JP2022110140A - アルポート症候群の処置方法 - Google Patents
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Abstract
Description
または線維症の更なる進行を阻止することができる。
ECSATCSAGTCSTGAUSAAGCSTAE-3’(配列番号3)を有してもよく、後に下付き文字がないヌクレオシドはβ-D-デオキシリボヌクレオシドを示し;後に下付き文字「E」があるヌクレオシドは2’-MOEヌクレオシドを示し;後に下付き文字「S」があるヌクレオシドはS-cEtヌクレオシドを示し、ヌクレオシド間結合は各々、ホスホロチオエートヌクレオシド間結合である。
「アルポート症候群」は、異常なレベルの糸球体基底膜(GBM)が産生され、間質線維症、糸球体硬化をきたし、最終的には腎機能の喪失に至る遺伝性の腎疾患を意味する。本疾患はさらに難聴および眼球異常を特徴とする場合が多い。
g/mmol(または20~<200mg/g)または女性の場合3.5~<35mg/mmol(または30~<300mg/g)を特徴とする高アルブミン尿を意味する。
できることを意味する。
レアーゼDroshaの基質であり、ヘアピン構造を有する非コードRNAを意味する。
意味する。
アルポート症候群は、異常なレベルの糸球体基底膜(GBM)が産生され、間質線維症
、糸球体硬化をきたし、典型的には末期腎臓病に至る遺伝性の腎疾患である。アルポート症候群の管理において、処置の主要な目的は、腎機能を維持し、末期腎臓病の発症(ESRD)を予防し、次いでアルポート症候群の被検体の平均余命を改善することである。
本明細書で提供されるのは、アルポート症候群の処置のための方法であって、アルポート症候群を有するまたはそれを有する疑いがある被検体にmiR-21と相補的な修飾オリゴヌクレオチドを投与することを含む方法である。
のα4鎖をコードする遺伝子(Col4a4)の突然変異を有しても、あるいはIV型コラーゲンのα5鎖をコードする遺伝子(Col4a5)の突然変異を有してもよい。ある種の実施形態では、被検体は男性(雄)である。ある種の実施形態では、被検体は女性(雌)である。
アルポート症候群または本明細書に列挙された状態の何れかの処置は、2つ以上の治療を含んでもよい。したがって、ある種の実施形態では、本明細書で記載されるのは、アルポート症候群を有するまたはそれを有する疑いがある被検体を処置するための方法であって、miR-21と相補的な核酸塩基配列を有する修飾オリゴヌクレオチドの投与に加えて、少なくとも1つ治療を投与することを含む方法である。
サルタン、オルメサルタン、ロサルタン、バルサルタン、テルミサルタンまたはエプロサルタンである。
本明細書に記載の修飾オリゴヌクレオチドは、miR-21(配列番号1)またはその前駆体(配列番号2)と相補的な核酸塩基配列を有する。ある種の実施形態では、修飾オリゴヌクレオチドの各核酸塩基はそれぞれ対応する位置で、miR-21またはその前駆体の核酸塩基配列の核酸塩基と塩基対の形成を行うことができる。ある種の実施形態では、修飾オリゴヌクレオチドの核酸塩基配列は、miR-21配列または前駆体配列の核酸
塩基配列に対して1つまたは複数のミスマッチ塩基対を有していてもよく、依然としてその標的配列にハイブリダイズすることができる。
の追加のヌクレオシドはオリゴヌクレオチドの5’末端にある。そうしたある種の実施形態では、2個の追加のヌクレオシドはオリゴヌクレオチドの3’末端にある。そうしたある種の実施形態では、1個の追加のヌクレオシドが5’末端に位置し、1個の追加のヌクレオシドがオリゴヌクレオチドの3’末端に位置する。ある種の実施形態では、オリゴヌクレオチドの領域はmiR-21の核酸塩基配列と完全に相補的である場合があるが、修飾オリゴヌクレオチド全体がmiR-21と完全に相補的であるとは限らない。例えば、24個連結したヌクレオシドからなる修飾オリゴヌクレオチドであって、ヌクレオシド1~22の各核酸塩基が、長さ22核酸塩基のmiR-21の対応する位置と相補的な修飾オリゴヌクレオチドは、miR-21の核酸塩基配列と完全に相補的である22個のヌクレオシド部分を有し、miR-21の核酸塩基配列に対して全体として約92%相補性を有する。
