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JPWO2019217708A5
JPWO2019217708A5 JP2020561893A JP2020561893A JPWO2019217708A5 JP WO2019217708 A5 JPWO2019217708 A5 JP WO2019217708A5 JP 2020561893 A JP2020561893 A JP 2020561893A JP 2020561893 A JP2020561893 A JP 2020561893A JP WO2019217708 A5 JPWO2019217708 A5 JP WO2019217708A5
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pharmaceutical composition
population
modified oligonucleotide
oligomer compound
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ＶＩＩＩ．ある特定のコンパレータ組成物
ある特定の実施形態では、Ｍｏｏｒｅ，ｅｔ ａｌ．，Ｍｏｌ．Ｔｈｅｒ．Ｎｕｃｌｅｉｃ Ａｃｉｄｓ，２０１７，７：２００－２１０（Ｍｏｏｒｅ，２０１７）（「ＡＳＯ－５」）、ＷＯ２０１８／０８９８０５、及びＭｃＬｏｕｇｈｌｉｎ ｅｔ ａｌ．，Ａｎｎ．Ｎｅｕｒｏｌ．，２０１８，８４：６４－７７（ＭｃＬｏｕｇｈｌｉｎ，２０１８）（これらは各々、参照により本明細書に組み込まれる）に記載されている化合物番号６５０５２８は、コンパレータ化合物として使用された。化合物番号６５０５２８は、配列（５’から３’に）ＧＣＡＴＣＴＴＴＴＣＡＴＡＣＴＧＧＣ（配列番号２７８８）を有する５－８－５ＭＯＥギャップマーであり、各シトシンは、５－メチルシトシンであり、各ヌクレオシド間結合は、ホスホジエステルヌクレオシド間結合またはホスホロチオエートヌクレオシド間結合のいずれかであり、ヌクレオシド間結合モチーフは、ｓｏｏｏｓｓｓｓｓｓｓｓｓｏｏｓｓであり、式中、「ｓ」は、ホスホロチオエートヌクレオシド間結合を表し、「ｏ」は、ホスホジエステルヌクレオシド間結合を表し、ヌクレオシド１～５及び１４～１８は各々、２’－ＭＯＥ糖部分を含む。 VIII. Certain Comparator Compositions In certain embodiments, Moore, et al. , Mol. The. Nucleic Acids, 2017, 7: 200-210 (Moore, 2017) (“ASO-5”), WO2018 / 089805, and McLoughlin et al. , Ann. Neurol. , 2018, 84: 64-77 (McLoughlin, 2018), each of which is incorporated herein by reference, compound number 650528 was used as the comparator compound. Compound No. 650528 is a 5-8-5 MOE gapmer having the sequence (from 5'to 3') GCATCTTTCATACTGGC (SEQ ID NO: 2788), where each cytosine is 5 -methylcytosine and each nucleoside-to-nucleoside bond is phospho. Either a diester nucleoside bond or a phosphorothioate nucleoside bond, the nucleoside bond motif is sooosssssssssooss, where "s" represents a phosphorothioate nucleoside bond and "o" is a phosphodiester nucleoside bond. Nucleosides 1-5 and 14-18 each contain a 2'-MOE sugar moiety.

ある特定の実施形態では、Ｍｏｏｒｅ，２０１７（「ＡＳＯ－２」）、ＷＯ２０１８／０８９８０５、及びＭｃＬｏｕｇｈｌｉｎ，２０１８に記載されている化合物番号６５０６６８は、コンパレータ化合物として使用された。化合物番号６５０６６８は、配列（５’から３’に）ＡＧＣＣＡＴＴＡＡＴＣＴＡＴＡＣＴＧ（配列番号２７９２）を有する５－８－５ＭＯＥギャップマーであり、各シトシンは、５－メチルシトシンであり、各ヌクレオシド間結合は、ホスホジエステルヌクレオシド間結合またはホスホロチオエートヌクレオシド間結合のいずれかであり、ヌクレオシド間結合モチーフは、ｓｏｏｏｓｓｓｓｓｓｓｓｓｏｏｓｓであり、式中、「ｓ」は、ホスホロチオエートヌクレオシド間結合を表し、「ｏ」は、ホスホジエステルヌクレオシド間結合を表し、ヌクレオシド１～５及び１４～１８は各々、２’－ＭＯＥ糖部分を含む。
In certain embodiments, Compound No. 650668 described in Moore, 2017 (“ASO-2”), WO2018 / 089805, and McLoughlin, 2018 was used as the comparator compound. Compound No. 650668 is a 5-8-5 MOE gapmer having the sequence (from 5'to 3') AGCCATTAATTCATACTG (SEQ ID NO: 2792), where each cytosine is 5 -methylcytosine and each nucleoside-to-nucleoside bond is phospho. Either a diester nucleoside bond or a phosphorothioate nucleoside bond, the nucleoside bond motif is sooosssssssssooss, where "s" represents a phosphorothioate nucleoside bond and "o" is a phosphodiester nucleoside bond. Nucleosides 1-5 and 14-18 each contain a 2'-MOE sugar moiety.

