JP6771387B2 - 遺伝子サイレンシング用トランスサイレチン対立遺伝子選択的unaオリゴマー - Google Patents
遺伝子サイレンシング用トランスサイレチン対立遺伝子選択的unaオリゴマー Download PDFInfo
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- JP6771387B2 JP6771387B2 JP2016558738A JP2016558738A JP6771387B2 JP 6771387 B2 JP6771387 B2 JP 6771387B2 JP 2016558738 A JP2016558738 A JP 2016558738A JP 2016558738 A JP2016558738 A JP 2016558738A JP 6771387 B2 JP6771387 B2 JP 6771387B2
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
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- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
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- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
- C12N2310/323—Chemical structure of the sugar modified ring structure
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/34—Spatial arrangement of the modifications
- C12N2310/344—Position-specific modifications, e.g. on every purine, at the 3'-end
Description
ある特定の疾患の存在は、変異対立遺伝子の発現と相関すると思われる。例えば、アミロイドーシスは、ある特定のトランスサイレチン(TTR)変異と相関し得る。そのような場合、野生型バリアントの発現を維持しつつ、変異対立遺伝子の発現を選択的にサイレンシングするのが望ましい。
本発明は、V30M TTR発現を選択的に阻害するためのUNAオリゴマーであって、アミロイドーシスの治療に使用することができるUNAオリゴマーを提供する。UNAオリゴマーは第1鎖および第2鎖を有し得、各鎖は19〜29モノマー長であり、該モノマーはUNAモノマーおよび核酸モノマーである。実施形態には、UNAオリゴマーを対象に投与することによってTTR関連アミロイドーシスを治療または予防するための医薬組成物および方法が含まれる。
(式中、R1およびR2はHであり、R1およびR2はホスホジエステル結合であり得、Baseは核酸塩基であり得、R3は以下に説明する官能基である。)
ここで、オリゴマー鎖の進行方向は、プロパン残基の1−端から3−端である。
UNA A末端形態:破線の結合は、プロパン−3−イル結合を示す。
したがって、末端UNAモノマーを有するUNAオリゴマーは、従来の核酸作用物質、例えばsiRNAと構造が大きく異なる。例えばsiRNAは、二重鎖における末端モノマーまたはオーバーハングを安定させることが必要となり得る。対照的に、末端UNAモノマーのなじみ性により、異なる特性を備えたUNAオリゴマーを提供することができる。
第1鎖上にUNAモノマーの1−端、第1鎖上にUNAモノマーの3−端、第2鎖上にUNAモノマーの3−端、および第2鎖上にヌクレオチド5’−端を有する。
ヒトTTR V30Mを過剰発現させたトランスジェニックマウスを、6ヶ月齢で使用する。TTR野生型マウスおよびTTRノックアウトマウスを、対照として使用する。動物を制御された環境に収容し、ケタミンおよびメデトミジンで安楽死させる。
Claims (20)
- V30M TTR発現を選択的に阻害するためのUNAオリゴマーであって、該オリゴマーは第1鎖および第2鎖を含み、各鎖は19〜29モノマー長であり、該モノマーはUNAモノマーおよび核酸モノマーを含み、オリゴマーは14〜29モノマー長の二重鎖構造を有し、該第1鎖は5’から3’方向において
- 前記オリゴマーは、V30M TTR発現を減少させるためのIC50が20pM未満である、請求項1に記載のUNAオリゴマー。
- 前記オリゴマーは、選択比が少なくとも10であり、該選択比が、野生型TTR発現を減少させるためのIC50対V30M TTR発現を減少させるためのIC50の比である、請求項1に記載のUNAオリゴマー。
- 前記オリゴマーは、選択比が少なくとも20である、請求項3に記載のUNAオリゴマー。
- 前記オリゴマーは、インビトロでの選択比が少なくとも50である、請求項3に記載のUNAオリゴマー。
- 前記オリゴマーが、インビボまたはエクスビボでのV30M TTR発現を選択的に阻害する、請求項1に記載のUNAオリゴマー。
- 塩基修飾、糖修飾または結合修飾された少なくとも1つの核酸モノマーをさらに含む、請求項1に記載のUNAオリゴマー。
- 前記オリゴマーが、平滑末端を有するか、または1つ以上のオーバーハングを有する、請求項1に記載のUNAオリゴマー。
- 前記第1鎖および前記第2鎖が接合されて、一末端でループによる二重鎖領域を形成する、請求項1に記載のUNAオリゴマー。
- 請求項1〜9のいずれか1項に記載のUNAオリゴマーおよび医薬的に許容され得る担体を含む、医薬組成物。
- 脂質配合物を含む、請求項10に記載の医薬組成物。
- カチオン性脂質、アニオン性脂質、ステロール、ペグ化脂質およびこれらの任意の組み合わせから選択される1つ以上の脂質を含む、請求項10に記載の医薬組成物。
- 前記組成物が実質的にリポソームを含まない、請求項10に記載の医薬組成物。
- 前記組成物がリポソームを含有する、請求項10に記載の医薬組成物。
- TTR関連アミロイドーシスの治療または予防のための、請求項10〜14のいずれか1項に記載の医薬組成物。
- 前記TTR関連アミロイドーシスがATTRである、請求項15に記載の医薬組成物。
- 対象においてV30M TTRを選択的に減少させる、請求項15に記載の医薬組成物。
- 静脈内、皮下、肺、筋肉内、腹腔内、経皮または経口的に投与される、請求項15に記載の医薬組成物。
- 対照よりも少なくとも10%超で対象におけるV30M TTRを選択的に減少させる、請求項15に記載の医薬組成物。
- TTR mRNA発現を少なくとも5日間減少させる、請求項15に記載の医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201461970319P | 2014-03-25 | 2014-03-25 | |
US61/970,319 | 2014-03-25 | ||
PCT/US2015/022345 WO2015148582A1 (en) | 2014-03-25 | 2015-03-24 | Transthyretin allele selective una oligomers for gene silencing |
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JP2017510583A JP2017510583A (ja) | 2017-04-13 |
JP6771387B2 true JP6771387B2 (ja) | 2020-10-21 |
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JP2016558738A Active JP6771387B2 (ja) | 2014-03-25 | 2015-03-24 | 遺伝子サイレンシング用トランスサイレチン対立遺伝子選択的unaオリゴマー |
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US (1) | US9982259B2 (ja) |
EP (1) | EP3122365B1 (ja) |
JP (1) | JP6771387B2 (ja) |
WO (1) | WO2015148582A1 (ja) |
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WO2015148582A1 (en) | 2014-03-25 | 2015-10-01 | Arcturus Therapeutics, Inc. | Transthyretin allele selective una oligomers for gene silencing |
CN106460025A (zh) * | 2014-03-25 | 2017-02-22 | 阿克丘勒斯治疗公司 | 在基因沉默中具有降低的脱靶效应的una寡聚物 |
JP6830441B2 (ja) | 2015-04-01 | 2021-02-17 | アークトゥラス・セラピューティクス・インコーポレイテッドArcturus Therapeutics,Inc. | 治療上のunaオリゴマーおよびその使用 |
WO2017015671A1 (en) * | 2015-07-23 | 2017-01-26 | Arcturus Therapeutics, Inc. | Compositions for treating amyloidosis |
JP2022534867A (ja) | 2019-06-04 | 2022-08-04 | リジェネロン・ファーマシューティカルズ・インコーポレイテッド | ベータスリップ変異を有するヒト化ttr遺伝子座を含む非ヒト動物と使用方法 |
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