WO2018098446A1 - Methods for modulating rna splicing - Google Patents

Methods for modulating rna splicing Download PDF

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Publication number
WO2018098446A1
WO2018098446A1 PCT/US2017/063323 US2017063323W WO2018098446A1 WO 2018098446 A1 WO2018098446 A1 WO 2018098446A1 US 2017063323 W US2017063323 W US 2017063323W WO 2018098446 A1 WO2018098446 A1 WO 2018098446A1
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WIPO (PCT)
Prior art keywords
amino
8alkyl
alkyl
salkyl
hydroxy
Prior art date
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PCT/US2017/063323
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English (en)
French (fr)
Inventor
Anuradha Bhattacharyya
Amal DAKKA
Kerstin EFFENBERGER
Vijayalakshmi GABBETA
Wencheng Li
Nikolai Naryshkin
Christopher Trotta
Kari WIEDINGER
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PTC Therapeutics Inc
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PTC Therapeutics Inc
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Priority to JP2019528527A priority Critical patent/JP2019535789A/ja
Priority to US16/463,775 priority patent/US11702646B2/en
Priority to EA201991309A priority patent/EA201991309A1/ru
Priority to MX2019005588A priority patent/MX2019005588A/es
Priority to AU2017363369A priority patent/AU2017363369A1/en
Priority to CN201780084649.8A priority patent/CN110352007A/zh
Application filed by PTC Therapeutics Inc filed Critical PTC Therapeutics Inc
Priority to CA3043755A priority patent/CA3043755A1/en
Priority to EP17873550.2A priority patent/EP3544435A4/en
Publication of WO2018098446A1 publication Critical patent/WO2018098446A1/en
Anticipated expiration legal-status Critical
Priority to JP2022108509A priority patent/JP2022153413A/ja
Priority to US18/316,871 priority patent/US20230272367A1/en
Ceased legal-status Critical Current

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Definitions

  • a recognition element for splicing modifier present in an intron (i.e., an "intronic REMS" or iREMS) that can be recognized as a 5' splice site by the Ul snRNP and/or other components of the pre-mRNA splicing machinery in the presence of a small molecule splicing modifier, wherein gene expression is modulated by inducing alternative splicing of intronic exons (iExons) in the transcribed RNA.
  • iExons intronic exons
  • described herein are methods for modulating the amount of a product of a gene, wherein a precursor RNA transcript transcribed from the gene contains an intronic REMS, a branch point and a 3' splice site, and the methods utilize a small molecule compound described herein to induce alternative splicing of iExons. More particularly, described herein are methods for modulating the amount of an RNA transcript or protein product encoded by a gene via alternative splicing of iExons, wherein a precursor RNA transcript transcribed from the gene comprises an endogenous or non-endogenous intronic REMS, and the methods utilize a compound described herein to induce iExon alternative splicing.
  • an intronic REMS including an endogenous or non-endogenous intronic REMS
  • methods for altering genes to comprise an endogenous or non-endogenous intronic REMS and the use of a small molecule compound described herein to induce alternative splicing of iExons, subsequently modulating the amount and type of protein produced from such altered endogenous or non-endogenous gene transcripts.
  • a recognition element for splicing modifier is provided herein.
  • the intronic REMS comprises the nucleotide sequence GAgurngn (SEQ ID NO: 2) at the RNA level, wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and n is any nucleotide.
  • the RNA transcript in addition to the intronic REMS sequence, comprises an upstream branch point and a functional upstream iExon 3' splice site.
  • iExons an exon 5' splice site
  • a branch point and the functional iExon 3' splice site upstream from the intronic REMS are further linked to a downstream branch point and 3' splice site of a downstream exon (see, for example, Figure 1A).
  • the branch point and the functional 3' splice site for an exon are downstream from the intronic REMS sequences (see, for example, Figures IB and 1C).
  • an RNA sequence comprises two exons and an intron, wherein one exon is upstream of the intron and the other exon is
  • the intron comprises in 5' to 3' order: a first 5' splice site, a first branch point, a first 3' splice site (also referred to as an iExon 3' splice site), an iREMS, a second branch point, and a second 3' splice site.
  • the iREMS sequence functions as a 5' splice site, causing the NNGA (SEQ ID NO: 3863) nucleotides of the iREMS and the intronic nucleotides downstream of the first 3' splice site to be retained and spliced as an intronic exon to provide a non-wild-type mRNA.
  • the nucleotides between the iREMS and the first 3' splice site are retained and form the intronic exon, which results in the expression of a non-wild-type mRNA sequence.
  • the iREMS sequence functions as a 5' splice site, causing the NNGA (SEQ ID NO: 3863) nucleotides of the iREMS and the intronic nucleotides between the 3' iExon splice site to be retained and spliced as an intronic exon to provide a non-wild-type mRNA.
  • the intronic REMS will undergo splicing with the 3' splice site of a downstream exon.
  • the intronic REMS is located downstream of an exon such that there is no intervening upstream branch point and iExon 3' splice site between the exon and the REMS sequence.
  • the exon 5' splice site does not undergo splicing with the downstream 3' splice site. Instead, functioning as a 5' splice site in the presence of a compound described herein, the iREMS sequence undergoes splicing with the downstream 3' splice site.
  • an upstream exon 5' splice site, an upstream branch point, and a functional iExon 3' splice site upstream from the intronic REMS will undergo splicing.
  • one or more sequence elements necessary to form an iExon splice junction may be present endogenously or non-endogenously.
  • one or more of the following sequence elements may be present naturally in an intron or an intron may be engineered to comprise one or more of the following sequences in 5' to 3' order: a first 5' splice site, a first branch point, a first 3' splice site, an iREMS, a second branch point, and a second 3' splice site.
  • one or more snRNPs and trans factor elements necessary for splicing may be present beyond endogenous levels as a result of the presence of a compound described herein at various splice inducing sequence combinations.
  • the small molecule compounds described herein, in conjunction with the iREMS sequence initiate the assembly of a splicing-competent spliceosome around a weak or incompletely defined exon (i.e., a nascent iExon).
  • Splicing modifier compounds most likely enable a functional Ul snRNP - REMS interaction and, at least, have been shown to increase the affinity of one or more snRNPs and trans factor elements necessary for splicing, including Ul, U2, U4, U5 and U6, whereby the interaction between the Ul snRNP, as well as other
  • the interaction of the Ul snRNP, the iREMS and the small molecule splicing modifier compounds described herein serve to define nascent exons by increasing the binding affinity of the pre-mRNA splicing machinery to the iREMS sequence, stabilizing Ul binding with the iREMS sequence, activating a 3' splice site and a branch point upstream from the iREMS and recruiting U2 snRNP and other transacting splicing factors such as U2AF (U2AF65 and U2AF35) and SF3A (SF3A1, SF3A2 and SF3A3) to the upstream branch point and 3' splice site.
  • U2AF U2AF65 and U2AF35
  • SF3A SF3A1, SF3A2 and SF3A3
  • the branch point and 3 'splice site may or may not be fully occupied in the absence of the compound but have been shown to become occupied after the compound has enabled the formation of a functional Ul snRNP - REMS complex.
  • these key splicing machinery elements showing that, in the presence of small molecule splicing modifier compounds such as, but certainly not limited to, those described herein, the mechanism of intronic spliceosome assembly can be mediated by iREMS interaction with such compounds, such that the intronic REMS sequence functions as a Ul snRNP binding site, resulting in intronic nucleotides spliced in the mature RNA transcript as an intronic exon.
  • Exon 1 5' splice site i.e., a 5' splice site at the 3' end of Exon 1
  • BP branch point
  • Exon 2 RNA transcript
  • the intronic REMS functions as a 5' splice site, whereby the nucleotides between the Exon 1 5' splice site and the first 3' splice site are removed to form a splice junction between Exon 1 and a nascent intronic exon and the nucleotides between the intronic REMS and the second 3' splice site sequence are removed to form a splice junction between iExon la and Exon 2, and allowing Exon 2 and the portion of the intron comprising nucloeotides from the first 3' splice site up to and including NNGA (SEQ ID NO: 3863) of the intronic REMS to be joined, thus introducing an intron-derived iExon la, generating a non-wildtype mRNA.
  • one or more elements necessary to form a splice junction may be present
  • the one or more elements are selected from the group consisting of the first branch point, the first 3' splice site, the intronic REMS, the second branch point and the second 3' splice site. While illustrated for Intron 1 here, this concept is generally applicable to any other intron in a pre-mRNA transcript.
  • the intronic REMS is located in an intron of an RNA transcript downstream from an Exon 1 5' splice site (i.e., a 5' splice site at the 3' end of Exon 1) and upstream from an Intron 1 branch point sequence and a 3' splice site sequence of Exon 2 (i.e., a 3' splice site at the 5' end of Exon 2).
  • the nucleotides between the Exon 1 5' splice site and the intronic REMS are retained and those between the intronic REMS and the Intron 1 3' splice site sequence (except the NNGA (SEQ ID NO: 3863) nucleotides of the intronic REMS) are removed, allowing Exon 1 and the portion of the intron comprising nucloeotides from those adjacent to the Exon 1 5' splice site up to and including NNGA (SEQ ID NO: 3863) of the intronic REMS and the Exon 2 nucleotides to be joined.
  • Exon 1 The scope of the invention described herein is merely illustrated in this configuration for Exon 1 but is generally applicable to any other nascent iExon in an intronic sequence.
  • the elements necessary to induce splicing of an iExon may be present in any configuration capable of recognition by the splicing machinery as an "exon.”
  • the spliceosome recognizes the elements as exonic boundaries for removal of intervening intronic nucleotides between those boundaries.
  • the configuration in this instance results in an iExon spliced between at least one upstream exon and one downstream exon of the same pre-mRNA transcript.
  • the intronic REMS is located in Intron 2 downstream from an Exon 2 5' splice site (i.e., a 5' splice site at the 3' end of Exon 2) and upstream from an Intron 2 branch point sequence and a 3' splice site sequence of Exon 3 (i.e., a 3' splice site at the 5' end of Exon 3) in an RNA transcript.
  • an Exon 2 5' splice site i.e., a 5' splice site at the 3' end of Exon 2
  • a 3' splice site sequence of Exon 3 i.e., a 3' splice site at the 5' end of Exon 3
  • the nucleotides between the intronic REMS and the Exon 3 3' splice site sequence are removed, allowing Exon 3 and the portion of the intron comprising nucloeotides from those adjacent to the Exon 2 5' splice site up to and including NNGA (SEQ ID NO: 3863) of the intronic REMS to be joined.
  • the endogenous splicing reaction between Exon 1 and Exon 2 is unaffected by the presence of a compound described herein, resulting in the complete removal of Intron 1. While illustrated for Exon 2 here, this concept is generally applicable to any other internal nascent intronic exon, i.e., an exon that is located between at least one upstream exon and one downstream exon of the same pre-mRNA transcript.
  • an "exon 5' splice site”, a “5' splice site of an exon” or the like refers to a 5' splice site at the 3' end of the exon
  • an "exon 3' splice site”, a “3' splice site of an exon” or the like refers to a 3' splice site at the 5' end of the exon.
  • the iREMS nucleotides retained in the formation of an iExon are selected from the group consisting of ANGA (SEQ ID NO: 5), CNGA (SEQ ID NO: 11), GNGA (SEQ ID NO: 17),
  • NGGA (SEQ ID NO: 18), NUGA (SEQ ID NO: 24), AAGA (SEQ ID NO: 7),
  • CAGA SEQ ID NO: 8
  • CCGA SEQ ID NO: 14
  • CGGA SEQ ID NO: 20
  • GGGA SEQ ID NO: 21
  • GUGA SEQ ID NO: 27
  • UAGA SEQ ID NO: 10
  • RNA transcripts having a non-functional open reading frame due to the inclusion of a frameshift, premature stop codon or internal deletions within the open reading frame.
