JP2023011614A - 筋萎縮症と筋緊張性ジストロフィーを処置するための組成物および方法 - Google Patents
筋萎縮症と筋緊張性ジストロフィーを処置するための組成物および方法 Download PDFInfo
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Abstract
Description
本出願は、2017年12月6日に出願された米国仮特許出願第62/595,545号と、2018年8月31日に出願された米国仮特許出願第62/725,883号の利益を主張するものであり、これらは各々、その全体において引用により本明細書に組み込まれる。
本出願は配列表を包含しており、これは、ASCIIフォーマットで電子的に提出され、その全体を引用することで本明細書に組み込まれる。2018年12月6日に作成された上記ASCIIのコピーは、45532-722_601_SL.txtのファイル名であり、3,143,382バイトのサイズである。
アトロジーンあるいは萎縮に関連する遺伝子は、委縮する筋肉でアップレギュレートあるいはダウンレギュレートされる遺伝子である。いくつかの例では、アップレギュレートされたアトロジーンは、ユビキチンリガーゼ、フォークヘッドボックス転写因子、成長因子、脱ユビキチン化酵素、あるいはグルココルチコイドにより誘導された萎縮に関与するタンパク質コードする遺伝子を含む。
いくつかの実施形態において、本明細書に記載されるアトロジーンは、E3ユビキチンリガーゼをコードする。例示的なE3ユビキチンリガーゼは、限定されないが、アトロジン-1(atrogin-1)/MAFbx、muscle RING finger1(MuRF1)、TNF受容体アダプタータンパク質6(TRAF6)、F-Boxタンパク質30(Fbxo30)、F-Boxタンパク質40(Fbxo40)、神経前駆細胞発現発達ダウンレギュレートタンパク質4(neural precursor cell expressed developmentally down-regulated protein 4)(Nedd4-1)、および三者モチーフ含有タンパク質32(Trim32)を含む。例示的なミトコンドリアのユビキチンリガーゼは、限定されないが、ミトコンドリアE3ユビキチンタンパク質リガーゼ1(Mul1)とHsc70相互作用タンパク質のカルボキシ末端(CHIP)を含む。
いくつかの実施形態において、本明細書に記載されるアトロジーンは、フォークヘッドボックス転写因子をコードする。例示的なフォークヘッドボックス転写因子は、限定されないが、アイソフォームフォークヘッドボックスタンパク質O1(FoxO1)およびフォークヘッドボックスタンパク質O3(FoxO3)を含む。
いくつかの実施形態において、本明細書に記載されるアトロジーンは成長因子をコードする。例示的な成長因子はミオスタチンを含む。
いくつかの実施形態において、本明細書に記載されるアトロジーンは脱ユビキチン化酵素をコードする。例示的な脱ユビキチン化酵素は、限定されないが、ユビキチン特異的ペプチダーゼ14(USP14)およびユビキチン特異的ペプチダーゼ19(USP19)を含む。いくつかの例では、本明細書に記載されるアトロジーンは、USP14(脱ユビキチン化酵素14あるいはTGTとしても知られている)をコードする。他の例では、本明細書に記載されるアトロジーンは、USP19(ジンクフィンガーMYNDドメイン含有タンパク質9、脱ユビキチン化酵素19、あるいはZMYND9としても知られている)をコードする。USP14はUSP14遺伝子によってコードされる。USP19はUSP19遺伝子によってコードされる。
いくつかの実施形態において、本明細書に記載されるアトロジーンは、DNA損傷誘導性転写物4(DDIT4)およびHIF-1反応性タンパク質RTP801としても知られている、regulated in development and DNA damage response1(Redd1)をコードする。Redd1は14-3-3を隔離することによりmTOR機能を抑制し、TSC1/2活性を増大させる。さらに、Redd1は、筋タンパク質合成に関与する4E-BP1とS6K1のリン酸化を減少させる。Redd1はDDIT4遺伝子によってコードされる。
ある実施形態では、ポリ核酸分子は、萎縮関連遺伝子(アトロジーンとも呼ばれる)の標的配列にハイブリダイズする。いくつかの例では、本明細書に記載されるポリ核酸分子は、ユビキチンリガーゼ(例えば、E3ユビキチンリガーゼあるいはミトコンドリアユビキチンリガーゼ)の標的配列にハイブリダイズする。いくつかの例では、本明細書に記載されるポリ核酸分子は、フォークヘッドボックス転写因子の標的配列にハイブリダイズする。いくつかの例では、本明細書に記載されるポリ核酸分子は、成長因子の標的配列にハイブリダイズする。いくつかの例では、本明細書に記載されるポリ核酸分子は、脱ユビキチン化酵素の標的配列にハイブリダイズする。
いくつかの実施形態において、本明細書に記載されるポリ核酸分子は、当該技術分野で知られている手順を用いて、化学合成および/または酵素ライゲーション反応を用いて構築される。例えば、ポリ核酸分子は、自然発生のヌクレオチドを使用して、あるいは、分子の生体安定性を増大させるために、または、ポリ核酸分子と標的核酸との間で形成された二重鎖の物理安定度を増大させるために設計されたさまざまな修飾ヌクレオチドを用いて、化学合成される。例示的な方法は、以下に記載されるものを含む:米国特許第5,142,047号;第5,185,444号;第5,889,136号;第6,008,400号;および、第6,111,086号;PCT国際公開第WO2009099942号;あるいは、欧州特許公開第1579015号。