JPWO2021239825A5

JPWO2021239825A5 -

Info

Publication number: JPWO2021239825A5
Application number: JP2022573137A
Authority: JP
Publication date: 2024-05-31

Description

本発明は以下の通りである。
［１］ＣＮＮＭ４の発現を阻害するための二本鎖核酸であって、第１鎖と第２鎖とを含み、前記第１鎖の配列が、配列番号３７１、２４３、２６７、２７７、２７９、２８７、３１７、３１９、３２５、３３３、３４５、３４７、３４９、３６１、３６７、３６９、３７７、４０１、４１１、４１３、４１５、４２０、４２１、５２４、５２６、５２８、５３０、５３２、５３４、５３６、５３８、５４０、５４２、５４４、５４６、５４８、５４９、５５０、５５１および５５２から選択される配列のいずれか１つと３ヌクレオチド以下だけ異なる少なくとも１５ヌクレオチドの配列を含む、二本鎖核酸。
［２］医薬として使用するためのＣＮＮＭ４の発現を阻害することが可能な二本鎖核酸であって、第１鎖と第２鎖とを含む、二本鎖核酸。
［３］前記第１鎖および前記第２鎖が１７～２５ヌクレオチド長の二本鎖領域を形成する、上記［１］または［２］に記載の核酸。
［４］ＲＮＡ干渉を媒介する、上記［１］～［３］のいずれかに記載の核酸。
［５］前記第１鎖および／または前記第２鎖の少なくとも１ヌクレオチドが修飾ヌクレオチドであり、好ましくは前記修飾ヌクレオチドが２’－Ｆ修飾ヌクレオチドなどの非天然起源ヌクレオチドである、上記［１］～［４］のいずれかに記載の核酸。
［６］前記第１鎖の５’末端のヌクレオチド番号１から連続的に番号付けされ、前記第１鎖の少なくとも第２ヌクレオチドおよび第１４ヌクレオチドが第１修飾によって修飾される、上記［１］～［５］のいずれかに記載の核酸。
［７］前記第１鎖がその５’末端に５’（Ｅ）－ビニルホスホネート末端ヌクレオチドを有する、上記［１］～［６］のいずれかに記載の核酸。
［８］前記第１鎖および／または前記第２鎖の２つまたは３つの３’末端ヌクレオチド間および／または５’末端ヌクレオチド間にホスホロチオエート結合を含み、好ましくは残りのヌクレオチド間の結合はホスホジエステル結合である、上記［１］～［７］のいずれかに記載の核酸。
［９］前記第１鎖の３’末端の２つ、３つ、もしくは４つの末端ヌクレオチドのそれぞれの間にホスホロジチオエート結合を含み、および／または、前記第２鎖の３’末端の２つ、３つ、もしくは４つの末端ヌクレオチドのそれぞれの間にホスホロジチオエート結合を含み、および／または、前記第２鎖の５’末端の２つ、３つ、もしくは４つの末端ヌクレオチドのそれぞれの間にホスホロジチオエート結合を含み、かつ、前記第１鎖の５’末端の２つ、３つ、または４つの末端ヌクレオチド間にホスホロジチオエート結合以外の結合を含む、上記［１］～［８］のいずれかに記載の核酸。
［１０］リガンドに結合している、上記［１］～［９］のいずれかに記載の核酸。
［１１］前記リガンドが、（ｉ）１つ以上のＮ－アセチルガラクトサミン（ＧａｌＮＡｃ）部分またはその誘導体と、（ｉｉ）リンカーとを含み、前記リンカーにより前記少なくとも１つのＧａｌＮＡｃ部分またはその誘導体に結合している、上記［１０］に記載の核酸。
［１２］上記［１］～［１１］のいずれかに記載の核酸および溶媒、および／または送達媒体、および／または生理学的に許容される賦形剤、および／または担体、および／または塩、および／または希釈剤、および／または緩衝剤、および／または保存剤、および／またはオリゴヌクレオチド、小分子、モノクローナル抗体、ポリクローナル抗体、およびペプチドを含む群から選択されるさらなる治療薬を含む、組成物。
［１３］医薬として使用するための、上記［１］および上記［３］～［１１］のいずれかに記載の核酸、または上記［１２］に記載の組成物。
［１４］疾患、障害または症候群の予防、それに罹患するリスクの減少、またはその治療に使用するための、上記［１］および上記［３］～［１１］のいずれかに記載の核酸または上記［１２］に記載の組成物であって、前記疾患、障害、または症候群が好ましくは肝疾患、腎疾患または肺疾患である、核酸または組成物。
［１５］疾患、障害または症候群の予防、それに罹患するリスクの減少、またはその治療における、上記［１］および上記［３］～［１１］のいずれかに記載の核酸または上記［１２］に記載の組成物の使用であって、前記疾患、障害または症候群が好ましくは肝疾患、腎疾患、または肺疾患である、使用。
［１６］疾患、障害または症候群を予防する方法、疾患、障害または症候群に罹患するリスクを減少させる方法、または疾患、障害または症候群を治療する方法であって、上記［１］および上記［３］～［１１］のいずれかに記載の核酸、または上記［１２］に記載の組成物の薬学的有効量を、治療を必要とする個体に投与することを含み、前記疾患、障害または症候群が好ましくは肝疾患、腎疾患、または肺疾患である、方法。
以下の非限定的な図面および実施例を参照して本発明を説明する。 The present invention is as follows.
[1] A double-stranded nucleic acid for inhibiting expression of CNNM4, comprising a first strand and a second strand, wherein the sequence of the first strand comprises a sequence of at least 15 nucleotides that differs by 3 nucleotides or less from any one of the sequences selected from SEQ ID NOs: 371, 243, 267, 277, 279, 287, 317, 319, 325, 333, 345, 347, 349, 361, 367, 369, 377, 401, 411, 413, 415, 420, 421, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 549, 550, 551, and 552.
[2] A double-stranded nucleic acid capable of inhibiting expression of CNNM4 for use as a pharmaceutical, the double-stranded nucleic acid comprising a first strand and a second strand.
[3] The nucleic acid according to [1] or [2] above, wherein the first strand and the second strand form a double-stranded region having a length of 17 to 25 nucleotides.
[4] The nucleic acid according to any one of [1] to [3] above, which mediates RNA interference.
[5] The nucleic acid according to any one of [1] to [4] above, wherein at least one nucleotide of the first strand and/or the second strand is a modified nucleotide, preferably the modified nucleotide is a non-naturally occurring nucleotide such as a 2'-F modified nucleotide.