ある種の実施形態では、修飾オリゴヌクレオチドは構造5’-AECSATCSAGTCSTGAUSAAGCSTAE-3’(配列番号3)を有し、ここで後に下付き文字がないヌクレオシドはβ-D-デオキシリボヌクレオシドを示し;後に下付き文字「E」があるヌクレオシドは2’-MOEヌクレオシドを示し;後に下付き文字「S」があるヌクレオシドはS-cEtヌクレオシドを示し;ヌクレオシド間結合は各々、ホスホロチオエートヌクレオシド間結合である。
5個連結したヌクレオシドからなる。ある種の実施形態では、修飾オリゴヌクレオチドは15~19個連結したヌクレオシドからなる。ある種の実施形態では、修飾オリゴヌクレオチドは15~16個連結したヌクレオシドからなる。ある種の実施形態では、修飾オリゴヌクレオチドは19~24個連結したヌクレオシドからなる。ある種の実施形態では、修飾オリゴヌクレオチドは21~24個連結したヌクレオシドからなる。
ある種の実施形態では、本明細書に提供されるオリゴヌクレオチドは、核酸塩基、糖及び/またはヌクレオシド間結合に対して1つまたは複数の修飾を含んでもよく、従って修飾オリゴヌクレオチドである。修飾された核酸塩基、糖及び/またはヌクレオシド間結合は、望ましい特性、例えば、細胞取り込みの増大、他のオリゴヌクレオチドまたは核酸標的に対する親和性の強化、及びヌクレアーゼの存在下での安定性の増強を理由に非修飾形態と比較して選択すればよい。
。4’-チオ修飾ヌクレオシドは、4’-Oが4’-Sで置換されたβ-D-リボヌクレオシドを有する。4’-チオ-2’-修飾ヌクレオシドは、2’-OHが2’-置換基で置換された4’-チオ修飾ヌクレオシドである。好適な2’-置換基は、2’-OCH3、2’-O-(CH2)2-OCH3、及び2’-Fを含む。
チドを保護し、細胞内の送達および/または局在化に役立ち得る。キャップは5’-末端(5’-キャップ)に存在しても、3’-末端(3’-キャップ)に存在してもよいし、あるいは両末端に存在してもよい。キャップ構造は、たとえば、逆位のデオキシ脱塩基キャップを含む。
本明細書で提供されるのは、オリゴヌクレオチドを含む医薬組成物である。ある種の実施形態では、本明細書で提供される医薬組成物は、15~25個連結したヌクレオシドからなる修飾オリゴヌクレオチドを含み、かつmiR-21と相補的な核酸塩基配列を有する化合物を含む。ある種の実施形態では、本明細書で提供される医薬組成物は、8~30個連結したヌクレオシドからなる修飾オリゴヌクレオチドを含み、かつmiR-21と相補的な核酸塩基配列を有する化合物を含む。ある種の実施形態では、本明細書で提供される医薬組成物は、12~25個連結したヌクレオシドからなる修飾オリゴヌクレオチドを含み、かつmiR-21と相補的な核酸塩基配列を有する化合物を含む。
g、700mg、705mg、710mg、715mg、720mg、725mg、730mg、735mg、740mg、745mg、750mg、755mg、760mg、765mg、770mg、775mg、780mg、785mg、790mg、795mg及び800mgから選択される用量で修飾オリゴヌクレオチドを含む。そうしたある種の実施形態では、医薬組成物は、25mg、50mg、75mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、500mg、600mg、700mg及び800mgから選択される用量の修飾オリゴヌクレオチドを含む。
部分は、筋肉組織への医薬品の分布が増加するように選択する。
を用いて調製される。
与しやすいため、有用である。例えば、場合によっては、プロドラッグは、その活性形態より(例えば、経口投与により)体内吸収される可能性がある。場合によっては、プロドラッグは、その活性形態と比較して溶解性を改善できたかもしれない。ある種の実施形態では、プロドラッグは、その活性形態より水溶性に乏しい。場合によっては、こうしたプロドラッグは、細胞膜(通り抜けるには水溶性が妨げになる)を通過する優れた送達性を有する。ある種の実施形態では、プロドラッグはエステルである。そうしたある種の実施形態では、エステルは、投与すると代謝によりカルボン酸に加水分解される。場合によっては、カルボン酸を含む化合物はその活性形態である。ある種の実施形態では、プロドラッグは、酸性基に結合した短いペプチド(ポリアミノ酸)を含む。こうした実施形態の一部では、ペプチドは、投与されると切断されてその活性形態となる。