  • the inclusion of an iExon may result in the mature mRNA having a functional open reading frame, producing a novel protein which may or may not be functional.
  • RNA transcripts having a non-functional open reading frame due to the inclusion of a frameshift, premature stop codon or internal deletions within the open reading frame can be substrates for nonsense-mediated decay and thus have low abundance.
  • any intronic REMS- mediated alternative splicing modified RNA transcripts may also have altered stability, altered intracellular transport, altered 3' end formation efficiency and altered translation efficiency.
  • methods for modulating the amount of RNA transcripts produced from precursor RNA containing an endogenous or non-endogenous intronic REMS are provided herein.
  • artificial gene constructs comprising an endogenous or non-endogenous intronic REMS, which may be used in the context of, e.g., gene therapy or reporter assays.
  • methods for altering endogenous genes so that they contain an intronic REMS or an additional intronic REMS.
  • RNA transcripts e.g., mRNA transcripts
  • precursor RNA transcripts transcribed by the one or more genes comprise an intronic REMS
  • RNA transcript produced from precursor RNA containing an intronic recognition element for splicing modifier comprising contacting a cell containing the precursor RNA with a compound of Formula (I) or a form thereof, wherein the intronic REMS comprises the sequence NNGAgurngn (SEQ ID NO: 1), wherein r is adenine or guanine and n or N is any nucleotide, wherein the precursor RNA is a gene in Table 1.
  • the precursor RNA is a gene in Table 7.
  • a method for modulating the amount of an RNA transcript produced from precursor RNA containing an intronic recognition element for splicing modifier comprising contacting the precursor RNA with a compound of Formula (I) or a form thereof, wherein the intronic REMS comprises the sequence NNGAgurngn (SEQ ID NO: 1), wherein r is adenine or guanine and n or N is any nucleotide, wherein the precursor RNA is a gene in Table 1.
  • the intronic REMS comprises the sequence NNGAguragu (SEQ ID NO: 3862) at the RNA level, wherein r is adenine or guanine and N is any nucleotide.
  • the intronic REMS comprises a sequence selected from the group consisting of ANGAgurngn (SEQ ID NO: 29),
  • NCGAgurngn SEQ ID NO: 36
  • NGGAgurngn SEQ ID NO: 42
  • the intronic REMS comprises a sequence selected from the group consisting of ANGAguragu (SEQ ID NO: 437), CNGAguragu (SEQ ID NO: 443),
  • GNGAguragu (SEQ ID NO: 449), UNGAguragu (SEQ ID NO: 455),
  • NAGAguragu SEQ ID NO: 438
  • NCGAguragu SEQ ID NO: 4444
  • CAGAguragu (SEQ ID NO: 440), CCGAguragu (SEQ ID NO: 446),
  • the intronic REMS referred to in a method or artificial gene construct described herein comprises, at the RNA level, a sequence presented in the following table (wherein r is adenine or guanine, and n or N is any nucleotide):
  • provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, by way of nonlimiting example, disclosed in Table 1, infra, the method comprising contacting a cell with a compound of Formula (I) or a form thereof.
  • methods for modulating the amount of one, two, three or more RNA transcripts of a gene, disclosed in Table 16 or Tables 2-7, infra, wherein the precursor transcript transcribed from the gene comprises an intronic REMS the method comprising contacting a cell with a compound of Formula (I) or a form thereof.
  • provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, disclosed in International Patent Application No.
  • PCT/US2014/071252 International Publication No. WO 2015/105657
  • the precursor transcript transcribed from the gene comprises an intronic REMS
  • the method comprising contacting a cell with a compound of Formula (I) or a form thereof.
  • methods for modulating the amount of one, two, three or more RNA transcripts of a gene disclosed in International Patent Application No. PCT/US2016/034864 (International Publication No. WO 2016/196386), wherein the precursor transcript transcribed from the gene comprises an intronic REMS, the method comprising contacting a cell with a compound of Formula (I) or a form thereof.
  • RNA transcripts of a gene disclosed in Table 1 , infra, wherein the precursor transcript transcribed from the gene comprises an intronic REMS, the method comprising contacting a cell with a compound of Formula (I) or a form thereof.
  • methods for modulating the amount of one, two, three or more RNA transcripts of a gene disclosed in Table 7, infra comprising contacting a cell with a compound of Formula (I) or a form thereof. See the example section for additional information regarding the genes in Table 7.
  • the cell is contacted with the compound of Formula (I) or a form thereof in a cell culture.
  • a compound of Formula (I) is a compound of Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV) described infra.
  • a compound of Formula (I) is a compound selected from a compound described herein.
  • RNA transcript transcribed from the gene comprises an intronic REMS
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcripts of a gene by way of nonlimiting example, disclosed in Table 1, infra, the methods comprising administering to a human or non-human subject thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcripts of a gene disclosed in Tables 2-7, infra, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcript transcribed from the gene comprises an intronic REMS
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • methods for modulating the amount of one, two, three or more RNA transcripts of a gene disclosed in International Patent Application No.
  • RNA transcripts of a gene disclosed in Table 1, infra, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcripts of a gene disclosed in Table 7, infra comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. See the example section for additional information regarding the genes in Table 7.
  • a compound of Formula (I) is a compound of Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV) described infra.
  • a compound of Formula (I) is a compound selected from a compound described herein.
  • RNA nucleotide sequence comprises two exons and an intron, wherein one exon is upstream of the intron and the other exon is downstream of the intron, wherein the RNA nucleotide sequence of the intron comprises in 5' to 3' order: a first 5' splice site, a first branch point, a first 3' splice site, an iREMS, a second branch point and a second 3' splice site, wherein the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), and wherein r is adenine or guanine and n is any nucleotide, the method comprising contacting the RNA transcript with a compound described herein (for example, a compound of Formula (I) or a form thereof or another splicing inducer).
  • a compound described herein for example, a compound of Formula (I) or a form thereof or another splicing inducer.
  • RNA nucleotide sequence comprises two exons and an intron, wherein one exon is upstream of the intron and the other exon is downstream of the intron, wherein the RNA nucleotide sequence of the intron comprises in 5' to 3' order: a first branch point, a first 3' splice site, and an iREMS, wherein the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), and wherein r is adenine or guanine and n is any nucleotide, the method comprising contacting the RNA transcript with a compound described herein (for example, a compound of Formula (I) or a form thereof or another splicing inducer).
  • a compound described herein for example, a compound of Formula (I) or a form thereof or another splicing inducer.
  • RNA transcript comprising a RNA nucleotide sequence, wherein the RNA nucleotide sequence comprises two exons and an intron, and wherein the RNA nucleotide sequence comprises exonic and intronic elements illustrated in Figure 1 A, the method comprising contacting the RNA transcript with a compound described herein (for example, a compound of Formula (I) or a form thereof or another splicing inducer).
  • a compound described herein for example, a compound of Formula (I) or a form thereof or another splicing inducer.
  • RNA transcript comprising a RNA nucleotide sequence, wherein the RNA nucleotide sequence comprises two exons and an intron, and wherein the RNA nucleotide sequence comprises exonic and intronic elements illustrated in Figure IB, the method comprising contacting the RNA transcript with a compound described herein (for example, a compound of Formula (I) or a form thereof or another splicing inducer).
  • a compound described herein for example, a compound of Formula (I) or a form thereof or another splicing inducer
  • RNA transcript comprising a RNA nucleotide sequence, wherein the RNA nucleotide sequence comprises three exons and two introns, and wherein the RNA nucleotide sequence comprises exonic and intronic elements illustrated in Figure 1C, the method comprising contacting the RNA transcript with a compound described herein (for example, a compound of Formula (I) or a form thereof or another splicing inducer).
  • a compound described herein for example, a compound of Formula (I) or a form thereof or another splicing inducer.
  • the RNA transcript is the RNA transcript of a gene described in a table in this disclosure.
  • a method for modulating the amount of the product of a gene in a subject, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, wherein the nucleotide sequence encoding one exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding the other exon is downstream of the nucleotide sequence encoding the intron, wherein the DNA nucleotide sequence encoding the intron comprises in 5' to 3' order: a nucleotide sequence encoding a first 5' splice site, a nucleotide sequence encoding a first branch point, a nucleotide sequence encoding a first 3' splice site, a nucleotide sequence encoding an iREMS, a nucleotide sequence encoding a second branch point and
  • a method for modulating the amount of the product of a gene in a subject, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, wherein the nucleotide sequence encoding one exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding the other exon is downstream of the nucleotide sequence encoding the intron, wherein the DNA nucleotide sequence of the intron comprises in 5' to 3' order: a nucleotide sequence encoding a first branch point, a nucleotide sequence encoding a first 3' splice site, and a nucleotide sequence encoding an iREMS, wherein the iREMS comprises a DNA sequence GAgtrngn (SEQ ID NO: 4), and wherein r is adenine or guanine and
  • RNA transcript or protein a gene (such as an RNA transcript or protein) in a subject, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence comprises exonic and intronic elements illustrated in Figure 1 A, the method
  • a compound described herein for example, a compound of Formula (I) or a form thereof or another splicing inducer
  • RNA transcript or protein a gene (such as an RNA transcript or protein) in a subject, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence comprises exonic and intronic elements illustrated in Figure IB, the method
  • a compound described herein for example, a compound of Formula (I) or a form thereof or another splicing inducer
  • RNA transcript or protein a gene (such as an RNA transcript or protein) in a subject, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence comprises exonic and intronic elements illustrated in Figure 1C, the method
  • a compound described herein for example, a compound of Formula (I) or a form thereof or another splicing inducer
  • the gene is a gene described in a table in this disclosure.
  • RNA transcript transcribed from the gene comprises an intronic REMS
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • a disease associated with aberrant expression of a product of a gene e.g., an mRNA, RNA transcript or protein
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcript transcribed from the gene comprises an intronic REMS
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • a disease associated with aberrant expression of a product of a gene e.g., an mRNA, RNA transcript or protein
  • RNA transcript transcribed from the gene comprises an intronic REMS
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • a disease associated with aberrant expression of a product of a gene e.g., an mRNA, RNA transcript or protein
  • RNA transcript transcribed from the gene comprises an intronic REMS
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcript transcribed from the gene comprises an intronic REMS
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • kits for preventing and/or treating a disease associated with aberrant expression of a product of a gene disclosed in Table 7, infra, ⁇ e.g., an mRNA, RNA transcript or protein comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. See the example section for additional information regarding the genes in Table 7.
  • a compound of Formula (I) is a compound of Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV) described infra.
  • a compound of Formula (I) is a compound selected from a compound described herein.
  • RNA transcript transcribed from the gene comprises an intronic REMS
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA isoforms encoded by a gene by way of nonlimiting example, disclosed in Table 1, infra, is beneficial to the prevention and/or treatment of the disease, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcript transcribed from the gene comprises an intronic REMS
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA isoforms encoded by a gene in another embodiment, provided herein are methods for preventing and/or treating a disease in which the alteration (e.g., increase or decrease) in the expression one, two, three or more RNA isoforms encoded by a gene, disclosed in International Patent Application No.
