JP7522095B2 - 原発性ミトコンドリア病のためのミトコンドリア増強療法 - Google Patents
原発性ミトコンドリア病のためのミトコンドリア増強療法 Download PDFInfo
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Description
HeLa-TurboGFP-Mitochondria細胞(CellTrend GmbH)から単離されたミトコンドリアを使用して、健康なドナーからのCD34+細胞をMitotrackerOrange(MTO)で処理し、MATの前に洗浄した。細胞を2%PFAで10分間固定し、DAPIで固定した。60X/1.42油浸対物レンズを備えた共焦点顕微鏡を使用して細胞をスキャンした。
ミトコンドリアの含有量および活性を増加させるために、異なるマウス細胞を、10%FCSを含有するDMEM中で、37℃、5%CO2雰囲気で、24時間、単離されたミトコンドリアとともにインキュベートした。表1は、プロセス前の細胞のCS活性と比較した、プロセス後の細胞のCS活性の相対的な増加によって決定される、ミトコンドリア増強プロセスの代表的な結果を示す。
健康なドナーCD34+細胞のミトコンドリア増強は、2つの異なる胎盤由来ミトコンドリアバッチで実行され、細胞は24時間のインキュベーション後に十分に洗浄された。IlluminaベースのmtDNA配列決定は、同じ細胞内に移動したミトコンドリアと内因性ミトコンドリアとの両方が存在することを示す。
ヒトCD34+細胞(1.4*105、ATCC PCS-800-012)は未処理であるか、ヒト胎盤細胞から単離されたGFP標識ミトコンドリアとともに20時間インキュベートされた。細胞を蒔く前に、ミトコンドリアを細胞と混合し、8000gで遠心分離し、再懸濁した。インキュベーション後、細胞をPBSで2回洗浄し、CS0720 Sigmaキットを使用してCS活性を測定した(図6A)。ATP含有量は、WO2016/135723で以前に説明されているように、ATPlite(Perkin Elmer)(図6B)を使用して測定された。
ピアソン患者の臍帯血細胞を0.88mUのヒトミトコンドリアとともに24時間インキュベートした後、培地を除去し、細胞を洗浄し、4.5%HSAに再懸濁した。富化された細胞をNSGSマウスにIV注射した(マウスあたり100,000個のCD34+細胞)。
ミトコンドリアは、2つの異なるバックグラウンドからの対照の健康なマウスの骨髄細胞に導入される。ミトコンドリアの供給源は、異なるmtDNA配列を有するマウスからのものである(Jenuth JP et al.,Nature Genetics,1996,Vol.14,pages 146-151)。
患者1は、PSと診断された6.5歳の男児患者であり、mtDNAのヌクレオチド5835~9753が欠失している。ミトコンドリア増強療法(MAT)前の、彼の体重は14.5 KGであり、100メートル以上歩くことも階段を上ることもできなかった。彼の成長は治療前の3年間大幅に遅れ、ベースラインでの体重は-4.1標準偏差スコア(SDS)であり、身長は-3.2SDS(母集団と比較して)であり、1年以上胃瘻管(G-チューブ)によって栄養補給されていたにもかかわらず、改善しなかった。彼は、腎不全(GFR 22ml/分)および電解質補給を必要とする近位尿細管症を有した。彼は、カルシウム補給を必要とする副甲状腺機能低下症、および心電図検査での不完全な右脚ブロック(ICRBB)を有した。
患者2は、PSと診断された7歳の女児患者であり、mtDNAの4977ヌクレオチドが欠失している。患者はまた、貧血、内分泌膵機能不全を患っており、彼女はまた、4年間インスリン依存性糖尿病を有した。患者は、乳酸値が高く(>25mg/dL)、体重が少なく、食事および体重増加に問題があった。患者はさらに高マグネシウム尿症(高レベルの尿中マグネシウム、低レベルの血中マグネシウム)を患っている。患者は、記憶および学習の問題、乱視があり、TMRE、ATP含有量、およびO2消費率(健康な母親と比較して)によって決定される末梢リンパ球のミトコンドリア活性が低い。
患者3は、PSと診断された10.5歳の女児患者であり、mtDNAのヌクレオチド12113~14421が欠失している。患者は、貧血、および腎不全ステージ4に発展したファンコニー症候群も患っていた。患者は週に3回透析で治療された。過去2ヶ月で、患者は、重度の視力障害、視野の狭小化、および近見視力の喪失も患っていた。患者は身体活動をまったく行うことができなかった(歩くことはなく、ベビーカーに座っている)。患者の乳酸レベルは高く(>50mg/dL)、インスリンで治療された膵臓障害を有した。脳MRIは多くの病変および萎縮領域を示した。患者は、胃瘻造設術によってのみ栄養補給された。患者には記憶および学習の問題があった。患者は、テトラメチルローダミンエチルエステル(TMRE)、ATP含有量、およびO2消費率(健康な母親と比較して)試験によって決定される末梢リンパ球のミトコンドリア活性が低い。