miR-21に関連する疾患の処置は、2つ以上の治療を含んでもよい。したがって、ある種の実施形態では、本明細書で記載されるのは、miR-21に関連する疾患を有するまたはそれを有する疑いがある被検体を処置するための方法であって、マイクロRNAと相補的な核酸塩基配列を有する修飾オリゴヌクレオチドに加えて少なくとも1つの治療を行うことを含む方法である。
あるが、これに限定されるものではない。ある種の実施形態では、ACE阻害剤はシラザプリル、ペリンドプリルおよびトランドラプリルから選択される。
ロックする医薬品である。
本発明はまたキットを提供する。いくつかの実施形態では、キットは、核酸塩基配列がmiR-21の核酸塩基配列と相補的な修飾オリゴヌクレオチドを含む、本発明の1種または複数種の化合物を含む。miR-21と相補的な化合物は、本明細書に記載のヌクレオシドパターンのいずれを有してもよい。いくつかの実施形態では、miR-21と相補的な化合物はバイアル内に存在してもよい。例えば、調剤容器には、10個などの複数のバイアルが存在してもよい。いくつかの実施形態では、バイアルは、シリンジが利用しやすいように製造する。キットは、miR-21と相補的な化合物の使用説明書を更に含んでもよい。
ある種の実施形態では、本発明は、実験モデルを用いて本発明の修飾オリゴヌクレオチドを使用及び/または試験する方法を提供する。当業者であれば、そうした実験モデルの
プロトコルを選択及び変更して本発明の医薬品を評価することができる。
修飾オリゴヌクレオチドの投与後のmiR-21のアンチセンス阻害の作用は、当該技術分野において公知の種々の方法により評価することができる。ある種の実施形態では、これらの方法を用いて、細胞または組織のマイクロRNAレベルをインビトロまたはインビボで定量する。ある種の実施形態では、マイクロアレイ解析によりマイクロRNAレベルの変化を測定する。ある種の実施形態では、市販されているいくつかのPCRアッセイの1つ、例えばTaqMan(登録商標)MicroRNA Assay(Applied Biosystems)によりマイクロRNAレベルの変化を測定する。ある種の実施形態では、miR-21の標的のmRNA及び/またはタンパク質レベルを測定することにより、miR-21のアンチセンス阻害を評価する。miR-21のアンチセンス阻害を行うと、一般にマイクロRNAの標的のmRNA及び/またはタンパク質のレベルが上昇する。
抗miRまたはマイクロRNA模倣物によるマイクロRNA活性の調節は、標的結合を測定することにより評価することができる。ある種の実施形態では、標的結合は、mRNAのマイクロアレイプロファイリングにより測定する。抗miRまたはマイクロRNA模倣物により調節される(増加或いは減少する)mRNAの配列についてマイクロRNAシード配列を検索し、マイクロRNAの標的であるmRNAの調節を、マイクロRNAの標的でないmRNAの調節と比較する。この方法では、抗miRとmiR-21と、またはmiR-21模倣物とその標的との相互作用を評価することができる。抗miRの場合には、発現レベルが上昇するmRNAについて、抗miRと相補的なマイクロRNAのシードマッチを含むmRNA配列をスクリーニングする。
129svの遺伝的背景のCol4a3-/-マウスは、ヒトアルポート症候群に類似した重度腎疾患を自然に発症する。したがって、アルポート症候群の実験モデルとしてCol4a3-/-マウスを使用する。
ミン/クレアチニン比の低下により認められるように、出現したアルブミン尿がはるかに少なかった。アルブミン尿の減少は7週目には観察され、9週目まで続いた。Col4a3-/-マウスの野生型同腹仔は、予想通りアルブミン尿を示さなかった。アルブミン尿は、糸球体および尿細管の損傷の高感度の指標である。アルブミン/クレアチニン比の低下は、糸球体および/または尿細管疾患の減少を示す。