追加の例示的な方法は、以下に記載されるものを含む:Griffey et al.,“2’-O-aminopropyl ribonucleotides: a zwitterionic modification that enhances the exonuclease resistance and biological activity of antisense oligonucleotides,” J. Med. Chem. 39(26):5100-5109 (1997)); Obika,et al. “Synthesis of 2’-O,4’-C-methyleneuridine and -cytidine. Novel bicyclic nucleosides having a fixed C3,-endo sugar puckering”. Tetrahedron Letters 38 (50): 8735 1997; Koizumi,M. “ENA oligonucleotides as therapeutics”. Current opinion in molecular therapeutics 8 (2): 144-149 (2006); and Abramova et al.,“Novel oligonucleotide analogues based on morpholino nucleoside subunits-antisense technologies: new chemical possibilities,” Indian Journal of Chemistry 48B:1721-1726 (2009)。代替的に、ポリ核酸分子は、ポリ核酸分子がアンチセンス配向にサブクローン化された発現ベクターを用いて生物学的に生成される(つまり、挿入されたポリ核酸分子の転写されたRNAは所望の標的ポリ核酸分子に対してアンチセンス配向になる)。
いくつかの実施形態において、ポリ核酸分子はさらに、所望の部位へ送達されるポリペプチドAに結合する。場合によっては、ポリ核酸分子はポリペプチドAと随意にポリマー部分に結合する。
いくつかの実施形態において、結合部分Aはポリペプチドである。いくつかの例では、ポリペプチドは、抗体またはそのそのフラグメントである。場合によっては、フラグメントは結合フラグメントである。いくつかの例では、抗体またはその結合フラグメントは、ヒト化抗体またはその結合フラグメント、マウス抗体またはその結合フラグメント、キメラ抗体またはその結合フラグメント、モノクローナル抗体またはその結合フラグメント、一価Fab’、二価Fab2、F(ab)’3フラグメント、単鎖可変フラグメント(scFv)、ビス-scFv、(scFv)2、ダイアボディ、ミニボディ、ナノボディ、三重特異性抗体、四重特異性抗体、ジスルフィド安定化Fvタンパク質(dsFv)、単一ドメイン抗体(sdAb)、Ig NAR、ラクダ科抗体またはその結合フラグメント、二重特異性抗体またはその結合フラグメント、あるいはその化学修飾された誘導体を含む。
いくつかの実施形態において、結合部分は血漿タンパク質である。いくつかの例では、血漿タンパク質はアルブミンを含む。いくつかの例では、結合部分Aはアルブミンである。いくつかの例では、アルブミンは、本明細書に記載される結合化学の1つ以上によって、ポリ核酸分子に結合する。いくつかの例では、アルブミンは、天然のライゲーション化学によってポリ核酸分子に結合する。いくつかの例では、アルブミンは、リジン結合によってポリ核酸分子に結合する。
いくつかの実施形態において、本明細書に記載されるポリペプチド(例えば、抗体とその結合フラグメント)は、とりわけ、化学合成によって、あるいは組換え発現によって、ポリペプチド(例えば、抗体)の合成に役立つように、当該技術分野で知られている任意の方法を使用して生成され、および、好ましくは組換え発現技術によって生成される。
いくつかの実施形態において、ポリ核酸分子Bは結合部分に結合する。いくつかの例では、結合部分は、アミノ酸、ペプチド、ポリペプチド、タンパク質、抗体、抗原、毒素、ホルモン、脂質、ヌクレオチド、ヌクレオシド、糖類、炭水化物、ポリエチレングリコールとポリプロピレングリコールなどのポリマー、ならびに、これらのクラスの物質のすべてのアナログあるいは誘導体を含む。結合部分の追加の例はさらに、コレステロール、リン脂質、ジアシルグリセロールおよびトリアシルグリセロール、脂肪酸、炭化水素(例えば、飽和、不飽和、または、置換を含む)、酵素基質、ビオチン、ジゴキシゲニン、および多糖類などのステロイドを含む。いくつかの例では、結合部分は、抗体またはその結合フラグメントである。いくつかの例では、ポリ核酸分子はさらにポリマーに結合され、随意にエンドソーム溶解性部分に結合する。
いくつかの実施形態において、ポリマー部分Cはさらに、本明細書に記載されるポリ核酸分子、本明細書に記載される結合部分、あるいはこれらの組み合わせに結合する。いくつかの例では、ポリマー部分Cはポリ核酸分子に結合する。場合によっては、ポリマー部分Cは結合部分に結合する。他の場合には、ポリマー部分Cはポリ核酸分子結合部分分子に結合する。さらなる場合には、ポリマー部分Cは上で例証されるように結合する。
いくつかの実施形態において、式(I):A-X1-B-X2-Cの分子はさらに、追加の結合部分を含む。いくつかの例では、追加の結合部分はエンドソーム溶解性部分である。場合によっては、エンドソーム溶解性部分は、細胞区画放出成分、例えば、エンドソーム、リソソーム、小胞体(ER)、ゴルジ体、微小管、ペルオキシソーム、あるいは細胞を有する他の小胞体などの、当該技術分野で知られている細胞の区分のいずれかから放出することができる化合物である。場合によっては、エンドソーム溶解性部分は、エンドソーム溶解性ポリペプチド、エンドソーム溶解性ポリマー、エンドソーム溶解性脂質、あるいはエンドソーム溶解性小分子を含む。場合によっては、エンドソーム溶解性部分はエンドソーム溶解性ポリペプチドを含む。他の場合では、エンドソーム溶解性部分はエンドソーム溶解性ポリマーを含む。
