JP2020019791A - ミトコンドリアdna枯渇症候群を含む不均衡なヌクレオチドプールによって引き起こされる疾患のためのデオキシヌクレオシド療法 - Google Patents
ミトコンドリアdna枯渇症候群を含む不均衡なヌクレオチドプールによって引き起こされる疾患のためのデオキシヌクレオシド療法 Download PDFInfo
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Abstract
Description
本発明はNIHによって認定されたHD080642に基づく政府支援によって実施された。政府は本発明に特定の権利を有する。
本出願は2015年6月17日出願、米国特許仮出願第62/180,194号の優先権を主張し、参考として本明細書に組み込まれる。
本発明は全般的にはヒト遺伝子疾患、具体的にはミトコンドリアDNA枯渇症候群などの不均衡なヌクレオチドプールによって特徴付けられる疾患、より具体的にはチミジンキナーゼ2(TK2)欠損症のための薬理学的治療法に関する。薬理学的治療法は、少なくとも1種類のデオキシヌクレオシド、またはこの混合物の投与を含む。TK2欠損症の治療では、薬理学的治療法はデオキシチミジン(dT)またはデオキシシチジン(dC)のいずれか、あるいはこれらの混合物の投与を含む。1種類以上のデオキシヌクレオシドのこの投与は、不均衡なヌクレオシドプールの他の障害、特にミトコンドリアDNA枯渇症候群で認められる障害に適用可能である。
本発明は、TK2欠損症を含むミトコンドリアDNA枯渇症候群がデオキシヌクレオシドによって治療され得るという驚くべき発見に基づいている。本明細書における結果によって示されるように、デオキシヌクレオシドの投与は、TK2欠損症のマウスモデルおよびTK2欠損症を有するヒト患者の両方における症状を大きく改善した。
本明細書で使用される用語は、本発明の文脈内および各用語が使用される特定の文脈内で、従来技術におけるこれらの通常の意味を一般的に有する。特定の用語が下記、または本明細書の他の箇所で記載され、本発明の方法およびこれらの使用方法を説明する上で専門家に付加的な手引きを提供する。さらに、同じことを1つの方法を超えて示すことができると認識される。従って、代替言語および同義語が本明細書で議論される用語のいずれか1つ以上のために使用され得、用語が本明細書で詳細または議論されるかどうか提起されることは特別に重要ではない。特定の用語の同義語が示される。1つ以上の同義語の詳述は、他の同義語の使用を除外しない。本明細書のいずれの箇所における例の使用は、本明細書で議論されるいずれかの用語の例を含め、説明だけのものであり、本発明の範囲および意味、あるいはいずれかの例示された用語を決して制限しない。同様に、本発明はその好ましい実施形態に限定されない。
ミトコンドリアDNA(mtDNA)枯渇症候群(MDS)は、影響を受けた組織におけるmtDNAコピー数の低下によって特徴付けられるいくつかの重篤な常染色体疾患を含む。MDS原因核遺伝子のほとんどは、mtDNA複製機構に属する、またはデオキシリボヌクレオシド三リン酸(dNTP)代謝に含まれるタンパク質をコードする。
本発明はデオキシヌクレオシドの投与、より具体的には1種類以上のデオキシヌクレオシドの投与を包含する。
本発明は次の非限定例を参考にすることによってさらに良く理解され得、それらは本発明の好ましい実施形態をより完全に説明するために提示される。これらは本発明の広範な範囲を限定するものとは決して解釈されるべきでない。
TK2欠損症のマウスモデル
ヒト幼児脳筋症と著しく類似した表現型を示すホモ接合Tk2 H126Nノックイン変異体(TK2−/−)マウスが既に報告されている(Akmanら,2008)。生後10〜13日に、Tk2−/−マウスは歩行機能低下、不安定な歩行、粗大振戦、発育遅滞、および14〜16日齢での早期死に至る急速な進行を特徴とする幼児脳筋症を急速に発症する。マウスモデルの分子的および生化学的分析は、疾患の病因が酵素活性の喪失に起因し、結果として脳におけるdTTPおよび肝臓におけるdTTPとdCTPの両方の量の低下を伴うdNTPプールの不均衡を起こし、これが次に、最も顕著には脳および脊髄において、mtDNAの枯渇およびmtDNAにコードされるサブユニットを含む呼吸鎖酵素の欠如を引き起こすことを示した。