4a3-/-対照マウスと比較して抗miR-21処置Col4a3-/-マウスでは、マクロファージ浸潤が減少していた(図5A)。CD31の免疫細胞化学的染色から、PBS処置Col4a3-/-対照マウスと比較して抗miR-21処置Col4a3-/-マウスでは、内皮細胞の安定性の改善が立証された(図示せず)。α-SMAの検出により、PBS処置Col4a3-/-対照マウスと比較して抗miR-21処置Col4a3-/-マウスの筋線維芽細胞の付着の減少が明らかになった(図5B)。Col4a3+/+マウスでは、α-SMA染色は約5%であった(図示せず)。
抗miR-21化合物#1(上記):5’-AECSATCSAGTCSTGAUSAAGCSTAE-3’(配列番号3)
抗miR-21化合物#2:5’-AECSATCSASGTCSUSGAUSASAGCSUsAE-3’(配列番号3);
抗miR-21化合物#3:5’-MeCEASASTECSUSAEAEUSASAEGECSTEAS-3’(配列番号4);および
抗miR-21化合物#4:5’-AECSAETECSAEGETECSTGAUSAAGCSUSAS-3’(配列番号3);
を用いて同様の研究を行った。(ここで後に下付き文字がないヌクレオシドはβ-D-デオキシリボヌクレオシドを示し;後に下付き文字「E」があるヌクレオシドは2’-MOEヌクレオシドを示し;後に下付き文字「S」があるヌクレオシドはS-cEtヌクレオシドを示し;および上付き文字「Me」はヌクレオシドの塩基の5-メチル基を示す)。ヌクレオシド間結合は各々ホスホロチオエートヌクレオシド間結合である。
アルポート症候群の実験モデルにおけるmiR-21の調節不全を評価するため、マウスから採取した腎臓組織のmiR-21レベルを測定した。腎全体からRNAを単離し、定量PCRによりmiR-21を測定した。Col4a3-/-マウスでは、miR-21レベルが野生型マウスのmiR-21レベルと比較して約3倍高かった。
野生型マウスは一般に、2~3年(730~1095日)生存する。129X1/SvJ背景のCol4a3-/-マウスの場合、末期腎不全が早ければ生後2ヶ月で起こることがある。C57BL/6J背景のCol4a3-/-の場合、末期腎不全が早ければ生後6ヶ月で起こることがある。背景に関係なく、Col4a3-/-マウスの寿命は野生型マウスのそれより著しく短い。このため、Col4a3-/-マウスは、どのような遺伝的背景でも、アルポート症候群における末期腎不全のモデルとすることができ、平均余
命に対する候補治療薬の作用を評価するのに使用することができる。
アルポート症候群の実験モデルの生存期間に対する抗miR-21の作用を評価するため、抗miR-21化合物をCol4a3-/-マウスに投与した。
アルポート症候群の実験モデルの生存期間に対する抗miR-21の用量反応性を評価するため、いくつかの用量の抗miR-21化合物をCol4a3-/-マウスに投与した。
(1)Col4a3-/-マウス、PBS投与、週1回、n=13;
(2)Col4a3-/-マウス、12.5mg/kgの抗miR-21投与、週1回、n=12;
(3)Col4a3-/-マウス、25mg/kgの抗miR-21投与、週1回、n=13;
(4)Col4a3-/-マウス、50mg/kgの抗miR-21投与、週1回、n=12;
(5)Col4a3-/-マウス、25mg/kgの抗miR-21投与、週2回、n=12;
であった。
抗miR化合物を含むオリゴヌクレオチドは、腎臓内のいくつかの細胞型に分布することが知られている。Chau et al.,Sci Transl Med.,2012,121ra18により報告されているように、正常なマウスあるいは腎臓傷害を生じさせたマウス(一側尿管閉塞、間質線維症モデル)にCy3標識抗miRの投与後、腎臓内の最大蛍光強度は近位尿細管上皮であった。内皮、周皮細胞、筋線維芽細胞およびマクロファージにもすべて、検出可能な量のCy3標識抗miRが含まれていた。しかしながら、糸球体、特に有足細胞は、相当量の抗miRを取り込んでいないようであり、化学修飾オリゴヌクレオチドの既知の分布と一致した(Masarjian et al.,O
ligonucleotides,2004,14,299-310)。
