JP2018515582A - 眼の障害の処置のためのカプセル化細胞療法の使用 - Google Patents
眼の障害の処置のためのカプセル化細胞療法の使用 Download PDFInfo
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Abstract
Description
本出願は、2015年5月27日に出願された米国出願番号第62/167,213号に基づく優先権を主張しており、この米国出願は、その全体が参考として本明細書中に援用される。
本発明は、一般に、カプセル化細胞療法の分野に関する。
多くの臨床的状態、欠損、および疾患状態は、生細胞によって産生される1種または複数の生物学的に活性な分子を患者に供給すること、または生細胞によって代謝される有害因子を患者から除去することによって、治療または軽減され得る。多くの場合において、これらの分子は、臓器または組織機能の障害または喪失を回復または補償できる。したがって、多くの研究者が、分泌産物を提供するまたは代謝機能に影響を与える臓器全体、臓器組織、および/または細胞を移植することによって、臓器または組織機能を再構成することを試みてきた。しかし、このような移植は、劇的な利点を提供できる一方で、移植することにとって好適で利用可能な臓器が比較的少数であるために、その適用が限定されている。さらに、一般に、移植患者は、移植片機能の喪失および移植された組織または細胞の最終的な壊死を生じる移植片の免疫学的拒絶を防ぐために、免疫抑制されなければならない。同様に、多くの場合において、移植片は、長期間にわたって、さらには患者の寿命の残りにわたって機能的なままでなければならない。かなりの期間にわたって患者を免疫抑制状態で維持することは、望ましくなく費用もかかる。
移植手順の望ましい代替物は、栄養素、代謝産物、および分泌産物の拡散を可能にするが、免疫学的拒絶の細胞エフェクターおよび分子エフェクターをブロックする物理的なバリア内での細胞または組織の移植である。選択された産物を産生する組織または細胞を免疫系から防御する様々なデバイスが探索されてきた。例えば、それぞれその全体が参照により本明細書に組み入れられる米国特許第5,158,881号;WO92/03327;WO91/00119;およびWO93/00128を参照されたい。これらのデバイスとしては、例えば、血管外拡散チャンバー、血管内拡散チャンバー、血管内限外濾過チャンバー、およびマイクロカプセル化細胞の移植が挙げられる。Scharp, D. W.ら、World J. Surg.、8巻、221〜9頁(1984年);Limら、Science 210巻:908〜910頁(1980年);Sun, A. M.、Methods in Enzymology 137巻:575〜579頁(1988年);WO93/03901;および米国特許第5,002,661号を参照されたい。このようなデバイスの使用は、患者を免疫抑制状態で維持する必要性を軽減する。しかし、これらのアプローチはいずれも、長期の移植片機能を提供する上で満足のいくものではなかった。
好適な方法および材料を後述するが、本発明の実施または試験において本明細書で説明したものに類似した、または同等な方法および材料を使用することができる。本明細書で述べられた全ての刊行物、特許出願、特許、および他の参考文献は、参照によりそれら全体が開示に組み入れられる。本明細書に記載される参考文献は、特許請求の範囲の発明の先行技術の自認ではない。矛盾がある場合、定義を含め本明細書を優先させる。加えて材料、方法、および例は単なる例示にすぎず、限定することを意図しない。本発明の他の特色および利点は、以下の詳細な説明および特許請求の範囲から明らかであろう。
a)生物学的に活性な分子の細胞源を含むコア、およびb)前記コアを取り囲む膜であって、前記生物学的に活性な分子のそれを通る拡散を許容する半透膜を含む生体適合性カプセルを、前記患者の眼に埋め込むステップによって眼の障害に罹患した患者においてそれを処置する方法であって、前記眼の障害は、異常な血管新生、炎症、網膜変性、またはそれらの任意の組合せを特徴とし、前記生体適合性デバイスは、移植後少なくとも12カ月の間(例えば、少なくとも13か月、少なくとも14か月、少なくとも15か月、少なくとも16か月、少なくとも17か月、少なくとも18か月、少なくとも19か月、少なくとも20か月、少なくとも21か月、少なくとも22か月、少なくとも23か月、少なくとも2年、またはそれより長く)、治療有効量の前記生物学的に活性な分子を生成する、方法が本明細書において提供される。