[6] The nucleic acid according to any one of [1] to [5] above, which is numbered consecutively from nucleotide number 1 at the 5'-end of the first strand, and at least the second nucleotide and the fourteenth nucleotide of the first strand are modified by a first modification.
[7] The nucleic acid according to any one of the above [1] to [6], wherein the first strand has a 5'(E)-vinylphosphonate terminal nucleotide at its 5' end.
[8] The nucleic acid according to any one of the above-mentioned [1] to [7], which comprises phosphorothioate bonds between two or three 3'-terminal nucleotides and/or between the 5'-terminal nucleotides of the first strand and/or the second strand, and preferably the bonds between the remaining nucleotides are phosphodiester bonds.
[9] The nucleic acid according to any one of [1] to [8] above, comprising a phosphorodithioate bond between each of the two, three, or four terminal nucleotides at the 3' end of the first strand, and/or a phosphorodithioate bond between each of the two, three, or four terminal nucleotides at the 3' end of the second strand, and/or a phosphorodithioate bond between each of the two, three, or four terminal nucleotides at the 5' end of the second strand, and comprising a bond other than a phosphorodithioate bond between the two, three, or four terminal nucleotides at the 5' end of the first strand.
[10] The nucleic acid according to any one of [1] to [9] above, which is bound to a ligand.
[11] The nucleic acid according to [10] above, wherein the ligand comprises (i) one or more N-acetylgalactosamine (GalNAc) moieties or derivatives thereof, and (ii) a linker, and is linked to the at least one GalNAc moiety or derivative thereof by the linker.
[12] A composition comprising the nucleic acid according to any one of [1] to [11] above and a solvent, and/or a delivery vehicle, and/or a physiologically acceptable excipient, and/or a carrier, and/or a salt, and/or a diluent, and/or a buffer, and/or a preservative, and/or an additional therapeutic agent selected from the group including oligonucleotides, small molecules, monoclonal antibodies, polyclonal antibodies, and peptides.
[13] The nucleic acid according to any one of [1] and [3] to [11] above, or the composition according to [12] above, for use as a pharmaceutical.
[14] The nucleic acid or composition according to any one of [1] and [3] to [11] above, or the composition according to [12] above, for use in preventing, reducing the risk of suffering from, or treating a disease, disorder, or syndrome, wherein the disease, disorder, or syndrome is preferably a liver disease, a kidney disease, or a lung disease.
[15] Use of the nucleic acid according to any one of [1] and [3] to [11] above or the composition according to [12] above in the prevention of, reduction of the risk of suffering from, or treatment of a disease, disorder, or syndrome, wherein the disease, disorder, or syndrome is preferably a liver disease, a kidney disease, or a lung disease.
[16] A method for preventing a disease, disorder or syndrome, a method for reducing the risk of suffering from a disease, disorder or syndrome, or a method for treating a disease, disorder or syndrome, comprising administering a pharmacologic effective amount of the nucleic acid according to any one of [1] and [3] to [11] above, or the composition according to [12] above, to an individual in need of treatment, wherein the disease, disorder or syndrome is preferably a liver disease, a kidney disease, or a lung disease.
The invention will now be described with reference to the following non-limiting figures and examples.