Claims (30)
- アルポート症候群を処置する方法であって、アルポート症候群を有するまたはそれを有する疑いがある被検体に、12~25個連結したヌクレオシドからなる修飾オリゴヌクレオチドを投与することを含み、前記修飾オリゴヌクレオチドの核酸塩基配列はmiR-21と相補的である方法。
- 前記被検体は前記修飾オリゴヌクレオチドを投与する前にアルポート症候群を有すると診断されている、請求項1に記載の方法。
- 前記被検体は、前記修飾オリゴヌクレオチドの投与の前に、前記被検体の腎臓中、尿中または血液中のmiR-21のレベルが増加していると判定された、請求項1に記載の方法。
- 前記投与は、
a. 腎機能を改善する;
b. 末期腎臓病の発症を遅延させる;
c. 透析までの時間を遅延させる;
d. 腎移植までの時間を遅延させる;および/または
e. 平均余命を改善する
請求項1~3の何れか一項に記載の方法。 - 前記投与は、
a. 血尿を減少させる;
b. 血尿の発症を遅延させる;
c. タンパク尿を減少させる;
d. タンパク尿の発症を遅延させる;
e. 腎線維症を抑制する;
f. 線維症の更なる進行を遅延させる;および/または
g. 線維症の更なる進行を阻止する
請求項1~4の何れか一項に記載の方法。 - 前記被検体は、IV型コラーゲンのα3鎖をコードする遺伝子の突然変異、IV型コラーゲンのα4鎖をコードする遺伝子の突然変異、またはIV型コラーゲンのα5鎖をコードする遺伝子の突然変異から選択される突然変異を有する、請求項1~5の何れか一項に記載の方法。
- 前記被検体は男性(雄)である、請求項1~6の何れか一項に記載の方法。
- 前記被検体は女性(雌)である、請求項1~7の何れか一項に記載の方法。
- 前記被検体は血尿および/またはタンパク尿を有すると確認される、請求項1~8の何れか一項に記載の方法。
- 前記被検体は腎機能が低下している、請求項1~9の何れか一項に記載の方法。
- 前記被検体は腎機能の改善を必要としている、請求項1~10の何れか一項に記載の方法。
- a. 前記被検体の血液中の血中尿素窒素を測定すること;
b. 前記被検体の血液中のクレアチニンを測定すること;
c. 前記被検体のクレアチニンクリアランスを測定すること;
d. 前記被検体のタンパク尿を測定すること;
e. 前記被検体のアルブミン:クレアチニン比を測定すること;
f. 前記被検体の糸球体濾過量を測定すること;
g. 前記被検体のシスタチンCを測定すること;
h. 前記被検体の血液中のβトレースタンパク質(BTP)を測定すること;
i. 前記被検体の血液中の2-ミクログロブリンを測定すること;
j. 前記被検体の尿中のN-アセチル-β-D-グルコサミニダーゼ(NAG)タンパク質を測定すること;
k. 前記被検体の尿中の好中球ゼラチナーゼ関連リポカリン(NGAL)タンパク質を測定すること;
l. 前記被検体の尿中の腎臓傷害分子-1(KIM-1)タンパク質を測定すること;
m. 前記被検体の尿中のインターロイキン-18(IL-18)タンパク質を測定すること;
n. 前記被検体の尿中の単球走化性タンパク質(MCP1)レベルを測定すること;
o. 前記被検体の尿中の結合組織増殖因子(CTGF)レベルを測定すること;
p. 前記被検体の尿中のコラーゲンIVフラグメントを測定すること;
q. 前記被検体の尿中のコラーゲンIIIフラグメントを測定すること;および/または
r. 前記被検体の尿中の有足細胞タンパク質レベルを測定することであって、前記有足細胞タンパク質はネフリンおよびポドシンから選択される測定すること、
を含む、請求項1~11の何れか一項に記載の方法。 - 前記投与は、
a. 前記被検体の血中尿素窒素の低下;
b. 前記被検体の血液中のクレアチニンの低下;
c. 前記被検体のクレアチニンクリアランスの改善;
d. 前記被検体のタンパク尿の減少;
e. 前記被検体のアルブミン:クレアチニン比の低下;
f. 前記被検体の糸球体濾過量の改善;
g. 前記被検体の血液中のシスタチンCの低下;
h. 前記被検体の血液中のβトレースタンパク質(BTP)の低下;
i. 被検体の血液中の2-ミクログロブリン(B2M)の低下;