デオキシシチジン(dC)およびデオキシチミジン(dT)を、生後4〜29日に、260mg/kg/日および520mg/kg/日の2用量を用いてTK2 H126Nノックインマウス(Tk2−/−)および同齢の対照野生型(Tk2+)に、毎日経口経管によって50μLの小型ペット用エスビラックミルクフォーミュラ(Pet−Ag)で投与した。21日齢でマウスを母親から離し、1.6mMおよび3.2mMのそれぞれ等モル用量を用いる飲用水中のdCおよびdTの投与によって処置を継続した。陰性対照群の未処置TK2変異体および対照野生型マウスを体重測定し、比較のために注意して観察した。
体重増加の能力のないことが疾患の最初の徴候であることが既に認められているため(Akmanら,2008)、体重を毎日評価した。
組織を、10倍容量(w/v)の冷却したMTSE緩衝液(210mMマンニトール、70mMスクロース、10mMトリス−HCl,pH7.5、0.2mM EGTA、0.5%BSA)中にて氷上でホモジナイズし、4℃で5分間1000gにて遠心分離し、続いて4℃で2分間13,000gにて3回遠心分離した。上清を、60%メタノールで沈殿させ、−80℃で2時間維持し、3分間沸騰させ、−80℃で保存し(1時間〜一昼夜)、4℃で10分間20,800gにて遠心分離した。上清を乾燥するまで蒸発させ、ペレットを65μLの水中に再懸濁化し、分析するまで−80℃で保存した。リボヌクレオチド干渉を最小限にするため、全dNTPプールを、報告されているように(Ferraroら,2010、Martiら,2012a)測定した。簡単に説明すると、20μL容量の反応液を、5μLのサンプルまたは標準dNTPを15μLの反応緩衝液[0.025U/mLのThermoSequenase DNAポリメラーゼ(GEヘルスケア、ピスカタウェイ、ニュージャージー州、米国)またはTaqポリメラーゼ(ライフテクノロジーズ、ニューヨーク州、米国)、0.75μMの3H−dTTPまたは3H−dATP(Moravek Biocemicals)、0.25μM特異的オリゴヌクレオチド、40mMトリス−HCl,pH7.5、10mMのMgCl2、5mMのDTT]と混合することにより調製した。48℃で60分間後に、18mLの反応液を、ワットマンDE81ろ紙上にスポットし、空気乾燥させ、5%Na2HPO4で10分間3回、蒸留水で1回、無水エタノールで1回洗浄した。残存する放射能を、シンチレーション計測によって測定した。
デオキシチミジン(dT)、デオキシウリジン(dU)、ウラシル(U)およびチミン(T)の量を、既に報告されている勾配溶出HPLC法(Lopezら,2009、Martiら,2012b)を少し変更して用いて評価した。簡単に説明すると、除タンパク質サンプルを、4種類の緩衝液:溶離液A(20mMリン酸カリウム、pH5.6)、溶離液B(水)および溶離液C(メタノール)を用いて1.5mL/分(指示されている場合以外)の一定流速で、Alltima C18NUC逆相カラム(Alltech)を備えるAlliance HPLCシステム(ウォーターズ社)に注入した。サンプルを、以下の勾配によって60分かけて溶出した:0〜5分、100%溶離液A;5〜25分、100〜71%溶離液A、29%溶離液B;25〜26分、0〜100%溶離液C;26〜30分、100%溶離液C;30〜31分、0〜100%溶離液B;31〜35分、100%溶離液B(1.5〜2mL/分);35〜45分、100%溶離液B(2mL/分);45〜46分、100%溶離液B(2〜1.5mL/分);46〜47分、0〜100%溶離液C;47〜50分、100%溶離液C;50〜51分、0〜100%溶離液A;51〜60分、100%溶離液A。
