WO2016161299A1 - Therapeutic una oligomers and uses thereof - Google Patents

Therapeutic una oligomers and uses thereof Download PDF

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WO2016161299A1
WO2016161299A1 PCT/US2016/025578 US2016025578W WO2016161299A1 WO 2016161299 A1 WO2016161299 A1 WO 2016161299A1 US 2016025578 W US2016025578 W US 2016025578W WO 2016161299 A1 WO2016161299 A1 WO 2016161299A1
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una
strand
oligomer
monomers
monomer
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French (fr)
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Padmanabh Chivukula
Kiyoshi Tachikawa
Joseph E. Payne
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Arcturus Therapeutics Inc
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Arcturus Therapeutics Inc
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Priority to JP2017551098A priority Critical patent/JP6830441B2/ja
Priority to US15/563,579 priority patent/US10519447B2/en
Priority to EP16774322.8A priority patent/EP3277289A4/en
Publication of WO2016161299A1 publication Critical patent/WO2016161299A1/en
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    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1131—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against viruses
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    • C12N2320/52—Methods for regulating/modulating their activity modulating the physical stability, e.g. GC-content

Definitions

  • nucleotides with structural modifications have so far provided only marginal improvement in the properties of gene silencing and RNA agents.
  • the oligomeric structures of this invention can contain one or more UNA monomers.
  • this invention provides unique oligomer structures that incorporate novel combinations of UNA monomers with certain natural nucleotides, non-natural nucleotides, modified nucleotides, or chemically-modified nucleotides.
  • Embodiments of this invention include the following:
  • a UNA oligomer having a first strand and a second strand, each of the strands being 19-29 monomers in length, the monomers comprising UNA monomers and nucleic acid monomers, wherein the oligomer has a duplex structure of from 14 to 29 monomers in length, wherein the second strand is a guide strand for RNA interference and the first strand is a passenger strand for RNA interference, and wherein the UNA oligomer reduces expression of a target gene.
  • Embodiments of this invention include pharmaceutical compositions having one or more UNA oligomers and a pharmaceutically acceptable carrier, diluent, or adjuvant.
  • Uses of a UNA oligomer include to regulate expression of a target gene.
  • aspects of this disclosure include UNA monomer-containing oligomers that are pharmacologically active molecules.
  • the UNA Oligomers of this invention can be used as active pharmaceutical ingredients for regulating or modulating gene expression, RNA interference methods, as well as antisense strategies.
  • this invention provides long acting UNA Oligomers having structures that incorporate novel combinations of UNA Monomers with certain natural nucleotides, non-natural nucleotides, modified nucleotides, or chemically- modified nucleotides.
  • this invention provides long acting properties for gene silencing drugs, and can reduce the dose levels required for efficacious therapy.
  • R 1 and R 2 are H, and R 1 and R 2 can be phosphodiester linkages
  • Base can be a nucleobase
  • R 3 is a functional group described below.
  • a UNA monomer can be a monomer in an overhang of an oligomer duplex, where the UNA monomer is flanked by other monomers on both sides. In this form, the UNA monomer does not participate in base pairing. Because the UNA monomers are flexible organic structures, unlike nucleotides, the overhang containing a UNA monomer will be a flexible terminator for the oligomer.
  • a UNA monomer can be a flexible molecule
  • a UNA monomer as a terminal monomer can assume widely differing conformations.
  • An example of an energy minimized UNA monomer conformation as a terminal monomer attached at the propane-3-yl position is shown below.
  • non-natural, modified, and chemically-modified nucleotide monomers include 3 '-end stabilized nucleotides, 3 '-glyceryl nucleotides, 3 '-inverted abasic nucleotides, and 3'-inverted thymidine.
  • non-natural, modified, and chemically-modified nucleotide monomers include 2'-amino nucleotides, 2'-0-amino nucleotides, 2'-C-allyl nucleotides, and 2'-0-allyl nucleotides.
  • oligomeric agents may incorporate one or more UNA monomers.
  • Oligomeric molecules of this invention can be used as active agents in formulations for gene regulating or gene silencing therapeutics.
  • this invention provides oligomeric compounds having a structure that incorporates novel combinations of UNA monomers with certain natural nucleotides, non-natural nucleotides, modified nucleotides, or chemically- modified nucleotides.