  • PCT/US2014/071252 (International Publication No. WO 2015/105657), is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • the alteration e.g., increase or decrease
  • the expression one, two, three or more RNA isoforms encoded by a gene disclosed in International Patent Application No.
  • PCT/US2016/034864 International Publication No. WO 2016/196386
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcript transcribed from the gene comprises an intronic REMS
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA isoforms encoded by a gene disclosed in Table 1, infra are beneficial to the prevention and/or treatment of the disease, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA isoforms encoded by a gene disclosed in Table 7, infra are decreased following administration of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. See the example section for additional information regarding the genes in Table 7.
  • a compound of Formula (I) is a compound of Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV) described infra.
  • a compound of Formula (I) is a compound selected from a compound described herein.
  • RNA transcript transcribed from the gene comprises an intronic REMS
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • provided herein are methods for preventing and/or treating a disease in which the alteration ⁇ e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene, by way of nonlimiting example, disclosed in Table 1, infra, is beneficial to the prevention and/or treatment of the disease, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • a pharmaceutically acceptable carrier excipient or diluent
  • RNA transcript transcribed from the gene comprises an intronic REMS
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcript transcribed from the gene comprises an intronic REMS
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcript transcribed from the gene comprises an intronic REMS
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcript transcribed from the gene comprises an intronic REMS
  • the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • kits for preventing and/or treating a disease in which the alteration (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene, disclosed in Table 1, infra, is beneficial to the prevention and/or treatment of the disease comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • a compound described herein for example, a compound of Formula (I) or a form thereof or another splicing inducer
  • a compound described herein for example, a compound of Formula (I) or a form thereof or another splicing inducer
  • a compound described herein for example, a compound of Formula (I) or a form thereof or another splicing inducer
  • the gene is a gene described in a table in this disclosure.
  • an artificial gene construct comprising endogenous DNA is modified to introduce a non-endogenous nucleotide sequence encoding an intron comprising a 3' splice site(s) and a branch point(s) and an intronic REMS.
  • an artificial gene construct comprising DNA encoding exons and one, two or more introns, wherein a nucleotide sequence encoding an intronic REMS 5' splice site, which may be downstream of an endogenous nucleotide sequence encoding a branch point and an endogenous nucleotide sequence encoding a 3' splice site, is modified to introduce a nucleotide sequence encoding a non-endogenous branch point and a non-endogenous 3' splice site further downstream from the endogenous intronic REMS.
  • an artificial gene construct comprising DNA encoding an intronic REMS, comprising nucleotides encoding an intronic REMS having one or more 5' splice site(s), 3' splice site(s) and branch point(s).
  • the artificial gene construct encodes a frameshift or premature stop codon or internal insertions or deletions within the open reading frame.
  • the artificial gene construct encodes a mature mRNA having a functional open reading frame, producing a novel protein which may or may not be functional.
  • the artificial gene construct encodes a detectable reporter protein.
  • RNA transcripts having a non-functional open reading frame due to the inclusion of a frameshift, premature stop codon or internal insertions or deletions within the open reading frame can be substrates for nonsense-mediated decay and thus have low abundance.
  • Any intronic REMS- mediated alternative splicing modified RNA transcripts may also have altered stability, altered intracellular transport, altered 3' end formation efficiency and altered translation efficiency.
  • nucleotide sequence of the intronic REMS introduced into the nucleotide sequence of the artificial gene construct comprises the sequence
  • the nucleotide sequence encoding the intronic REMS comprises a sequence selected from the group consisting of
  • NCGAgtrngn SEQ ID NO: 1836
  • CTGAgtrngn SEQ ID NO: 1850
  • TTGAgtrngn SEQ ID NO: 1852
  • r is adenine or guanine and n or N is any nucleotide.
  • ANGAgtragt (SEQ ID NO: 2237), CNGAgtragt (SEQ ID NO: 2243),
  • GNGAgtragt (SEQ ID NO: 2249), TNGAgtragt (SEQ ID NO: 2255),
  • NAGAgtragt SEQ ID NO: 2238
  • NCGAgtragt SEQ ID NO: 2244
  • NGGAgtragt (SEQ ID NO: 2250), NTGAgtragt (SEQ ID NO: 2256),
  • CAGAgtragt (SEQ ID NO: 2240), CCGAgtragt (SEQ ID NO: 2246),
  • GGGAgtragt (SEQ ID NO: 2253), GTGAgtragt (SEQ ID NO: 2259),
  • TAGAgtragt SEQ ID NO: 2242
  • TCGAgtragt SEQ ID NO: 2248
  • the nucleotide sequence encoding the intronic REMS is a nucleotide sequence encoding a non-endogenous intronic REMS, i.e., a precursor RNA transcript comprising the non-endogenous intronic REMS not naturally found in the DNA sequence of the artificial construct.
  • the intronic REMS referred to in a method or artificial gene construct described herein comprises, at the DNA level, a sequence presented in the following table (wherein r is adenine or guanine, and n or N is any nucleotide):
  • provided herein is a vector comprising the artificial gene construct described herein.
  • a cell comprising an artificial gene construct described herein or a vector comprising an artificial gene construct described herein.
  • provided herein is a method of modulating the amount and type of a protein produced by a cell containing an artificial gene construct described herein.
  • a method of modulating the amount and type of a protein produced by a cell containing an artificial gene construct described herein the method comprising contacting the cell with a compound of Formula (I) or a form thereof.
  • the artificial gene construct encodes a therapeutic protein.
  • the artificial gene construct encodes a non-functional protein. In some embodiments producing a therapeutic protein, the artificial gene construct may also encode a detectable reporter protein. In some embodiments producing a non-functional protein, the artificial gene construct may also encode a detectable reporter protein.
  • provided herein is a method of modulating the amount of a protein produced by a subject, wherein the subject is or was administered an artificial gene construct described herein.
  • method of regulating the amount of a protein produced by a subject comprising: (a) administering an artificial gene construct or a vector comprising the artificial gene construct described herein to the subject; and (b) administering a compound of Formula (I) or a form thereof to the subject.
  • provided herein is a method of regulating the amount of a protein produced by a subject, the method comprising administering a compound of Formula (I) or a form thereof to a subject carrying a gene containing a nucleotide sequence encoding an intronic REMS.
  • a method of regulating the amount of a protein produced by a subject the method comprising administering a compound of Formula (I) to the subject, wherein the subject was previously administered an artificial gene construct described herein.
  • the artificial gene construct may encode a therapeutic or a non-functional protein.
  • the artificial gene construct encodes a detectable reporter protein.
  • the subject is a non-human. In specific embodiments, the subject is a human.
  • RNA transcript produced from precursor RNA containing an endogenous or non-endogenous intronic recognition element for splicing modifier comprising contacting the precursor RNA with a compound of Formula (I) or a form thereof, wherein the endogenous or non-endogenous intronic REMS comprises the sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide, and wherein Formula (I) is
  • wi and ws are independently C-Ra or N;
  • W2 is C-Rb or N
  • W3, W4 and W7 are independently C-Ri, C-R2, C-Ra or N;
  • one of w 3 , W4, W6 and W7 is C-Ri and one other of w 3 , W4, W6 and W7 is C-R2, provided that,
  • Ri is Ci-8alkyl, amino, Ci-salkyl-amino, (Ci-8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino, (Ci-8alkoxy-Ci-8alkyl)
  • Ci-8alkyl-amino-Ci-8alkoxy (Ci-8alkyl)2-amino-Ci-8alkoxy,
  • Ci-8alkoxy-Ci-8alkyl-amino-Ci-8alkoxy Ci-salkoxy-Ci-salkyl-amino-Ci-salkoxy, (Ci-8alkoxy-Ci-8alkyl)(Ci-8alkyl)amino-Ci-8alkoxy, amino-C2-8alkenyl,
  • heterocyclyl-Ci-8alkyl-amino (heterocyclyl-Ci-8alkyl)2-amino,
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino
  • heterocyclyl-Ci-salkyl-amino-Ci-salkyl (heterocyclyl-Ci-8alkyl)2-amino-Ci-8alkyl
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino-Ci-8alkyl, heterocyclyl-oxy,
  • heteroaryl-Ci-8alkyl-amino (heteroaryl-Ci-8alkyl)2-amino
  • heteroaryl-Ci-8alkyl (Ci-8alkyl)amino
  • heteroaryl-Ci-salkyl-amino-Ci-salkyl
  • heterocyclyl C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R3 substituents;
  • R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino; wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R 6 substituents and optionally, with one additional R7 substituent;
  • Ra is, in each instance, independently selected from hydrogen, halogen, Ci-salkyl or deuterium;
  • Rb is hydrogen, halogen, Ci-salkyl, Ci-salkoxy or deuterium;
  • Rc is hydrogen, halogen, Ci-salkyl or deuterium
  • R3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci- 8 alkyl, halo-Ci- 8 alkyl, Ci- 8 alkyl-carbonyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy,