いくつかの実施形態において、式(I):A-X1-B-X2-Cの分子は、エンドソーム溶解性ポリペプチドとさらに結合する。場合によっては、エンドソーム溶解性ポリペプチドはpH依存性膜活性ペプチドである。場合によっては、エンドソーム溶解性ポリペプチドは両親媒性ポリペプチドである。追加の場合には、エンドソーム溶解性ポリペプチドはペプチド模倣薬である。いくつかの例では、エンドソーム溶解性ポリペプチドは、INF、メリチン、ムチン(meucin)、あるいはそのそれぞれの誘導体を含む。いくつかの例では、エンドソーム溶解性ポリペプチドは、INFまたはその誘導体を含む。他の場合には、エンドソーム溶解性ポリペプチドは、メリチンまたはその誘導体を含む。さらなる場合には、エンドソーム溶解性ポリペプチドは、ムチンまたはその誘導体を含む。
いくつかの実施形態において、エンドソーム溶解性部分は脂質(例えば、融合性脂質)である。いくつかの実施形態において、式(I):A-X1-B-X2-Cの分子は、エンドソーム溶解性脂質(例えば、融合性脂質)とさらに結合する。例示的な融合性脂質は、1,2-ジレオイル(dileoyl)-sn-3-ホスホエタノールアミン(DOPE)、ホスファチジルエタノールアミン(POPE)、パルミトイルオレオイルホスファチジルコリン(POPC)、(6Z、9Z、28Z、31Z)-ヘプタトリアコンタ-6、9、28、31-テトラエン-19-オール(Di-Lin)、およびN-メチル(2,2-ジ(9Z、12Z)-オクタデカ-9,12-ジエニル)-1,3-ジオキソラン-4-イル)メタンアミン(DLin-k-DMA)ならびにN-メチル-2-(2,2-ジ(9Z、12Z)-オクタデカ-9,12-ジエニル)-1,3-ジオキソラン-4-イル)エタンアミン(XTC)を含む。
いくつかの実施形態では、エンドソーム溶解性部分は小分子である。いくつかの実施形態において、式(I):A-X1-B-X2-Cの分子は、エンドソーム溶解性小分子とさらに結合する。エンドソーム溶解性部分として適切な例示的な小分子としては、限定されないが、キニーネ、クロロキン、水酸化クロロキン、アモジアキン(carnoquines)、アモピロキン、プリマキン、メフロキン、nivaquines、ハロファントリン、キノンイミン、あるいはそれらの組み合わせを含む。いくつかの例では、キノリンエンドソーム溶解性部分としては、限定されないが、7-クロロ-4-(4-ジエチルアミノ-1-メチルブチル-アミノ)キノリン(クロロキン);7-クロロ-4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチル-アミノ)キノリン(ヒドロキシクロロキン);7-フルオロ-4-(4-ジエチルアミノ-1-メチルブチル-アミノ)キノリン;4-(4-ジエチルアミノ-1-メチルブチルアミノ)キノリン;7-ヒドロキシ-4-(4-ジエチル-アミノ-1-メチルブチルアミノ)キノリン;7-クロロ-4-(4-ジエチルアミノ-1-ブチルアミノ)キノリン(デスメチルクロロキン);7-フルオロ-4-(4-ジエチルアミノ-1-ブチルアミノ)キノリン;4-(4-ジエチル-アミノ-1-ブチルアミノ)キノリン;7-ヒドロキシ-4-(4-ジエチルアミノ-1-ブチルアミノ)キノリン;7-クロロ-4-(1-カルボキシ-4-ジエチルアミノ-1-ブチルアミノ)キノリン;7-フルオロ-4-(1-カルボキシ-4-ジエチル-アミノ-1-ブチルアミノ)キノリン;4-(1-カルボキシ-4-ジエチルアミノ-1-ブチルアミノ)キノリン;7-ヒドロキシ-4-(1-カルボキシ-4-ジエチルアミノ-1-ブチルアミノ)キノリン;7-クロロ-4-(1-カルボキシ-4-ジエチルアミノ-1-メチルブチルアミノ)キノリン;7-フルオロ-4-(1-カルボキシ-4-ジエチル-アミノ-1-メチルブチルアミノ)キノリン;4-(1-カルボキシ-4-ジエチルアミノ-1-メチルブチルアミノ)キノリン;7-ヒドロキシ-4-(1-カルボキシ-4-ジエチルアミノ-1-メチルブチルアミノ)キノリン;7-フルオロ-4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン;4-(4-エチル-(2-ヒドロキシ-エチル)-アミノ-1-メチルブチルアミノ-)キノリン;7-ヒドロキシ-4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン;ヒドロキシクロロキンホスフェート;7-クロロ-4-(4-エチル-(2-ヒドロキシエチル-1)-アミノ-1-ブチルアミノ)キノリン(デスメチルヒドロキシクロロキン);7-フルオロ-4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン;4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン;7-ヒドロキシ-4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ(キノリン;7-クロロ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン;7-フルオロ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン;4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン;7-ヒドロキシ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン;7-クロロ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン;7-フルオロ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン;4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン;7-ヒドロキシ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン;8-[(4-アミノペンチル)アミノ-6-メトキシジヒドロクロリドキノリン;1-アセチル-1,2,3,4-テトラヒドロキノリン;8-[(4-アミノペンチル)アミノ]-6-メトキシキノリンジヒドロクロリド;1-ブチリル-1,2,3,4-テトラヒドロキノリン;3-クロロ-4-(4-ヒドロキシ-α,α’-ビス(2-メチル-1-ピロリジニル)-2,5-キシリジノキノリン)(4-[(4-ジエチル-アミノ)-1-メチルブチル-アミノ]-6-メトキシキノリン;3-フルオロ-4-(4-ヒドロキシ-α,α’-ビス(2-メチル-1-ピロリジニル)-2,5-キシリジノキノリン(4-[(4-ジエチルアミノ)-1-メチルブチル-アミノ]-6-メトキシキノリン;4-(4-ヒドロキシ-α、α’-ビス(2-メチル-1-ピロリジニル)-2,5-キシリジノキノリン;4-[(4-ジエチルアミノ)-1-メチルブチル-アミノ]-6-メトキシキノリン;3,4-ジヒドロ-1-(2H)-キノリンカルボキシアルデヒド;1、1’-ペンタメチレンキノリニウムヨージド;8-硫酸キノリノールおよびアミノ、アルデヒド、カルボン酸、ヒドロキシル、ハロゲン、ケト、スルフヒドリル、ならびにビニル誘導体またはそのアナログ。いくつかの例では、エンドソーム溶解性部分は、Naisbitt et al (1997,J Pharmacol Exp Therapy 280:884-893)および米国特許第5,736,557号に記載される小分子である。
いくつかの実施形態において、本明細書に記載されるリンカーは、切断可能なリンカーまたは切断不可能なリンカーである。いくつかの例では、リンカーは切断可能なリンカーである。他の例では、リンカーは切断不可能なリンカーである。
筋萎縮症は、筋肉量の喪失および/または筋肉の進行性の低下と変性を指す。場合によっては、筋肉量の喪失あるいは筋肉の進行性の低下と変性は、高いタンパク質分解率、低いタンパク質合成率、あるいは両方の組み合わせによって生じる。場合によっては、高い筋タンパク質分解率は、筋タンパク質異化作用(つまり、糖新生のために基質としてアミノ酸を使用するための筋タンパク質の分解)による。
悪液質は、基礎疾患によって引き起こされる筋肉の後天性の加速度的低下である。いくつかの例では、悪液質は、栄養では回復させることができない体重の喪失を指し、一般的には、基礎疾患、例えば、癌、COPD、AIDS、心不全などに関連付けられる。悪液質が末期癌の患者で見られるとき、それは「癌性悪液質」と呼ばれる。癌性悪液質は、進行癌の患者の大部分に影響を与え、処置耐性、治療に対する反応、生活の質、および生存期間の減少に関連付けられる。いくつかの例では、癌性悪液質は、体脂肪量の喪失を伴ってまたは伴わずに、骨格筋量の進行中の喪失を特徴とする他因子症候群として定義され、従来の栄養学的なサポートでは完全には回復できず、進行性の機能障害を引き起こしかねない。場合によっては、骨格筋の喪失は、癌性悪液質で最も有意な事象であると思われる。加えて、癌性悪液質の分類は、診断基準が、体重減少が悪液質のプロセスのシグナル事象であることだけでなく、患者の当初の蓄え、低いBMIあるいは低レベルの筋肉質も考慮されなければならないと提唱している。
除神経は、臓器と中枢神経系の間の神経線維の部分的あるいは完全な遮断を伴う末梢性の運動ニューロンに対する損傷であり、神経伝導と運動ニューロン発火の遮断を引き起こし、順に、骨格筋の収縮性(contractability )を妨げる。神経機能のこの喪失は、運動ニューロン単位全体の喪失により局在化または一般化される。骨格筋が収縮できないと、筋萎縮症が引き起こされる。いくつかの例では、除神経は、変性、代謝性、あるいは炎症性の神経障害(例えば、ギランバレー症候群、末梢神経障害、あるいは環境毒物あるいは薬物への暴露)に関連付けられ、あるいはこれらの結果として関連付けられる。さらなる例では、除神経は肉体損傷、例えば、外科手術に関連付けられる。
ミオパシーは筋肉の疾患を記載する総称である。いくつかの例では、ミオパシーは筋緊張症;先天性ミオパシー、例えば、ネマリンミオパシー、マルチコア/ミニコアミオパシー、および筋細管(中心核)ミオパシー;ミトコンドリアミオパシー;家族性周期性四肢麻痺;炎症性ミオパシー;例えば、グリコーゲンまたは脂質蓄積疾患によって引き起こされた代謝性ミオパシー;皮膚筋炎;多発性筋炎;封入体筋炎;骨化性筋炎;横紋筋融解症;および、ミオグロビン尿症を含む。いくつかの例では、ミオパシーは、デュシェンヌ型、ベッカー型、筋緊張性、顔面肩甲上腕型、エメリ・ドレフュス型、眼咽頭型、肩甲上腕骨型、肢帯型、福山型、先天性筋ジストロフィー、あるいは遺伝的な遠位型ミオパシーなどの筋ジストロフィー症候群によって引き起こされる。いくつかの例では、ミオパシーは筋緊張性ジストロフィー(例えば、筋緊張性ジストロフィー1型あるいはDM1)によって引き起こされる。いくつかの例では、ミオパシーはDM1によって引き起こされる。
運動ニューロン疾患(MND)は、運動ニューロン(身体の随意筋を制御する細胞)に影響を与える神経異常を包含する。例示的な運動ニューロン疾患は、限定されないが、成人の運動ニューロン疾患、乳児脊髄性筋萎縮症、筋萎縮性側索硬化症、若年性脊髄性筋萎縮症、多焦点伝導ブロックによる自己免疫性のモーター神経障害、脳卒中あるいは脊髄損傷による麻痺、または外傷による骨格の固定化を含む。
糖尿病(真性糖尿病、DM)は、1型糖尿病、2型糖尿病、3型糖尿病、4型糖尿病、二重糖尿病、潜在性自己免疫性糖尿病(LAD)、妊娠性糖尿病、新生児真性糖尿病(NDM)、若年発症成人型糖尿病(MODY)、ウルフラム症候群、アルストレーム症候群、糖尿病前症、あるいは尿崩症を含む。非インスリン依存性糖尿病とも呼ばれる2型糖尿病は、すべての糖尿病症例の95%を占める最も一般的な型の糖尿病である。いくつかの例では、2型糖尿病は、膵臓のβ細胞機能障害によるインスリン抵抗性を含む因子の組み合わせによって引き起こされ、これは高血圧グルコース濃度に結びつく。場合によっては、グルカゴンレベルの増加が肝臓を刺激して、異常な量の必要のないグルコースを生成させ、これが高血圧グルコース濃度の原因となる。
