii) a second effector moiety, such as KRAB, such as a sequence according to SEQ ID NO: 18; and

[1553] (viii) a fourth nuclear localization signal, such as a nucleoplasmin NLS, such as a sequence according to SEQ ID NO: 136.

[1554] 254. The composition of any one of embodiments 121-203, 205, 212, 213, 216, 217, 219, 221, 230-237, 239, 240, 242, 243, or 246-250, wherein:

[1555] The first expression repressor comprises, from N-terminus to C-terminus:

[1556] (i) a first nuclear localization signal, such as the SV40 NLS; for example, a sequence according to SEQ ID NO: 135;

[1557] (ii) a first targeting moiety, such as a zinc finger binding domain, such as ZF9; for example, a sequence according to SEQ ID NO: 13;

[1558] (iii) a first effector moiety, such as a DNA methyltransferase, such as MQ1; for example, a sequence according to SEQ ID NO: 19 or 87;

[1559] (iv) a second nuclear localization signal, such as a nucleoplasmin NLS; for example, a sequence according to SEQ ID NO: 136;

[1560] And the second expression repressor comprises from N-terminus to C-terminus:

[1561] (v) a third nuclear localization signal, such as SV40 NLS; for example, a sequence according to SEQ ID NO: 135;

[1562] (vi) a second targeting moiety, such as a zinc finger binding domain, such as ZF67; for example, a sequence according to SEQ ID NO: 171;

[1563] (vii) a second effector moiety, such as KRAB, such as a sequence according to SEQ ID NO: 18; and

[1564] (viii) a fourth nuclear localization signal, such as a nucleoplasmin NLS, such as a sequence according to SEQ ID NO: 136.

[1565] 255. The composition of any one of embodiments 121-254, wherein the composition is capable of reducing the expression of MYC to a greater extent than the first expression repressor alone or the second expression repressor alone.

[1566] 256. The composition of any one of embodiments 131-200 or 248-255, wherein the composition is capable of reducing the expression of MYC to a greater extent than any expression repressor of SEQ ID: 22, 23, 25-29, 31-37, alone or in combination.

[1567] 257. The composition of any one of embodiments 121-256, which is capable of reducing tumor volume, e.g., in a human subject or a mammalian model.

[1568] 258. The composition of any of embodiments 131-199 or 248-255, wherein the composition is capable of reducing tumor volume to a similar or greater extent than 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 at a dose of 3 mg / kg every 5 days, e.g., in a model composition as described in Example 15.

[1569] 259. The composition of any of embodiments 131-199 or 248-258, wherein the composition is capable of reducing tumor volume to a similar extent 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 at a dose of 6 mg / kg every 5 days, e.g., in a model composition as described in Example 14.

[1570] 260. The composition of any of embodiments 131-199 or 248-259, wherein 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 initiation of treatment.

[1571] 261. The composition of embodiment 260, wherein the chemotherapeutic agent is sorafenib or cisplatin.

[1572] 262. The composition of any one of embodiments 131-199 or 248-259, wherein the composition is capable of reducing tumor volume to a similar or greater extent than a small molecule MYC inhibitor.

[1573] 263. The composition 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 MYCi975, e.g., at day 20 after initiation of treatment.

[1574] 264. The composition of any one of embodiments 121-263, which causes no weight loss, or causes less than 3%, 2% or 1% weight loss compared to the start of treatment.

[1575] 265. The composition of any one 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.

[1576] 266. The composition of any one 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.

[1577] 267. The composition of any one of embodiments 121-266, wherein the first targeting moiety comprises a CRISPR / Cas domain (e.g., a first CRISPR / Cas domain).

[1578] 268. The composition of any one of embodiments 121-267, wherein the second targeting moiety comprises a second CRISPR / Cas domain (e.g., a second CRISPR / Cas domain).

[1579] 269. The composition 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).

[1580] 270. The composition of embodiment 268 or 269, wherein the first CRISPR / Cas domain does not bind to the second guide RNA or binds to the second guide RNA with a K of at least 10, 20, 50, 100, 1000, or 10,000 nM. DThe second CRISPR / Cas domain binds to the first guide RNA, and the second CRISPR / Cas domain does not bind to the first guide RNA or binds to the first guide RNA with a K of at least 10, 20, 50, 100, 1000, or 10,000 nM. D combination.

[1581] 271. The composition of any of embodiments 266-270, wherein the first CRISPR / Cas domain comprises an amino acid sequence that is different from the second CRISPR / Cas domain.

[1582] 272. The composition of any of embodiments 266-271, wherein the first or second CRISPR / Cas domain comprises an amino acid sequence selected from a Cas protein or a Cpf1 protein of Table 1 or a variant (e.g., mutant) of any one thereof.

[1583] 273. The composition of any of embodiments 266-272, wherein the first CRISPR / Cas domain comprises an amino acid sequence selected from a Cas protein or Cpf1 protein of Table 1 or a variant (e.g., mutant) of any thereof, and the second CRISPR / Cas domain comprises an amino acid sequence selected from a different Cas protein or Cpf1 protein of Table 1 or a variant (e.g., mutant) of any thereof.

[1584] 274. The composition of any one of embodiments 121-266, wherein the first targeting moiety comprises a zinc finger domain (e.g., a first zinc finger domain).

[1585] 275. The composition of any one of embodiments 121-266 or 274, wherein the second targeting moiety comprises a zinc finger domain (e.g., a second zinc finger domain).

[1586] 276. The composition 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.

[1587] 277. The composition of any one of embodiments 274-276, wherein the first zinc finger domain and the second zinc finger domain bind to the same genomic locus, e.g., have the same amino acid sequence.

[1588] 278. The composition 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 to different genomic loci.

[1589] 279. The composition of any one 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).

[1590] 280. The composition of any one 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.

[1591] 281. The composition of any one of embodiments 274-280, wherein the first zinc finger domain comprises 3 or 9 zinc fingers.

[1592] 282. The composition of any one 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).

[1593] 283. The composition of any one of embodiments 274-282, wherein the 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.

[1594] 284. The composition of any one of embodiments 274-283, wherein the second zinc finger domain comprises 3 or 9 zinc fingers.

[1595] 285. The composition of any of embodiments 121-284, wherein the first targeting moiety comprises a TAL effector domain (e.g., a first TAL effector domain).

[1596] 286. The composition of any of embodiments 121-266 or 285, wherein the second targeting moiety comprises a TAL effector domain (e.g., a second TAL effector domain).

[1597] 287. The composition 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).

[1598] 288. The composition of any of embodiments 285-287, wherein the 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.

[1599] 289. The composition 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).

[1600] 290. The composition of any of embodiments 285-289, wherein the second 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.

[1601] 291. The composition of any one of embodiments 121-290, wherein the first targeting moiety comprises a nucleic acid (e.g., a first nucleic acid).

[1602] 292. The composition of any one of embodiments 131-291, wherein the second targeting moiety comprises a nucleic acid (e.g., a second nucleic acid).

[1603] 293. The composition of any one of embodiments 131-292, wherein the first targeting moiety comprises a polypeptide (e.g., a first polypeptide).

[1604] 294. The composition of any one of embodiments 131-293, wherein the second targeting moiety comprises a polypeptide (e.g., a second polypeptide).

[1605] 295. The composition of embodiment 293 or 294, wherein the nucleic acid is covalently linked to a polypeptide.

[1606] 296. The composition of embodiment 294 or 295, wherein the nucleic acid is non-covalently associated with the polypeptide.

[1607] 297. The composition 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.

[1608] 298. The composition of any of embodiments 281-297, wherein the nucleic acid comprises a sequence that is complementary to an 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 an anchor sequence or a sequence proximal thereto.

