JP2017519819A - 心筋内細胞送達及びサイトカイン投与による心筋症治療法 - Google Patents
心筋内細胞送達及びサイトカイン投与による心筋症治療法 Download PDFInfo
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Abstract
Description
1.骨髄をCell Culture Laboratoryへ通す。
2.採取物を200μmフィルタに通し、1つのバッグにプールする。フィルタラインを0.9%生理食塩水でフラッシュする。
3.滅菌針と5mLシリンジとを用いて骨髄採取物3mlを取り出し、採取物がよく混合された状態を確保する(注射部位に70%滅菌濾過エタノールを噴霧)。
4.採取物1mlを2mlラベルのクライオバイアル1本に計数前の手順のために入れ、1mlずつ「Bact Alert」とラベルされた培養ボトルに入れる。
5.適切な数のチューブラックを拭き、エタノールをスプレーし、層流キャビネットに入れる。
6.層流キャビネット内で、適切な量の50mlコニカルチューブにラベル付けし、各チューブに25mlの骨髄が入るようにする。
7.50mlチューブのスクリューキャップを慎重に取り外し、キャビネット内に逆さにして置き、シリンジ及び充填管を用いて25mlの「Lymphoprep」(浸透圧と密度(280±15mOsm、1.077±0.001g/ml)の多糖類)を加える。
8.骨髄を50ml取り出して、充填管を加え、骨髄を「Lymphoprep」上で注意深く層状にして、混合が起こらない状態とする(図5a参照)。
9.全ての骨髄を「Lymphoprep」上に重ねた後、蓋をしっかりとねじ戻す。
10.Cell Processing Labの遠心分離機を用いて、チューブを1900rpmで30分間、ブレーキを「1」に設定して遠心分離する。ブレーキは掛けない。
11.チューブを遠心分離機から慎重に取り出し、層流キャビネットに戻す。遠心分離後、単核細胞が別個の帯を形成する(図5b参照)。4乃至8本以上の50mlチューブにラベル付けする。
12.層流キャビネットにおいて、滅菌したパスツールピペットを用いて、単核細胞の明瞭な帯を吸引し、空の50mlチューブに移す。帯が全て吸引されるまで繰り返し、廃棄物を捨てる。帯の両側から取り出す量が多すぎる方が、取り出す量が少なすぎて細胞を失うリスクを冒すよりも良い。図5参照。
13.細胞の帯が全て新しいチューブに移されるまで、これを全てのチューブで繰り返す。
14.これらのチューブを2500rpmで10分間遠心分離する。チューブを層流キャビネットに戻し、慎重に上清を滅菌50mlチューブに取り出す。
15.各細胞ペレットに、滅菌したパスツールピペットを用いて3乃至5mlの0.9%生理食塩水を加え再懸濁する。
16.細胞懸濁液を1本のチューブに移し、チューブを更に2回洗浄する。
17.完了後、空のチューブを捨てる。
18.残りのチューブを50mlレベルまで充填し、2500rpmで10分間遠心分離する。層流キャビネット内で上清を除去して捨てる。
19.無作為化群に応じて、細胞ペレットを0.9%生理食塩水に13ml又は5mlまで再懸濁する。
20.細胞懸濁液1mlを「Bact Alert」ボトルのそれぞれに加え、1mlを分析用にクライオバイアルに加える。
21.必要量をシリンジに取り、内容物が見えないようにラベルで包む。患者の詳細のラベルを付ける:試験番号、生年月日、固有認識番号、日付、及び量。
22.シリンジに開封防止シリンジキャップを取り付け、付属の滅菌紙袋に入れる。オーバーラップバッグとヒートシールに入れる。クールバッグですぐに輸送するために準備領域を通して配布する。
23.使用したロット番号及び心臓試験解析結果ワークシートを記録する。
Assmus B, Fischer-Rasokat U, Honold J, et al. Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure: results of the TOPCARE-CHD Registry. Circulation research. Apr 27 2007;100(8):1234-1241.