  • Ci-8alkyl-carbonyl-amino Ci-salkoxy-carbonyl-amino, hydroxy-Ci-salkyl
  • R4 is C3-i4cycloalkyl, C3-i4cycloalkyl-Ci-8alkyl, C3-i4cycloalkyl-amino, aryl-Ci-salkyl, aryl-Ci-8alkoxy-carbonyl, aryl-sulfonyloxy-Ci-salkyl, heterocyclyl or
  • heterocyclyl-Ci-8alkyl wherein, each instance of C3-i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R5 substituents;
  • R5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, Ci-salkoxy, halo-Ci-salkoxy, amino, Ci-salkyl-amino,
  • R 6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci- 8 alkyl, C2- 8 alkenyl, halo-Ci- 8 alkyl, hydroxy-Ci- 8 alkyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy, Ci- 8 alkoxy-Ci- 8 alkyl, amino, Ci- 8 alkyl-amino, (Ci- 8 alkyl)2-amino or Ci- 8 alkyl-thio; and, R7 is C3-i4cycloalkyl, C3-i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
  • RNA transcript produced from precursor RNA containing an endogenous or non-endogenous intronic recognition element for splicing modifier comprising contacting the precursor RNA with a compound of Formula (I) or a form thereof, wherein the endogenous or non-endogenous intronic REMS comprises the sequence NNGAgurngn (SEQ ID NO: 1), wherein r is adenine or guanine and n or N is any nucleotide, and wherein Formula (I) is
  • wi and ws are independently C-Ra or N;
  • W2 is C-Rb or N;
  • W3, W4 and W7 are independently C-Ri, C-R2, C-Ra or N;
  • one of w 3 , W4, W6 and W7 is C-Ri and one other of w 3 , w 4 , W6 and W7 is C-R2, provided that,
  • Ri is Ci-8alkyl, amino, Ci-salkyl-amino, (Ci-8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino, (Ci-8alkoxy-Ci-8alkyl)
  • Ci-8alkyl-amino-Ci-8alkoxy (Ci-8alkyl)2-amino-Ci-8alkoxy,
  • Ci-8alkoxy-Ci-8alkyl-amino-Ci-8alkoxy Ci-salkoxy-Ci-salkyl-amino-Ci-salkoxy, (Ci-8alkoxy-Ci-8alkyl)(Ci-8alkyl)amino-Ci-8alkoxy, amino-C2-8alkenyl,
  • heterocyclyl (heterocyclyl)(Ci-8alkyl)amino, heterocyclyl-amino-Ci-salkyl,
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino
  • heterocyclyl-Ci-salkyl-amino-Ci-salkyl (heterocyclyl-Ci-8alkyl)2-amino-Ci-8alkyl
  • heteroaryl-Ci-8alkyl-amino (heteroaryl-Ci-8alkyl)2-amino
  • heteroaryl-Ci-8alkyl (Ci-8alkyl)amino
  • heteroaryl-Ci-salkyl-amino-Ci-salkyl
  • each instance of heterocyclyl, C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R3 substituents and optionally, with one additional R4 substituent; or,
  • heterocyclyl C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R3 substituents;
  • R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino; wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R 6 substituents and optionally, with one additional R7 substituent;
  • Ra is, in each instance, independently selected from hydrogen, halogen, Ci-salkyl or deuterium;
  • Rc is hydrogen, halogen, Ci-salkyl or deuterium;
  • R.3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci-8alkyl, halo-Ci-salkyl, Ci-salkyl-carbonyl, Ci-salkoxy, halo-Ci-salkoxy,
  • Ci-8alkyl-carbonyl-amino Ci-salkoxy-carbonyl-amino, hydroxy-Ci-salkyl
  • R4 is C3-i4cycloalkyl, C3-i4cycloalkyl-Ci-8alkyl, C3-i4cycloalkyl-amino, aryl-Ci-salkyl, aryl-Ci-8alkoxy-carbonyl, aryl-sulfonyloxy-Ci-salkyl, heterocyclyl or
  • R 6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci-salkyl, C2- 8 alkenyl, halo-Ci- 8 alkyl, hydroxy-Ci- 8 alkyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy, Ci- 8 alkoxy-Ci- 8 alkyl, amino, Ci- 8 alkyl-amino, (Ci- 8 alkyl)2-amino or Ci- 8 alkyl-thio; and, R7 is C3-i4cycloalkyl, C3-i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
  • nucleotide sequence encoding an endogenous or non- endogenous intronic REMS in a subject comprises the sequence GAgtrngn (SEQ ID NO: 4), wherein r is adenine or guanine and n is any nucleotide
  • the method comprising administering a compound of Formula (I) to the subject, wherein Formula (I) is
  • wi and ws are independently C-Ra or N;
  • W2 is C-Rb or N
  • W3, W4 and W7 are independently C-Ri, C-R2, C-Ra or N;
  • one of w 3 , W4, W6 and W7 is C-Ri and one other of w 3 , w 4 , W6 and W7 is C-R2, provided that,
  • Ri is Ci-8alkyl, amino, Ci-salkyl-amino, (Ci-8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino, (Ci-8alkoxy-Ci-8alkyl)
  • Ci-8alkoxy-Ci-8alkyl-amino-Ci-8alkoxy Ci-salkoxy-Ci-salkyl-amino-Ci-salkoxy, (Ci-8alkoxy-Ci-8alkyl)(Ci-8alkyl)amino-Ci-8alkoxy, amino-C2-8alkenyl,
  • heterocyclyl (heterocyclyl)(Ci-8alkyl)amino, heterocyclyl-amino-Ci-salkyl,
  • heterocyclyl-Ci-8alkyl-amino (heterocyclyl-Ci-8alkyl)2-amino,
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino
  • heterocyclyl-Ci-salkyl-amino-Ci-salkyl (heterocyclyl-Ci-8alkyl)2-amino-Ci-8alkyl
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino-Ci-8alkyl, heterocyclyl-oxy,
  • heteroaryl-Ci-8alkyl (Ci-8alkyl)amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl, (heteroaryl-Ci-8alkyl)2-amino-C i-8alkyl or
  • each instance of heterocyclyl, C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R 3 substituents and optionally, with one additional R 4 substituent; or,
  • Rb is hydrogen, halogen, C i-salkyl, C i-salkoxy or deuterium;
  • Rc is hydrogen, halogen, Ci-salkyl or deuterium
  • R 3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci- 8 alkyl, halo-Ci- 8 alkyl, C i- 8 alkyl-carbonyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy,
  • Ci- 8 alkyl-carbonyl-amino Ci- 8 alkoxy-carbonyl-amino, hydroxy-Ci- 8 alkyl,
  • R4 is C 3 -i4cycloalkyl, C 3 -i4cycloalkyl-Ci- 8 alkyl, C 3 -i4cycloalkyl-amino, aryl-Ci- 8 alkyl, aryl-Ci- 8 alkoxy-carbonyl, aryl-sulfonyloxy-Ci- 8 alkyl, heterocyclyl or
  • heterocyclyl-Ci- 8 alkyl wherein, each instance of C 3 -i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R5 substituents;
  • R.5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci-8alkyl, halo-Ci-salkyl, Ci-salkoxy, halo-Ci-salkoxy, amino, Ci-salkyl-amino,
  • R 6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci- 8 alkyl, C 2 - 8 alkenyl, halo-Ci- 8 alkyl, hydroxy-Ci- 8 alkyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy, Ci- 8 alkoxy-Ci- 8 alkyl, amino, Ci- 8 alkyl-amino, (Ci- 8 alkyl) 2 -amino or Ci- 8 alkyl-thio; and, R7 is C3-i4cycloalkyl, C3-i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
  • nucleotide sequence encoding an endogenous or non- endogenous intronic REMS in a subject comprises the sequence NGAgtrngn (SEQ ID NO: 3), wherein r is adenine or guanine and n or N is any nucleotide
  • the method comprising administering a compound of Formula (I) to the subject, wherein Formula (I) is
  • wi and ws are independently C-Ra or N;
  • W2 is C-Rb or N
  • W3, W4 and W7 are independently C-Ri, C-R2, C-Ra or N;
  • Ri is Ci-8alkyl, amino, Ci-salkyl-amino, (Ci-8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino, (Ci-8alkoxy-Ci-8alkyl)
  • Ci-8alkyl-amino-Ci-8alkoxy (Ci-8alkyl)2-amino-Ci-8alkoxy,
  • Ci-8alkoxy-Ci-8alkyl-amino-Ci-8alkoxy Ci-salkoxy-Ci-salkyl-amino-Ci-salkoxy, (Ci-8alkoxy-Ci-8alkyl)(Ci-8alkyl)amino-Ci-8alkoxy, amino-C2-8alkenyl,
  • heterocyclyl (heterocyclyl)(Ci-8alkyl)amino, heterocyclyl-amino-Ci-salkyl,
  • heterocyclyl-Ci-8alkyl-amino (heterocyclyl-Ci-8alkyl)2-amino,
  • each instance of heterocyclyl, C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R3 substituents and optionally, with one additional R4 substituent; or,
  • heterocyclyl C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R3 substituents;
  • Ra is, in each instance, independently selected from hydrogen, halogen, Ci-salkyl or deuterium;
  • Rc is hydrogen, halogen, Ci-salkyl or deuterium
  • Ci- 8 alkyl-carbonyl-amino Ci- 8 alkoxy-carbonyl-amino, hydroxy-Ci- 8 alkyl, hydroxy-Ci-8alkoxy-Ci-8alkyl, hydroxy-Ci-salkyl-amino, (hydroxy-Ci-8alkyl)2-amino or (hy droxy-C i- 8 alkyl)(C i-8alkyl)amino;
  • R.4 is C3-i4cycloalkyl, C3-i4cycloalkyl-Ci-8alkyl, C3-i4cycloalkyl-amino, aryl-Ci-salkyl, aryl-Ci-8alkoxy-carbonyl, aryl-sulfonyloxy-Ci-salkyl, heterocyclyl or
  • R5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, Ci-salkoxy, halo-Ci-salkoxy, amino, Ci-salkyl-amino,
  • R 6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci- 8 alkyl, C 2 - 8 alkenyl, halo-Ci- 8 alkyl, hydroxy-Ci- 8 alkyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy, Ci- 8 alkoxy-Ci- 8 alkyl, amino, Ci- 8 alkyl-amino, (Ci- 8 alkyl) 2 -amino or Ci- 8 alkyl-thio; and, R7 is C3-i4cycloalkyl, C3-i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
  • the gene is, or the RNA transcript is transcribed from a gene that is selected from: ABCA1, ABCAIO, ABCB7, ABCB8, ABCCl, ABCC3, ABHDIO, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ACTA2, ADAL, ADAM 12, ADAM15, ADAM 17, ADAM33, ADAMTSl, ADCY3, ADDl, ADGRG6, ADH6, ADHFEl, AFF2, AFF3, AGK, AGPAT3, AGPAT4, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAPl, AKAP3, AKAP9, AKNA, ALCAM, ALDH4A1, AMPD2, A K1, A K2, A K3, A KFY1, A KHD1-EIF4EBP3, A KRA2, A KRD17, ANKRD33B, A KRD36, A KS
  • RAPIGDSI RAPIGDSI, RAPGEFl, RARG, RARS, RARS2, RASSF8, RBBP8, RBCKl, RBFOX2, RBKS, RBM10, RCC1, RDX, RERE, RFTN1, RFWD2, RFX3-AS1, RGCC, RGS10, RGS3, RIF1, R F14, RNF19A, R F38, R FT1, ROR1, ROR2, RPA1, RPL10, RPS10, RPS6KB2,
  • TMEM134 TMEM154, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM47, TMEM50B, TMEM63A, TNC, TNFAIP3, TNFAIP8L3, TNFRSF12A, TNFRSF14, TNIPl, TNKSIBPI, TNP03, TNRC18P1, TNRC6A, TNSl, TNS3, TNXB, TOEl, TOMM40, TOMM5, TOPORS, TP53AIP1, TP53INP1, TPRG1, TRAF3, TRAKl, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRIM66, TRMT1L, TRPC4, TRPS1, TSC2, TSHZ1, TSHZ2, TSPAN11, TSPAN18, TSPAN2, TSPAN7, TSSK3, TTC7A, TTC7B, TUBB2C,
  • the gene is, or the RNA transcript is transcribed from a gene that is selected from: ABCAIO, ABCB8, ABCC3, ACTA2, ADAL, ADAMTS1, ADCY3, ADD1, ADGRG6, ADH6, ADHFE1, AFF3, AGPAT4, AKAP3, ANK1, ANK3, ANKRA2, ANKRD33B, ANKRD36, AP4B1-AS1, APIP, ARHGAPl, ARHGAP12, ARHGEF16, ARID5B, ARL15, ARL9, ARMCX6, ASIC1, ATG5, ATP2A3, ATXN1, B3GALT2, B3GNT6, BCL2L15, BCYRNl, BECN1, BHMT2, BIN3-IT1, BIRC3, BIRC6, BTG2, BTN3A1, C10orf54, Cl lorf70, Cl lorf94, C12orf4,
  • the gene is, or the RNA transcript is transcribed from a gene that is not described in International Publication No. WO 2015/105657.
  • the gene is, or the RNA transcript is transcribed from a gene that is not described in International Publication No. WO 2016/196386.