[1609] 299. A composition as described in any of embodiments 281-298, wherein the nucleic acid comprises DNA, peptide nucleic acid (PNA), peptide-oligonucleotide conjugate, locked nucleic acid (LNA), bridged nucleic acid (BNA), polyamide, triplex-forming oligonucleotide, antisense oligonucleotide, tRNA, mRNA, rRNA, miRNA, gRNA, siRNA or other RNAi molecules.

[1610] 300. The composition of any of embodiments 281-299, wherein the nucleic acid comprises gRNA.

[1611] 301. The composition of any of embodiments 281-300, wherein the nucleic acid comprises a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOs: 1-4, or that differs therefrom at no more than 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 positions.

[1612] 302. The composition of any of embodiments 281-301, wherein the first nucleic acid comprises a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOs: 1-4, or differs from it in no more than 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 positions, and the second nucleic acid comprises a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOs: 1-4, or differs from it in no more than 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 positions.

[1613] 303. The composition of any of embodiments 281-301, wherein the first nucleic acid comprises a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOs: 96-110, or differs from it at no more than 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 positions, and the second nucleic acid comprises a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOs: 96-110, or differs from it at no more than 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 positions.

[1614] 304. The composition of any one of embodiments 121-303, wherein the transcriptional regulatory element comprises a promoter.

[1615] 305. The composition of any one of embodiments 121-304, wherein the transcriptional regulatory element comprises an enhancer; e.g., a super enhancer.

[1616] 306. The composition of any of embodiments 121-305, wherein the anchor sequence comprises a CTCF binding motif.

[1617] 307. The composition of any of embodiments 121-306, wherein the anchor sequence comprises a YY1 binding motif.

[1618] 308. The composition of any one of embodiments 121-307, wherein the anchor sequence comprises the sequence of SEQ ID NO: 71 or 72, or a sequence having no more than 8, 7, 6, 5, 4, 3, 2, or 1 alterations thereto.

[1619] 309. The composition of any of embodiments 121-308, wherein the anchor sequence comprises a sequence according to the nucleic acid sequence of CCGCCATNTT or AANATGGCGG, or a sequence having no more than 8, 7, 6, 5, 4, 3, 2, or 1 alterations thereto, wherein N is any nucleotide.

[1620] 310. The composition of any one of embodiments 121-309, wherein the anchor sequence is located on the same chromosome as the MYC gene.

[1621] 311. The composition of any one of embodiments 121-310, wherein the anchor sequence is upstream of the MYC gene (eg, upstream of the TSS or upstream of the promoter).

[1622] 312. The composition of any one of embodiments 121-311, wherein the anchor sequence is at least 1, 5, 10, 50, 100, or 1000 kilobases from the MYC gene (eg, from the TSS or promoter of the MYC gene).

[1623] 313. The composition of any one of embodiments 121-312, 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 or 500-1000 kilobases.

[1624] 314. The composition of any one of embodiments 121-309 or 311-313, wherein the anchor sequence and the MYC gene are on different chromosomes.

[1625] 315. The composition of any of embodiments 121-314, wherein the second targeting moiety binds to the anchor sequence or a sequence proximal to the anchor sequence with an affinity sufficient to compete with an endogenous polypeptide (e.g., CTCF or YY1) for binding.

[1626] 316. The composition of any of embodiments 121-315, wherein the first targeting moiety binds to a sequence at chromosome coordinates 128746342-128746364, 128746321-128746343, or 128746525-128746547, or a sequence proximal thereto.

[1627] 317. The composition 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.

[1628] 318. The composition of any of embodiments 121-317, wherein the second targeting moiety binds to a sequence at chromosome coordinates 128748014-128748036 or a sequence proximal thereto.

[1629] 319. The composition 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.

[1630] 320. The composition of any one of embodiments 121-319, wherein the first expression repressor is a fusion molecule.

[1631] 321. The composition of any of embodiments 121-319, wherein the second expression repressor is a fusion molecule.

[1632] 322. The composition of any one of embodiments 121-321, wherein the first expression repressor comprises a linker.

[1633] 323. The composition of any one of embodiments 121-322, wherein the second expression repressor comprises a linker.

[1634] 324. The composition of any one of embodiments 121-173 or 291-323, wherein:

[1635] The first expression repressor comprises a targeting moiety and an effector moiety, the targeting moiety comprising a first CRISPR / Cas molecule, for example comprising a first catalytically inactive CRISPR / Cas protein, and the effector moiety comprising an epigenetic modification moiety; and

[1636] 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 effector moiety optionally comprising a transcriptional repressor.

[1637] 325. The composition of any one of embodiments 121-166, 274-184, or 281-323, wherein:

[1638] The first expression repressor comprises a targeting portion comprising a first zinc finger domain and an effector portion comprising an epigenetic modification portion; and

[1639] The second expression repressor comprises a targeting portion comprising a second zinc finger domain and an optional effector portion comprising a transcriptional repressor.

[1640] 326. The composition of any one of embodiments 121-123, 268, 274, or 181-324, wherein:

[1641] The first expression repressor comprises a targeting moiety and an effector moiety, wherein the targeting moiety comprises a CRISPR / Cas molecule, for example, a catalytically inactive CRISPR / Cas protein, and the effector moiety comprises an epigenetic modification moiety; and

[1642] The second expression repressor comprises a targeting portion comprising a zinc finger domain and an optional effector portion comprising a transcriptional repressor.

[1643] 327. The composition of any one of embodiments 121-266, 274, or 281-324, wherein:

[1644] The first expression repressor comprises a targeting portion comprising a zinc finger domain and an effector portion comprising an epigenetic modification portion; and

[1645] The second expression repressor comprises a targeting moiety comprising a CRISPR / Cas domain, e.g., a catalytically inactive CRISPR / Cas protein, and optionally an effector moiety comprising a transcriptional repressor.

[1646] 328. The composition of any one of embodiments 266 or 274-324, wherein the zinc finger domain (e.g., a 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.

[1647] 329. The composition of any of embodiment 328, wherein the epigenetic modification portion comprises a DNA methyltransferase.

[1648] 330. The composition of any one of embodiments 121-328, wherein the epigenetic modification portion comprises MQ1 or a functional variant or fragment thereof.

[1649] 331. The composition of any of embodiments 121-330, wherein the second expression repressor comprises an effector portion comprising a transcriptional repressor.

[1650] 332. The composition of any one of embodiments 121-329, wherein the transcriptional repressor comprises KRAB or a functional variant or fragment thereof.

[1651] 333. The composition of any of embodiments 121-332, wherein the first expression repressor comprises the amino acid sequence of any one of SEQ ID NOs: 28-33 or 35-37, 145-149, 151, 152, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1652] 334. The composition of any of embodiments 121-333, wherein the second expression repressor comprises the amino acid sequence of any one of SEQ ID NOs: 22-27, 34, 139-144, 150, 177-180, 183-186, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1653] 335. The composition of any of embodiments 121-334, wherein binding of the first expression repressor to the transcriptional regulatory element or a sequence proximal thereto reduces expression of MYC in the cell.

[1654] 336. The composition of embodiment 333, wherein expression is reduced 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.

[1655] 337. The composition of embodiment 332 or 333, wherein binding of the first expression repressor to the transcriptional regulatory element results in a significant reduction in expression of MYC for a 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.

[1656] 338. The composition of any of embodiments 335-338, wherein the binding of the first expression repressor to the transcriptional regulatory element significantly reduces the 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 after transfection.

[1657] 339. The composition of any one of embodiments 334-338, wherein binding of the second expression repressor to the anchor sequence or a sequence proximal thereto reduces expression of MYC in the cell.

[1658] 340. The composition of embodiment 339, wherein expression is reduced 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.

[1659] 341. The composition of embodiment 339 or 340, wherein binding of the second expression repressor to the anchor sequence or its proximal sequence significantly reduces expression of MYC for a 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.

[1660] 342. The composition of embodiment 340 or 341, wherein binding of the second expression repressor to the anchor sequence or a sequence proximal thereto significantly reduces 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.