Claims (20)

以下の化学構造：
Figure 2019217708000001
 に従う修飾されたオリゴヌクレオチド
またはその塩。 The following chemical structure:
Figure 2019217708000001
 Modified oligonucleotides or salts thereof according to. ナトリウム塩またはカリウム塩である、請求項１の修飾されたオリゴヌクレオチド。The modified oligonucleotide of claim 1, which is a sodium salt or a potassium salt. 以下の化学構造：
Figure 2019217708000002
 に従う修飾されたオリゴヌクレオチド。 The following chemical structure:
Figure 2019217708000002
 Modified oligonucleotide according to. 以下の化学表記法（５’から３’に）、Ｇｅｓ ｍＣｅｏ Ｔｅｏ ｍＣｅｏ Ａｅｓ Ｔｄｓ Ｔｄｓ Ｔｄｓ Ａｄｓ Ｔｄｓ Ｔｄｓ ｍＣｄｓ Ｔｄｓ ｍＣｄｓ Ａｄｓ Ａｅｏ Ｇｅｏ Ｔｅｓ Ａｅｓ ｍＣｅ（配列番号４２３）に従う修飾されたオリゴヌクレオチドを含むオリゴマー化合物であって、式中、
Ａが、アデニン核酸塩基であり、
ｍＣが、５－メチルシトシン核酸塩基であり、
Ｇが、グアニン核酸塩基であり、
Ｔが、チミン核酸塩基であり、
ｅが、２’ＭＯＥ糖部分であり、
ｄが、２’－β－Ｄデオキシリボシル糖部分であり、
ｓが、ホスホロチオエートヌクレオシド間結合であり、
ｏが、ホスホジエステルヌクレオシド間結合である、前記オリゴマー化合物。 The following chemical notation (from 5'to 3'), Ges m Ceo Teo m Ceo Aes Tds Tds Tds Tds Ads Tds Tds m Cds Tds m Cds Ads Aeo Geo Tes Aes m Ce (SEQ ID NO: 4) An oligomer compound containing, in the formula,
A is an adenine nucleobase,
m C is a 5-methylcytosine nucleobase ,
G is a guanine nucleobase,
T is a thymine nucleobase,
e is the 2'MOE sugar portion,
d is the 2'-β-D deoxyribosyl sugar moiety,
s is an interphosphorothioate nucleoside bond,
The oligomer compound in which o is a phosphodiester nucleoside bond. 請求項１～３のいずれかに記載の修飾されたオリゴヌクレオチドの集団、または請求項４に記載のオリゴマー化合物の集団であって、前記修飾されたオリゴヌクレオチドの前記ホスホロチオエートヌクレオシド間結合が全てステレオランダムである、前記集団。 A population of modified oligonucleotides according to any one of claims 1 to 3 , or a population of oligomer compounds according to claim 4, wherein the phosphorothioate nucleoside linkages of the modified oligonucleotide are all stereo. The population , which is random. 請求項１～３のいずれかに記載の修飾されたオリゴヌクレオチド、請求項４に記載のオリゴマー化合物、請求項５に記載の修飾されたオリゴヌクレオチドの集団、または請求項５に記載のオリゴマー化合物の集団と、薬学的に許容される希釈剤と、を含む、医薬組成物。The modified oligonucleotide according to any one of claims 1 to 3, the oligomer compound according to claim 4, the group of modified oligonucleotides according to claim 5, or the oligomer compound according to claim 5. A pharmaceutical composition comprising a population and a pharmaceutically acceptable diluent. 前記薬学的に許容される希釈剤が、人工脳脊髄液またはリン酸緩衝食塩水（ＰＢＳ）である、請求項６に記載の医薬組成物。The pharmaceutical composition according to claim 6, wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid or phosphate buffered saline (PBS). 前記医薬組成物が、前記修飾されたオリゴヌクレオチドまたは前記オリゴマー化合物及び人工脳脊髄液から本質的になる、請求項７に記載の医薬組成物。The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is essentially composed of the modified oligonucleotide or the oligomer compound and artificial cerebrospinal fluid. 前記医薬組成物が、前記修飾されたオリゴヌクレオチドまたは前記オリゴマー化合物及びＰＢＳから本質的になる、請求項７に記載の医薬組成物。The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is essentially composed of the modified oligonucleotide or the oligomer compound and PBS. 前記医薬組成物が、前記修飾されたオリゴヌクレオチドの集団または前記オリゴマー化合物の集団及び人工脳脊髄液から本質的になる、請求項７に記載の医薬組成物。The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition essentially comprises a population of the modified oligonucleotide or a population of the oligomer compound and an artificial cerebrospinal fluid. 前記医薬組成物が、前記修飾されたオリゴヌクレオチドの集団または前記オリゴマー化合物の集団及びＰＢＳから本質的になる、請求項７に記載の医薬組成物。The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition essentially comprises a population of the modified oligonucleotide or a population of the oligomer compound and PBS. 請求項１～３のいずれかに記載の修飾されたオリゴヌクレオチド、請求項４に記載のオリゴマー化合物、請求項５に記載の修飾されたオリゴヌクレオチドの集団、請求項５に記載のオリゴマー化合物の集団、または請求項６～１１のいずれかに記載の医薬組成物を含む医薬組成物であって、前記修飾されたオリゴヌクレオチド、オリゴマー化合物、修飾されたオリゴヌクレオチドの集団、オリゴマー化合物の集団、または医薬組成物を動物に投与することを含む該動物における治療のための、前記医薬組成物。