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Honold J, Fischer-Rasokat U, Lehmann R, et al. G-CSF stimulation and coronary reinfusion of mobilized circulating mononuclear proangiogenic cells in patients with chronic ischemic heart disease:five-year results of the TOPCARE-G-CSF trial. Cell transplantation. 2012;21(11):2325-2337.
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Jeevanantham V, Butler M, Saad A, Abdel-Latif A, Zuba-Surma EK, Dawn B. Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and meta-analysis. Circulation. Jul 31 2012;126(5):551-56
MacIntyre K, Capewell S, Stewart S, et al. Evidence of improving prognosis in heart failure: trends in case fatality in 66 547 patients hospitalized between 1986 and 1995. Circulation. Sep 5 2000;102(10):1126-1131.
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Perin EC, Dohmann HF, Borojevic R, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation. May 13 2003;107(18):2294-2302.
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Yeo C, Mathur A. Autologous bone marrow-derived stem cells for ischemic heart failure: REGENERATE-IHD trial. Regenerative medicine. Jan 2009;4(1):119-127.
Assessed for eligibility: 適格性の評価
Exclusions: 除外
Reasons: 理由
NYHA<LVEF normal: NYHA<LVEF正常
No informed concent: インフォームド・コンセント無し
Predominant valvular heart disease: 優勢な心臓弁膜症
Non-ischaemic: 非虚血性
Other (comorbidities, frailty): その他(併存症、虚弱)
Renal function: 腎機能
Randomised: 無作為化
PERIPHERAL: 末梢
Randomised: 無作為化
Received G-CSF/placebo: G-CSF/プラセボ投与
withdrawn: 脱落
INTRACORONARY: 冠動脈内
Received cells/placebo: 細胞/プラセボ投与
INTRAMYOCARDIAL: 心筋内
Allocated: 割り当て
Received: 投与
Stem Cells: 幹細胞
Placebo: プラセボ
Allocation: 割り当て
Completed follow-up: 追跡完了
Lost to follow-up/DNA: 追跡不能/データなし
6 month follow-up: 6ヶ月追跡
1 year follow-up-primary endpoint: 主要エンドポイント1年追跡
[図2、3、4]
Baseline: ベースライン
1 year: 1年
Time: 時間
6 months: 6ヶ月
NYHA Class: NYHAクラス
[図5]
Bone Marrow: 骨髄
Lymphoprep: リンホプレップ Layered bone marrow: 層状の骨髄
Plasma: 血漿
Mononuclear Cell Band: 単核細胞帯
Red Cells etc.: 赤血球等
Centrifuged bone marrow: 遠心分離後の骨髄
Claims (26)
- 骨髄穿刺により取得可能な細胞と顆粒球コロニー刺激因子(G-CSF)とを、対象者における心筋症の治療法において同時に、個別に、又は連続して使用する複合調製物として含む組成物であって、前記細胞は、前記対象者の心筋に直接投与される、組成物。