[1661] 343. The composition of any of embodiments 335-342, wherein binding of the first expression repressor to the transcriptional regulatory element or a sequence proximal thereto and binding of the second expression repressor to the anchor sequence or a sequence proximal thereto reduces expression of MYC in the cell.

[1662] 344. The composition of any of embodiments 335-342, wherein the binding of the first expression repressor to the transcriptional regulatory element or a sequence proximal thereto and the binding of the second expression repressor to the anchor sequence or a sequence proximal thereto significantly reduces the 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.

[1663] 345. The composition of any of embodiments 343 or 344, wherein expression is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% compared to expression in the absence of the first and second expression repressors, e.g., as measured by QPCR or ELISA.

[1664] 346. The composition of any of embodiments 335-345, wherein binding of the first expression repressor to the transcriptional regulatory element or its proximal sequence and binding of the second expression repressor to the anchor sequence or its proximal sequence significantly reduces expression of MYC for 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 for a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cell divisions, e.g., as measured by QPCR or ELISA.

[1665] 347. The composition of any of embodiments 335-346, wherein the reduction in expression caused by binding of the first expression repressor to the transcriptional regulatory element or its proximal sequence and binding of the second expression repressor to the anchor sequence or its proximal sequence is greater than the reduction in expression caused by binding of the first expression repressor to the transcriptional regulatory element or its proximal sequence or binding of the second expression repressor to the anchor sequence or its proximal sequence alone.

[1666] 348. The composition of embodiment 347, wherein the reduction in expression by binding of the first expression repressor to the transcriptional regulatory element or its proximal sequence and binding of the second expression repressor to the anchor sequence or its proximal sequence is greater than 1.05x (i.e., 1.05-fold), 1.1x, 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, 10x, 20x, 50x, or 100x the reduction in expression by either binding of the first expression repressor to the transcriptional regulatory element or its proximal sequence or binding of the second expression repressor to the anchor sequence or its proximal sequence, e.g., as measured by QPCR or ELISA.

[1667] 349. The composition of any of embodiments 335-348, wherein the reduction in expression caused by binding of the first expression repressor to the transcriptional regulatory element or its proximal sequence and binding of the second expression repressor to the anchor sequence or its proximal sequence persists for a longer period of time (e.g., more hours, days, or cell divisions) than the reduction in expression caused by binding of the first expression repressor to the transcriptional regulatory element or its proximal sequence or binding of the second expression repressor to the anchor sequence or its proximal sequence alone.

[1668] 350. The composition of embodiment 349, wherein the reduction in expression by binding of the first expression repressor to the transcriptional regulatory element or its proximal sequence and binding of the second expression repressor to the anchor sequence or its proximal sequence is longer (e.g., measured in hours, days, or cell divisions) than the reduction in expression by either binding of the first expression repressor to the transcriptional regulatory element or its proximal sequence or binding of the second expression repressor to the anchor sequence or its proximal sequence, e.g., as measured by QPCR or ELISA.

[1669] 351. The composition of any of embodiments 335-350, wherein binding of the first expression repressor to the promoter or its proximal sequence and binding of the second expression repressor to the super enhancer or its proximal sequence significantly reduces expression of MYC for 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 for a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cell divisions, e.g., as measured by QPCR or ELISA.

[1670] 352. The composition of any of embodiments 335-351, wherein the reduction in expression caused by binding of the first expression repressor to the promoter or its proximal sequence and binding of the second expression repressor to the super enhancer or its proximal sequence is greater than the reduction in expression caused by binding of the first expression repressor to the promoter or its proximal sequence or binding of the second expression repressor to the super enhancer or its proximal sequence alone.

[1671] 353. The composition of embodiment 352, wherein the reduction in expression by binding of the first expression repressor to the promoter or its proximal sequence and the binding of the second expression repressor to the super enhancer or its proximal sequence is greater than the reduction in expression by either binding of the first expression repressor to the promoter or its proximal sequence or binding of the second expression repressor to the super enhancer or its proximal sequence, e.g., as measured by QPCR or ELISA.

[1672] 354. The composition of any of embodiments 335-353, wherein the reduction in expression caused by binding of the first expression repressor to the promoter or its proximal sequence and binding of the second expression repressor to the super enhancer or its proximal sequence persists for a longer period of time (e.g., more hours, days, or cell divisions) than the reduction in expression caused by binding of the first expression repressor to the promoter or its proximal sequence or binding of the second expression repressor to the super enhancer or its proximal sequence alone.

[1673] 355. The composition of embodiment 354, wherein the reduction in expression by binding of the first expression repressor to the promoter or its proximal sequence and the binding of the second expression repressor to the super enhancer or its proximal sequence is longer (e.g., measured in hours, days, or cell divisions) than the reduction in expression by either binding of the first expression repressor to the promoter or its proximal sequence or binding of the second expression repressor to the super enhancer or its proximal sequence, e.g., as measured by QPCR or ELISA.

[1674] 356. The composition of any one of embodiments 335-355, wherein expression is significantly reduced indefinitely (e.g., for a period longer than can be measured experimentally).

[1675] 357. The composition of any of embodiments 335-356, wherein binding of the first expression repressor to the transcriptional regulatory element or a sequence proximal thereto reduces the viability of a cell comprising the transcriptional regulatory element or a sequence proximal thereto.

[1676] 358. The composition of any of embodiments 335-357, wherein contacting a plurality of cells with the first expression repressor or the nucleic acid encoding the first expression repressor reduces the viability of the plurality of cells, optionally wherein the plurality of cells includes cancerous and non-cancerous cells and / or infected and uninfected cells.

[1677] 359. The composition of embodiment 358, wherein the viability is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% compared to the viability in the absence of the first expression repressor, e.g., as measured by CellTiterGlo.

[1678] 360. The composition 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).

[1679] 361. The composition of any of embodiments 335-360, wherein binding of the second expression repressor to the anchor sequence or a sequence proximal thereto reduces the viability of a cell comprising the anchor sequence or a sequence proximal thereto.

[1680] 362. The composition of any one of embodiments 335-361, wherein contacting a plurality of cells with the second expression repressor or the nucleic acid encoding the second expression repressor reduces viability of the plurality of cells.

[1681] 363. The composition of any of embodiments 335-362, wherein binding of the second expression repressor to the super enhancer or a sequence proximal thereto reduces the viability of a cell comprising the transcriptional regulatory element or a sequence proximal thereto.

[1682] 364. The composition of any of embodiments 335-363, wherein contacting a plurality of cells with the second expression repressor or the nucleic acid encoding the first expression repressor reduces the viability of the plurality of cells, optionally wherein the plurality of cells includes cancerous and non-cancerous cells and / or infected and uninfected cells.

[1683] 365. The composition of embodiment 364, wherein the viability is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% compared to the viability in the absence of the second expression repressor, e.g., as measured by CellTiterGlo.

[1684] 366. The composition 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).

[1685] 367. The composition of any of embodiments 335-366, wherein binding of the first expression repressor to the transcriptional regulatory element or a sequence proximal thereto and binding of the second expression repressor to the anchor sequence or a sequence proximal thereto reduces the viability of a cell comprising the anchor sequence or a sequence proximal thereto.

[1686] 368. The composition of any one of embodiments 335-367, wherein the binding of the first expression repressor to the promoter or a proximal sequence thereof and the binding of the second expression repressor to the super enhancer or a proximal sequence thereof reduces cell viability

[1687] 369. The composition of any of embodiments 335-368, wherein contacting a plurality of cells with the composition reduces the viability of the plurality of cells.

[1688] 370. The composition of embodiments 335-369, wherein the viability is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% compared to the viability in the absence of the composition, e.g., as measured by CellTiter Glo.