  • the gene is, or the RNA transcript is transcribed from a gene that is not described in International Publication No. WO
  • the gene is, or the RNA transcript is transcribed from a gene that is selected from: ABCA1, ABCB7, ABCCl, ABHDIO, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ADAM 12, ADAM15, ADAM 17, ADAM33, AFF2, AGK, AGPAT3, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP9, AKNA, ALCAM, ALDH4A1, AMPD2, ANK2, ANKFYl, ANKUD 1 -EIF4EBP3 , ANKRD17, ANKS6, ANP32A, ANXAl l, ANXA6, AP2B1, APAFl, APLP2, APP, APPL2, APTX, ARHGAP22, ARID 1 A, ARID2, ARMCX3, ASAPl, ASL, ASNS,
  • CASP8AP2 CAV1, CCARl, CCDC77, CCDC88A, CCDC92, CCT6A, CD276, CD46,
  • the gene is, or the RNA transcript is transcribed from a gene that is selected from: ABCB8,
  • the gene is, or the RNA transcript is transcribed from a gene that is selected from: ABCB8,
  • the gene is, or the RNA transcript is transcribed from a gene that is selected from: ABCAIO, ABCCl, ACTA2, ADAL, ADAM12, ADAMTS1, ADAMTS5, ADD1, ADGRG6, ADH6, ADHFEl, AFF2, AFF3, AGK, AGPS, AKAP3, ANKl, ANK2, ANK3, ANKRD33B, ANXAl l, ANXA6, AP4B 1-AS1, ARHGEF16, ARID5B, ARL9, ARMCX3, ASAPl, ASIC1, ATP2A3, B3GALT2, B3GNT6, BCL2L15, BCYRN1, BIN3-IT1, BIRC3, BTG2, C10orf54, Cl lorf70, Cl lorf73, Cl lorf94, C12orf56, C19orf47, C3, C4orf27, C7orf31, C8orf34, CA13
  • the gene is, or the RNA transcript is transcribed from a gene that is selected from: ABCAIO, ACTA2, ADAL, ADAMTSl, ADAMTS5, ADDl, ADGRG6, ADH6, ADHFEl, AFF3, AKAP3, ANK1, ANK3, ANKRD33B, AP4B 1-AS1, ARHGEF16, ARID5B, ARL9, ASIC1, ATP2A3, B3GALT2, B3GNT6, BCL2L15, BCYRN1, BIN3-IT1, BIRC3, BTG2, C10orf54, Cl lorf70, Cl lorf94, C12orf56, C19orf47, C3, C7orf31, C8orf34, CA13, CA3, CACNA2D2, CACNB l, CADMl, CAND2, CCDC79, CCER2, CCNF, CELSR1, CEMIP, CEP 170, CFH,
  • TMEM102 TMEM119, TMEM256-PLSCR3, TMEM50B, TNFAIP8L3, TNFRSF14,
  • the gene is, or the RNA transcript is transcribed from a gene that is selected from: ABCB8, ABCC3, ADAM 17, ADCY3, AGPAT4, ANKRA2, ANXA11, APIP, APLP2, APLP2, ARHGAPl, ARL15, ASAPl, ASPH, ATAD2B, ATXN1, AXIN1, BECN1, BHMT2, BICDl, BTN3A1, Cl lorf30, Cl lorf73, C12orf4, C14orfl32, C8orf44, C8orf44-SGK3, C8orf88, CASC3, CASP7, CCDC122, CDH13, CECR7, CENPI, CEP112, CEP192, CHEK1, CMAHP, CNRIPl, COPS7B, CPSF4, CRISPLD2, CRYBG3, CSNK1E, CSNKIGI, DAGLB, DCAF17, DCUN1D4, DD
  • the gene is, or the RNA transcript is transcribed from a gene that is selected from: ABCB8, ABCC3, ADAM 17, ADCY3, AGPAT4, ANKRA2, ANXA11, APIP, APPL2, ARHGAPl, ARL15, ASAPl, ASPH, ATAD2B, ATXN1, BECN1, BHMT2, BICDl, BTN3A1, Cl lorf30, Cl lorf73, C12orf4, C14orfl32, C8orf44, C8orf44-SGK3, C8orf88, CASC3, CASP7, CCDC122, CDH13, CECR7, CENPI, CEP112, CEP192, CHEKl, CMAHP, CNRIPl, COPS7B, CPSF4, CRISPLD2, CRYBG3, CSNK1E, CSNK1G1, DCAF17, DCUN1D4, DDX42, DENND1A,
  • UBAP2L URGCP, VAV2, WDR27, WDR37, WDR91, W K1, XRN2, ZCCHC8, ZFP82, Z F138, Z F232 or Z F37BP.
  • the gene is, or the RNA transcript is transcribed from a gene that is selected from: APLP2, AXIN1, CECR7, DAGLB, DLGAP4, ERCCl, ERGIC3, FAM198B, GGCT, HAT1, HPS1, INPP5K, MADD, PPHLNl, PRUNE2, RAPIA, RNFTl, RPS6KB2, SH3YL1, SKA2, SPATA18, STRN3, TMEM189-UBE2V1, TRFM65, TUBE1, UBE2V1, VPS29 or ZNF680.
  • a gene that is selected from: APLP2, AXIN1, CECR7, DAGLB, DLGAP4, ERCCl, ERGIC3, FAM198B, GGCT, HAT1, HPS1, INPP5K, MADD, PPHLNl, PRUNE2, RAPIA, RNFTl, RPS6KB2, SH3YL1, SKA2, SPATA18, STRN3, TMEM189-UB
  • the gene is, or the RNA transcript is transcribed from a gene that is selected from: ABCB8, ABCC3, ADCY3, AGPAT4, ANKRA2, APIP, ARHGAP1, ARL15, ATXN1, BECN1, BHMT2,
  • wi and ws are independently C-Ra or N;
  • W2 is C-Rb or N
  • W3, W4 and W7 are independently C-Ri, C-R2, C-Ra or N;
  • one of w 3 , W4, W6 and W7 is C-Ri and one other of w 3 , w 4 , W6 and W7 is C-R2, provided that,
  • Ri is Ci-8alkyl, amino, Ci-salkyl-amino, (Ci-8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino, (Ci-8alkoxy-Ci-8alkyl)
  • Ci-8alkyl-amino-Ci-8alkoxy Ci-8alkyl-amino-Ci-8alkoxy, (Ci-8alkyl)2-amino-Ci-8alkoxy, Ci-8alkoxy-Ci-8alkyl-amino-Ci-8alkoxy, Ci-salkoxy-Ci-salkyl-amino-Ci-salkoxy, (Ci-8alkoxy-Ci-8alkyl)(Ci-8alkyl)amino-Ci-8alkoxy, amino-C2-8alkenyl,
  • heterocyclyl (heterocyclyl)(Ci-8alkyl)amino, heterocyclyl-amino-Ci-salkyl,
  • heterocyclyl-Ci-8alkyl-amino (heterocyclyl-Ci-8alkyl)2-amino,
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino
  • heterocyclyl-Ci-salkyl-amino-Ci-salkyl (heterocyclyl-Ci-8alkyl)2-amino-Ci-8alkyl
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino-Ci-8alkyl, heterocyclyl-oxy,
  • heteroaryl-Ci-8alkyl-amino (heteroaryl-Ci-8alkyl)2-amino
  • heteroaryl-Ci-8alkyl (Ci-8alkyl)amino
  • heteroaryl-Ci-salkyl-amino-Ci-salkyl
  • heteroaryl-Ci-8alkyl (Ci-8alkyl)amino-Ci-8alkyl; wherein, each instance of heterocyclyl, C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R 3 substituents and optionally, with one additional R 4 substituent; or,
  • each instance of heterocyclyl, C 3 -i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R 3 substituents;
  • R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino; wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R 6 substituents and optionally, with one additional R7 substituent;
  • Ra is, in each instance, independently selected from hydrogen, halogen, Ci-salkyl or deuterium;
  • Rb is hydrogen, halogen, Ci-salkyl, Ci-salkoxy or deuterium;
  • Rc is hydrogen, halogen, Ci-salkyl or deuterium
  • R 3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci- 8 alkyl, halo-Ci- 8 alkyl, Ci- 8 alkyl-carbonyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy,
  • Ci- 8 alkyl-carbonyl-amino Ci- 8 alkoxy-carbonyl-amino, hydroxy-Ci- 8 alkyl,
  • R4 is C 3 -i4cycloalkyl, C 3 -i4cycloalkyl-Ci- 8 alkyl, C 3 -i4cycloalkyl-amino, aryl-Ci- 8 alkyl, aryl-Ci- 8 alkoxy-carbonyl, aryl-sulfonyloxy-Ci- 8 alkyl, heterocyclyl or
  • heterocyclyl-Ci- 8 alkyl wherein, each instance of C 3 -i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R5 substituents;
  • R5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci- 8 alkyl, halo-Ci- 8 alkyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy, amino, Ci- 8 alkyl-amino,
  • R.6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci-8alkyl, C 2 -8alkenyl, halo-Ci-salkyl, hydroxy-Ci-salkyl, Ci-salkoxy, halo-Ci-salkoxy, Ci-salkoxy-Ci-salkyl, amino, Ci-salkyl-amino, (Ci-8alkyl)2-amino or Ci-salkyl-thio; and, R7 is C3-i4cycloalkyl, C3-i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
  • the nucleotide sequence encoding the intronic REMS comprises a sequence selected from the group consisting of
  • ANGAgtrngn (SEQ ID NO: 1829), CNGAgtrngn (SEQ ID NO: 1835),
  • GNGAgtrngn (SEQ ID NO: 1841), TNGAgtrngn (SEQ ID NO: 1847),
  • NAGAgtrngn SEQ ID NO: 1830
  • NCGAgtrngn SEQ ID NO: 1836
  • TGGAgtragt (SEQ ID NO: 2254) and TTGAgtragt (SEQ ID NO: 2260), wherein r is adenine or guanine and N is any nucleotide. In one or more embodiments provided herein, N is adenine or guanine.