慢性閉塞性肺疾患(COPD)は、長期的な呼吸障害と空気の流れの悪さを特徴とする閉塞性肺疾患の一種である。慢性気管支炎と気腫は2つの異なる型のCOPDである。いくつかの例では、被験体において、COPD(例えば、慢性気管支炎または気腫)に関連するか、あるいは、これにより誘導される、筋萎縮症を処置する方法が本明細書に記載され、当該方法は、治療上有効な量の本明細書に記載されるポリ核酸分子を被験体に投与する工程を含む。他の実施形態では、被験体において、COPD(例えば、慢性気管支炎または気腫)に関連するか、あるいは、これにより誘導される、筋萎縮症を処置する方法が本明細書に記載され、当該方法は、治療上有効な量の本明細書に記載されるポリ核酸分子抱合体を被験体に投与する工程を含む。
肝疾患(あるいは肝臓病)は、線維症、肝硬変、肝炎、アルコール性肝臓疾患、脂肪肝、遺伝性疾患、あるいは原発性肝癌を含む。いくつかの例では、被験体の肝疾患に関連付けられる、あるいは肝疾患によって誘導される筋萎縮症を処置する方法が本明細書に記載され、当該方法は、治療上有効な量の本明細書に記載されるポリ核酸分子を被験体に投与する工程を含む。他の実施形態において、被験体の肝疾患に関連付けられる、あるいは肝疾患によって誘導される筋萎縮症を処置する方法が本明細書に記載され、当該方法は、治療上有効な量の本明細書に記載されるポリ核酸分子抱合体を被験体に投与する工程を含む。
うっ血性心不全は、心臓が身体の組織に対して十分な血液と酸素を送ることができない状態である。いくつかの例では、被験体のうっ血性心不全に関連付けられる、あるいはうっ血性心不全によって誘導される筋萎縮症を処置する方法が本明細書に記載され、当該方法は、治療上有効な量の本明細書に記載されるポリ核酸分子を被験体に投与する工程を含む。他の実施形態において、被験体のうっ血性心不全に関連付けられる、あるいはうっ血性心不全によって誘導される筋萎縮症を処置する方法が本明細書に記載され、当該方法は、治療上有効な量の本明細書に記載されるポリ核酸分子抱合体を被験体に投与する工程を含む。
慢性腎不全または慢性腎臓病は、時間の経過とともに腎臓機能が徐々に失われていくことを特徴とする疾病である。いくつかの例では、被験体の慢性腎不全に関連付けられる、あるいは慢性腎不全によって誘導される筋萎縮症を処置する方法が本明細書に記載され、当該方法は、治療上有効な量の本明細書に記載されるポリ核酸分子を被験体に投与する工程を含む。他の実施形態において、被験体の慢性腎不全に関連付けられる、あるいは慢性腎不全によって誘導される筋萎縮症を処置する方法が本明細書に記載され、当該方法は、治療上有効な量の本明細書に記載されるポリ核酸分子抱合体を被験体に投与する工程を含む。
いくつかの実施形態において、AIDSなどの慢性感染症はさらに、筋萎縮症を引き起こす。いくつかの例では、被験体において、慢性感染症(例えば、AIDS)に関連するか、あるいは、これにより誘導される筋萎縮症を処置する方法が本明細書に記載され、当該方法は、治療上有効な量の本明細書に記載されるポリ核酸分子を被験体に投与する工程を含む。他の実施形態において、被験体において、慢性感染症(例えば、AIDS)に関連するか、あるいは、これにより誘導される筋萎縮症を処置する方法が本明細書に記載され、当該方法は、治療上有効な量の本明細書に記載されるポリ核酸分子抱合体を被験体に投与する工程を含む。
敗血症は、組織損傷、臓器機能不全、および/または死亡に結びつく感染症に対する免疫応答である。他の実施形態において、被験体の敗血症に関連付けられる、あるいは敗血症によって誘導される筋萎縮症を処置する方法が本明細書に記載され、当該方法は、治療上有効な量の本明細書に記載されるポリ核酸分子を被験体に投与する工程を含む。他の実施形態において、被験体の敗血症に関連付けられる、あるいは敗血症によって誘導される筋萎縮症を処置する方法が本明細書に記載され、当該方法は、治療上有効な量の本明細書に記載されるポリ核酸分子抱合体を被験体に投与する工程を含む。
絶食は、一定の期間、一部のあるいはすべての食物、飲み物、あるいはその両方を自発的に断つこと、あるいは、減らすことである。他の実施形態において、被験体の絶食に関連付けられる、あるいは絶食によって誘導される筋萎縮症を処置する方法が本明細書に記載され、当該方法は、治療上有効な量の本明細書に記載されるポリ核酸分子を被験体に投与する工程を含む。他の実施形態において、被験体の絶食に関連付けられる、あるいは絶食によって誘導される筋萎縮症を処置する方法が本明細書に記載され、当該方法は、治療上有効な量の本明細書に記載されるポリ核酸分子抱合体を被験体に投与する工程を含む。
サルコペニアとは、数ヶ月から数年にわたって徐々に筋肉量や筋力が低下していくことを特徴とする、通常の老化の過程における筋萎縮症の継続的なプロセスである。通常の老化プロセスは、骨格筋神経変性を促す障害および疾患の存在によって影響を受けないし加速されない老化作用を本明細書では意味する。
いくつかの実施形態において、グルココルチコイドを用いる処置はさらに、筋萎縮症を引き起こす。例示的なグルココルチコイドは、限定されないが、コルチゾール、デキサメタゾン、ベタメタゾン、プレドニゾン、メチルプレドニゾロン、およびプレドニゾロンを含む。