[1689] 371. The composition of any of embodiments 335-370, wherein the reduction in motility caused by binding of the first expression repressor to the transcriptional regulatory element or its proximal sequence and binding of the second expression repressor to the anchor sequence or its proximal sequence is greater than the reduction in motility caused by binding of the first expression repressor to the transcriptional regulatory element or its proximal sequence or binding of the second expression repressor to the anchor sequence or its proximal sequence alone.

[1690] 372. The composition of any of embodiments 335-371, wherein the reduction in motility caused by binding of the first expression repressor to the promoter or its proximal sequence and binding of the second expression repressor to the super enhancer or its proximal sequence is greater than the reduction in motility caused by binding of the first expression repressor to the promoter or its proximal sequence or binding of the second expression repressor to the super enhancer or its proximal sequence alone.

[1691] 373. The composition of embodiment 372, wherein the reduction in viability by binding of the first expression repressor to the transcriptional regulatory element or its proximal sequence and binding of the second expression repressor to the anchor sequence or its proximal sequence is 1.05x (i.e., 1.05-fold), 1.1x, 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, 10x, 20x, 50x, or 100x greater than the reduction in viability by either binding of the first expression repressor to the transcriptional regulatory element or its proximal sequence or binding of the second expression repressor to the anchor sequence or its proximal sequence, e.g., as measured by CellTiter Glo.

[1692] 374. The composition of embodiment 372 or 373, wherein the reduction in viability by binding of the first expression repressor to the promoter or its proximal sequence and the second expression repressor to the super enhancer or its proximal sequence is 1.05x (i.e., 1.05-fold), 1.1x, 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, 10x, 20x, 50x, or 100x greater than the reduction in viability by either binding of the first expression repressor to the promoter or its proximal sequence or binding of the second expression repressor to the super enhancer or its proximal sequence, e.g., as measured by CellTiter Glo.

[1693] 375. The composition of any of embodiments 335-374, wherein administration of the first expression repressor and 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).

[1694] 376. The composition of embodiments 335-375, wherein the plurality of cells comprises a plurality of cancer cells and a plurality of non-cancerous cells.

[1695] 377. The composition of embodiment 376, wherein contacting the plurality of cells with the composition reduces the viability of the plurality of cancer cells more than the composition reduces the viability of the plurality of non-cancerous cells.

[1696] 378. The composition of embodiment 376 or 377, wherein contacting the plurality of cells with the composition reduces the viability of the plurality of cancer cells by 1.05x (i.e., 1.05-fold), 1.1x, 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, 10x, 20x, 50x, or 100x more than the reduction in viability of the plurality of non-cancerous cells.

[1697] 379. The composition of any preceding embodiment, which does not reduce the viability of non-cancerous cells (eg, primary hepatocytes) by more than 5%, 10%, 15%, or 20%, eg, when assayed according to Example 18.

[1698] 380. The composition of embodiment 379, wherein viability is determined 72 hours after contacting the cells with the composition.

[1699] 381. The composition of embodiment 380, wherein the assay comprises contacting the non-cancerous cells with 2.5, 2, 1.25, 1, 0.6, or 0.5 μg / ml of the composition.

[1700] 382. The composition of any one of embodiments 358-381, which, when contacted with a plurality of infected cells and a plurality of uninfected cells, reduces the viability of the plurality of infected cells more than the viability of the plurality of uninfected cells, and / or reduces the viability of the plurality of cancerous cells more than the viability of the plurality of non-cancerous cells.

[1701] 383. The composition of any one 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 cancer, or pancreatic cancer.

[1702] 384. The composition of any one of embodiments 358-383, wherein the cancer cells are gastric cancer cells, gastrointestinal cancer cells, colorectal cancer cells, pancreatic cancer cells, or liver cancer cells.

[1703] 385. The composition of any of embodiments 358-384, wherein the infection is a viral infection.

[1704] 386. The composition of embodiment 385, wherein the viral infection is hepatitis, e.g., hepatitis B.

[1705] 387. The composition of any of embodiments 384-386, wherein the infected cells are human hepatocytes.

[1706] 388. The composition of any of embodiments 358-387, wherein the viral infection is a chronic infection.

[1707] 389. A composition comprising:

[1708] (1) A nucleic acid encoding a fusion protein comprising:

[1709] a first amino acid region comprising a sequence encoding a first expression repressor of the composition of any one of embodiments 121-388; and

[1710] a second amino acid region comprising a sequence encoding a second expression repressor of the composition of any one of embodiments 121-388; and

[1711] (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)):

[1712] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[1713] (i') compounds having the general structure of formula (I)

[1714]

[1715] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[1716] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[1717] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[1718] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[1719] R a Is H or C1-C 12 alkyl;

[1720] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[1721] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 、-NR 11 R 12 or -NR 5 C(=O)R 4 ;

[1722] R 4 It is C1-C 12 alkyl;

[1723] R 5 is H or C1-C6 alkyl;

[1724] R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6-, or 7-membered heterocyclic ring;

[1725] G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and

[1726] x is 0, 1, or 2;

[1727] (i") compounds having the general structure of Formula (IX):

[1728]

[1729] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[1730] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[1731] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[1732] G 2 is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[1733] G 3 is C1-C6 alkylene;

[1734] R a Is H or C1-C 12 alkyl;

[1735] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1736] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1737] R 3aand R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1738] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1739] R 5 and R 6 are each independently H or methyl;

[1740] R 7 It is C4-C 20 alkyl;

[1741] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[1742] a, b, c, and d are each independently an integer from 1 to 24; and

[1743] x is 0, 1, or 2;

[1744] as well as,

[1745] (i'") compounds having the general structure of formula (XI):

[1746]

[1747] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[1748] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[1749] R2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[1750] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[1751] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[1752] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[1753] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[1754] n is an integer greater than 0;

[1755] (ii) a second compound having the general structure of formula (II):

[1756]

[1757] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (II):

[1758] R 6 and R 7 each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms (e.g., 12 to 18 carbon atoms), wherein the alkyl chain is optionally interrupted by one or more ester linkages; and

[1759] The mean value of y ranges from 30 to 60;

[1760] (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1761] (iv) a steroid (eg, a sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1762] 390. The composition of embodiment 389, wherein the fusion protein comprises a third amino acid region, wherein the third amino acid region is located between the first amino acid region and the second amino acid region.

[1763] 391. The composition of embodiment 390, wherein the third amino acid region comprises a protease cleavage peptide sequence, such as a self-cleavage peptide sequence, such as a T2A self-cleavage peptide sequence, such as a sequence according to SEQ ID NO: 120.

[1764] 392. The composition of embodiment 391, wherein the third amino acid region comprises a protease cleavage peptide sequence, such as a self-cleavage peptide sequence, such as a tandem 2A peptide sequence, such as a tPT2A sequence, such as a sequence according to SEQ ID NO: 124.

[1765] 393. The composition of embodiment 390, wherein the peptide sequence comprises a T2A peptide sequence and a P2A peptide sequence.

[1766] 394. The composition of any one of embodiments 389-393, wherein:

[1767] The first expression suppressor comprises an amino acid sequence according to SEQ ID NO: 30 or 129, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto; and

[1768] The second expression repressor comprises the amino acid sequence according to SEQ ID NO: 24 or 142, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto.

[1769] 395. The composition of any one of embodiments 389-393, wherein:

[1770] The first expression suppressor comprises an amino acid sequence according to SEQ ID NO: 30 or 129, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto; and

[1771] The second expression repressor comprises the amino acid sequence according to SEQ ID NO: 177 or 183, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto.

[1772] 396. The composition of any one of embodiments 389-393, wherein:

[1773] The first expression suppressor comprises an amino acid sequence according to SEQ ID NO: 30 or 129, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto; and

[1774] The second expression repressor comprises the amino acid sequence according to SEQ ID NO: 179 or 185, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto.