  • RNA transcript comprising a RNA nucleotide sequence comprising in 5' to 3' order: a branch point, a 3' splice site and an endogenous intronic recognition element for splicing modifier (iREMS), wherein the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide, and wherein the RNA transcript is an RNA transcript of a gene that is selected from: ABCAIO, ABCB8, ABCC3, ACTA2, ADAL, ADAMTS1, ADCY3, ADDl, ADGRG6, ADH6, ADHFEl, AFF3, AGPAT4, AKAP3, ANK1, ANK3, ANKRA2, ANKRD33B, ANKRD36, AP4B1-AS1, APIP, ARHGAP1, ARHGAP12,
  • W2 is C-Rb or N
  • Ri is Ci-8alkyl, amino, Ci-salkyl-amino, (Ci-8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino, (Ci-8alkoxy-Ci-8alkyl)
  • Ci-8alkyl-amino-Ci-8alkoxy Ci-8alkyl-amino-Ci-8alkoxy, (Ci-8alkyl)2-amino-Ci-8alkoxy, Ci-8alkoxy-Ci-8alkyl-amino-Ci-8alkoxy, Ci-salkoxy-Ci-salkyl-amino-Ci-salkoxy, (Ci-8alkoxy-Ci-8alkyl)(Ci-8alkyl)amino-Ci-8alkoxy, amino-C2-8alkenyl,
  • heterocyclyl (heterocyclyl)(Ci-8alkyl)amino, heterocyclyl-amino-Ci-salkyl,
  • heterocyclyl-Ci-8alkyl-amino (heterocyclyl-Ci-8alkyl)2-amino,
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino-Ci-8alkyl, heterocyclyl-oxy,
  • heteroaryl-Ci-8alkyl-amino (heteroaryl-Ci-8alkyl)2-amino
  • heteroaryl-Ci-8alkyl (Ci-8alkyl)amino
  • heteroaryl-Ci-salkyl-amino-Ci-salkyl
  • heteroaryl-Ci-8alkyl (Ci-8alkyl)amino-Ci-8alkyl; wherein, each instance of heterocyclyl, C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R 3 substituents and optionally, with one additional R 4 substituent; or,
  • Rb is hydrogen, halogen, Ci-salkyl, Ci-salkoxy or deuterium;
  • R 3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci- 8 alkyl, halo-Ci- 8 alkyl, Ci- 8 alkyl-carbonyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy,
  • R4 is C 3 -i4cycloalkyl, C 3 -i4cycloalkyl-Ci- 8 alkyl, C 3 -i4cycloalkyl-amino, aryl-Ci- 8 alkyl, aryl-Ci- 8 alkoxy-carbonyl, aryl-sulfonyloxy-Ci- 8 alkyl, heterocyclyl or
  • heterocyclyl-Ci- 8 alkyl wherein, each instance of C 3 -i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R5 substituents;
  • R5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci- 8 alkyl, halo-Ci- 8 alkyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy, amino, Ci- 8 alkyl-amino,
  • RNA transcript comprising a RNA nucleotide sequence comprising in 5' to 3' order: a branch point, a 3' splice site and an endogenous intronic recognition element for splicing modifier (iREMS); wherein the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide, and wherein the RNA transcript is an RNA transcript of a gene not disclosed in either International Publication No. WO 2015/105657, International Publication No. WO 2016/196386, or both; the method comprising contacting the RNA transcript with a compound of Formula (I) or a form thereof, wherein Formula (I) is:
  • wi and ws are independently C-Ra or N;
  • W2 is C-Rb or N
  • W3, W4 and W7 are independently C-Ri, C-R2, C-Ra or N;
  • one of w 3 , W4, W6 and W7 is C-Ri and one other of w 3 , w 4 , W6 and W7 is C-R2, provided that,
  • Ri is Ci-salkyl, amino, Ci-salkyl-amino, (Ci-8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino, (Ci-8alkoxy-Ci-8alkyl
  • heterocyclyl (heterocyclyl)(Ci-8alkyl)amino, heterocyclyl-amino-Ci-salkyl,
  • heteroaryl-Ci-8alkyl-amino (heteroaryl-Ci-8alkyl)2-amino
  • heteroaryl-Ci-8alkyl (C i-8alkyl)amino
  • heteroaryl-Ci-salkyl-amino-Ci-salkyl
  • each instance of heterocyclyl, C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R 3 substituents and optionally, with one additional R 4 substituent; or,
  • each instance of heterocyclyl, C 3 -i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R 3 substituents;
  • Rb is hydrogen, halogen, C i-salkyl, C i-salkoxy or deuterium;
  • Rc is hydrogen, halogen, Ci-salkyl or deuterium
  • R 3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci- 8 alkyl, halo-Ci- 8 alkyl, C i- 8 alkyl-carbonyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy,
  • Ci- 8 alkyl-carbonyl-amino Ci- 8 alkoxy-carbonyl-amino, hydroxy-Ci- 8 alkyl,
  • R.4 is C3-i4cycloalkyl, C3-i4cycloalkyl-Ci-8alkyl, C3-i4cycloalkyl-amino, aryl-Ci-salkyl, aryl-Ci-8alkoxy-carbonyl, aryl-sulfonyloxy-Ci-salkyl, heterocyclyl or
  • heterocyclyl-Ci-8alkyl wherein, each instance of C3-i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three Rs substituents;
  • R5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci- 8 alkyl, halo-Ci- 8 alkyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy, amino, Ci- 8 alkyl-amino,
  • R 6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci- 8 alkyl, C 2 - 8 alkenyl, halo-Ci- 8 alkyl, hydroxy-Ci- 8 alkyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy, Ci- 8 alkoxy-Ci- 8 alkyl, amino, Ci- 8 alkyl-amino, (Ci- 8 alkyl) 2 -amino or Ci- 8 alkyl-thio; and, R7 is C3-i4cycloalkyl, C3-i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
  • RNA transcript comprising a RNA nucleotide sequence comprising in 5' to 3' order: a branch point, a 3' splice site and a non-endogenous intronic recognition element for splicing modifier (iREMS),; wherein the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide, the method comprising contacting the RNA transcript with a compound of Formula (I) or a form thereof, wherein Formula (I) is:
  • wi and ws are independently C-Ra or N;
  • W2 is C-Rb or N
  • W3, W4 and W7 are independently C-Ri, C-R2, C-Ra or N;
  • one of w 3 , w 4 , W6 and W7 is C-Ri and one other of w 3 , w 4 , W6 and W7 is C-R2, provided that,
  • Ri is Ci-8alkyl, amino, Ci-salkyl-amino, (Ci-8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino, (Ci-8alkoxy-Ci-8alkyl)
  • Ci-8alkyl-amino-Ci-8alkoxy (Ci-8alkyl)2-amino-Ci-8alkoxy,
  • Ci-8alkoxy-Ci-8alkyl-amino-Ci-8alkoxy Ci-salkoxy-Ci-salkyl-amino-Ci-salkoxy, (Ci-8alkoxy-Ci-8alkyl)(Ci-8alkyl)amino-Ci-8alkoxy, amino-C2-8alkenyl,
  • heterocyclyl (heterocyclyl)(Ci-8alkyl)amino, heterocyclyl-amino-Ci-salkyl, heterocyclyl-Ci-8alkyl-amino, (heterocyclyl-Ci-8alkyl)2-amino,
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino
  • heterocyclyl-Ci-salkyl-amino-Ci-salkyl (heterocyclyl-Ci-8alkyl)2-amino-Ci-8alkyl
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino-Ci-8alkyl, heterocyclyl-oxy,
  • heteroaryl-Ci-8alkyl-amino (heteroaryl-Ci-8alkyl)2-amino
  • heteroaryl-Ci-8alkyl (Ci-8alkyl)amino
  • heteroaryl-Ci-salkyl-amino-Ci-salkyl
  • each instance of heterocyclyl, C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R3 substituents and optionally, with one additional R4 substituent; or,
  • heterocyclyl C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R3 substituents;
  • R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino; wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R 6 substituents and optionally, with one additional R7 substituent;
  • Ra is, in each instance, independently selected from hydrogen, halogen, Ci-salkyl or deuterium;
  • Rb is hydrogen, halogen, Ci-salkyl, Ci-salkoxy or deuterium;
  • Rc is hydrogen, halogen, Ci-salkyl or deuterium
  • R3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci- 8 alkyl, halo-Ci- 8 alkyl, Ci- 8 alkyl-carbonyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy,
  • Ci-8alkyl-carbonyl-amino Ci-salkoxy-carbonyl-amino, hydroxy-Ci-salkyl
  • R4 is C3-i4cycloalkyl, C3-i4cycloalkyl-Ci-8alkyl, C3-i4cycloalkyl-amino, aryl-Ci-salkyl, aryl-Ci-8alkoxy-carbonyl, aryl-sulfonyloxy-Ci-salkyl, heterocyclyl or
  • heterocyclyl-Ci-8alkyl wherein, each instance of C3-i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R5 substituents;
  • R5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, Ci-salkoxy, halo-Ci-salkoxy, amino, Ci-salkyl-amino,
  • R 6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci- 8 alkyl, C2- 8 alkenyl, halo-Ci- 8 alkyl, hydroxy-Ci- 8 alkyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy, Ci- 8 alkoxy-Ci- 8 alkyl, amino, Ci- 8 alkyl-amino, (Ci- 8 alkyl)2-amino or Ci- 8 alkyl-thio; and, R7 is C3-i4cycloalkyl, C3-i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
  • the iREMS comprises an RNA sequence
  • the iREMS comprises an RNA sequence NNGAgurngn (SEQ ID NO: 1), wherein r is adenine or guanine and n or N is any nucleotide.
  • the RNA sequence NNGAgurngn (SEQ ID NO: 1) is selected from the group consisting of ANGAgurngn (SEQ ID NO: 29), CNGAgurngn (SEQ ID NO: 35), GNGAgurngn (SEQ ID NO: 41),
  • NCGAgurngn SEQ ID NO: 36
  • NGGAgurngn SEQ ID NO: 42
  • GUGAgurngn (SEQ ID NO: 51), UAGAgurngn (SEQ ID NO: 34), UCGAgurngn (SEQ ID NO: 40), UGGAgurngn (SEQ ID NO: 46) and
  • UUGAgurngn (SEQ ID NO: 52), wherein r is adenine or guanine and n or N is any nucleotide. In certain embodiments, n is adenine or guanine.
  • the iREMS comprises an RNA sequence
  • RNA sequence NNGAguragu (SEQ ID NO: 3862), wherein r is adenine or guanine and N is any nucleotide.
  • the RNA sequence NNGAguragu (SEQ ID NO: 3862) is selected from the group consisting of ANGAguragu (SEQ ID NO: 437), CNGAguragu (SEQ ID NO: 443),
  • GNGAguragu (SEQ ID NO: 449), UNGAguragu (SEQ ID NO: 455),
  • NAGAguragu SEQ ID NO: 438
  • NCGAguragu SEQ ID NO: 4444
  • CAGAguragu (SEQ ID NO: 440), CCGAguragu (SEQ ID NO: 446),
  • UGGAguragu SEQ ID NO: 454) and UUGAguragu (SEQ ID NO: 460), wherein r is adenine or guanine, and N is any nucleotide
  • the iREMS comprises an RNA sequence presented in Table 13.
  • n is adenine or guanine.