廃用に関連する筋萎縮症は、四肢が固定される結果として生じる(例えば、四肢または関節の骨折、あるいは殿部または膝の置換外科療法などの整形手術による)。本明細書で使用されるように、「固定」あるいは「固定された」とは、長期間(例えば、2日、3日、4日、5日、6日、1週間、2週間、あるいはそれ以上)、四肢、筋肉、骨、腱、関節、あるいは他の身体部分の運動の部分的あるいは完全な制約を指す。いくつかの例では、固定化の期間は、入浴、外部装置の交換、外部装置の調整など、短期間または短時間の拘束されない動きを含む。四肢の固定化は、限定されないが、装具、スリング、ギプス、包帯、およびスプリント(これらはのいずれも随意に、限定されないが、布、ガーゼ、ガラス線維、プラスチック、石膏、または金属を含む硬質材料または軟質材料で構成される)を含む任意の様々な外部装置と、外科的に移植されたスプリント、プレート、装具などを含む任意の様々な内部装置によって実施される。四肢の固定化の文脈において、動きの制約は、単関節または多関節(例えば、肩関節または股関節などの単関節、橈骨手根関節などの複合関節、および、限定されないが、以下の1つ以上を含む、膝関節などの複関節:手の関節、肩関節、肘関節、手首の関節、補助関節、胸鎖関節、椎骨の関節、顎関節、仙腸関節、股関節、膝関節、および足の関節)、単一の腱または靭帯、あるいは複数の腱または靭帯(例えば、限定されないが、以下の1つ以上を含む:前十字靱帯、後十字靱帯、回旋腱板腱、肘と膝の内側側副靱帯、手の屈筋腱、足首の外側靱帯、顎または顎関節の腱と靭帯)、単一の骨あるいは複数の硬骨(例えば、限定されないが、以下の1つ以上を含む:頭蓋、下顎、鎖骨、肋骨、橈骨、尺骨、上腕骨、骨盤、仙骨、大腿骨、膝蓋骨、指骨、手根骨、中手骨、足根骨、中足骨、腓骨、脛骨、肩甲骨、および椎骨)、単一の筋肉あるいは複数の筋肉(例えば、限定されないが、以下の1つ以上を含む:広背筋、僧帽筋、三角筋、胸筋、二頭筋、三頭筋、外腹斜筋、腹筋、大殿筋、大腿屈筋、四頭筋、腓腹筋、および横隔膜);一本の四肢または複数の四肢、腕と脚の1つ以上)、あるいは、骨格筋系全体またはその一部(例えば、全身ギプスあるいはスパイカギプスの場合)を含む。
いくつかの実施形態において、本明細書に記載される医薬製剤は、限定されないが、非経口(例えば、静脈内、皮下、筋肉内)、経口、鼻腔内、頬側、直腸、または経皮の投与経路を含む複数の投与経路によって、被験体に投与される。いくつかの例では、本明細書に記載される医薬組成物は、非経口(例えば、静脈内、皮下、筋肉内、動脈内、腹腔内、髄腔内、大脳内、脳室内、あるいは頭蓋内)投与のために製剤化される。他の例において、本明細書に記載される医薬組成物は、経口投与のために製剤化される。また他の例において、本明細書に記載される医薬組成物は、経鼻投与のために製剤化される。
いくつかの実施形態において、本明細書に記載される医薬組成物は治療用途のために投与される。いくつかの実施形態において、医薬組成物は、1日に一回、1日に2回、1日に3回、またはそれ以上投与される。医薬組成物は、毎日、1日おき、週5日、週1日、1週おき、月2週間、月3週間、月1回、月2回、月3回、またはそれ以上投与される。医薬組成物は、少なくとも1か月、2か月、3か月、4か月、5か月、6か月、7か月、8か月、9か月、10か月、11か月、12か月、18か月、2年、3年、またはそれ以上の間投与される。
ある実施形態において、本明細書に記載される1つ以上の組成物と方法とともに使用されるキットおよび製品が本明細書で開示される。このようなキットは、バイアル、チューブなどの1つ以上の容器を収容するために仕切られた運搬装置、包装または容器を含み、各容器は、本明細書中に記載されている方法を使用するための別個の要素の1つを備える。適切な容器は、例えば、ボトル、バイアル、シリンジ、および試験管を含む。一実施形態において、容器は、ガラスまたはプラスチックなどの様々な材料から形成される。
別段の定めのない限り、本明細書で使用される技術用語と科学用語はすべて、主題が属する当該技術分野の当業者によって一般に理解されるものと同じ意味を有する。前述の一般的な記載および以下の詳細な記載は例示的かつ説明的なものに過ぎず、任意の主題に限定されるものではないことが理解されよう。本出願では、単数の使用は、特別に別記しない限り複数を含む。明細書および添付の請求項内で用いられる場合、単数形「a」、「an」、および「the」は、その文脈が明確に他のことを定めていない限り、複数の指示対象を含む。本出願において、「または」の使用は特に明記しない限り、「および/または」を意味する。さらに、用語「含む(including)」の使用は、「含む(include)」、「含む(includes)」、および「含まれる(included)」といった他の形態と同じく、限定的なものではない。
ガイド/アンチセンス鎖の配列は、MSTN(UUAUUAUUUGUUCUUUGCCUU;SEQ ID NO:14226)のマウスmRNAの転写産物に対して塩基位置1169で始まる遺伝子配列に相補的であった。塩基、糖、およびリン酸塩の修飾を使用して、二重鎖の能力を最適化して免疫原性を減らした。すべてのsiRNA一本鎖を、標準的なホスホロアミダイト(phospharamidite)化学を使用して固相上で完全に組み立てて、HPLC上で精製した。精製された一本鎖を二重にし、二本鎖siRNAを得た。パッセンジャー鎖は、図1で以下に記載されるように結合した5’コレステロールを含んでいた。
1.カラム:Tosoh Bioscience、TSKGel SuperQ-5PW、21.5mm ID X 15cm、13um
2.溶媒A:20mMのTRIS緩衝液、pH8.0;溶媒B:20mMのTRIS、1.5MのNaCl、pH8.0;流速:6.0mL/分
3.勾配:
a.%A %B カラム体積
b.100 0 1.00
c.60 40 18.00
d.40 60 2.00
e.40 60 5.00
f.0 100 2.00
g.100 0 2.00
1.カラム:Thermo Scientific、ProPacTM SAX-10、Bio LCTM、4×250mm
2.溶媒A:80%、10mMのTRIS、pH8、20%のエタノール;溶媒B:80%、10mMのTRIS、ph8、20%のエタノール、1.5MのNaCl;流速:0.75mL/分
3.勾配:
a.時間 %A %B
b.0.0 90 10
c.3.00 90 10
d.11.00 40 60
e.13.00 40 60
f.15.00 90 10
g.20.00 90 10
1.カラム:Thermo Scientific、ProPacTM SAX-10、Bio LCTM、4×250mm
2.溶媒A:80%、10mMのTRIS、pH8、20%のエタノール;溶媒B:80%、10mMのTRIS、pH8、20%のエタノール、1.5MのNaCl;
3.流速:0.75mL/分
4.勾配:
a.時間 %A %B
b.0.0 90 10
c.3.00 90 10
d.11.00 40 60
e.23.00 40 60
f.25.00 90 10
g.30.00 90 10
1.カラム:TOSOH Biosciences、TSKgelG3000SW XL、7.8×300mm、5μM
2.移動相:150mMのリン酸塩緩衝液
3.流速:15分間で1.0ml/分
HPRT:19の塩基の相補性および3’ジヌクレオチドオーバーハングを持つ21量体の二重鎖を、マウスMSTNに対して設計した。ガイド/アンチセンス鎖の配列(5’~3’)は、UUAAAAUCUACAGUCAUAGUU(SEQ ID NO:14227)であった。RNAiの分野で十分に説明される塩基、糖、およびリン酸塩の修飾を使用して、二重鎖の能力を最適化して免疫原性を減らした。すべてのsiRNA一本鎖を、標準的なホスホロアミダイト(phospharamidite)化学を使用して固相上で完全に組み立てて、HPLC上で精製した。精製された一本鎖を二重にし、二本鎖siRNAを得た。パッセンジャー鎖は、1つの抱合ハンドル、すなわち、5’のC6-NH2を含んでおり、これは、ホスホロチオエート逆脱塩基ホスホロチオエートリンカーを介してsiRNAパッセンジャー鎖に接続されていた。
a.%A%B カラム体積
b.1000 1
c.81 19 0.5
d.50 50 13
e.40 60 0.5
f.0 100 0.5
g.1000 2
a.時間 %A %B
b.0.0 90 10
c.3.00 90 10
d.11.00 40 60
e.14.00 40 60
f.15.00 20 80
g.16.00 90 10
h.20.00 90 10
a.%A %B カラム体積
b.100 0 1
c.81 19 0.5
d.50 50 13
e.40 60 0.5
f.0 100 0.5
g.100 0 2
a.時間 %A %B
b.0.0 90 10
c.3.00 90 10
d.11.00 40 60
e.14.00 40 60
f.15.00 20 80
g.16.00 90 10
h.20.00 90 10
a.%A %B カラム体積
b.100 0 1
c.81 19 0.5
d.50 50 13
e.40 60 0.5
f.0 100 0.5
g.100 0 2
a.時間 %A %B
b.0.0 90 10
c.3.00 90 10
d.11.00 40 60
e.14.00 40 60
f.15.00 20 80
g.16.00 90 10
h.20.00 90 10
a.%A %B カラム体積
b.100 0 1
c.81 19 0.5
d.50 50 13
e.40 60 0.5
f.0 100 0.5
g.100 0 2
a.時間 %A %B
b.0.0 90 10
c.3.00 90 10
d.11.00 40 60
e.14.00 40 60
f.15.00 20 80
g.16.00 90 10
h.20.00 90 10
a.%A %B カラム体積
b.100 0 1
c.81 19 0.5
d.50 50 13
e.40 60 0.5
f.0 100 0.5
g.100 0 2
a.時間 %A %B
b.0.0 90 10
c.3.00 90 10
d.11.00 40 60
e.14.00 40 60
f.15.00 20 80
g.16.00 90 10
h.20.00 90 10
a.%A %B カラム体積
b.100 0 1
c.81 19 0.5
d.50 50 13
e.40 60 0.5
f.0 100 0.5
g.100 0 2
a.時間 %A %B
b.0.0 90 10
c.3.00 90 10
d.11.00 40 60
e.14.00 40 60
f.15.00 20 80
g.16.00 90 10
h.20.00 90 10
Claims (39)
- アトロジーンの標的配列にハイブリダイズするポリ核酸分子に結合した、抗体またはその結合フラグメントを含むポリ核酸分子抱合体であって、
ポリ核酸分子は、少なくとも1つの2’修飾ヌクレオチド、少なくとも1つの修飾されたヌクレオチド間結合、あるいは少なくとも1つの逆脱塩基部分を含み;
ポリ核酸分子抱合体は、アトロジーンに対するRNA干渉を媒介し、それによって、被験体の筋萎縮症あるいは筋緊張性ジストロフィーを処置する、ポリ核酸分子抱合体。 - アトロジーンは、IGF1-Akt-FoxO経路、グルココルチコイド-GR経路、PGC1α-FoxO経路、TNFα-NFκB経路、あるいはミオスタチン-ActRIIb-Smad2/3経路内の示差的に調節された遺伝子を含む、請求項1に記載のポリ核酸分子抱合体。
- アトロジーンは、IGF1-Akt-FoxO経路、グルココルチコイド-GR経路、PGC1α-FoxO経路、TNFα-NFκB経路、あるいはミオスタチン-ActRIIb-Smad2/3経路内のダウンレギュレートされた遺伝子である、請求項2に記載のポリ核酸分子抱合体。
- アトロジーンは、IGF1-Akt-FoxO経路、グルココルチコイド-GR経路、PGC1α-FoxO経路、TNFα-NFκB経路、あるいはミオスタチン-ActRIIb-Smad2/3経路内のアップレギュレートされた遺伝子である、請求項2に記載のポリ核酸分子抱合体。
- アトロジーンはE3リガーゼをコードする、請求項1に記載のポリ核酸分子抱合体。
- アトロジーンは、フォークヘッドボックス転写因子をコードする、請求項1に記載のポリ核酸分子抱合体。
- アトロジーンはアトロジン-1遺伝子(FBXO32)、MuRF1遺伝子(TRIM63)、FOXO1、FOXO3、あるいはMSTNを含む、請求項1に記載のポリ核酸分子抱合体。
- アトロジーンはDMPKを含む、請求項1に記載のポリ核酸分子抱合体。
- 抗体またはその結合フラグメントは、ヒト化抗体またはその結合フラグメント、キメラ抗体またはその結合フラグメント、モノクローナル抗体またはその結合フラグメント、一価Fab’、二価Fab2、一本鎖可変フラグメント(scFv)、ダイアボディ、ミニボディ、ナノボディ、単一ドメイン抗体(sdAb)、またはラクダ抗体、あるいはその結合フラグメントを含む、請求項1に記載のポリ核酸分子抱合体。