a)前記コアが、0.5×106〜1.0×106個の間のARPE−19細胞を含む;
b)前記デバイスの長さが、0.4mm〜11mmの間である;
c)前記デバイスの内径が、0.9mm〜1.2mmの間である;
d)前記デバイスの端部が、メタクリル酸メチルを使用してシールされている;
e)前記半透膜が、約100nmの孔サイズの中央値を有する;
f)前記半透膜の公称分子量カットオフ(MWCO)が500KDである;
g)前記半透膜が、90〜120μmの間の厚さである;
h)コアが、前記デバイスの内部体積の40〜85%を占めるポリエチレンテレフタレート(PET)繊維を含む内部の足場を含む;および
i)それらの組合せ
からなる群から選択される2個またはそれより多くの追加の特徴(例えば、3、4、5、6、7または全て)を含み得る。
タンパク質は、眼疾患の処置において使用される治療薬の支配的なクラスである。カプセル化細胞技術(ECT)眼球内デバイスが、2年まで一貫して眼に生物治療薬を直接送達できることは、ヒト臨床試験において以前に実証されている(Kauperら 2012年. Invest Ophthalmol. Vis. Sci. 53巻(12号):7484〜91頁を参照)。
網膜色素変性症の臨床試験
(患者プロファイルおよび研究設計)
網膜色素変性症(RP)患者を採用して、徐放性のCNTF分泌性の眼用のECTデバイスを受ける臨床研究に参加させた。研究は、無作為化、二重盲検、擬対照であり、複数の研究センター(11の関係場所)で実施した。RP患者を、2つの研究群:CNTF3およびCNTF4に分けた。
(徐放性CNTF分泌性デバイス)
(CNTF分泌性デバイスの移植)
(移植の12カ月後の患者査定−CNTF3研究)
**外科的創傷に関連し、10日以内に続発症なしに回復した。
***既存の白内障(軽度)の悪化
(移植の12カ月後の患者査定−CNTF4研究)
(実施例2)
緑内障の臨床試験
(患者プロファイルおよび研究設計)
(徐放性CNTF分泌性デバイス)
(CNTF分泌性デバイスの移植)
(移植後の患者査定)
(実施例3)
地図状萎縮の試験
(患者プロファイルおよび研究設計)
(徐放性CNTF分泌性デバイス)
CNTF分泌性デバイスの移植
移植後の患者査定
**手順のおよそ10日後に起こり、数週間以内に続発症なしに回復した
(実施例4)
外植されたデバイスの特徴
本発明の1つまたは複数の実施形態の詳細は、上記の添付の説明に記載される。本発明の実施または試験において本明細書で説明したものに類似した、または同等な任意の方法および材料を使用することができるが、ここでは好ましい方法および材料を記載する。本発明の他の特色、目的、および利点は、記載および特許請求の範囲から明らかであろう。本明細書および添付の特許請求の範囲において、単数形は、文章中に明らかな他の指示がない限り、複数形の指示対象を含む。特に他の指定がない限り、本明細書において使用される全ての技術用語や科学用語は、本発明が属する分野の当業者が一般的に理解するものと同じ意味を有する。本明細書で引用された全ての特許および刊行物は、参考として援用される。
Claims (54)
- 眼の障害に罹患した患者においてそれを処置する方法であって、
a)生物学的に活性な分子の細胞源を含むコア、および
b)前記コアを取り囲む膜であって、前記生物学的に活性な分子のそれを通る拡散を許容する半透膜を含む生体適合性カプセルを、前記患者の眼に埋め込むステップを含み、
前記眼の障害は、異常な血管新生、炎症、網膜変性、またはそれらの任意の組合せを特徴とし、前記生体適合性デバイスは、移植後少なくとも12カ月の間、治療有効量の前記生物学的に活性な分子を生成する、方法。 - 前記生体適合性デバイスが、移植後少なくとも2年の間、治療有効量の前記生物学的に活性な分子を生成する、請求項1に記載の方法。
- 前記生物学的に活性な分子の前記細胞源が、前記生物学的に活性な分子を分泌するように遺伝子操作された0.5×106〜1×106個の間のARPE−19細胞である、請求項1に記載の方法。
- 前記眼の障害が緑内障である、請求項3に記載の方法。
- 前記眼の障害が網膜色素変性症(RP)である、請求項3に記載の方法。
- 前記眼の障害が、地図状萎縮または加齢性黄斑変性症(AMD)である、請求項3に記載の方法。
- 前記眼の障害が黄斑部毛細血管拡張症である、請求項3に記載の方法。