  • the oligomeric compounds can be pharmacologically active molecules.
  • a UNA oligomer of this invention can be used as an active
  • Examples of UNA oligomers of this invention include duplex pairs, which are in general complementary.
  • SEQ ID NO: l can represent a first strand of a duplex and SEQ ID NO:2 can represent a second strand of the duplex, which is complementary to the first strand.
  • the terminal position has a 1-end, according to the positional numbering shown above, instead of a 5'- end as for a nucleotide, or the terminal position has a 3 -end, according to the positional numbering shown above, instead of a 3 '-end as for a nucleotide.
  • the UNA oligomer terminates in a UNA monomer, the terminal position has a 1-end, according to the positional numbering shown above, instead of a 5'- end as for a nucleotide, or the terminal position has a 3 -end, according to the positional numbering shown above, instead of a 3 '-end as for a nucleotide.
  • the UNA oligomer terminates in a UNA monomer
  • an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a Q monomer.
  • an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a Q monomer, and where the number of Q monomers is from 1 to 15.
  • an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a Q monomer, and where the number of Q monomers is from 1 to 9.
  • an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a 2'-0- Methyl modified ribonucleotide, and where the number of 2'-0-Methyl modified ribonucleotides is less than ten.
  • an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a 2'-0- Methyl modified ribonucleotide, and where the number of 2'-0-Methyl modified ribonucleotides is less than eight.
  • an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a 2'-0- Methyl modified ribonucleotide, and where the number of 2'-0-Methyl modified ribonucleotides is from 1 to 20.
  • an oligomeric compound of this invention may have a single strand being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a Q monomer, and where the number of Q monomers is from 1 to 20.
  • an oligomeric compound of this invention may have a single strand being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a 2'-0-Methyl modified ribonucleotide, and where the number of 2'-0-Methyl modified ribonucleotides is less than twenty.
  • an oligomeric compound of this invention may have a single strand being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a 2'-0-Methyl modified ribonucleotide, and where the number of 2'-0-Methyl modified ribonucleotides is less than twelve.
  • an oligomeric compound of this invention may have a single strand being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a 2'-0-Methyl modified ribonucleotide, and where the number of 2'-0-Methyl modified ribonucleotides is from 1 to 15.
  • Methods of this invention include the treatment and prevention of various diseases in mammalian subjects.
  • a subject can be human.
  • An effective amount of an oligomeric compound of this invention can be a dose ranging from 0.001 mg/kg to 50.0 mg/kg.
  • Embodiments of this invention can provide oligomeric molecules that are active agents targeted to TTR.
  • Tables 14 to 17 Examples of UNA oligomers of this invention that are targeted to TTR are shown in Tables 14 to 17.
  • Tables 14 and 15 represent “sense” and “antisense” pairs, and Tables 16 and 17 represent additional “sense” and “antisense” pairs.
  • SEQ ID Nos:237 and 238 are a sense and antisense pair.
  • a UNA oligomer may have a strand being SEQ ID NO: 105.
  • a UNA oligomer may have a strand being SEQ ID NO: 106.
  • a UNA oligomer may have a strand being SEQ ID NO: 105, and a strand being SEQ ID NO: 106.
  • These UNA oligomers can have a nucleobase sequence corresponding to a target sequence of TTR.
  • These UNA oligomers can have a nucleobase sequence corresponding to any of SEQ ID NOs:237 to 284.
  • Examples of UNA oligomers of this invention that are targeted to TTR are shown in Tables 18 and 19.
  • Tables 18 and 19 represent "sense” and “antisense” pairs.
  • SEQ ID NOs:285 and 286 are a sense and antisense pair.
  • a UNA oligomer may have a strand being SEQ ID NO:87.
  • a UNA oligomer may have a strand being SEQ ID NO:88.
  • a UNA oligomer may have a strand being SEQ ID NO:87, and a strand being SEQ ID NO:88.
  • These UNA oligomers can have a nucleobase sequence corresponding to a target sequence of APOB.
  • These UNA oligomers can have a nucleobase sequence corresponding to any of SEQ ID NOs:285 to 304.
  • a UNA oligomer may have a strand being SEQ ID NO: 105.
  • a UNA oligomer may have a strand being SEQ ID NO: 106.
  • a UNA oligomer may have a strand being SEQ ID NO: 105, and a strand being SEQ ID NO: 106.