- 抗体またはその結合フラグメントは、抗トランスフェリン受容体抗体またはその結合フラグメントである、請求項1に記載のポリ核酸分子抱合体。
- ポリ核酸分子はセンス鎖とアンチセンス鎖を含み、センス鎖とアンチセンス鎖はそれぞれ独立して、少なくとも1つの2’修飾ヌクレオチド、少なくとも1つの修飾されたヌクレオチド間結合、あるいは少なくとも1つの逆脱塩基部分を含む、請求項1に記載のポリ核酸分子抱合体。
- ポリヌクレオチドは、アトロジーンの標的配列の少なくとも8つの隣接する塩基にハイブリダイズする、請求項1に記載のポリ核酸分子抱合体。
- 標的配列は、SEQ ID NO:28-141、370-480、あるいは703-3406で記載される配列に対して少なくとも80%、85%、90%、95%、96%、97%、98%、99%、あるいは100%の配列同一性を含む、請求項1に記載のポリ核酸分子抱合体。
- ポリヌクレオチドは、約8~約50ヌクレオチド長さ、あるいは約10~約30ヌクレオチド長さである、請求項1に記載のポリ核酸分子抱合体。
- センス鎖はSEQ ID NO:142-255、481-591、3407-6110、あるいは8815-11518で記載される配列に対して少なくとも80%、85%、90%、95%、96%、97%、98%、99%、あるいは100%の配列同一性を有する配列を含む、請求項1に記載のポリ核酸分子抱合体。
- アンチセンス鎖はSEQ ID NO:256-369、592-702、6111-8814、あるいは11519-14222で記載される配列に対して少なくとも80%、85%、90%、95%、96%、97%、98%、99%、あるいは100%の配列同一性を有する配列を含む、請求項1に記載のポリ核酸分子抱合体。
- ポリ核酸分子抱合体は、ポリヌクレオチドに結合部分を接続するリンカーを含む、請求項1に記載のポリ核酸分子抱合体。
- ポリ核酸分子抱合体は、追加のリンカーによってポリヌクレオチドに随意に間接的に結合したポリマーを含む、請求項1に記載のポリ核酸分子抱合体。
- リンカーと追加のリンカーはそれぞれ独立して非ポリマーリンカーである、請求項17あるいは18に記載のポリ核酸分子抱合体。
- ポリ核酸分子抱合体は、式(I):
A-X1-B-X2-C
式I
の分子を含み、
式中、
Aは抗体あるいはその結合フラグメントであり;
Bはアトロジーンの標的配列にハイブリダイズするポリ核酸分子であり;
Cはポリマーであり;および、
X1とX2はそれぞれ、単結合あるいは非ポリマーリンカーから独立して選択され;および、
AとCは同じ末端でBに結合しない、
請求項1に記載のポリ核酸分子抱合体。 - Cはポリエチレングリコール(PEG)である、請求項20に記載のポリ核酸分子抱合体。
- A-X1はBの5’末端へ結合し、X2-CはBの3’末端へ結合する、請求項20に記載のポリ核酸分子抱合体。
- X2-CはBの5’末端へ結合し、A-X1はBの3’末端へ結合する、請求項20に記載のポリ核酸分子抱合体。
- Bはセンス鎖とアンチセンス鎖を含む、請求項20に記載のポリ核酸分子抱合体。
- AおよびCはそれぞれセンス鎖の異なる末端に結合される、請求項24に記載のポリ核酸分子抱合体。
- 少なくとも1つの2’修飾ヌクレオチドは、2’-O-メチル、2’-O-メトキシエチル(2’-O-MOE)、2’-O-アミノプロピル、2’-デオキシ、T-デオキシ-2’-フルオロ、2’-O-アミノプロピル(2’-O-AP)、2’-O-ジメチルアミノエチル(2’-O-DMAOE)、2’-O-ジメチルアミノプロピル(2’-O-DMAP)、T-O-ジメチルアミノエチルオキシエチル(2’-O-DMAEOE)、または、2’-O-N-メチルアセトアミド(2’-O-NMA)修飾ヌクレオチドを含む、請求項1に記載のポリ核酸分子抱合体。
- 少なくとも1つの2’修飾ヌクレオチドは、ロックド核酸(LNA)あるいはエチレン核酸(ENA)を含む、請求項1に記載のポリ核酸分子抱合体。
- 少なくとも1つの修飾されたヌクレオチド間結合は、ホスホロチオエート結合あるいはホスホロジチオエート結合を含む、請求項1に記載のポリ核酸分子抱合体。
- 少なくとも1つの逆脱塩基部分は少なくとも1つの末端にある、請求項1に記載のポリ核酸分子抱合体。
- 筋萎縮症は、糖尿病に関連する筋萎縮症あるいは癌性悪液質に関連する筋萎縮症である、請求項1に記載のポリ核酸分子抱合体。
- 筋萎縮症は、インスリン欠乏症に関連し、慢性腎不全に関連し、うっ血性心不全に関連し、慢性呼吸病に関連し、慢性感染症に関連し、絶食に関連し、除神経に関連し、サルコペニアに関連し、あるいは、グルココルチコイド処置に関連する、請求項1に記載のポリ核酸分子抱合体。
- 筋萎縮症は筋緊張性ジストロフィー1型(DM1)に関連する、請求項1に記載のポリ核酸分子抱合体。
- 筋緊張性ジストロフィーはDM1である、請求項1に記載のポリ核酸分子抱合体。
- 請求項1-33のポリ核酸分子抱合体と、薬学的に許容可能な賦形剤を含む、医薬組成物。
- 医薬組成物はナノ粒子製剤として製剤化される、請求項34に記載の医薬組成物。
- 医薬組成物は、非経口投与、経口投与、鼻腔内投与、バッカル投与、直腸投与、または経皮投与のために製剤化される、請求項34に記載の医薬組成物。
- 被験体の筋萎縮症あるいは筋緊張性ジストロフィーを処置するための方法であって、
被験体の筋萎縮症または筋緊張性ジストロフィーを処置するために、請求項1-33の治療上有効な量のポリ核酸分子抱合体、あるいは請求項34-36の医薬組成物を、被験体に投与する工程を含む、方法。 - 被験体はヒトである、請求項37に記載の方法。
- 請求項1-33のポリ核酸分子抱合体あるいは請求項34-36の医薬組成物を含むキット。
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