- 前記処置が、視神経再生を改善する、視野感度、コントラスト感度、Garway−Heathトータル偏差を保存もしくは改善する、神経節細胞複合体および/もしくは外側網膜層の厚さを保存もしくは改善する、網膜繊維層を保存もしくは改善する、またはそれらの任意の組合せである、請求項4に記載の方法。
- 視野感度またはコントラスト感度の保存または改善が、網膜の解剖学的構造の保存または改善と対応する、請求項8に記載の方法。
- 前記処置が、視力を改善する、黄斑部体積を増加させる、網膜の厚さを増加させる、またはそれらの任意の組合せである、請求項5に記載の方法。
- 前記処置が、対象において視力喪失を安定化する、最良矯正視力の喪失を減少させる、地図状萎縮を減少させる、またはそれらの任意の組合せである、請求項6に記載の方法。
- 前記処置が、最良矯正視力を増加させる、請求項6に記載の方法。
- 前記カプセルが、中空繊維として構成されている、請求項1に記載の方法。
- 前記デバイスが、硝子体、房水、眼周囲空間、前眼房、後眼房、またはテノン嚢下空間に埋め込まれる、請求項1に記載の方法。
- 前記コアが、前記半透膜内に配置されたマトリックスをさらに含む、請求項1に記載の方法。
- 前記マトリックスが、複数のモノフィラメントを含み、前記モノフィラメントが、
a)撚られてヤーンとなっており、もしくは織られてメッシュとなっており、または
b)撚られて、不織糸中にあるヤーンとなっており、その上に前記細胞が分散されている、
請求項15に記載の方法。 - 前記モノフィラメントが、アクリル、ポリエステル、ポリエチレン、ポリプロピレン、ポリアクリロニトリル、ポリエチレンテレフタレート、ナイロン、ポリアミド、ポリウレタン、ポリブトエステル、絹、綿、キチン、カーボン、および生体適合性の金属からなる群から選択される生体適合性材料を含む、請求項16に記載の方法。
- 前記モノフィラメントが、前記デバイスの内部体積の40〜85%を占めるポリエチレンテレフタレート(PET)繊維を含む、請求項17に記載の方法。
- 前記生物学的に活性な分子がサイトカインである、請求項1に記載の方法。
- 前記サイトカインが、CNTF、BDNF、TGF−β、GDNF、NGF、bFGF、aFGF、IL−1β、IL−10、IFN−β、IFN−α、およびVEGF阻害剤からなる群から選択される、請求項19に記載の方法。
- 前記サイトカインがCNTFである、請求項20に記載の方法。
- CNTFの治療有効量が、50pg/眼/日から500ng/眼/日の間である、請求項21に記載の方法。
- CNTFの治療有効量が、0.1ng/眼/日から50ng/眼/日の間である、請求項22に記載の方法。
- a)生物学的に活性な分子の細胞源を含むコアと
b)前記コアを取り囲む半透膜であって、前記生物学的に活性な分子のそれを通る拡散を許容する半透膜とを含む移植型細胞培養デバイスであって、
前記デバイスは、埋め込まれたときに、0.1ng/日から20ng/日の間の前記生物学的に活性な分子を分泌し;
治療有効レベルでの生物学的に活性な分子の分泌が、移植後少なくとも2年にわたって維持される、移植型細胞培養デバイス。 - 前記生物学的に活性な分子の前記細胞源が、前記生物学的に活性な分子を分泌するように遺伝子操作された0.5×106〜1×106個の間のARPE−19細胞である、請求項24に記載のデバイス。
- 前記生物学的に活性な分子がCNTFである、請求項25に記載のデバイス。
- 埋め込まれたときに、0.1ng/日から20ng/日の間のCNTFを分泌し、移植後少なくとも2年にわたって、外殖すると0.1ng/日から0.4ng/日の間のCNTFを分泌する、請求項26に記載のデバイス。
- 埋め込まれたときに、0.1ng/日から20ng/日の間のCNTFを分泌し、移植後少なくとも2年にわたって0.6ng/日から2.8ng/日の間のCNTFを分泌する、請求項26に記載のデバイス。
- 前記コアが、前記半透膜内に配置されたマトリックスをさらに含む、請求項26に記載のデバイス。
- 前記マトリックスが、複数のモノフィラメントを含み、前記モノフィラメントが、
a)撚られてヤーンとなっており、もしくは織られてメッシュとなっており、または
b)撚られて、不織糸中にあるヤーンとなっており、その上に前記細胞が分散されている、
請求項29に記載のデバイス。 - 前記モノフィラメントが、アクリル、ポリエステル、ポリエチレン、ポリプロピレン、ポリアセトニトリル、ポリエチレンテレフタレート、ナイロン、ポリアミド、ポリウレタン、ポリブトエステル、絹、綿、キチン、カーボン、および生体適合性の金属からなる群から選択される生体適合性材料を含む、請求項30に記載のデバイス。