- 複能性又は多能性前駆細胞と顆粒球コロニー刺激因子(G-CSF)とを、対象者における心筋症の治療法において同時に、個別に、又は連続して使用する複合調製物として含む組成物であって、前記細胞は、前記対象者の心筋に直接投与される、組成物。
- 前記細胞は、骨髄穿刺により取得可能であり、好ましくは取得されている請求項1又は2記載の使用のための組成物。
- 前記心筋症は、虚血性心筋症である、何れかの先行請求項に記載の使用のための組成物。
- 前記心筋症は、原因が非虚血性である、請求項1乃至3の何れかに記載の使用のための組成物
- 前記細胞は、複能性又は多能性成体幹細胞、好ましくはCD34+骨髄幹細胞を含む、何れかの先行請求項に記載の使用のための組成物。
- 前記細胞は、自己由来である、何れかの先行請求項に記載の使用のための組成物。
- 前記細胞は、経皮心筋内注射により投与される、何れかの先行請求項に記載の使用のための組成物。
- 前記細胞の投与の前に、対象者の心臓、好ましくは左心室の三次元電気機械的マッピングを実施し、マッピングの結果を用いて投与部位又は投与部位群が決定される、何れかの先行請求項に記載の使用のための組成物。
- 前記細胞は、前記電気機械的マッピングにより決定された、6.9mV乃至11mVの単極電圧を有する心筋の少なくとも1つの領域に直接投与される、請求項9記載の使用のための組成物。
- 前記細胞は、前記電気機械的マッピングにより決定された、少なくとも5mmの心筋壁厚を有する少なくとも1箇所の心筋の領域に直接投与される、請求項9又は10記載の使用のための組成物。
- 前記細胞は、心筋内の少なくとも5箇所、好ましくは少なくとも10箇所の異なる場所に投与され、前記場所のうち任意の2箇所間の最小距離は、約1cmである、請求項9乃至11の何れかに記載の使用のための組成物。
- 前記電気機械的マッピング及び経皮心筋内注射は、2014年6月10日現在、NOGA XP Cardiac Navigation Systemの商標名で販売されている機器を含むシステムにより実施されている、請求項8乃至12の何れかに記載の使用のための組成物。
- 前記G-CSFは、皮下投与される、何れかの先行請求項に記載の使用のための組成物。
- 前記G-CSFは、少なくとも5日の期間に亘り投与される、何れかの先行請求項に記載の使用のための組成物。
- 前記細胞は、G-CSF投与終了直後の1日以内に投与される、何れかの先行請求項に記載の使用のための組成物。
- 骨髄穿刺により得られた前記細胞は、非自動方法により取得可能であり、前記非自動方法は、骨髄穿刺後、単核細胞が血漿及び無核細胞から実質的に分離されるように実施される、骨髄穿刺により対象者から得られた試料の遠心分離を含む、請求項3乃至16の何れかに記載の使用のための組成物。
- 前記遠心分離は、多糖類を含む溶液中にある時に試料に対して実施され、前記溶液は、単核細胞を血漿及び無核細胞から実質的に分離するのに十分な浸透圧及び密度を有する、請求項17記載の使用のための組成物。
- 前記方法は、濾過と生理食塩水による前記試料の洗浄とを、その遠心分離前に含む、請求項17又は18記載の使用のための組成物。
- 前記方法は、更に、前記細胞の投与前に、ステップ(a)乃至(d)、及び任意にステップ(e)を含み、即ち、
(a)前記単核細胞の遠心分離による細胞ペレットの作成と、
(b)好ましくは生理食塩水中での前記細胞ペレットの再懸濁と、
(c)前記再懸濁細胞ペレットの更なる遠心分離による別の細胞ペレットの作成と、
(d)好ましくは生理食塩水中での前記別の細胞ペレットの再懸濁と、
(e)対象者から得られた自己血清中での(d)で得られた懸濁液の希釈と、を含む、請求項17乃至19の何れかに記載の使用のための組成物。 - 骨髄穿刺により取得可能な細胞、又は複能性若しくは多能性前駆細胞と、G-CSFと、前記細胞の心筋への直接投与を明記する使用説明書とを含む無菌要素を備えるキット。
- 骨髄穿刺により取得可能な細胞、又は複能性若しくは多能性前駆細胞と、G-CSFと、前記細胞を心筋に直接送達するように構成された注射器とを含む無菌要素を備えるキット。
- 更に、心臓、好ましくは左心室の三次元電気機械的マッピング用のシステムを含む、請求項22記載の無菌要素を備えるキット。
- 心筋症の治療又は予防を、そのような治療又は予防を必要とする対象者において行う方法であって、治療有効量の顆粒球コロニー刺激因子(G-CSF)及び骨髄穿刺により取得可能な細胞を前記対象者に投与することを含み、前記細胞は、前記対象者の心筋に直接投与される、方法。
- 心筋症の治療又は予防を、そのような治療又は予防を必要とする対象者において行う方法であって、治療有効量の顆粒球コロニー刺激因子(G-CSF)及び複能性又は多能性前駆細胞を前記対象者に投与することを含み、前記細胞は、前記対象者の心筋に直接投与される、方法。
- 請求項3乃至20記載の追加の特徴の何れかを有する、請求項24又は25に記載の方法。
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