[1775] 397. The composition of any of embodiments 389-396, wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 91, 92, 121 or 122, or a sequence that is at least 80%, 85%, 90%, 95% or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

[1776] 398. The composition of any of embodiments 389-397, wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 181, 182, 187, or 188, or a sequence that is at least 80%, 85%, 90%, 95%, or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1777] 399. The composition of any one of embodiments 121-398, comprising a nucleic acid comprising:

[1778] a first region comprising a sequence encoding a first expression repressor of the composition of any one of embodiments 121-398; and

[1779] A second region comprising a sequence encoding a second expression repressor of the composition of any one of embodiments 121-398.

[1780] 400. The composition of embodiment 399, wherein the nucleic acid comprises a third region, wherein the third region is located between the first region and the second region.

[1781] 401. The composition of embodiment 399 or 400, wherein the third region encodes a ribosomal skipping sequence.

[1782] 402. The composition of embodiment 400 or 401, wherein the third region encodes a tPT2A peptide sequence, eg, a sequence according to SEQ ID NO: 124.

[1783] 403. The composition of any one of embodiments 400-402, wherein the third region encodes a protease-cleaving 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.

[1784] 404. The composition of any one of embodiments 400-403, wherein the third region encodes a protease-cleaving 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.

[1785] 405. A composition as described in any of embodiments 399-404, wherein

[1786] The first expression suppressor comprises an amino acid sequence according to SEQ ID NO: 30, 129, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto; and

[1787] The second expression suppressor comprises the amino acid sequence according to SEQ ID NO: 24, 142, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto.

[1788] 406. A composition as described in any of embodiments 399-404, wherein

[1789] The first expression suppressor comprises an amino acid sequence according to SEQ ID NO: 30, 129, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto; and

[1790] The second expression repressor comprises the amino acid sequence according to SEQ ID NO: 177, 179, 183 or 185, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto.

[1791] 407. The composition of any of embodiments 399-406, wherein the nucleic acid encodes the amino acid sequence of SEQ ID NO: 91, 92, 121, 122, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

[1792] 408. The composition of any of embodiments 399-407, wherein the nucleic acid encodes the amino acid sequence of SEQ ID NO: 181, 182, 187, 188, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

[1793] 409. The composition of any of embodiments 399-408, wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 93, 94, 112, or 113, or a sequence at least 80%, 85%, 90%, 95%, or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

[1794] 410. The composition of any of embodiments 399-409, wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 196, 197, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

[1795] 411. The composition of any of embodiments 46-410, wherein the nucleic acid comprises RNA, e.g., mRNA.

[1796] 412. The composition of any one of embodiments 399-411, wherein the nucleic acid comprises an N7-methylated guanosine, eg, an N7-methylated guanosine linked to the 5' end of the RNA via an inverted 5' to 5' triphosphate bond.

[1797] 413. The composition of any one of embodiments 399-412, wherein the nucleic acid comprises a 5'UTR.

[1798] 414. The composition of any one of embodiments 399-413, wherein the nucleic acid comprises a Kozak sequence, eg, between the 5'UTR and the sequence encoding the expression repressor.

[1799] 415. The composition of any one of embodiments 121-398, wherein the first nucleic acid has the nucleotide sequence of SEQ ID NO: 63, 130, or a sequence at least 80%, 85%, 90%, 95%, or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position, and the second nucleic acid has SEQ ID NO: or a nucleotide sequence of NO:57, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

[1800] 416. The composition of embodiment 414, wherein the first nucleic acid has the nucleotide sequence of SEQ ID NO: 63, 130, or a sequence at least 80%, 85%, 90%, 95%, or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position, and the second nucleic acid has SEQ ID NO: or a nucleotide sequence of NO:189 or 194, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

[1801] 417. The composition of embodiment 416, wherein the first nucleic acid has the nucleotide sequence of SEQ ID NO: 189, 194, or a sequence at least 80%, 85%, 90%, 95%, or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position, and the second nucleic acid has SEQ ID NO: NO:63, 130, or a sequence at least 80%, 85%, 90%, 95% or 99% identical thereto, or a sequence that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

[1802] 418. The composition of any of embodiments 399-417, wherein the nucleic acid comprises mRNA.

[1803] 419. The composition of any preceding embodiment, comprising lipid nanoparticles.

[1804] 420. The lipid nanoparticle or composition of any preceding embodiment, wherein the first compound has the general structure of Formula (III):

[1805]

[1806] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[1807] Among them L 1 and L 2 are each independently -(C=O)O- or -O(C=O)-;

[1808] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[1809] R 3 Appears once and is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 or -NR 5 C(=O)R 4 ;

[1810] R 4 It is C1-C 12 alkyl;

[1811] R 5 is H or C1-C6 alkyl;

[1812] R 8 occurs n times and each occurrence is independently H, OH or C1-C 24 alkyl;

[1813] n is an integer ranging from 1 to 15;

[1814] And m and l are each independently an integer ranging from 1 to 12.

[1815] 421. The lipid nanoparticle or composition of any preceding embodiment, wherein the first compound has the general structure of Formula (IV):

[1816]

[1817] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[1818] where R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[1819] R 3 It is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 or -NR 5 C(=O)R 4 ;

[1820] R 4 It is C1-C 12 alkyl;

[1821] R 5 is H or C1-C6 alkyl;

[1822] R 8 Is H, OH or C1-C 24 alkyl;

[1823] n is an integer ranging from 1 to 15; and

[1824] m and l are each independently an integer ranging from 1 to 12.

[1825] 422. The lipid nanoparticle or composition of any preceding embodiment, wherein the first compound comprises any one of:

[1826]

[1827]

[1828]

[1829]

[1830] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1831] 423. The lipid nanoparticle or composition of any preceding embodiment, wherein the first compound comprises:

[1832]

[1833] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1834] 424. The composition of any one of embodiments 1-419, wherein the first compound comprises a compound having the general structure of Formula (IX):

[1835]

[1836] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for Formula (IX):

[1837] L 1 and L 2 are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond;

[1838] G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond;

[1839] G 2 is –C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key;

[1840] G 3is C1-C6 alkylene;

[1841] R a Is H or C1-C 12 alkyl;

[1842] R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1843] R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1844] R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1845] R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond;

[1846] R 5 and R 6 are each independently H or methyl;

[1847] R 7 It is C4-C 20 alkyl;

[1848] R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-, 6-, or 7-membered heterocyclic ring;

[1849] a, b, c and d are each independently an integer from 1 to 24; and

[1850] x is 0, 1, or 2.

[1851] 425. The composition of any one of embodiments 1-419, wherein the first compound comprises a compound having the general structure of Formula (XI):

[1852]

[1853] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (XI):

[1854] R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl;

[1855] R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl;

[1856] R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;

[1857] L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 alkylene;

[1858] G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-;

[1859] G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and

[1860] n is an integer greater than 0.

[1861] 426. The lipid nanoparticle or composition of any preceding embodiment, wherein the second compound comprises any one of:

[1862] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[1863] The average value of n ranges from 30 to 60.

[1864] 427. The lipid nanoparticle or composition of any one of the preceding embodiments, wherein the second compound comprises

[1865] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1866] 428. The lipid nanoparticle or composition of any one of the preceding embodiments, wherein

[1867] The first compound comprises:

[1868] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1869] The second compound comprises:

[1870] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1871] 429. A lipid nanoparticle or composition as described herein, wherein

[1872] The first compound comprises:

[1873] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1874] The second compound comprises:

[1875] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1876] 430. A lipid nanoparticle or composition as described herein, wherein

[1877] The first compound comprises:

[1878] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1879] The second compound comprises:

[1880] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1881] 431. A lipid nanoparticle or composition as disclosed herein, wherein

[1882] Contains (e.g., as ionizable lipids):

[1883] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1884] The second compound comprises:

[1885] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1886] 432. A lipid nanoparticle or composition as disclosed herein, wherein

[1887] Contains (e.g., as ionizable lipids):

[1888] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1889] The second compound comprises:

[1890] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1891] 433. The lipid nanoparticle or composition of any preceding embodiment, wherein the neutral lipid (e.g., phosphatidylcholine) comprises distearoylphosphatidylcholine (DSPC) (Formula V):

[1892]

[1893] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1894] 434. The lipid nanoparticle or composition of any preceding embodiment, wherein the steroid (e.g., sterol, e.g., cholesterol) comprises cholesterol (Formula VI):

[1895]

[1896] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1897] 435. The lipid nanoparticle or composition of any preceding embodiment, wherein:

[1898] The first compound comprises:

[1899] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1900] The second compound comprises:

[1901] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof;

[1902] The neutral lipid (e.g., phosphatidylcholine) comprises distearoylphosphatidylcholine (DSPC) (Formula V):

[1903]

[1904] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1905] The steroid (eg, sterol, eg, cholesterol) comprises cholesterol (Formula VI):

[1906]

[1907] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1908] 436. The lipid nanoparticle or composition of any preceding embodiment, wherein:

[1909] The first compound comprises:

[1910] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1911] The second compound comprises:

[1912] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof;

[1913] The neutral lipid (e.g., phosphatidylcholine) comprises distearoylphosphatidylcholine (DSPC) (Formula V):

[1914]

[1915] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1916] The steroid (eg, sterol, eg, cholesterol) comprises cholesterol (Formula VI):

[1917]

[1918] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1919] 437. The lipid nanoparticle or composition of any preceding embodiment, wherein:

[1920] The first compound comprises:

[1921] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1922] The second compound comprises:

[1923] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof;

[1924] The neutral lipid (e.g., phosphatidylcholine) comprises distearoylphosphatidylcholine (DSPC) (Formula V):

[1925]

[1926] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1927] The steroid (eg, sterol, eg, cholesterol) comprises cholesterol (Formula VI):

[1928]

[1929] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1930] 438. The lipid nanoparticle or composition of any preceding embodiment, wherein:

[1931] Contains (e.g., as ionizable lipids):

[1932] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1933] The second compound comprises:

[1934] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof;

[1935] The neutral lipid (e.g., phosphatidylcholine) comprises distearoylphosphatidylcholine (DSPC) (Formula V):

[1936]

[1937] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1938] The steroid (eg, sterol, eg, cholesterol) comprises cholesterol (Formula VI):

[1939]

[1940] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1941] 439. The lipid nanoparticle or composition of any one of the preceding embodiments,

[1942] Contains (e.g., as ionizable lipids):

[1943] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1944] The second compound comprises:

[1945] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof;

[1946] The neutral lipid (e.g., phosphatidylcholine) comprises distearoylphosphatidylcholine (DSPC) (Formula V):

[1947]

[1948] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and

[1949] The steroid (eg, sterol, eg, cholesterol) comprises cholesterol (Formula VI):

[1950]

[1951] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[1952] 440. The lipid nanoparticle or composition of any preceding embodiment, wherein the molar ratio of (i):(ii):(iii):(iv) is (47.5±20%):(2.5±20%):(10±20%):(40±20%).

[1953] 441. The lipid nanoparticle or composition of any preceding embodiment, wherein the molar ratio of (i):(ii):(iii):(iv) is (47.5±10%):(2.5±10%):(10±10%):(40±10%).

[1954] 442. The lipid nanoparticle or composition of any preceding embodiment, wherein the molar ratio of (i):(ii):(iii):(iv) is (47.5±5%):(2.5±5%):(10±5%):(40±5%).

[1955] 443. The lipid nanoparticle or composition of any preceding embodiment, wherein the molar ratio of (i):(ii):(iii):(iv) is any of:

[1956] (38-57):(2-3):(8-12):(32-48);

[1957] (42.75-52.25):(2.25-2.75):(9-11):(36-44);

[1958] (45.125-49.875):(2.375-2.625):(9.5-10.5):(38-42); or

[1959] 47.5:2.5:10:40.

[1960] 444. The lipid nanoparticle or composition of any preceding embodiment, wherein the molar ratio of (i):(ii):(iii):(iv) is about 47.5:2.5:10:40.

[1961] 445. The lipid nanoparticle or composition of any preceding embodiment, wherein one or more of:

[1962] The first compound comprises about 47.5 mole percent of the sum of (i), (ii), (iii), and (iv);

[1963] The second compound comprises about 2.5 mole percent of the sum of (i), (ii), (iii), and (iv);

[1964] The neutral lipid, such as phosphatidylcholine or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, comprises about 10 mole % of the sum of (i), (ii), (iii) and (iv); and

[1965] The steroid (eg, sterol, eg, cholesterol) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof comprises about 40 mole percent of the sum of (i), (ii), (iii), and (iv).

[1966] wherein the first compound, the second compound, the neutral lipid (e.g., phosphatidylcholine or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof) and the steroid (e.g., sterol, such as cholesterol) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof account for 100 mol % of the total of (i), (ii), (iii) and (iv).

[1967] 446. The lipid nanoparticle of any preceding embodiment, wherein the nucleic acid is encapsulated within the LNP.

[1968] 447. A reaction mixture comprising the composition or lipid nanoparticle of any preceding embodiment.

[1969] 448. The reaction mixture of embodiment 447, further comprising cells.

[1970] 449. A pharmaceutical composition comprising the composition or lipid nanoparticle or reaction mixture of any preceding embodiment.

[1971] 450. A method for reducing MYC gene expression in a cell, the method comprising:

[1972] contacting a cell (e.g., a cancer cell) with a composition, reaction mixture, or pharmaceutical composition as described in any one of embodiments 1-449,

[1973] This reduces the expression of the MYC gene in the cell.

[1974] 451. A method for treating cancer in a subject in need thereof, the method comprising:

[1975] administering to the subject a composition, lipid nanoparticle, or pharmaceutical composition as described in any one of Examples 1-446,

[1976] The cancer is thereby treated in the subject.

[1977] 452. A method of reducing tumor growth in a subject in need thereof, the method comprising:

[1978] administering to the subject a composition, lipid nanoparticle, or pharmaceutical composition as described in any one of Examples 1-449,

[1979] thereby reducing tumor size in the subject.

[1980] 453. The method of embodiment 452, wherein the reduction in tumor growth comprises a decrease in tumor volume compared to the tumor volume at the start of treatment.

[1981] 454. The method of embodiment 453, wherein the reduction in tumor growth is greater in the subject compared to untreated subjects.

[1982] 455. A method of delivering an expression repressor to the liver of a subject, the method comprising:

[1983] Administering the composition or pharmaceutical composition of any one of Examples 1-449 to the subject, thereby delivering the expression repressor to the subject's liver.

[1984] 456. The method of embodiment 455, wherein the administration is parenteral administration, eg, intravenous administration.

[1985] 457. A method of increasing or restoring the sensitivity of a cancer to a kinase inhibitor, such as sorafenib, comprising administering to a subject having cancer a composition described herein.

[1986] 458. The method of embodiment 457, wherein administration of the composition results in an IC of the kinase inhibitor 50 A 10%, 20%, 30% or 40% reduction, for example in a cancer cell viability assay, for example an assay according to Example 26.

[1987] 459. The method of embodiment 457 or 458, wherein the kinase inhibitor inhibits one or more (eg, all) of VEGFR, PDGFR, or RAF kinases.

[1988] 460. A method of increasing or restoring the sensitivity of a cancer to a bromodomain inhibitor, such as a BET inhibitor, such as JQ1, comprising administering to a subject having cancer a composition described herein (e.g., any one of Examples 1-448), wherein optionally the administration of the composition results in an IC of the bromodomain inhibitor being increased. 50 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% reduction, e.g. in a cancer cell viability assay, e.g. an assay according to Example 29.

[1989] 461. The method of embodiment 460, wherein the bromodomain inhibitor is or comprises JQ1, BET672, or birabresib.