リアルタイムPCRを、Step One Plus Real Time PCRシステム(アプライドバイオシステムズ)でddCt法を用いて、報告されているように(Doradoら,2011)、ネズミCOXI遺伝子(mtDNA)およびマウスグリセルアルデヒド−3−リン酸デヒドロゲナーゼ(GAPDH、nDNA)(アプライドバイオシステムズ、インビトロジェン、フォスターシティー、カリフォルニア州、米国)用のプライマーおよびプローブを用いて実施した。mtDNA値を、nDNA値に対し基準化し、野生型(100%)に対するパーセントとして表した。
30μgの全大脳または大脳抽出物を、SDS−12%PAGEゲルで電気泳動し、Immun−BlotTMPVDFメンブラン(バイオラッド、ハーキュリーズ、カリフォルニア州、米国)に移し、MitoProfile(登録商標)TotalOXPHOSげっ歯類WB抗体カクテル(MitoScience、ユージーン、オレゴン州、米国)の抗体で探査した。タンパク質−抗体相互作用を、AmershamTMECL Plusウェスタンブロッティング検出システム(GEヘルスケアライフサイエンス、英国)を用いて、ペルオキダーゼ共役体化抗マウスIgGマウス抗体(シグマ−アルドリッチ、セントルイス、ミズーリ州、米国)によって検出した。タンパク質の定量を、NIH ImageJ 1.37Vソフトウェアを用いて実施した。平均グレー値を、ピクセルの数によって除された選択したすべてのピクセルのグレー値の合計として選択した領域内で計算した。
ミトコンドリアRC酵素分析を、既に報告されているように(DiMauroら,1987)大脳組織で実施した。
データを、群あたり少なくとも3回の実験の平均±SDとして表す。ゲーハン−ブレスロウ−ウィルコクソン検定を使用して、マウスの各群の生存率を比較した。<0.05のp値を、統計学的に有意であるとみなした。
デオキシヌクレオシド(dC/dT)の260および520mg/kg/日それぞれの用量を、Tk2−/−マウスに投与した。デオキシヌクレオシドのこれらの用量は、dCMP+dTMPのそれぞれ400および800mg/kg/日と等モルだった。
ミトコンドリア抽出物中のdNTPの測定は、Tk2−/− 260mg/kg/日 dC/dTおよびTk2−/− 520mg/kg/日 dC/dTはいずれも生後13日でミトコンドリアdNTPプール不均衡を完全には修正できず、組織において異なる効果を表し、脳中でdCTPの完全な回復を示し、一方肝臓中でdTTPが修正されたことを示した。これに対し、脳中のdTTPおよび肝臓中のdCTPの欠如は、デオキシヌクレオシドの補充にも関わらず、重篤なままだった(図3)。
呼吸鎖酵素(RCE)活性およびタンパク質量は、生後13日でTk2−/− 260mg/kg/日 dC/dTの脳で完全に回復した(図6)。RCE活性も生後29日で回復し、複合体I活性のほんのわずかな低下が、Tk2−/− 520mg/kg/日 dC/dTで認められた(図6)。脳中のRCEタンパク質量は、生後29日で部分的に回復し、Tk2−/− 260mg/kg/日 dC/dTよりもTk2−/− 520mg/kg/日 dC/dTでより高い量であった(図7)。タンパク質量のこれらの差は、生後29日での処置した変異体マウスの脳中のmtDNA枯渇の差と一致し、より高い用量で認められた生存の延長をおそらく説明する。
本発明らの監督および管理下でデオキシヌクレオシド療法を受けていたTK2欠損症を有する患者の症状、投与量、および転帰を下に要約する。
本患者は2011年2月に米国で生まれた。彼の症状は、12ヶ月で低緊張性および首下がりを示した。彼は一度も歩行したことがなかった。患者はまた呼吸筋衰弱を有し、19ヶ月で人工呼吸器を装着され、それは依然として24時間/日装着されている。患者はまた19ヶ月以降、栄養チューブを使用している。
本患者は1987年にスペインで生まれた。彼は3歳で近位筋衰弱を含む症状を示し始めた。患者は13歳で歩行能力を失い、24時間呼吸器を使用した。患者は過去に200mg/kg/日のdAMPおよびdCMPを受けており、体重増加および呼吸器使用の1日24から22時間への低下を示した。
