JP7018877B2 - 白質卒中の治療のための幹細胞由来オリゴデンドロサイト前駆細胞 - Google Patents
白質卒中の治療のための幹細胞由来オリゴデンドロサイト前駆細胞 Download PDFInfo
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Description
本出願は、その内容が本明細書に全体が組み込まれる、2015年8月15日に出願された米国特許仮出願第62/205,723号の優先権を主張する。
ヒト胚性幹細胞から高純度の特徴付けられたオリゴデンドロサイト前駆細胞を多数産生する方法は以前に記載されたことがある(例えば、米国特許仮出願第62/162,739号および第62/144,921号)。ヒト胚性幹細胞からオリゴデンドロサイト前駆細胞(OPC)を誘導することによって、脳の虚血傷害の治療を含む、いくつかの重要な治療、研究、開発および商用目的のためのOPCの再生可能で大規模な原料がもたらされる。オリゴデンドロサイト前駆細胞はヒト胚性幹細胞以外の原料由来であってもよいことも認められている。このような原料としては、これらに限定されないが、成体幹細胞、誘導性多能性幹細胞IPSC、培養した幹細胞系などが挙げられる。
オリゴデンドロサイト前駆細胞はそれ自体を、療法を必要とする対象に投与することができる。あるいは、細胞は、適切な担体と混合した医薬組成物で、および/またはデポー送達系を使用して、療法を必要とする対象に投与することができる。
動物対象。使用した手法は全て、有資格の獣医師によって承認され、米国国立衛生研究所の実験動物の管理と使用に関する指針に従って実施された。NSGマウス(Shultzら(2007)Nat Rev Immunol.7(20:118;jaxmice.jax.org/nod-scid-gamma)は、Jackson Laboratories(Bar Harbor、ME)から入手した。動物対象は全て、明暗12時間周期の標準的条件下で飼育し、食物および水は自由に与えた。
AST-OPC1(以前はGRNOPC1として知られていた)は、材料および方法で記載したようにマスター細胞バンク(MCB)からWA01(HI)hESCを分化させることによって生成した。AST-OPC1を産生するための分化工程は41日を要し、hESCを未分化細胞コロニーから胚様体に移行させて、収穫され、凍結保存される接着性の分散した細胞集団となる必要がある。
AST-OPC1異種移植の完全な試験を可能にするために、中等度から進行型のヒト白質虚血または血管性認知症において認められる大きな白質病変を模倣した、以前に確立された皮質下白質卒中のマウスモデル(Sozmenら(2009)Neurosci Methods 180(2):261;Hinmanら(2013)Stroke 44(1):182)を免疫不全NSGマウスに適応させた(Shultzら(2007)Nat Rev Immunol.7(20:118;jaxmice.jax.org/nod-scid-gamma)。簡単に説明すると、局所性虚血病変を誘導するために、図3に例示したように、N5-(1-イミノエチル)-L-オルニチン2塩酸塩(L-Nio、Calbiochem)を各マウス脳の脳梁に、3次元定位座標で直接注射した。実験の予定表を図2に例示する。研究の目標およびパラメータは表2に詳細に記載する。脳組織は、卒中誘導して15日後(すなわち、AST-OPC1または偽注射の2週間後)に処理し、ミエリン化の範囲、軸索損失、星状細胞活性化、ミクログリア/マクロファージ応答およびオリゴデンドロサイト応答を判定するために蛍光免疫染色を実施した。代表的な結果を図1~24に示す。
実施例2で記載したようなWMSのNSGマウスモデルを使用して、行動回復に対するAST-OPC1移植の効果ならびにMRIおよびエキソビボ組織化学染色に基づいてAST-OPC1移植が白質保存を改善するかどうかを評価した。実験の予定表を図25に例示する。試験の目標およびパラメータは表3に詳細に記載する。行動試験(シリンダー試験およびグリッド歩行)は以下に詳細に記載する。代表的な結果を図26~28に示す。
Claims (18)
- 脳虚血傷害により損傷を受けた運動または認知機能の治療薬を製造するための、治療有効量のヒト幹細胞由来オリゴデンドロサイト前駆細胞の使用であって、前記ヒト幹細胞由来オリゴデンドロサイト前駆細胞がネスチン、NG2、及びPDGR-Rαを発現し、梗塞中心部から0.05mm~3mmに投与される、使用。
- 前記傷害が卒中である、請求項1に記載の使用。
- 前記傷害が皮質下白質卒中である、請求項2に記載の使用。
- 前記ヒト幹細胞由来オリゴデンドロサイト前駆細胞が、虚血傷害の亜急性期中に投与される、請求項1に記載の使用。
- 前記オリゴデンドロサイト前駆細胞が、ヒト胚性幹細胞(hESC)由来である、請求項1に記載の使用。
- 前記オリゴデンドロサイト前駆細胞が、ヒト誘導性多能性幹細胞(iPSC)由来である、請求項1に記載の使用。
- 前記ヒト幹細胞由来オリゴデンドロサイト前駆細胞が、デポー送達系を使用して投与される、請求項1に記載の使用。
- 前記デポー送達系がハイドロゲルを含む、請求項7に記載の使用。
- ヒト幹細胞由来オリゴデンドロサイト前駆細胞を含み、前記オリゴデンドロサイト前駆細胞がネスチン、NG2、及びPDGR-Rαを発現し、梗塞中心部から0.05mm~3mmに投与される、皮質下白質卒中の治療のための医薬組成物。
- デポー送達系をさらに含む、請求項9に記載の医薬組成物。
- 前記デポー送達系がハイドロゲルを含む、請求項10に記載の医薬組成物。