[1990] 462. A method of increasing or restoring sensitivity of cancer to a MEK inhibitor, such as trametinib, comprising administering to a subject having cancer a composition described herein (e.g., any one of Examples 1-448), wherein optionally administration of the composition results in an IC of the MEK inhibitor being 1: 5010%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% reduction, for example in a cancer cell viability assay.

[1991] 463. The method of any one of embodiments 452-462, wherein the reduction in tumor growth in the subject is greater than or similar to the reduction in tumor size when the subject is treated with a chemotherapeutic agent or a small molecule MYC inhibitor.

[1992] 464. The method of embodiment 463, wherein the chemotherapeutic agent is sorafenib or cisplatin.

[1993] 465. The method of embodiment 464, wherein the small molecule MYC inhibitor is MYCi975.

[1994] 466. A method of reducing tumor size in a subject in need thereof, the method comprising:

[1995] The composition, lipid nanoparticle, or pharmaceutical composition of 1-448 is administered to the subject, wherein the reduction in tumor size is greater than or similar to the reduction in tumor size when the subject is treated with a chemotherapeutic agent.

[1996] 467. The method of 466, wherein the chemotherapeutic agent is sorafenib or cisplatin.

[1997] 468. The method of any preceding embodiment, wherein the subject does not experience any significant side effects compared to treatment with a chemotherapeutic agent or a small molecule MYC inhibitor.

[1998] 469. The method of any one of embodiments 463-468, wherein the chemotherapeutic agent is sorafenib or cisplatin.

[1999] 470. The method of embodiment 469, wherein the small molecule MYC inhibitor is MYCi975.

[2000] 471. The method of any one of embodiments 451-470, wherein the cancer is stage I, stage II, stage III, or stage IV cancer.

[2001] 472. The method of any one of the preceding embodiments, wherein the subject's body weight remains approximately the same before and after treatment.

[2002] 473. The method of any one of the preceding embodiments, wherein the subject does not experience weight loss, or wherein the subject experiences less than 3%, 2%, or 1% weight loss compared to the start of treatment.

[2003] 474. The method of any one of the preceding embodiments, wherein the subject does not lose or gain weight after treatment compared to the subject's weight before treatment.

[2004] 475. A method for treating liver disease in a subject in need thereof, the method comprising:

[2005] administering to the subject a composition, wherein the composition comprises:

[2006] (1) a first nucleic acid encoding an expression repressor; and

[2007] (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)):

[2008] (i) a first compound selected from the group consisting of (i'), (i") and (i'"):

[2009] (i') compounds having the general structure of formula (I)

[2010]

[2011] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein for formula (I):

[2012] L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or a direct bond;

[2013] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene, or C2-C 12 alkenylene;

[2014] G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene;

[2015] R a Is H or C1-C 12 alkyl; [2016...

Claims

1. 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 the MYC promoter, and (b) optionally, an effector moiety, wherein the expression repressor is capable of reducing the expression of MYC; and (2) A preparation containing one or both of the following: (i) a first compound having the general structure of formula (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, Where L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or direct bond; G 1 and G 2 Each is independently unsubstituted C1-C 12 Alkylene or C2-C 12 alkenylene; G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; R a Is H or C1-C 12 alkyl; R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl; R 3 is H, OR 5 , CN, -C(=O)OR 4 , -OC(=O)R 4 , -NR 11 R 12 or -NR 5 C(=O)R 4 ; R 4 It is C1-C 12 alkyl; R 5 is H or C1-C6 alkyl; R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6- or 7-membered heterocyclic ring; G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1, or 2; and (ii) a second compound having the general structure of formula (II): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, Where R 6 and R 7 are each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and The mean value of y ranges from 30 to 60.

2. The composition of claim 1, comprising (i).

3. The composition of claim 1 or 2, comprising (ii).

4. The composition according to any one of claims 1 to 3, comprising: (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

5. The composition of any one of claims 1 to 4, comprising: (iv) a sterol, such as cholesterol, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

6. A composition comprising: (1) A nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein the expression repressor comprises: (a) a first targeting moiety that binds to a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of a sequence of any one of SEQ ID NOs: 83, 2, 3, 75-86, 97-107, 109, 110, 190-192, or 199-202, and (b) optionally, a first effector moiety, wherein the expression repressor is capable of reducing the expression of MYC; and (2) A preparation containing one or both of the following: (i) a first compound having the general structure of formula (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, Where L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O-, or direct bond; G 1 and G 2 Each is independently unsubstituted C1-C 12 Alkylene or C2-C 12 alkenylene; G 3 It is C1-C 24 Alkylene, C2-C 24 Alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; R a Is H or C1-C 12 alkyl; R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl; R 3 is H, OR 5 , CN, -C(=O)OR 4 , -OC(=O)R 4 , -NR 11 R 12 or -NR 5 C(=O)R 4 ; R 4 It is C1-C 12 alkyl; R 5 is H or C1-C6 alkyl; R 11 and R 12 Each is independently C1-C 12 Alkyl or -G 4 -OR 5 , or R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-, 6- or 7-membered heterocyclic ring; G 4 It is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene; and x is 0, 1, or 2; and (ii) a second compound having the general structure of formula (II): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, Where R 6 and R 7 are each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and The mean value of y ranges from 30 to 60.

7. The composition of claim 6, comprising (i).

8. The composition of claim 6 or 7, comprising (ii).

9. The composition of any one of claims 6 to 8, comprising: (iii) a neutral lipid, such as phosphatidylcholine, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

10. The composition of any one of claims 6 to 9, comprising: (iv) a sterol, such as cholesterol, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

11. A composition as claimed in any one of the preceding claims, wherein the first compound has the general structure of formula (III): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, Where L 1 and L 2 are each independently -(C=O)O- or -O(C=O)-; R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl; R 3 Appears once and is H, OR 5 、CN、-C(=O)OR 4 、-OC(=O)R 4 or -NR 5 C(=O)R 4 ; R 4 It is C1-C 12 alkyl; R 5 is H or C1-C6 alkyl; R 8 appears n times and each occurrence is independently H, OH or C1-C 24 alkyl; n is an integer ranging from 1 to 15; And m and l are each independently an integer ranging from 1 to 12.

12. The composition of any one of claims 1-11, wherein the first compound has the general structure of formula (IV): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, Where R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl; R 3 is H, OR 5 , CN, -C(=O)OR 4 , -OC(=O)R 4 or -NR 5 C(=O)R 4 ; R 4 It is C1-C 12 alkyl; R 5 is H or C1-C6 alkyl; R 8 is H, OH or C1-C 24 alkyl; n is an integer ranging from 1 to 15; and m and l are each independently an integer ranging from 1 to 12.

13. The composition of any one of claims 1-12, wherein the first compound comprises any one of: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

14. The composition of any one of claims 1-13, wherein the first compound comprises:

15. The composition of any one of claims 1-13, wherein the first compound comprises:

16. The composition of any one of claims 1-13, wherein the first compound comprises or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

17. The composition of any one of claims 1-16, wherein the second compound comprises any one of: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, The average value of n ranges from 30 to 60.

18. The composition of any one of claims 1-17, wherein the second compound comprises: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

19. The composition of any one of claims 1 to 18, wherein: The first compound comprises: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and The second compound comprises: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

20. The composition of any one of claims 1-19, wherein the phosphatidylcholine comprises distearoylphosphatidylcholine (DSPC) (Formula V): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

21. The composition of any one of claims 1-20, wherein the sterol comprises cholesterol (Formula VI): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

22. The composition of claims 1-21, comprising: The first compound comprises: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and The second compound comprises: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; The neutral lipid (e.g., phosphatidylcholine), comprising distearoylphosphatidylcholine (DSPC) (Formula V): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof; and Cholesterol (Formula VI): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

23. The composition of any one of claims 1-22, wherein the molar ratio of (i):(ii):(iii):(iv) is any one of: (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); or 47.5:2.5:10:40。 24. The composition of any one of claims 1-22, wherein the molar ratio of (i):(ii):(iii):(iv) is about 47.5:2.5:10:

40.