  • RNA transcript produced from a DNA sequence comprising a DNA nucleotide sequence encoding exons and one or more introns, comprising in 5' to 3' order: a branch point, a 3' splice site and an endogenous iREMS; wherein the iREMS comprises a DNA sequence GAgtrngn (SEQ ID NO: 4), wherein r is adenine or guanine and n is any nucleotide, the method comprising contacting the RNA transcript with a compound of Formula (I) or a form thereof, wherein Formula (I) is:
  • wi and ws are independently C-Ra or N;
  • W2 is C-Rb or N
  • W3, W4 and W7 are independently C-Ri, C-R2, C-Ra or N;
  • one of w 3 , W4, W6 and W7 is C-Ri and one other of w 3 , w 4 , W6 and W7 is C-R2, provided that,
  • Ri is Ci-8alkyl, amino, Ci-salkyl-amino, (Ci-8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino, (Ci-8alkoxy-Ci-8alkyl)
  • Ci-8alkyl-amino-Ci-8alkoxy (Ci-8alkyl)2-amino-Ci-8alkoxy,
  • Ci-8alkoxy-Ci-8alkyl-amino-Ci-8alkoxy Ci-salkoxy-Ci-salkyl-amino-Ci-salkoxy, (Ci-8alkoxy-Ci-8alkyl)(Ci-8alkyl)amino-Ci-8alkoxy, amino-C2-8alkenyl,
  • heterocyclyl-Ci-8alkyl-amino (heterocyclyl-Ci-8alkyl)2-amino,
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino
  • heterocyclyl-Ci-salkyl-amino-Ci-salkyl (heterocyclyl-Ci-8alkyl)2-amino-Ci-8alkyl
  • heteroaryl-Ci-8alkyl-amino (heteroaryl-Ci-8alkyl)2-amino
  • heteroaryl-Ci-8alkyl (Ci-8alkyl)amino
  • heteroaryl-Ci-salkyl-amino-Ci-salkyl
  • each instance of heterocyclyl, C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R3 substituents and optionally, with one additional R4 substituent; or,
  • heterocyclyl C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R3 substituents;
  • R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino; wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R 6 substituents and optionally, with one additional R7 substituent;
  • Ra is, in each instance, independently selected from hydrogen, halogen, Ci-salkyl or deuterium;
  • Rb is hydrogen, halogen, Ci-salkyl, Ci-salkoxy or deuterium;
  • Rc is hydrogen, halogen, Ci-salkyl or deuterium
  • R3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci- 8 alkyl, halo-Ci- 8 alkyl, Ci- 8 alkyl-carbonyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy,
  • Ci- 8 alkyl-carbonyl-amino Ci- 8 alkoxy-carbonyl-amino, hydroxy-Ci- 8 alkyl,
  • R4 is C3-i4cycloalkyl, C3-i4cycloalkyl-Ci- 8 alkyl, C3-i4cycloalkyl-amino, aryl-Ci- 8 alkyl, aryl-Ci- 8 alkoxy-carbonyl, aryl-sulfonyloxy-Ci- 8 alkyl, heterocyclyl or
  • heterocyclyl-Ci- 8 alkyl wherein, each instance of C3-i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R5 substituents;
  • R5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci- 8 alkyl, halo-Ci- 8 alkyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy, amino, Ci- 8 alkyl-amino,
  • R 6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci- 8 alkyl, C2- 8 alkenyl, halo-Ci- 8 alkyl, hydroxy-Ci- 8 alkyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy, Ci- 8 alkoxy-Ci- 8 alkyl, amino, Ci- 8 alkyl-amino, (Ci- 8 alkyl)2-amino or Ci- 8 alkyl-thio; and, R7 is C3-i4cycloalkyl, C3-i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
  • the DNA sequence is in a gene selected from: ABCA10, ABCB8, ABCC3, ACTA2, ADAL, ADAMTSl, ADCY3, ADDl, ADGRG6, ADH6, ADHFEl, AFF3, AGPAT4, AKAP3, ANKl, ANK3, ANKRA2, ANKRD33B, ANKRD36, AP4B1-AS1, APIP, ARHGAPl, ARHGAPl 2, ARHGEF16, ARID5B, ARL15, ARL9, ARMCX6, ASICl, ATG5, ATP2A3, ATXN1, B3GALT2, B3GNT6, BCL2L15, BCYRN1, BECN1, BHMT2, BIN3-IT1, BIRC3, BIRC6, BTG2, BTN3A1, C10orf54, Cl lorf70, Cl lorf94, C12orf4,
  • MLLTIO MMP10, MMP24, MN1, MOXD1, MRPL45, MRPL55, MRPS28, MRVI1, MSH4, MTERF3, MXRA5, MYCBP2, NA, NAALADL2, NAEl, NAGS, NDNF, NGF, NGFR, NHLH1, NLN, NOTCH3, NOTUM, NOVA2, NOX4, NRROS, OCLN, OLR1, OSBPL10, OXCT1, OXCT2, PAIP2B, PBLD, PDE1C, PDE5A, PDGFD, PDGFRB, PDS5B, PEARl, PHACTR3, PIGN, PIK3CD, PIK3R1, PIKFYVE, PFM2, PITPNM3, PLEK2, PLEKHA1, PLEKHA6, PLEKHH2, PLSCR1, PNISR, PODN, POLN, POLR1A, POMT2, PPARG, PPIP5K2, PPMIE, PPP1R26
  • RNA transcript produced from a DNA sequence comprising a DNA nucleotide sequence encoding exons and one or more introns, comprising in 5' to 3' order: a branch point, a 3' splice site and a non-endogenous iREMS; wherein the iREMS comprises a DNA sequence GAgtrngn (SEQ ID NO: 4), wherein r is adenine or guanine and n is any nucleotide, the method comprising contacting the RNA transcript with a compound of Formula (I) or a form thereof, wherein Formula (I) is:
  • I l l - wi and ws are independently C-Ra or N;
  • W2 is C-Rb or N
  • W3, W4 and W7 are independently C-Ri, C-R2, C-Ra or N;
  • one of w 3 , W4, W6 and W7 is C-Ri and one other of w 3 , w 4 , W6 and W7 is C-R2, provided that,
  • Ri is Ci-8alkyl, amino, Ci-salkyl-amino, (Ci-8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino, (Ci-8alkoxy-Ci-8alkyl)
  • Ci-8alkyl-amino-Ci-8alkoxy (Ci-8alkyl)2-amino-Ci-8alkoxy,
  • Ci-8alkoxy-Ci-8alkyl-amino-Ci-8alkoxy Ci-salkoxy-Ci-salkyl-amino-Ci-salkoxy, (Ci-8alkoxy-Ci-8alkyl)(Ci-8alkyl)amino-Ci-8alkoxy, amino-C2-8alkenyl,
  • heterocyclyl (heterocyclyl)(Ci-8alkyl)amino, heterocyclyl-amino-Ci-salkyl,
  • heterocyclyl-Ci-8alkyl-amino (heterocyclyl-Ci-8alkyl)2-amino,
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino
  • heterocyclyl-Ci-salkyl-amino-Ci-salkyl (heterocyclyl-Ci-8alkyl)2-amino-Ci-8alkyl
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino-Ci-8alkyl, heterocyclyl-oxy,
  • heteroaryl-Ci-8alkyl-amino (heteroaryl-Ci-8alkyl)2-amino
  • heteroaryl-Ci-8alkyl (Ci-8alkyl)amino
  • heteroaryl-Ci-salkyl-amino-Ci-salkyl
  • each instance of heterocyclyl, C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R3 substituents and optionally, with one additional R4 substituent; or,
  • heterocyclyl C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R3 substituents;
  • R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino; wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R 6 substituents and optionally, with one additional R7 substituent;
  • Ra is, in each instance, independently selected from hydrogen, halogen, Ci-salkyl or deuterium;
  • Rb is hydrogen, halogen, Ci-salkyl, Ci-salkoxy or deuterium;
  • Rc is hydrogen, halogen, Ci-salkyl or deuterium;
  • R3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci-8alkyl, halo-Ci-salkyl, Ci-salkyl-carbonyl, Ci-salkoxy, halo-Ci-salkoxy,
  • Ci-8alkoxy-Ci-8alkyl Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci-8alkyl)2-amino, amino-Ci-8alkyl, Ci-salkyl-amino-Ci-salkyl, (Ci-8alkyl)2-amino-Ci-8alkyl,
  • Ci-8alkyl-carbonyl-amino Ci-salkoxy-carbonyl-amino, hydroxy-Ci-salkyl
  • R4 is C3-i4cycloalkyl, C3-i4cycloalkyl-Ci-8alkyl, C3-i4cycloalkyl-amino, aryl-Ci-salkyl, aryl-Ci-8alkoxy-carbonyl, aryl-sulfonyloxy-Ci-salkyl, heterocyclyl or
  • heterocyclyl-Ci-8alkyl wherein, each instance of C3-i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R5 substituents;
  • R5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, Ci-salkoxy, halo-Ci-salkoxy, amino, Ci-salkyl-amino,
  • R 6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci- 8 alkyl, C2- 8 alkenyl, halo-Ci- 8 alkyl, hydroxy-Ci- 8 alkyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy, Ci- 8 alkoxy-Ci- 8 alkyl, amino, Ci- 8 alkyl-amino, (Ci- 8 alkyl)2-amino or Ci- 8 alkyl-thio; and, R7 is C3-i4cycloalkyl, C3-i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
  • the iREMS comprises a DNA sequence GAgtrngn (SEQ ID NO: 4), wherein r is adenine or guanine and n is any nucleotide. In certain embodiments, n is adenine or guanine. In certain embodiments, the iREMS comprises a DNA sequence
  • NNGAgtrngn (SEQ ID NO: 3), wherein r is adenine or guanine and n or N is any nucleotide.
  • the DNA sequence NNGAgtrngn (SEQ ID NO: 3) is selected from the group consisting of ANGAgtrngn (SEQ ID NO: 1829), CNGAgtrngn (SEQ ID NO: 1835), GNGAgtrngn (SEQ ID NO: 1841), TNGAgtrngn (SEQ ID NO: 1847), NAGAgtrngn (SEQ ID NO: 1830), NCGAgtrngn (SEQ ID NO: 1836),
  • NGGAgtrngn (SEQ ID NO: 1842), NTGAgtrngn (SEQ ID NO: 1848),
  • CAGAgtrngn (SEQ ID NO: 1832), CCGAgtrngn (SEQ ID NO: 1838),
  • GGGAgtrngn (SEQ ID NO: 1845), GTGAgtrngn (SEQ ID NO: 1851),
  • TAGAgtrngn (SEQ ID NO: 1834), TCGAgtrngn (SEQ ID NO: 1840),
  • TGGAgtrngn (SEQ ID NO: 1846) and TTGAgtrngn (SEQ ID NO: 1852).
  • n is adenine or guanine.
  • the iREMS comprises a DNA sequence NNGAgtragt (SEQ ID NO: 1]
  • r is adenine or guanine and N is any nucleotide.
  • the DNA sequence NNGAgtragt (SEQ ID NO: 3864) is selected from the group consisting of ANGAgtragt (SEQ ID NO: 2237), CNGAgtragt (SEQ ID NO: 2243),
  • GNGAgtragt (SEQ ID NO: 2249), TNGAgtragt (SEQ ID NO: 2255),
  • NAGAgtragt SEQ ID NO: 2238
  • NCGAgtragt SEQ ID NO: 2244
  • NGGAgtragt (SEQ ID NO: 2250), NTGAgtragt (SEQ ID NO: 2256),
  • CAGAgtragt (SEQ ID NO: 2240), CCGAgtragt (SEQ ID NO: 2246),
  • GGGAgtragt (SEQ ID NO: 2253), GTGAgtragt (SEQ ID NO: 2259),
  • TAGAgtragt SEQ ID NO: 2242
  • TCGAgtragt SEQ ID NO: 2248
  • n is adenine or guanine. In certain embodiments of the aspects and embodiments described herein, n is adenine or guanine.
  • modulation of the amount of the RNA transcript is modulation of the amount of the RNA transcript in a cell or a lysate of the cell, the method comprising contacting the compound of Formula (I) or a form thereof with the cell or the cell lysate.
  • modulation of the amount of the RNA transcript is modulation of the amount of the RNA transcript in a cell, the method comprising contacting the compound of Formula (I) or a form thereof with the cell.
  • the modulation modulates the amount and/or type of a protein translated from the RNA transcript and produced in the cell or lysate of the cell.
  • modulation of the amount of the RNA transcript is modulation of the amount of the RNA transcript in a subject, the method comprising administering the compound of Formula (I) or a form thereof to the subject.
  • the modulation modulates the amount and/or type of a protein translated from the RNA transcript and produced in the subject.
  • the subject is a non-human subject. In another specific embodiment, the subject is a human subject.
  • the RNA transcript encodes a detectable reporter protein.
  • an artificial gene construct comprising an RNA sequence comprising exons and one or more introns, wherein at least one intron comprises an iREMS that is downstream of a branch point and a 3' splice site and wherein the iREMS comprises the sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide. In certain embodiments, n is adenine or guanine. In certain embodiments, one, two, or all of the iREMS, the branch point, and the 3' splice site are non-endogenous. In certain embodiments, one, two, or all of the iREMS, the branch point, and the 3' splice site are endogenous.
  • an artificial gene construct comprising a DNA sequence encoding exons and one or more introns, wherein the nucleotide sequence encoding at least one intron comprises an iREMS that is downstream of the nucleotide sequence encoding a branch point and the nucleotide sequence encoding a 3' splice site, and wherein the iREMS comprises the sequence GAgtrngn (SEQ ID NO: 4), wherein r is adenine or guanine and n is any nucleotide. In certain embodiments, n is adenine or guanine.
  • one, two, or all of the iREMS, the branch point, and the 3' splice site are non-endogenous. In certain embodiments, one, two, or all of the iREMS, the branch point, and the 3' splice site are endogenous.