- 前記モノフィラメントが、前記デバイスの内部体積の40〜85%を占めるポリエチレンテレフタレート(PET)繊維を含む、請求項31に記載のデバイス。
- テザーアンカーをさらに含む、請求項24に記載のデバイス。
- 前記テザーアンカーが、アンカーループを含む、請求項33に記載のデバイス。
- 前記アンカーループが、前記デバイスを眼の構造に固着させるように適合されている、請求項34に記載のデバイス。
- 眼の硝子体、房水、テノン嚢下空間、眼周囲空間、後眼房、または前眼房に埋め込まれる、請求項24に記載のデバイス。
- 前記半透膜が、選択透過性、免疫防御性の膜を含む、請求項24に記載のデバイス。
- 前記半透膜が、限外濾過膜または精密濾過膜を含む、請求項24に記載のデバイス。
- 前記半透膜が、100nmの孔サイズの中央値を有する、請求項37または38に記載のデバイス。
- 前記半透膜が、非多孔質膜材料を含む、請求項24に記載のデバイス。
- 前記非多孔質膜材料が、ヒドロゲルまたはポリウレタンである、請求項40に記載のデバイス。
- 前記半透膜の公称分子量カットオフ(MWCO)が500kDである、請求項24に記載のデバイス。
- 前記半透膜が、90〜120μmの間の厚さである、請求項24に記載のデバイス。
- カプセルが、中空繊維またはフラットシートとして構成されている、請求項24に記載のデバイス。
- 長さが、4mm〜11mmの間である、請求項24に記載のデバイス。
- 0.9mm〜1.2mmの間の内径を有する、請求項24に記載のデバイス。
- 前記デバイスの端部が、メタクリル酸メチルを使用してシールされている、請求項24に記載のデバイス。
- 少なくとも1種の追加の生物学的に活性な分子が、前記デバイスから共送達される、請求項24に記載のデバイス。
- 前記少なくとも1種の追加の生物学的に活性な分子が、非細胞源からである、請求項24に記載のデバイス。
- 前記少なくとも1種の追加の生物学的に活性な分子が、細胞源からである、請求項24に記載のデバイス。
- 前記少なくとも1種の追加の生物学的に活性な分子が、前記コア中の1つまたは複数の遺伝子操作されたARPE−19細胞によって産生される、請求項50に記載のデバイス。
- a)前記コアが、0.5×106〜1.0×106個の間のARPE−19細胞を含む;
b)前記デバイスの長さが、0.4mm〜11mmの間である;
c)前記デバイスの内径が、0.9mm〜1.2mmの間である;
d)前記デバイスの端部が、メタクリル酸メチルを使用してシールされている;
e)前記半透膜が、約100nmの孔サイズの中央値を有する;
f)前記半透膜の公称分子量カットオフ(MWCO)が500KDである;
g)前記半透膜が、90〜120μmの間の厚さである;
h)コアが、前記デバイスの内部体積の40〜85%を占めるポリエチレンテレフタレート(PET)繊維を含む内部の足場を含む;および
i)それらの組合せ
からなる群から選択される2個またはそれより多くの追加の特徴をさらに含む、請求項24に記載のデバイス。 - 追加の特徴a)〜i)のうち3個、4個、5個、6個、7個または全てを含む、請求項52に記載のデバイス。
- 請求項25に記載の眼用の生体適合性デバイスを作製する方法であって、
a)サイトカインを分泌するように少なくとも1つのARPE−19細胞を遺伝子操作するステップ、および
b)半透膜内に前記遺伝子操作されたARPE−19細胞をカプセル化するステップであって、前記膜が、前記サイトカインのそれを通る拡散を可能にする、ステップ
を含む方法。
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JP2020200347A (ja) * | 2015-05-27 | 2020-12-17 | ニューロテック ユーエスエー, インコーポレイテッド | 眼の障害の処置のためのカプセル化細胞療法の使用 |
CN112672732A (zh) * | 2018-06-19 | 2021-04-16 | 细胞疗法有限责任公司 | 包含神经营养剂、凋亡信号传导片段抑制剂(FAS)或FAS配体(FASL)抑制剂、肿瘤坏死因子-α(TNF-α)或TNF受体抑制剂、线粒体肽、寡核苷酸、趋化因子抑制剂或半胱氨酸-天冬氨酸蛋白酶的药物递送系统 |