25. The composition of any one of claims 1-24, wherein one or more of the following: The first compound comprises about 47.5 mole % of the sum of (i), (ii), (iii) and (iv); the second compound comprises about 2.5 mole % of the sum of (i), (ii), (iii) and (iv); The phosphatidylcholine or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof comprises about 10 mole % of the sum of (i), (ii), (iii) and (iv); and The sterol or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof constitutes about 40 mol% of the total of (i), (ii), (iii) and (iv). wherein the first compound, the second compound, the phosphatidylcholine or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and the sterol or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof account for 100 mol % of the total of (i), (ii), (iii) and (iv).

26. A composition as described in any one of claims 1-25, wherein (1) and (2) form lipid nanoparticles (LNPs), wherein optionally, the nucleic acid is encapsulated within the LNPs.

27. The composition of any one of the preceding claims, wherein the formulation forms a lipid nanoparticle (LNP) and the nucleic acid is encapsulated within the LNP.

28. The composition of any one of claims 1-27, wherein the nucleic acid comprises RNA, such as mRNA.

29. The composition of any one of claims 1-28, having 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. The composition of any one of claims 6-29, wherein: The first targeting moiety binds to 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 composition of claim 30, wherein the first targeting moiety comprises a zinc finger domain.

32. compositions as claimed in claim 30 or 31, wherein this first targeting moiety comprises according to the aminoacid sequence of SEQ ID NO:13, or have at least 80%, 85%, 90%, 95%, 99% or 100% homogeneity thereto or the sequence that differs from it by no more than 20,19,18,17,16,15,14,13,12,11,10,9,8,7,6,5,4,3,2 or 1 position.

33. The composition of any one of claims 30-32, wherein the first effector moiety comprises MQ1 or a functional variant or fragment thereof.

34. The composition of any of claims 30-33, wherein the first effector portion comprises a sequence of SEQ ID NO: 19 or 87, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

35. The composition of any one of claims 30-34, wherein the first effector portion comprises the sequence of SEQ ID NO: 129, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

36. A composition as described in 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 having at least 80%, 85%, 90%, 95%, 99% or 100% identity thereto, or differing therefrom by no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

37. The composition of any one of claims 30-36, wherein the RNA comprises a nucleotide sequence encoding the first effector portion, wherein the nucleotide sequence encoding the first effector portion comprises a sequence according to SEQ ID NO: 132, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 position.

38. A composition as described in any one of claims 30-37, wherein the RNA comprises the nucleotide sequence according to SEQ ID NO: 130, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

39. The composition of any one 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 The second effector moiety.

40. The composition of claim 39, wherein the second targeting moiety binds to 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. The composition of claim 39 or 40, wherein the second targeting moiety comprises a zinc finger domain.

42. A composition as described in any one of claims 39-41, wherein the second targeting portion comprises an amino acid sequence according to SEQ ID NO:7, or a sequence having at least 80%, 85%, 90%, 95%, 99% or 100% identity thereto or differing therefrom by no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

43. The composition of any one of claims 39-42, wherein the second effector moiety comprises KRAB or a functional variant or fragment thereof.

44. The composition of any one of claims 39-43, wherein the second effector portion comprises an amino acid sequence according to SEQ ID NO: 18, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto, or that differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

45. A composition as described in any of claims 39-44, wherein the second expression repressor comprises the amino acid sequence according to SEQ ID NO:24, or a sequence that is at least 80%, 85%, 90%, 95%, 99% or 100% identical thereto or differs therefrom at no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 position.

46. ​​The composition of any one of claims 39-45, wherein the RNA comprises a nucleotide sequence according to SEQ ID NO:

113.

47. The composition of any one of claims 39-46, wherein contacting a plurality of cells with the composition reduces the viability of the plurality of cells.

48. A method for treating cancer in a subject in need thereof, the method comprising: The subject is administered the composition of any one of claims 1-47.

49. The method of claim 48, wherein the cancer is hepatocellular carcinoma (HCC), fibrolamellar hepatocellular carcinoma (FHCC), cholangiocarcinoma, angiosarcoma, or secondary liver cancer.

50. 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 the MYC promoter or a genomic locus comprising at least 16, 17, 18, 19 or 20 nucleotides of the sequence of any one of SEQ ID NOs: 83, 2, 3, 75-86, 97-107, 109, 110, 190-192, or 199-202, and (b) optionally, an effector moiety, wherein the expression repressor is capable of reducing the expression of MYC; and (2) A preparation containing one or both of the following: (i) a first compound having the general structure of formula (IX) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: L 1 and L 2 are independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -、-NR a C(=O)O- or direct bond; G 1 C1-C2 alkylene, -(C=O)-, -O(C=O)-, -SC(=O)-, -NR a C(=O)- or direct bond; G 2 Is -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR a - or direct key; G 3 is C1-C6 alkylene; R a Is H or C1-C 12 alkyl; R 1a and R 1b is independently one of the following at each occurrence: (a) H or C1-C 12 Alkyl; or (b) R 1a Is H or C1-C 12 Alkyl, and R 1b Together with the carbon atom to which it is bonded and the adjacent R 1b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond; R 2a and R 2b is independently one of the following at each occurrence: (a) H or C1-C 12 Alkyl; or (b) R 2a Is H or C1-C 12 Alkyl, and R 2b Together with the carbon atom to which it is bonded and the adjacent R 2b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond; R 3a and R 3b is independently one of the following at each occurrence: (a) H or C1-C 12 Alkyl; or (b) R 3a Is H or C1-C 12 Alkyl, and R 3b Together with the carbon atom to which it is bonded and the adjacent R 3b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond; R 4a and R 4b is independently one of the following at each occurrence: (a) H or C1-C 12 Alkyl; or (b) R 4a Is H or C1-C 12 Alkyl, and R 4b Together with the carbon atom to which it is bonded and the adjacent R 4b Together with the carbon atom to which it is bonded, it forms a carbon-carbon double bond; R 5 and R 6 are each independently H or methyl; R 7 It is C4-C 20 alkyl; R 8 and R 9 Each independently is C1-C 12 Alkyl; or R 8 and R 9 Together with the nitrogen atom to which they are attached, they 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 the general structure of formula (II): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, Where R 6 and R 7 are each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and The mean value of y ranges from 30 to 60.

51. 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 the MYC promoter or a genomic locus comprising at least 16, 17, 18, 19 or 20 nucleotides of the sequence of any one of SEQ ID NOs: 83, 2, 3, 75-86, 97-107, 109, 110, 190-192, or 199-202, and (b) optionally, an effector moiety, wherein the expression repressor is capable of reducing the expression of MYC; and (2) A preparation containing one or both of the following: (i) a first compound having the general structure of formula (XI) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: R 1 is an optionally substituted C1-C 24 Alkyl or optionally substituted C2-C 24 alkenyl; R 2 and R 3 are each independently an optionally substituted C1-C 36 alkyl; R 4 and R 5 are each independently an optionally substituted C1-C6 alkyl group, or R 4 and R 5 Together with the N to which they are attached, they form a heterocyclyl or heteroaryl group; L 1 , L 2 and L 3 are each independently an optionally substituted C1-C 18 Alkylene; G 1 Is a direct bond, -(CH2) n O(C=O)-、-(CH2) n (C=O)O-, or -(C=O)-; G 2 and G 3 are each independently -(C=O)O- or -O(C=O)-; and n is an integer greater than 0; and (ii) a second compound having the general structure of formula (II): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, Where R 6 and R 7 are each independently a linear or branched saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and The mean value of y ranges from 30 to 60.

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