JP2021532093A - 脳疾患のミトコンドリア増強療法 - Google Patents
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Abstract
Description
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、単離されたマウスまたはヒトのミトコンドリアとともに、DMEM(24時間、37℃、5%CO2)中で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療法プロセスの代表的な結果を示す。
ミトコンドリアはC57/BLマウス(野生型mtDNAのドナー)の胎盤から単離された。骨髄細胞はFVB/Nマウス(ATP8にmtDNA突然変異を担持する)から単離された。FVB/N細胞は、C57/BL外因性ミトコンドリア(1×106個の細胞あたり4.4mUのミトコンドリア)をロードされ、その後、FVB/NマウスにI.V.注射で戻された。その後、FVB/Nマウスは種々の時点で屠殺され、器官の生体内分布が試験された。
患者1は、ピアソン症候群と診断された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)の前の彼の体重は14.5KGであった。彼の成長は治療前の3年間大幅に遅れ、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。患者は腎不全(GFR 22ml/分)、電解質補給を必要とする近位尿細管症、およびカルシウム補給を必要とする副甲状腺機能低下症を有した。
患者2は、ピアソン症候群と診断された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、かつ糖尿病である(ヘモグロビンA1C 7.1%)。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る。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、ピアソン症候群と診断された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かった。
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7.4Kb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。
中年(12ヶ月齢)C57BL/6Jマウスは、ミトコンドリア富化骨髄(BM)細胞(MNV−BM−PLC、1×106個の細胞、n=24)、骨髄細胞(BM、1×106細胞、n=23)、または対照ビヒクル溶液(VEHICLE、0.9%w/vのNaCl中4.5%のアルブミン、n=23)のいずれかを投与され、投与は約3ヶ月ごとに繰り返された。初回投与の1週間前および初回投与の9ヶ月後に、マウスは開放地での行動試験に供された。
全体的運動能力および協調は、ミトコンドリア強化骨髄(BM)細胞(MNV−BM−PLC、1×106個の細胞、n=24)、骨髄細胞(BM、1×106細胞、n=23)、または対照ビヒクル溶液(VEHICLE、0.9%w/vのNaCl中4.5%のアルブミン、n=23)のいずれかを投与された中年(12ヶ月齢)C57BL/6Jマウスにおいて、Rotarod装置を使用して評価された。
標題:脳疾患および障害を有する患者におけるミトコンドリアで富化された幹細胞の移植の安全性、生着、および治療効果を評価するための第I/II相非盲検単回投与臨床試験。
Claims (36)
- 脳疾患、障害、またはそれら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105〜2×107個のヒト幹細胞を含み、前記ヒト幹細胞は、凍結−解凍した健康な機能的ヒト外因性ミトコンドリアで富化され、前記脳疾患または障害は、ミトコンドリアDNAの病原性突然変異によってまたはミトコンドリアタンパク質をコードする核DNAの病原性突然変異によって引き起こされるミトコンドリア病または障害ではない、医薬組成物。
- 前記富化が、百万個の細胞あたり少なくとも0.088〜最大176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、請求項1に記載の医薬組成物。
- 前記富化が、百万個の細胞あたり0.88〜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2に記載の医薬組成物。
- 前記健康な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1〜3のいずれか一項に記載の医薬組成物。
- 前記疾患または障害が、後天性ミトコンドリア機能障害に関連している、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記疾患または障害が、後天性ミトコンドリア機能障害に関連していない、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記疾患または障害が、パーキンソン病(PD)、アルツハイマー病(AD)、脳卒中、てんかん、多発性硬化症(MS)、認知症、副腎白質ジストロフィー(ALD)、ハンチントン病(HD)、ギランバレー症候群(GBS)、自閉症、およびフリードライヒ運動失調症からなる群から選択される、請求項1〜6のいずれか一項に記載の医薬組成物。