  • a cell comprising an RNA sequence comprising exons and one or more introns, wherein at least one intron comprises an iREMS that is downstream of a branch point and a 3' splice site and wherein the iREMS comprises the sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide. In certain embodiments, n is adenine or guanine. In certain embodiments, one, two, or all of the iREMS, the branch point, and the 3' splice site are non-endogenous. In certain embodiments, one, two, or all of the iREMS, the branch point, and the 3' splice site are endogenous.
  • a cell comprising a DNA sequence encoding exons and one or more introns, wherein the nucleotide sequence encoding at least one intron comprises an iREMS that is downstream of the nucleotide sequence encoding a branch point and the nucleotide sequence encoding a 3' splice site, and wherein the iREMS comprises the sequence GAgtrngn (SEQ ID NO: 4), wherein r is adenine or guanine and n is any nucleotide.
  • one, two, or all of the iREMS, the branch point, and the 3' splice site are non-endogenous.
  • one, two, or all of the iREMS, the branch point, and the 3' splice site are endogenous.
  • a cell comprising an artificial gene construct described herein.
  • a cell comprising a vector comprising an artificial gene construct described herein.
  • RNA transcript comprising a RNA nucleotide sequence comprising in 5' to 3' order: a branch point, a 3' splice site, and an endogenous intronic recognition element for splicing modifier (iREMS), wherein the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide, and wherein the RNA transcript is an RNA transcript of a gene that is selected from ABCAIO, ABCB8, ABCC3, ACTA2, ADAL, ADAMTSl, ADCY3, ADDl, ADGRG6, ADH6, ADHFEl, AFF3, AGPAT4, AKAP3, ANK1, ANK3, ANKRA2, ANKRD33B, ANKRD36, AP4B1-AS1, APIP, ARHGAPl, ARHGAP12,
  • HAPLNl HAPLN2, HAS3, HAVCR2, HDAC5, HDX, HECTD2-AS1, HEPH, HEY1,
  • TANG06 TASP1, TCF12, TCF4, TGFA, TGFB2, TGFB3, TGM2, THBS2, TIAM1, TMC3, TMEM102, TMEM119, TMEM134, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM50B, T FAIP8L3, TNFRSF14, T RC18P1, T RC6A, TNXB, TP53AIP1, TPRG1, TRIM66, TRPC4, TSHZ2, TSPANl l, TSPAN18, TSPAN7, TSSK3, TTC7B, TUBEl, TXNIP, TYW5, URGCP, USP27X, UVRAG, VAV2, VIM-AS1, VPS41, VSTM2L, VWF, WDR27, WDR91, WISP1, WNK1, WNT10B, YDJC, ZBTB26, ZCCHC5, ZCCHC8, ZFP82, ZMIZ1
  • wi and ws are independently C-Ra or N;
  • W2 is C-Rb or N
  • W3, W4 and W7 are independently C-Ri, C-R2, C-Ra or N;
  • one of w 3 , W4, W6 and W7 is C-Ri and one other of w 3 , W4, W6 and W7 is C-R2, provided that,
  • Ri is Ci-8alkyl, amino, Ci-salkyl-amino, (Ci-8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino, (Ci-8alkoxy-Ci-8alkyl)
  • Ci-8alkyl-amino-Ci-8alkoxy (Ci-8alkyl)2-amino-Ci-8alkoxy,
  • heterocyclyl (heterocyclyl)(Ci-8alkyl)amino, heterocyclyl-amino-Ci-salkyl, heterocyclyl-Ci-8alkyl-amino, (heterocyclyl-Ci-8alkyl)2-amino,
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino
  • heterocyclyl-Ci-salkyl-amino-Ci-salkyl (heterocyclyl-Ci-8alkyl)2-amino-Ci-8alkyl
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino-Ci-8alkyl, heterocyclyl-oxy,
  • heteroaryl-Ci-8alkyl-amino (heteroaryl-Ci-8alkyl)2-amino
  • heteroaryl-Ci-8alkyl (Ci-8alkyl)amino
  • heteroaryl-Ci-salkyl-amino-Ci-salkyl
  • each instance of heterocyclyl, C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R3 substituents and optionally, with one additional R4 substituent; or,
  • heterocyclyl C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R3 substituents;
  • R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino; wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R 6 substituents and optionally, with one additional R7 substituent;
  • Ra is, in each instance, independently selected from hydrogen, halogen, Ci-salkyl or deuterium;
  • Rb is hydrogen, halogen, Ci-salkyl, Ci-salkoxy or deuterium;
  • Rc is hydrogen, halogen, Ci-salkyl or deuterium
  • R3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci- 8 alkyl, halo-Ci- 8 alkyl, Ci- 8 alkyl-carbonyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy,
  • Ci-8alkyl-carbonyl-amino Ci-salkoxy-carbonyl-amino, hydroxy-Ci-salkyl
  • R4 is C3-i4cycloalkyl, C3-i4cycloalkyl-Ci-8alkyl, C3-i4cycloalkyl-amino, aryl-Ci-salkyl, aryl-Ci-8alkoxy-carbonyl, aryl-sulfonyloxy-Ci-salkyl, heterocyclyl or
  • heterocyclyl-Ci-8alkyl wherein, each instance of C3-i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R5 substituents;
  • R5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, Ci-salkoxy, halo-Ci-salkoxy, amino, Ci-salkyl-amino,
  • R 6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci- 8 alkyl, C2- 8 alkenyl, halo-Ci- 8 alkyl, hydroxy-Ci- 8 alkyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy, Ci- 8 alkoxy-Ci- 8 alkyl, amino, Ci- 8 alkyl-amino, (Ci- 8 alkyl)2-amino or Ci- 8 alkyl-thio; and, R7 is C3-i4cycloalkyl, C3-i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
  • RNA transcript comprising a RNA nucleotide sequence comprising in 5' to 3' order: a branch point, a 3' splice site and an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS); wherein the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide, the method comprising contacting the RNA transcript with a compound of Formul thereof, wherein Formula (I) is:
  • wi and ws are independently C-Ra or N;
  • W2 is C-Rb or N
  • W3, W4 and W7 are independently C-Ri, C-R2, C-Ra or N; we is C-Ri, C-R2, C-Rc or N;
  • one of w 3 , W4, W6 and W7 is C-Ri and one other of w 3 , W4, W6 and W7 is C-R 2 , provided that,
  • Ri is Ci-8alkyl, amino, Ci-salkyl-amino, (Ci-8alkyl) 2 -amino, Ci-salkoxy-Ci-salkyl-amino, (Ci-8alkoxy-C
  • Ci-8alkoxy-Ci-8alkyl-amino-Ci-8alkyl Ci-8alkoxy-Ci-8alkyl-amino-Ci-8alkyl, (Ci-8alkoxy-Ci-8alkyl) 2 -amino-Ci-8alkyl,
  • Ci-8alkyl-amino-Ci-8alkyl-amino (Ci-8alkyl-amino-Ci-8alkyl) 2 -amino,
  • Ci-8alkyl-amino-Ci-8alkoxy (Ci-8alkyl) 2 -amino-Ci-8alkoxy,
  • Ci-8alkoxy-Ci-8alkyl-amino-Ci-8alkoxy Ci-salkoxy-Ci-salkyl-amino-Ci-salkoxy, (Ci-8alkoxy-Ci-8alkyl)(Ci-8alkyl)amino-Ci-8alkoxy, amino-C 2 -8alkenyl,
  • heterocyclyl (heterocyclyl)(Ci-8alkyl)amino, heterocyclyl-amino-Ci-salkyl,
  • heterocyclyl-Ci-8alkyl-amino (heterocyclyl-Ci-8alkyl)2-amino,
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino
  • heterocyclyl-Ci-salkyl-amino-Ci-salkyl (heterocyclyl-Ci-8alkyl)2-amino-Ci-8alkyl
  • heterocyclyl-Ci-8alkyl (Ci-8alkyl)amino-Ci-8alkyl, heterocyclyl-oxy,
  • heteroaryl-Ci-8alkyl-amino (heteroaryl-Ci-8alkyl)2-amino
  • heteroaryl-Ci-8alkyl (Ci-8alkyl)amino
  • heteroaryl-Ci-salkyl-amino-Ci-salkyl
  • each instance of heterocyclyl, C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R3 substituents and optionally, with one additional R4 substituent; or,
  • heterocyclyl C3-i4cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R3 substituents;
  • R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino; wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R 6 substituents and optionally, with one additional R7 substituent;
  • Ra is, in each instance, independently selected from hydrogen, halogen, Ci-salkyl or deuterium;
  • Rb is hydrogen, halogen, Ci-salkyl, Ci-salkoxy or deuterium;
  • Rc is hydrogen, halogen, Ci-salkyl or deuterium
  • R3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci- 8 alkyl, halo-Ci- 8 alkyl, Ci- 8 alkyl-carbonyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy, Ci-8alkoxy-Ci-8alkyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci-8alkyl)2-amino, amino-Ci-8alkyl, Ci-salkyl-amino-Ci-salkyl, (Ci-8alkyl)2-amino-Ci-8alkyl,
  • Ci-8alkyl-carbonyl-amino Ci-salkoxy-carbonyl-amino, hydroxy-Ci-salkyl
  • R4 is C3-i4cycloalkyl, C3-i4cycloalkyl-Ci-8alkyl, C3-i4cycloalkyl-amino, aryl-Ci-salkyl, aryl-Ci-8alkoxy-carbonyl, aryl-sulfonyloxy-Ci-salkyl, heterocyclyl or
  • heterocyclyl-Ci-8alkyl wherein, each instance of C3-i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R5 substituents;
  • R5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, Ci-salkoxy, halo-Ci-salkoxy, amino, Ci-salkyl-amino,
  • R 6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci- 8 alkyl, C2- 8 alkenyl, halo-Ci- 8 alkyl, hydroxy-Ci- 8 alkyl, Ci- 8 alkoxy, halo-Ci- 8 alkoxy, Ci- 8 alkoxy-Ci- 8 alkyl, amino, Ci- 8 alkyl-amino, (Ci- 8 alkyl)2-amino or Ci- 8 alkyl-thio; and, R7 is C3-i4cycloalkyl, C3-i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
  • the RNA transcript is an RNA transcript of a gene that is selected from ABCB8, ABCC3, ADAM 17, ADCY3, AGPAT4, ANKRA2, ANXA11, APIP,
  • DLGAP4 DNAJC13, DNMBP, DOCKl, DYRKl A, EIF2B3, ENAH, ENOXl, EP300, ERCl,
  • ERCCl ERGIC3, ERLIN2, ERRFIl, EVC, FAFl, FAIM, FAM126A, FAM13A, FAM162A,
  • RNA nucleotide sequence comprises two exons and an intron, wherein one exon is upstream of the intron and the other exon is downstream of the intron
  • the RNA nucleotide sequence of the intron comprises in 5' to 3' order: a first 5' splice site, a first branch point, a first 3' splice site, an iREMS, a second branch point and a second 3' splice site
  • the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide
  • the method comprising contacting the RNA transcript with a compound of Formula (I) or a form thereof, wherein Formula (I) is:
  • wi and ws are independently C-Ra or N; W2 is C-Rb or N;
  • W3, W4 and W7 are independently C-Ri, C-R2, C-Ra or N;
  • one of w 3 , W4, W6 and W7 is C-Ri and one other of w 3 , w 4 , W6 and W7 is C-R2, provided that,
  • Ri is Ci-8alkyl, amino, Ci-salkyl-amino, (Ci-8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino, (Ci-8alkoxy-Ci-8alkyl)

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