本患者は1985年にスペインで生まれた。彼の症状は、顔面筋、近位筋、および体軸筋の衰弱を伴い6歳で始まった。患者は2015年6月に200mg/kg/日のdTおよびdCを開始して、現在まで症状は改善し、6分間歩行試験、ゲットアップアンドゴーの時間、および4段の上り下りにおいて改善した。
本患者は2009年2月にスペインで生まれた。彼の症状は、成長しないことによって6ヶ月で示された。患者は2015年6月に230mg/kg/日のdCおよびdTを開始した。2016年1月までに、患者は症状に改善を示し、より良く食べていた。
本患者は1957年にスペインで生まれ、50歳で起座呼吸、および横隔膜衰弱の症状を有し始めた。夜にBiPAPを使用している。患者は2015年11月に200mg/kg/日のdCおよびdTを開始した。
本患者は2011年10月にスペインで生まれ、15ヶ月で、筋緊張低下および衰弱を含む症状を示し始めた。彼は22ヶ月で歩行不能となり、呼吸筋衰弱を有する。患者は16ヶ月で人工呼吸器を開始し、現在は1日に12時間BiPAPを使用する。患者は過去に100mg/kg/日のdCMPおよびdAMPを受け、それは400mg/kg/日に増加された。患者の力は、Egen Klassificationスケールによって示されるように改善し(28/30から13/30)、体重は9.8kgから12.3kgに増加した。
本患者は2012年11月にスペインで生まれた。彼は17ヶ月で、衰弱および筋緊張低下を含む症状を示し始めた。患者は22ヶ月で歩行不能となり、29ヶ月で人工呼吸器を開始した。患者は過去に100mg/kg/日のdCMPおよびdAMPを受け、それは400mg/kg/日に増加された。患者の力は、Egen Klassificationスケールによって示されるように改善し(30/30から24/30)、体重は11kgから15.7kgに増加した。
本患者は1989年9月にチリで生まれ、11ヶ月で頻繁な落下および進行性歩行困難を伴う症状を示し始めた。彼女は約4歳で一人歩きする能力を失った。患者は過去にヌクレオチド療法を受けており、補助のない歩行、より長い起立、階段の昇段、ジムクラスへの参加、および下の世話をすることを含む移動性に改善を示した。
本患者は1989年9月にグアテマラで生まれた。彼は2015年8月に130mg/kg/日のdCおよびdTを開始し、2016年2月に260mg/kg/日に増加した。患者は改善したエネルギーを示した。
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Claims (23)
- それを必要とするヒト被験体におけるチミジンキナーゼ2(TK2)欠損症を治療する方法において使用するための、デオキシシチジン(dC)であって、前記方法は、デオキシチミジン(dT)および前記デオキシシチジン(dC)の治療上効果的な量を投与することを含む、デオキシシチジン(dC)。
- それを必要とするヒト被験体におけるチミジンキナーゼ2(TK2)欠損症を治療する方法において使用するための、デオキシチミジン(dT)であって、前記方法は、デオキシシチジン(dC)および前記デオキシチミジン(dT)の治療上効果的な量を投与することを含む、デオキシチミジン(dT)。
- 前記治療上効果的な量が、
a)前記組成物中の各デオキシヌクレオシドの100mg/kg/日と1000mg/kg/日の間であるか、
b)前記組成物中の各デオキシヌクレオシドの200mg/kg/日と800mg/kg/日の間であるか、または
c)前記組成物中の各デオキシヌクレオシドの250mg/kg/日と400mg/kg/日の間である、請求項1に記載のdCまたは請求項2に記載のdT。 - 前記治療上効果的な量が、前記組成物中の各デオキシヌクレオシドの100mg/kg/日と400mg/kg/日の間である、請求項1に記載のdCまたは請求項2に記載のdT。
- 前記治療上効果的な量が、前記組成物中の各デオキシヌクレオシドの250mg/kg/日と400mg/kg/日の間である、請求項1に記載のdCまたは請求項2に記載のdT。
- 前記治療上効果的な量が、