患者4は、14歳、19.5kgの女児患者で、カーンズ・セイヤー症候群と診断され、トンネル状視野、眼瞼下垂、眼筋麻痺、および網膜萎縮を経験していた。患者は、視力の問題、CPEO、てんかん発作、病的EEG、座位または歩行障害を伴う重度のミオパチー、心不整脈を有した。患者は、ミトコンドリアDNAに7.4 Kbの欠失があり、これには次の遺伝子が含まれる:TK、NC8、ATP8、ATP6、CO3、TG、ND3、TR、ND4L、TH、TS2、TL2、ND5、ND6、TE、NC9、およびCYB。
予想外に、健康なミトコンドリアでわずか3%富化されたCD34+による1回の治療の4ヶ月後、患者はてんかん発作を伴わずにEEGの顕著な改善を示した。治療の5ヶ月後、患者は疾患に関連した房室(AV)ブロックを患い、ペーサーが取り付けられた。患者は回復し、改善が続いた。図13に示されるように、末梢血中のATP含有量は、治療の6ヶ月後に測定され、治療前と比較してATP含有量が約100%増加したことを示す。治療の7ヶ月後、患者は一人で座り、助けを借りて歩き、話すことができ、食欲が増し、3.6KG増えた。
患者は、ミトコンドリアまたは核DNAの1つ以上の突然変異(複数可)、経験している症状、またはその両方に基づいて、ミトコンドリア病と診断される。
患者は、年齢、体重、および臨床状態に合わせたタイムラインに従って、健康なドナーから得られ、単離された健康な機能的ミトコンドリアで富化された自家または同種異系のヒト幹細胞で治療される。投与されるヒト幹細胞は、ナイーブヒト幹細胞を健康な機能的ミトコンドリアとともにインキュベートすることによって調製される。
Claims (12)
- 原発性ミトコンドリア病または障害の症状の治療を必要とするヒト患者において、かかる治療に使用するための医薬組成物であって、前記組成物が、細胞の生存能力を支援することができる薬学的に許容可能な液体培地中、前記患者の体重1キログラムあたり少なくとも1.1×106~2.8×106個のヒト幹細胞を含み、
前記ヒト幹細胞は、ミトコンドリアDNAに病原性突然変異がないヒト外因性ミトコンドリアで富化され、ミトコンドリア富化前の前記ヒト幹細胞のミトコンドリアDNA含有量と比較して増加したミトコンドリアDNA含有量を有し、
前記ヒト外因性ミトコンドリアは、前記ミトコンドリア富化ヒト幹細胞中の全ミトコンドリアの少なくとも3%を構成し、
前記症状が、歩行能力障害、運動技能障害、言語技能障害、記憶障害、体重増加障害、発育不良、低血中アルカリホスファターゼレベル、低血中マグネシウムレベル、高血中クレアチニンレベル、低血中重炭酸塩レベル、低血中塩基過剰レベル、高尿中グルコース/クレアチニン比、高尿中塩化物/クレアチニン比、高尿中ナトリウム/クレアチニン比、高血中乳酸レベル、高尿マグネシウム/クレアチニン比、高尿中カリウム/クレアチニン比、高尿中カルシウム/クレアチニン比、糖尿、マグネシウム尿、高血中尿素レベル、低C-ペプチドレベル、高HbA1Cレベル、副甲状腺機能低下症、眼瞼下垂、聴力損失、心伝導障害、てんかん発作、脳卒中様発作、EEG障害、高血中アスパラギン酸アミノトランスフェラーゼ(AST)レベル、高血中アラニンアミノトランスフェラーゼ(ALT)レベル、低ATP含有量、およびリンパ球における低酸素消費量からなる群から選択され、
前記ミトコンドリア富化ヒト幹細胞が、ミトコンドリア富化前の前記ヒト幹細胞における対応するレベルと比較して、コハク酸デヒドロゲナーゼ複合体フラボタンパク質サブユニットA(SDHA)およびチトクロームCオキシダーゼ(COX1)から選択される少なくとも1つのミトコンドリアタンパク質の増加したレベルを有し、
前記ヒト幹細胞が、CD34 + である、
医薬組成物。 - 前記富化が、百万個の細胞あたり少なくとも0.044~最大17.6ミリユニットのCS活性のミトコンドリアの用量を前記幹細胞に導入することを含むか、または
前記富化が、百万個の細胞あたり0.044~最大17.6ミリユニットのCS活性のミトコンドリアの用量と前記幹細胞を接触させることを含む、
請求項1に記載の医薬組成物。 - 前記ヒト外因性ミトコンドリアが、同系または同種異系である、請求項1または請求項2に記載の医薬組成物。
- 前記原発性ミトコンドリア病もしくは障害が、ミトコンドリアDNAの突然変異に関連しているか、または