  • These UNA oligomers can have a nucleobase sequence corresponding to a target sequence of PCSK9.
  • These UNA oligomers can have a nucleobase sequence corresponding to any of SEQ ID NOs:305 to 316.
  • a UNA oligomer may have a strand being SEQ ID NO:87.
  • a UNA oligomer may have a strand being SEQ ID NO:88.
  • a UNA oligomer may have a strand being SEQ ID NO:87, and a strand being SEQ ID NO:88.
  • These UNA oligomers can have a nucleobase sequence corresponding to a target sequence of APOC3.
  • These UNA oligomers can have a nucleobase sequence corresponding to any of SEQ ID NO:
  • a UNA oligomer may comprise a first strand being SEQ ID NO:321 and a second strand being SEQ ID NO:322.
  • Embodiments of this invention can provide oligomeric molecules that are active agents targeted to HBV.
  • Examples of UNA oligomers of this invention that are targeted to HBV are shown in Tables 24 to 27.
  • Tables 24 and 25 represent "sense” and “antisense” pairs
  • Tables 26 and 27 represent additional “sense” and “antisense” pairs.
  • SEQ ID NOs:333 and 353 are a sense and antisense pair, and so on through SEQ ID NOs:352 and 372.
  • a UNA oligomer of this invention can retain at least 80% activity in vitro six days after transfection.
  • a UNA oligomer of this invention can retain at least 50% potency in vivo six days after administration.
  • UNA oligomers of this invention can provide long acting properties, and reduce the dose levels required for efficacious therapy.
  • hypercholesterolemia or cholesterol disorder in a subject in need thereof.
  • a UNA oligomer targeted to a proprotein convertase subtilisin/kexin type 9 nucleic acid, PCSK9 can be used as an active agent for preventing or treating hypercholesterolemia, or cholesterol disorder in a subject in need thereof.
  • a pharmaceutical composition can be capable of local or systemic administration.
  • a pharmaceutical composition can be capable of any modality of administration.
  • the administration can be intravenous, subcutaneous, pulmonary, intramuscular, intraperitoneal, dermal, oral, or nasal administration.
  • a pharmaceutical composition can include liposomes or nanoparticles.
  • lipids and lipid compositions for delivery of an active molecule of this invention are given in WO/2015/074085, which is hereby incorporated by reference in its entirety.
  • excipients for a pharmaceutical composition include antioxidants, suspending agents, dispersing agents, preservatives, buffering agents, tonicity agents, and surfactants.
  • HepB3 cells American Type Culture Collection
  • the cells were incubated at 37°C in 100 ⁇ of DMEM (Life Technologies, Carlsbad, CA) supplemented with 0.1 mM nonessential amino acids and 10% FBS (Life Technologies, Carlsbad, CA).
  • the culture medium was changed to 90 ⁇ of fresh medium just before the transfection.
  • Example 2 UNA oligomer stability.
  • Example 3 UNA oligomer longevity.
  • Protocol for determining the longevity of a UNA oligomer in vitro or in vivo Total RNA samples from cell lines or mouse tissue are isolated. Reverse transcription reactions are performed using Superscript III First-Strand (Life
  • UNA oligomers of this invention were found to exhibit IC50 as shown in Table 28.
  • the UNA oligomers correspond to the structures shown in Tables 24-27 having the same reference position.
  • Example 5 In addition, in experimental results the UNA oligomers of this invention targeted to HBV provide increased activity in vitro, as well as increased potency in vivo.
  • the UNA oligomers of this invention targeted to HBV provide long lasting activity in vitro, as well as long lasting potency in vivo.
  • Example 6 A dose dependent inhibitory effect of UNA oligomers targeted to TTR was observed in HepG2 cells, as shown in Table 29.
  • Example 9 A dose dependent inhibitory effect of UNA oligomers targeted to APOB was observed in mouse Hepal-6 cells, as shown in Table 31.
  • Example 10 A dose dependent inhibitory effect of UNA oligomers targeted to APOB was observed in mouse Hep3B cells, as shown in Table 32.
  • Example 11 In addition, in experimental results the UNA oligomers of this invention targeted to APOB provide increased activity in vitro, as well as increased potency in vivo.
  • the UNA oligomers of this invention targeted to APOB provide long lasting activity in vitro, as well as long lasting potency in vivo.
  • the UNA oligomers of this invention targeted to PCSK9 provide long lasting activity in vitro, as well as long lasting potency in vivo.
  • Example 16 In addition, in experimental results the UNA oligomers of this invention targeted to APOC3 provide increased activity in vitro, as well as increased potency in vivo.
  • the UNA oligomers of this invention targeted to APOC3 provide long lasting activity in vitro, as well as long lasting potency in vivo.

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