a)前記組成物中の全デオキシヌクレオシドの100mg/kg/日と1000mg/kg/日の間であるか、
b)前記組成物中の全デオキシヌクレオシドの200mg/kg/日と800mg/kg/日の間であるか、または
c)前記組成物中の全デオキシヌクレオシドの250mg/kg/日と400mg/kg/日の間である、請求項1に記載のdCまたは請求項2に記載のdT。 - デオキシシチジン(dC)とデオキシチミジン(dT)の比は、50/50、5/95、10/90、15/85、20/80、25/75、30/70、35/65、40/60、45/55、55/45、60/40、65/35、70/30、75/25、80/20、85/15、90/10、または95/5である、請求項1〜6のいずれか1項に記載のdCまたはdT。
- 前記デオキシシチジン(dC)とデオキシチミジン(dT)の比は、50/50である、請求項7に記載のdCまたはdT。
- 前記組成物が、1日に1回、1日に2回、1日に3回、1日に4回、1日に5回または1日に6回投与される、請求項1〜8のいずれか1項に記載のdCまたはdT。
- 前記組成物が、経口、髄腔内、経腸、または静脈内で投与される、請求項1〜9のいずれか1項に記載のdCまたはdT。
- 前記組成物が、経口投与され、かつ前記組成物が、牛乳、ヒト母乳、乳児用人工乳または水をさらに含む、請求項10に記載のdCまたはdT。
- 前記方法は、前記被験体にチミジンホスホリラーゼの阻害剤を投与することをさらに含む、請求項1〜11のいずれか1項に記載のdCまたはdT。
- 前記チミジンホスホリラーゼの阻害剤が、チピラシルである、請求項12に記載のdCまたはdT。
- 前記方法は、前記被験体にシチジンデアミナーゼの阻害剤を投与することをさらに含む、請求項1〜13のいずれか1項に記載のdCまたはdT。
- 前記シチジンデアミナーゼ阻害剤が、テトラヒドロウリジン(THU)である、請求項14に記載のdCまたはdT。
- 前記被験体に投与される前記組成物の前記治療上効果的な量が、経時的に増加され、任意で前記被験体に投与される前記組成物の最初の治療上効果的な量が、組成物の約100mg/kg/日であり、かつ前記組成物の前記治療上効果的な量が、経時的に200mg/kg/日に、400mg/kg/日に、800mg/kg/日に、1000mg/kg/日にまで増加される、請求項1に記載のdCまたは請求項2に記載のdT。
- 前記組成物が、医薬品として許容可能な担体を含む、請求項1〜16のいずれか1項に記載のdCまたはdT。
- 前記治療する方法は、前記組成物の前記投与後に前記被験体をモニタリングすることをさらに含み、
a.筋の強度および制御を観察すること、
b.身長と体重における差を観察すること、
c.移動性を観察すること、および
d.前記組成物の投与後に観察(a)〜(c)のいずれかが増加する場合に前記被験体の症状における改善を決定すること、および前記組成物の投与後に観察(a)〜(c)のいずれかが同じであるか低下する場合に改善がないと決定すること
を含む、請求項1に記載のdCまたは請求項2に記載のdT。 - ステップ(d)において改善がないという前記決定がされる場合、前記組成物の前記治療上効果的な量が増加される、請求項18に記載のdCまたはdT。
- 前記治療する方法は、前記組成物の投与後に前記被験体を有害効果についてモニタリングすることをさらに含み、ここで有害効果が認められる場合、前記組成物の前記治療上効果的な量が低減される、請求項1に記載のdCまたは請求項2に記載のdT。
- 前記組成物の前記治療上効果的な量が低減された後に前記被験体を前記認められた有害効果についてモニタリングすることをさらに含み、ここで前記有害効果がもはや認められない場合、前記組成物の前記治療上効果的な量が増加される、請求項20に記載のdCまたはdT。
- 有害効果が、胃腸不耐性である、請求項20に記載のdCまたはdT。
- 前記有害効果が、下痢および腹部膨満からなる群から選択される、請求項20に記載のdCまたはdT。
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