- 前記症状が、指示を実行する能力の低下、話す能力の低下、応答時間障害、運動技能の低下、学習障害、歩行能力の低下、階段を上る能力の低下、EEG障害、発作、描画能力の低下、言語技能の低下、および記憶障害からなる群から選択される、請求項1〜6のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が、中枢神経系(CNS)に直接投与される、請求項1〜8のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が、全身投与によって投与される、請求項1〜8のいずれか一項に記載の医薬組成物。
- 前記患者の体重1キログラムあたり約106個のミトコンドリア富化ヒト幹細胞を含む、請求項10に記載の医薬組成物。
- ヒトミトコンドリアで富化された合計約5×105〜5×109個のヒト幹細胞を含む、請求項1〜9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)増加したミトコンドリアDNA含有量、
(ii)増加したCS活性レベル、
(iii)増加したSDHAおよびCOX1から選択された少なくとも1つのミトコンドリアタンパク質の含有量、
(iv)増加したO2消費率、
(v)増加したATP産生率、または
(vi)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1〜12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または由来する、請求項1〜13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とは異なるドナーから得られるかまたは由来する、請求項1〜13のいずれか一項に記載の医薬組成物。
- 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15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、請求項1〜16のいずれか一項に記載の医薬組成物。
- 前記ヒト幹細胞が、間葉系幹細胞である、請求項1〜16のいずれか一項に記載の医薬組成物。
- 前記ヒト幹細胞が、多能性幹細胞(PSC)または人工多能性幹細胞(iPSC)である、請求項1〜16のいずれか一項に記載の医薬組成物。
- 前記ヒト幹細胞が、CD34+である、請求項1〜19のいずれか一項に記載の医薬組成物。
- ヒト幹細胞が、健康な機能的ヒト外因性ミトコンドリアを前記ヒト幹細胞に導入する前に、少なくとも1回の凍結−解凍サイクルを受けている、請求項2〜20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、または臍帯血の細胞から単離されるか、由来するか、または得られる、請求項1〜21のいずれか一項に記載の医薬組成物。
- 前記健康な機能的ヒト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、または血液細胞から単離されるかまたは得られる、請求項1〜22のいずれか一項に記載の医薬組成物。
- 前記ヒト幹細胞が、前記健康な機能的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1〜23のいずれか一項に記載の医薬組成物。
- 前記健康な機能的ヒト外因性ミトコンドリアが、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%を構成する、請求項1〜24のいずれか一項に記載の医薬組成物。
- 前記健康な機能的ヒト外因性ミトコンドリアが、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10%を構成する、請求項25に記載の医薬組成物。
- 非富化幹細胞、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1〜26のいずれか一項に記載の医薬組成物。
- 脳疾患、障害、またはそれらの症状の治療を、かかる治療を必要とするヒト患者において行う方法であって、前記方法が、前記患者に医薬組成物を非経口投与するステップを含み、前記医薬組成物が、少なくとも約5×105〜5×109個のヒト幹細胞を含み、前記ヒト幹細胞が、凍結−解凍した健康な機能的ヒト外因性ミトコンドリアで富化され、前記脳疾患または障害が、ミトコンドリアDNAの病原性突然変異によってまたはミトコンドリアタンパク質をコードする核DNAの病原性突然変異によって引き起こされる原発性ミトコンドリア病または障害ではない、方法。
- 前記医薬組成物の前記投与が、中枢神経系(CNS)に直接行われる、請求項28に記載の方法。
- 前記投与が髄腔内である、請求項29に記載の方法。
- 前記医薬組成物の前記投与が、全身投与によるものである、請求項28に記載の方法。
- 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または由来する、請求項28〜31のいずれか一項に記載の方法。
- 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または由来する、請求項28〜31のいずれか一項に記載の方法。
- 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33に記載の方法。
- 前記患者と前記ミトコンドリア富化ヒト幹細胞との間の有害な免疫原性反応を防止、遅延、最小化、または無効化する薬剤を前記患者に投与するステップをさらに含む、請求項33または請求項34に記載の方法。
- 前記有害な免疫原性反応が、移植片対宿主病(GvHD)である、請求項35に記載の方法。
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