JP2021531327A (ja) * | 2018-06-19 | 2021-11-18 | セラ セラピューティクス エルエルシー | 眼圧降下剤、cnp化合物、nrp−b化合物、tie−2アゴニスト、または神経栄養剤を含む、緑内障または高眼圧症を治療するための徐放性薬剤送達系 |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2020200347A (ja) * | 2015-05-27 | 2020-12-17 | ニューロテック ユーエスエー, インコーポレイテッド | 眼の障害の処置のためのカプセル化細胞療法の使用 |
JP7078683B2 (ja) | 2015-05-27 | 2022-05-31 | ニューロテック ユーエスエー, インコーポレイテッド | 眼の障害の処置のためのカプセル化細胞療法の使用 |
CN112672732A (zh) * | 2018-06-19 | 2021-04-16 | 细胞疗法有限责任公司 | 包含神经营养剂、凋亡信号传导片段抑制剂(FAS)或FAS配体(FASL)抑制剂、肿瘤坏死因子-α(TNF-α)或TNF受体抑制剂、线粒体肽、寡核苷酸、趋化因子抑制剂或半胱氨酸-天冬氨酸蛋白酶的药物递送系统 |
JP2021531328A (ja) * | 2018-06-19 | 2021-11-18 | セラ セラピューティクス エルエルシー | 神経栄養剤、アポトーシスシグナリング断片化阻害剤(FAS)もしくはFASリガンド(FASL)阻害剤、腫瘍壊死因子α(TNF−α)もしくはTNF受容体阻害剤、ミトコンドリアペプチド、オリゴヌクレオチド、ケモカイン阻害剤、またはシステイン−アスパラギン酸プロテアーゼを含む薬剤送達系 |
JP2021531327A (ja) * | 2018-06-19 | 2021-11-18 | セラ セラピューティクス エルエルシー | 眼圧降下剤、cnp化合物、nrp−b化合物、tie−2アゴニスト、または神経栄養剤を含む、緑内障または高眼圧症を治療するための徐放性薬剤送達系 |
JP2023508006A (ja) * | 2018-06-19 | 2023-02-28 | セラ セラピューティクス エルエルシー | 眼圧降下剤、神経栄養剤、c型ナトリウム利尿ペプチド、ナトリウム利尿ペプチド受容体b、アポトーシスシグナリング断片化阻害剤またはfasリガンド阻害剤を含む、緑内障または高眼圧症を治療するための薬剤送達系 |
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US20160346197A1 (en) | 2016-12-01 |
IL255917A (en) | 2018-01-31 |
JP7078683B2 (ja) | 2022-05-31 |
AU2016267579A1 (en) | 2017-12-07 |
CA2986769A1 (en) | 2016-12-01 |
EP3302524A1 (en) | 2018-04-11 |
JP2020200347A (ja) | 2020-12-17 |
ES2833457T3 (es) | 2021-06-15 |
US20220071897A1 (en) | 2022-03-10 |
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EP3302524B1 (en) | 2020-09-23 |
EP3662923A1 (en) | 2020-06-10 |
AU2016267579B2 (en) | 2024-02-01 |
US20240285521A1 (en) | 2024-08-29 |
US11207266B2 (en) | 2021-12-28 |
WO2016191645A1 (en) | 2016-12-01 |
JP6850734B2 (ja) | 2021-03-31 |
US20200197297A1 (en) | 2020-06-25 |
IL283713B (en) | 2022-03-01 |
US20180055766A1 (en) | 2018-03-01 |
IL255917B (en) | 2021-06-30 |
IL283713A (en) | 2021-07-29 |
US10456356B2 (en) | 2019-10-29 |
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