Nucleic acid complex

{
  "publication_number": "US2021024929A1",
  "country": "US",
  "kind": "A1",
  "title": "Nucleic acid complex",
  "abstract": "Developed and provided is: a nucleic acid agent that is efficiently delivered to the central nervous system, to which drug delivery is inhibited by the blood brain barrier mechanism, and that provides an antisense effect to a target transcription product at the delivery site; and a composition containing such a nucleic acid agent. Provided is a double-stranded nucleic acid complex consisting of a first nucleic acid strand and a second nucleic acid strand that are annealed to each other; wherein the first nucleic acid strand hybridizes with part of a target transcription product and has an antisense effect on the target transcription product; and wherein the second nucleic acid strand includes a base sequence complementary to the first nucleic acid strand and is conjugated to a phosphatidylethanolamine or an analog thereof.",
  "claims": [
    "1. A nucleic acid complex comprising a first nucleic acid strand and a second nucleic acid strand, wherein the first nucleic acid strand comprises a base sequence capable of hybridizing with at least part of a target transcription product and has an antisense effect on the target transcription product; wherein the second nucleic acid strand comprises a base sequence complementary to the first nucleic acid strand and is bound to a phosphatidylethanolamine or an analog thereof; and wherein the first nucleic acid strand is annealed to the second nucleic acid strand. 2. The nucleic acid complex according to claim 1, wherein the phosphatidylethanolamine or an analog thereof is represented by the general formula I: (wherein R 1 and R 2 independently represent a substituted or unsubstituted C 5 -C 32 alkyl group, or a substituted or unsubstituted C 5 -C 32 alkenyl group). 3. The nucleic acid complex according to claim 2, wherein R 1 and R 2 independently represent a C 15 -C 19 alkyl group, or a C 17 alkenyl group. 4. The nucleic acid complex according to claim 1, wherein the phosphatidylethanolamine or an analog thereof is represented by the general formulae XV to XXII: 5. The nucleic acid complex according to claim 1, wherein the second nucleic acid strand is bound to a phosphatidylethanolamine or an analog thereof via a linker represented by the general formula II: (wherein n is 0 or 1.) 6. The nucleic acid complex according to claim 5, wherein the 5′ end of the second nucleic acid strand is bound to a phosphatidylethanolamine or an analog thereof via the linker. 7. The nucleic acid complex according to claim 1, wherein the first nucleic acid strand comprises at least 4 consecutive deoxyribonucleosides. 8. The nucleic acid complex according to claim 1, wherein the first nucleic acid strand is a gapmer. 9. The nucleic acid complex according to claim 7, wherein the second nucleic acid strand comprises at least 4 consecutive ribonucleosides complementary to the at least 4 consecutive deoxyribonucleosides in the first nucleic acid strand. 10. The nucleic acid complex according to claim 1, wherein the first nucleic acid strand is a mixmer. 11. The nucleic acid complex according to claim 1, wherein the first nucleic acid strand has a length of 13 to 20 bases. 12. The nucleic acid complex according to claim 1, wherein the second nucleic acid strand comprises no natural ribonucleoside. 13. The nucleic acid complex according to claim 1, wherein the nucleic acid portion of the second nucleic acid strand consists of deoxyribonucleosides and/or sugar-modified nucleosides, which are linked by modified or unmodified internucleoside bonds. 14. A composition for regulating the expression or editing of a target transcription product in the central nervous system, containing the nucleic acid complex according to claim 1. 15. The composition according to claim 14 for the treatment of a central nervous system disease. 16. A composition for delivering a central nervous system agent, containing the nucleic acid complex according to claim 1. 17. The composition according to claim 14, wherein the central nervous system is selected from the group consisting of cerebral cortex, basal ganglion, cerebral white matter, diencephalon, brainstem, cerebellum, and spinal cord. 18. The composition according to claim 14, wherein the central nervous system is selected from the group consisting of frontal lobe, temporal lobe, hippocampus, parahippocampal gyms, parietal lobe, occipital lobe, striatum, globus pallidus, claustrum, thalamus, subthalamic nucleus, midbrain, substantia nigra, pons, medulla oblongata, cerebellar cortex, cerebellar nucleus, cervical spinal cord, thoracic spinal cord, and lumbar spinal cord. 19. The composition according to claim 14 for intravenous administration or subcutaneous administration. 20. The composition according to claim 14, wherein one dose of the composition contains 5 mg/kg or more of the nucleic acid complex. 21. The composition according to claim 14, wherein the nucleic acid complex permeates blood brain barrier (BBB)."
  ],
  "description_excerpt": "The present invention relates to a nucleic acid complex or a salt thereof that can provide an antisense effect in the nervous system, particularly the central nervous system, and to a composition or the like that contains the complex or a salt thereof.\n\nRecent interest has focused on oligonucleotides in the ongoing development of pharmaceuticals called nucleic acid pharmaceuticals, and, in particular, in view of the high selectivity and low toxicity of target genes, nucleic acid pharmaceuticals utilizing an antisense method is being actively developed. An antisense method comprises that the expression of a protein encoded by the target gene or the activity of the miRNA is selectively altered or inhibited, using the introduction of an oligonucleotide (an antisense oligonucleotide: herein, frequently referred to as an “ASO (AntiSense Oligonucleotide)”) complementary to a target sense strand, a partial sequence of an mRNA or miRNA transcribed from a target gene, into cells.\n\nPatent Literature 1 discloses a double-stranded nucleic acid molecule consisting of a first oligomer compound and a second oligomer compound containing a coupling group such as cholesterol and that can regulate the amount and activity of a target nucleic acid in the extrahepatic tissue or extrahepatic cell or in the hepatic tissue or hepatocyte, and an antisense compound consisting of the double-stranded nucleic acid molecule.\n\nNow, a nucleic acid agent such as the ASO needs to be delivered to the central nervous system so that the antisense effect can be provided in the central nervous system including the brain.",
  "cpc": [
    "C12N 15/113",
    "A61K 31/711",
    "A61K 31/713",
    "A61K 47/544",
    "A61K 47/549",
    "A61P 25/00",
    "C12N 2310/11",
    "C12N 2310/113",
    "C12N 2310/341",
    "C12N 2310/53"
  ],
  "ipc": [
    "A61P 25/00",
    "C12N 15/113",
    "C07H 21/04"
  ],
  "assignees": [
    "Takeda Pharmaceutical Co Ltd",
    "Tokyo Medical and Dental University NUC"
  ],
  "inventors": [
    "Takanori Yokota",
    "Tetsuya Nagata",
    "Hideki Furukawa",
    "Yasuo Nakagawa",
    "Takatoshi Yogo",
    "Ryosuke Tokunoh",
    "Shigekazu Sasaki",
    "Kosuke Hidaka",
    "Tomohiro Seki",
    "Kenichi Miyata",
    "Akio Uchida"
  ],
  "filing_date": "2019-03-13",
  "publication_date": "2021-01-28",
  "priority_date": "2018-03-14",
  "application_number": "US-201916980191-A",
  "family_id": "67907945",
  "cited_by_count": 10
}