前記原発性ミトコンドリア病もしくは障害が、ピアソン症候群;カーンズ・セイヤー症候群;ミトコンドリア脳症乳酸アシドーシスおよび脳卒中様発作(MELAS)症候群;レーバー遺伝性視神経症(LHON);ニューロパチー、運動失調、および色素性網膜炎(NARP)症候群;赤色ぼろ線維を伴うミオクローヌスてんかん(MERRF)症候群;母性遺伝性糖尿病および難聴(MIDD);アルパース様症候群;慢性進行性外眼筋麻痺(CPEO);ミトコンドリアDNA関連型の先天性乳酸アシドーシス(CLA);ミトコンドリアDNA枯渇症候群(MDDS);ならびにミトコンドリアDNA関連型のリー症候群からなる群から選択される、ミトコンドリアDNAの突然変異に関連しているか、または
前記原発性ミトコンドリア病もしくは障害が、核DNAの突然変異に関連しているか、または
前記原発性ミトコンドリア病もしくは障害が、ミトコンドリア神経胃腸脳症(MNGIE)症候群;アルパース症候群;フリードライヒ運動失調症(FA);進行性外眼筋麻痺(PEO);鉄芽球性貧血;運動失調ニューロパチー症候群(ANS);メンデルの神経変性ミトコンドリア病(mitochondriopathy);3-メチルグルタコン酸尿症(MEG)難聴(D)、脳症(E)およびリー様病(L)症候群(MEGDEL);ゼンガー症候群(Sengers syndrome);微小変化群ネフローゼ症候群(MCNS);核DNA関連型の先天性乳酸アシドーシス(CLA);ミトコンドリアDNA枯渇症候群(MDDS)ならびに核DNA関連型のリー症候群からなる群から選択される、核DNAの突然変異に関連しているか、または
前記原発性ミトコンドリア病もしくは障害が、腎臓、肝臓、脳、筋肉、膵臓、眼、およびそれらの任意の組み合わせからなる群から選択される器官に関連している、請求項1~3のいずれか一項に記載の医薬組成物。 - 前記医薬組成物が特定の組織もしくは器官に投与されるか、または
前記医薬組成物が、全身投与によって投与される、
請求項1~4のいずれか一項に記載の医薬組成物。 - 前記ミトコンドリア富化ヒト幹細胞が、ミトコンドリア富化前の前記幹細胞における対応するレベルと比較して、
(i)増加したCS活性レベル、
(ii)増加したO2消費率、
(iii)増加したATP産生率、または
(iv)それらの任意の組み合わせ
のうちの少なくとも1つを有する、請求項1~5のいずれか一項に記載の医薬組成物。 - 前記ヒト幹細胞が、前記外因性ミトコンドリアで富化される前の前記患者から得られるかもしくは由来する、または
前記ヒト幹細胞が、前記外因性ミトコンドリアで富化される前の前記患者とは異なるドナーから得られるかもしくは由来する、または
前記ヒト幹細胞が、前記外因性ミトコンドリアで富化される前の前記患者とは異なるドナーから得られるかもしくは由来し、前記ドナーが、少なくとも部分的に前記患者とHLA適合する、
請求項1~6のいずれか一項に記載の医薬組成物。 - 前記ヒト幹細胞が、造血幹細胞であるか、または
前記ヒト幹細胞が、間葉系幹細胞であるか、または
前記ヒト幹細胞が、多能性幹細胞(PSC)もしくは人工多能性幹細胞(iPSC)である、請求項1~7のいずれか一項に記載の医薬組成物。 - 前記ヒト幹細胞が、前記ヒト外因性ミトコンドリアを前記ヒト幹細胞と接触させる前に、少なくとも1回の凍結-解凍サイクルを受けているか、または
前記ヒト幹細胞が、前記ヒト外因性ミトコンドリアでの富化後に、少なくとも1回の凍結-解凍サイクルを受けている、
請求項2~8のいずれか一項に記載の医薬組成物。 - 前記ヒト幹細胞が、骨髄、脂肪組織、口腔粘膜、皮膚線維芽細胞、血液、もしくは臍帯血の細胞から単離されるか、由来するか、もしくは得られる、または
前記外因性ミトコンドリアが、胎盤、培養で成長させた胎盤細胞、もしくは血液細胞から単離されるかもしくは得られる、
請求項1~9のいずれか一項に記載の医薬組成物。 - 富化されていない幹細胞、巨核球、赤血球、肥満細胞、骨髄芽球、好塩基球、好中球、好酸球、単球、マクロファージ、ナチュラルキラー(NK)細胞、小リンパ球、Tリンパ球、Bリンパ球、形質細胞、細網細胞、またはそれらの任意の組み合わせをさらに含む、請求項1に記載の医薬組成物。
- 前記増加したミトコンドリアDNA含有量が、内因性および/または外因性ミトコンドリアに由来する、請求項6に記載の医薬組成物。
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AU2019311859A1 (en) | 2021-02-04 |
US20210260137A1 (en) | 2021-08-26 |
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IL280163A (en) | 2021-03-01 |
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