The modified oligonucleotide according to any one of claims 1 to 3, the oligomer compound according to claim 4, the group of modified oligonucleotides according to claim 5, and the group of oligomer compounds according to claim 5. , Or a pharmaceutical composition comprising the pharmaceutical composition according to any one of claims 6 to 11, wherein the modified oligonucleotide, the oligomer compound, the modified oligonucleotide group, the oligomer compound group, or the drug. The pharmaceutical composition for treatment in an animal comprising administering the composition to the animal. 前記動物がヒトである、請求項１２の医薬組成物。The pharmaceutical composition according to claim 12, wherein the animal is a human. 治療が細胞におけるＡＴＸＮ３の発現を減少させることを含む、請求項１２の医薬組成物。12. The pharmaceutical composition of claim 12, wherein the treatment reduces the expression of ATXN3 in cells. 細胞がヒトの細胞である、請求項１４の医薬組成物。The pharmaceutical composition of claim 14, wherein the cells are human cells. 請求項１～３のいずれかに記載の修飾されたオリゴヌクレオチド、請求項４に記載のオリゴマー化合物、請求項５に記載の修飾されたオリゴヌクレオチドの集団、請求項５に記載のオリゴマー化合物の集団、または請求項６～１１のいずれかに記載の医薬組成物を含む、ＡＴＸＮ３に関連する疾患を治療するための医薬組成物であって、治療の方法が個体に、ＡＴＸＮ３に関連する疾患を有するか、またはそれを発症する危険性のある個体に、該医薬組成物の治療有効量を投与することを含む、前記医薬組成物。The modified oligonucleotide according to any one of claims 1 to 3, the oligomer compound according to claim 4, the group of modified oligonucleotides according to claim 5, and the group of oligomer compounds according to claim 5. , Or a pharmaceutical composition for treating a disease related to ATXN3, comprising the pharmaceutical composition according to any one of claims 6 to 11, wherein the method of treatment has a disease related to ATXN3 in an individual. The pharmaceutical composition comprising administering to an individual at risk of developing it, a therapeutically effective amount of the pharmaceutical composition. ＡＴＸＮ３に関連する前記疾患が神経変性疾患である、前記修飾されたオリゴヌクレオチド、オリゴマー化合物、修飾されたオリゴヌクレオチドの集団、オリゴマー化合物の集団、または医薬組成物を含む、請求項１６に記載の医薬組成物。16. The apparatus of claim 16, wherein the disease associated with ATXN3 is a neurodegenerative disease, comprising the modified oligonucleotide, an oligomer compound, a population of modified oligonucleotides, a population of oligomeric compounds, or a pharmaceutical composition. Composition. 前記神経変性疾患がＳＣＡ３である、前記修飾されたオリゴヌクレオチド、オリゴマー化合物、修飾されたオリゴヌクレオチドの集団、オリゴマー化合物の集団、または医薬組成物を含む、請求項１７に記載の医薬組成物。17. The pharmaceutical composition according to claim 17, wherein the neurodegenerative disease is SCA3, comprising the modified oligonucleotide, an oligomer compound, a population of modified oligonucleotides, a population of oligomeric compounds, or a pharmaceutical composition. 前記神経変性疾患の少なくとも１つの症状または特徴が改善される、前記修飾されたオリゴヌクレオチド、オリゴマー化合物、修飾されたオリゴヌクレオチドの集団、オリゴマー化合物の集団、または医薬組成物を含む、請求項１７または請求項１８に記載の医薬組成物。17 or claim comprising the modified oligonucleotide, an oligomer compound, a population of modified oligonucleotides, a population of oligomeric compounds, or a pharmaceutical composition that ameliorate at least one symptom or characteristic of the neurodegenerative disease. The pharmaceutical composition according to claim 18. 前記症状または特徴が、運動失調、神経障害、及び凝集体形成である、前記修飾されたオリゴヌクレオチド、オリゴマー化合物、修飾されたオリゴヌクレオチドの集団、オリゴマー化合物の集団、または医薬組成物を含む、請求項１９に記載の医薬組成物。Claimed to include said modified oligonucleotides, oligomeric compounds, populations of modified oligonucleotides, populations of oligomeric compounds, or pharmaceutical compositions whose symptoms or characteristics are ataxia, neuropathy, and aggregate formation. Item 19. The pharmaceutical composition according to Item 19.
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