- 前記ハイドロゲルがヒアルロナンおよび/またはゼラチンを含む、請求項11に記載の医薬組成物。
- 前記ハイドロゲルがチオール化ヒアルロン酸を含む、請求項11又は12に記載の医薬組成物。
- 前記ハイドロゲルがチオール化ゼラチンを含む、請求項11から13のいずれか一項に記載の医薬組成物。
- 前記ハイドロゲルが架橋結合剤を含む、請求項11から14のいずれか一項に記載の医薬組成物。
- 前記前駆細胞が成体幹細胞由来である、請求項9から15のいずれか一項に記載の医薬組成物。
- 前記前駆細胞が誘導性多能性幹細胞(IPSC)由来である、請求項9から16のいずれか一項に記載の医薬組成物。
- 前記前駆細胞が、胚性胎児組織から得られたものではない幹細胞由来である、請求項9から17のいずれか一項に記載の医薬組成物。
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WO2019200152A1 (en) * | 2018-04-13 | 2019-10-17 | Thomas Zarembinski | Compositions and methods for the treatment of brain damage |
JP2022546317A (ja) | 2019-08-23 | 2022-11-04 | サナ バイオテクノロジー,インコーポレイテッド | Cd24発現細胞およびそれらの用途 |
JP2023520997A (ja) | 2020-03-25 | 2023-05-23 | サナ バイオテクノロジー,インコーポレイテッド | 神経学的障害及び神経学的病態の処置のための低免疫原性神経細胞 |
EP4196568A1 (en) | 2020-08-13 | 2023-06-21 | Sana Biotechnology, Inc. | Methods of treating sensitized patients with hypoimmunogenic cells, and associated methods and compositions |
WO2022251367A1 (en) | 2021-05-27 | 2022-12-01 | Sana Biotechnology, Inc. | Hypoimmunogenic cells comprising engineered hla-e or hla-g |
JP2024530403A (ja) | 2021-07-14 | 2024-08-21 | サナ バイオテクノロジー,インコーポレイテッド | 低免疫原性細胞におけるy染色体連鎖抗原の変化した発現 |
JP2024534772A (ja) | 2021-08-11 | 2024-09-26 | サナ バイオテクノロジー,インコーポレイテッド | 同種異系細胞療法用の遺伝子改変細胞 |
WO2023019227A1 (en) | 2021-08-11 | 2023-02-16 | Sana Biotechnology, Inc. | Genetically modified cells for allogeneic cell therapy to reduce complement-mediated inflammatory reactions |
CA3227613A1 (en) | 2021-08-11 | 2023-02-16 | William Dowdle | Inducible systems for altering gene expression in hypoimmunogenic cells |
AU2022325955A1 (en) | 2021-08-11 | 2024-02-08 | Sana Biotechnology, Inc. | Genetically modified cells for allogeneic cell therapy to reduce instant blood mediated inflammatory reactions |
WO2023183313A1 (en) | 2022-03-22 | 2023-09-28 | Sana Biotechnology, Inc. | Engineering cells with a transgene in b2m or ciita locus and associated compositions and methods |
CN115844927B (zh) * | 2023-03-02 | 2023-05-12 | 深圳汉盛再生医学科技有限公司 | 干细胞在制备治疗脑白质病的制剂中的用途 |
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EP3334414A1 (en) | 2018-06-20 |
AU2016308555B2 (en) | 2022-04-21 |
EP3334414A4 (en) | 2019-03-20 |
AU2016308555A1 (en) | 2018-03-15 |
CA2995634A1 (en) | 2017-02-23 |
HK1256610A1 (zh) | 2019-09-27 |
WO2017031092A1 (en) | 2017-02-23 |
US20180236004A1 (en) | 2018-08-23 |
JP2018528265A (ja) | 2018-09-27 |
CN108135839A (zh) | 2018-06-08 |
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