Claims

A double-stranded nucleic acid for inhibiting expression of CNNM4, comprising a first strand and a second strand, the sequence of the first strand comprising a sequence of at least 15 nucleotides that differs by 3 nucleotides or less from any one of the sequences selected from SEQ ID NOs: 371, 243, 267, 277, 279, 287, 317, 319, 325, 333, 345, 347, 349, 361, 367, 369, 377, 401, 411, 413, 415, 420, 421, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 549, 550, 551, and 552.

A pharmaceutical composition comprising a double-stranded nucleic acid capable of inhibiting expression of CNNM4 for use as a medicament, the pharmaceutical composition comprising a first strand and a second strand.

2. The nucleic acid of claim 1 , wherein the first strand and the second strand form a double-stranded region of 17 to 25 nucleotides in length.

A nucleic acid according to claim 1 or 3 , which mediates RNA interference.

The nucleic acid according to any one of claims 1, 3 and 4, wherein at least one nucleotide of the first strand and/or the second strand is a modified nucleotide, preferably said modified nucleotide is a non-naturally occurring nucleotide such as a 2'-F modified nucleotide.

6. The nucleic acid of any one of claims 1 and 3 to 5, numbered consecutively from nucleotide number 1 at the 5' end of the first strand, and wherein at least the second and fourteenth nucleotides of the first strand are modified by a first modification.

The nucleic acid of any one of claims 1 and 3 to 6 , wherein the first strand has a 5'(E)-vinylphosphonate terminal nucleotide at its 5' end.

8. The nucleic acid according to any one of claims 1 and 3 to 7, comprising phosphorothioate bonds between the two or three 3'-terminal nucleotides and/or between the 5'-terminal nucleotides of the first strand and/or the second strand, preferably the bonds between the remaining nucleotides are phosphodiester bonds.

9. The nucleic acid of any one of claims 1 and 3 to 8, comprising a phosphorodithioate bond between each of the two, three, or four terminal nucleotides at the 3' end of the first strand, and/or a phosphorodithioate bond between each of the two, three, or four terminal nucleotides at the 3' end of the second strand, and/or a phosphorodithioate bond between each of the two, three, or four terminal nucleotides at the 5' end of the second strand, and comprising bonds other than phosphorodithioate bonds between the two , three, or four terminal nucleotides at the 5' end of the first strand.

A nucleic acid according to any one of claims 1 and 3 to 9 , which is bound to a ligand.

The nucleic acid of claim 10, wherein the ligand comprises (i) one or more N-acetylgalactosamine (GalNAc) moieties or derivatives thereof, and (ii) a linker, and the linker is used to bind the at least one GalNAc moiety or derivative thereof.

A composition comprising a nucleic acid according to any one of claims 1 and 3 to 11 and a solvent, and/or a delivery vehicle, and/or a physiologically acceptable excipient, and/or a carrier, and/or a salt, and/or a diluent, and/or a buffer, and/or a preservative, and/or a further therapeutic agent selected from the group comprising oligonucleotides, small molecules, monoclonal antibodies, polyclonal antibodies, and peptides.

A composition comprising the nucleic acid according to any one of claims 1 and 3 to 11, or the composition according to claim 12, for use as a medicament.

A nucleic acid or composition according to any one of claims 1 and 3 to 11 or a composition according to claim 12 for use in the prevention, reduction of the risk of suffering from or treatment of a disease, disorder or syndrome, said disease, disorder or syndrome being preferably a liver disease, a kidney disease or a lung disease.