j. 前記被検体の尿中のNAGタンパク質の低下;
k. 前記被検体の尿中のNGALタンパク質の低下;
l. 前記被検体の尿中のKIM-1タンパク質の低下;
m. 前記被検体の尿中のIL-18タンパク質の低下;
n. 前記被検体の尿中の単球走化性タンパク質(MCP1)レベルの低下;
o. 前記被検体の尿中の結合組織増殖因子(CTGF)レベルの低下;
p. 前記被検体の尿中のコラーゲンIVフラグメントの低下;
q. 前記被検体の尿中のコラーゲンIIIフラグメントの低下;および/または
r. 前記被検体の尿中の有足細胞タンパク質レベルの低下であって、前記有足細胞タンパク質はネフリンおよびポドシンから選択される低下
から選択される前記被検体の腎機能の1つまたは複数のマーカーの改善を行う、請求項1~12の何れか一項に記載の方法。 - 前記タンパク尿はアルブミン尿である、請求項5、12または13の何れか一項に記載の方法。
- 前記アルブミン尿は正常高値アルブミン尿、微量アルブミン尿または顕性アルブミン尿である、請求項14に記載の方法。
- 前記アルポート症候群はX連鎖型アルポート症候群である、請求項1~15の何れか一項に記載の方法。
- 前記アルポート症候群は常染色体性型のアルポート症候群である、請求項1~16の何れか一項に記載の方法。
- アンジオテンシンII変換酵素(ACE)阻害剤、アンジオテンシンII受容体遮断薬(ARB)、降圧薬、ビタミンDアナログ、経口リン吸着薬、透析および腎臓移植から選択される少なくとも1つの追加治療を行うことを含む、請求項1~17の何れか一項に記載の方法。
- 前記アンジオテンシンII変換酵素(ACE)阻害剤はカプトプリル、エナラプリル、リシノプリル、ベナゼプリル、キナプリル、ホシノプリルおよびラミプリルから選択される、請求項17に記載の方法。
- 前記アンジオテンシンII受容体遮断薬(ARB)はカンデサルタン、イルベサルタン、オルメサルタン、ロサルタン、バルサルタン、テルミサルタンおよびエプロサルタンから選択される、請求項17に記載の方法。
- 前記修飾オリゴヌクレオチドの核酸塩基配列はmiR-21の核酸塩基配列(配列番号1)と少なくとも90%相補的、少なくとも95%相補的または100%相補的である、請求項1~20の何れか一項に記載の方法。
- 前記修飾オリゴヌクレオチドは15~25個連結したヌクレオシドからなる、請求項1~21の何れか一項に記載の方法。
- 前記修飾オリゴヌクレオチドは15個、16個、17個、18個、19個、20個、21個または22個連結したヌクレオシドからなる、請求項1~22の何れか一項に記載の方法。
- 前記修飾オリゴヌクレオチドは少なくとも1個の修飾ヌクレオシドを含む、請求項1~23の何れか一項に記載の方法。
- 前記修飾ヌクレオシドはS-cEtヌクレオシド、2’-O-メトキシエチルヌクレオシドおよびLNAヌクレオシドから選択される、請求項21に記載の方法。
- 前記修飾オリゴヌクレオチドは少なくとも1つの修飾ヌクレオシド間結合を含む、請求項1~25の何れか一項に記載の方法。
- 前記修飾オリゴヌクレオチドのヌクレオシド間結合は各々、修飾ヌクレオシド間結合である、請求項1~26の何れか一項に記載の方法。
- 前記修飾ヌクレオシド間結合はホスホロチオエートヌクレオシド間結合である、請求項23または24に記載の方法。
- 前記修飾オリゴヌクレオチドは構造5’-AECSATCSAGTCSTGAUSAA
GCSTAE-3’を有し、ここで後に下付き文字がないヌクレオシドはβ-D-デオキシリボヌクレオシドを示し;後に下付き文字「E」があるヌクレオシドは2’-MOEヌクレオシドを示し;後に下付き文字「S」があるヌクレオシドはS-cEtヌクレオシドを示し、ヌクレオシド間結合は各々、ホスホロチオエートヌクレオシド間結合である、請求項1~28の何れか一項に記載の方法。 - 12~25個連結したヌクレオシドからなる修飾オリゴヌクレオチドであって、前記修飾オリゴヌクレオチドの核酸塩基配列はmiR-21と相補的である修飾オリゴヌクレオチドの、アルポート症候群の処置のための使用。
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