JP2015533122A - 網膜変性処置のための方法および組成物 - Google Patents
網膜変性処置のための方法および組成物 Download PDFInfo
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Abstract
Description
本願は、2012年10月9日に出願した米国仮出願第61/711,665号の利益を主張する。米国仮出願第61/711,665号の開示は、その全体が本明細書中に参考として援用される。
適用なし
本出願は、例えば、網膜色素変性および加齢黄斑変性(AMD)で起こるような網膜変性の細胞治療の分野にある。
網膜変性(例えば、脈絡膜血管新生から生じるもの(「ウェット型AMD」)もしくは網膜と脈絡膜の間の細胞破片の付着から生じるもの(「ドライ型AMD」))は、現在、世界における失明の大きな原因のうちの1つである。Cai et al. (2012) Front Biosci. 17:1976−95。同様に、網膜色素変性で起こるような光受容細胞(桿体細胞および錐体細胞)の変性および死滅はまた、視力の悪化および/もしくは喪失をもたらし得る。よって、網膜変性を妨げるおよび/もしくは逆転させる処置、特に、光受容体機能を回復させる処置が必要である。
本明細書で開示されるのは、網膜変性を、外因性Notch細胞内ドメインを発現するように操作された骨髄接着性幹細胞(MASC)の系統である細胞を使用して処置するための方法および組成物である。このような細胞は、本開示の目的のためにSB623細胞と称される。
実施形態1。網膜変性を処置する必要性のある被験体における網膜変性を処置するための方法であって、該方法は、SB623細胞を該被験体に投与する工程を包含する、方法。
実施形態2。SB623細胞は、前記被験体の眼に移植される、実施形態1に記載の方法。
実施形態3。前記移植は、硝子体中である、実施形態2に記載の方法。
実施形態4。前記移植は、網膜下である、実施形態2に記載の方法。
実施形態5。前記網膜変性は、網膜色素変性で起こる、実施形態1〜4のいずれかに記載の方法。
実施形態6。前記網膜変性は、加齢黄斑変性(AMD)で起こる、実施形態1〜4のいずれかに記載の方法。
本明細書で開示されるのは、網膜変性および網膜変性状態の処置のための方法および組成物である。特に、SB623細胞(Notch細胞内ドメインをコードする配列で間葉系幹細胞をトランスフェクトすることによって得られた細胞)の、網膜変性を受けている(もしくは網膜変性状態を被っている)被験体の眼への移植は、網膜変性を防止し、網膜機能の長期間の救出を生じる。
最も一般に起こる網膜変性状態のうちの2つは、網膜色素変性(RP)および加齢黄斑変性(AMD)である。網膜色素変性は、網膜の光受容細胞(桿体および錐体としても公知)の変性から生じる。黄斑は、網膜の中心部に与えられた名称であり、視覚の周辺ではなく、視覚の中心を担う。AMDには2つの形態がある。より一般的な形態であるドライ型AMDは、網膜と脈絡膜(網膜の直ぐ下にある眼の層)との間の細胞破片(ドルーゼン)の付着によって引き起こされ、光受容細胞の萎縮をもたらす。他の形態のAMDであるウェット型AMDは、脈絡膜における血管の異常な増殖から生じる。これら血管は漏れる可能性があり、脈絡膜および網膜に損傷が生じる。AMDに関する他の用語としては、脈絡膜新生血管、網膜下血管新生、滲出型および円板状変性が挙げられる。
本開示は、SB623細胞を、網膜変性を処置する必要性のある被験体、すなわち、網膜変性が起こっている被験体の眼に移植することによって、網膜変性を処置するための方法を提供する。SB623細胞は、骨髄接着性間質細胞(MASC)(間葉系幹細胞(MSC)としても公知)においてNotchタンパク質の細胞内ドメインを発現させることによって、MASCから得られる。MASCは、骨髄から接着性細胞を選択することによって得られる。
本明細書で開示されるとおりのSB623細胞を含む治療組成物もまた、提供される。このような組成物は、代表的には、SB623細胞および薬学的に受容可能なキャリアを含む。
網膜変性(例えば、AMD)をSB623細胞で処置するために、眼への物質の送達に関して当該分野で公知の任意の方法が利用され得る。本開示の目的のために、「移植」とは、任意の方法による、被験体の眼へのSB623細胞の移入をいう。例えば、眼への直接注射は、SB623細胞の懸濁物の送達のために使用され得る。特定の実施形態において、SB623細胞の懸濁物は、硝子体液の中に注射される。他の実施形態において、網膜下注射が使用される。さらなる実施形態において、局所投与が使用される;例えば、治療組成物は、点眼剤として使用される予定の溶液の中に製剤化され得る。さらに他の実施形態において、懸濁物、ゲルなどの局所適用は、SB623細胞の投与のために利用され得る。
SB623細胞を、ヒトNotchタンパク質の細胞内ドメインをコードするDNAで、ヒト骨髄接着性幹細胞(MASC)をトランスフェクトすることによって得た。MASCを、以下のようにヒト骨髄から得た。ヒト成人骨髄吸引物を、Lonza(Walkersville, MD)から購入した。細胞を1回洗浄し、増殖培地:10% ウシ胎仔血清(FBS)(Hyclone, Logan, UT)、2mM L−グルタミンおよびペニシリン/ストレプトマイシン(両方ともInvitrogen, Carlsbad, CA)を補充したα−MEM(Mediatech, Herndon, VA)中で、Corning T225フラスコ(Corning, Inc. Lowell, MA.)にプレートした。3日後、付着しなかった細胞を除去した;そのMASC培養物を、増殖培地中で約2週間維持した。その期間の間に、0.25% トリプシン/EDTAを使用して細胞を2回継代した。
RCSラットを、生後2日目に開始して移植まで継続する経口シクロスポリンA(飲料水中200mg/l)の投与によって免疫抑制した。注射によるSB623細胞の移植を、生後4週間で行った。移植の前に、動物を、キシラジン塩酸塩(Celactal(登録商標), Bayer Medical, Ltd.)およびケタミン塩酸塩(Ketalar(登録商標), Daiichi Sankyo Co., Ltd.)の混合物で全身麻酔し、0.4% オキシブプロカイン塩酸塩(Benoxyl(登録商標), Santen Pharmaceutical Co., Ltd.)で局所麻酔した。5μlのSB623細胞懸濁物を硝子体腔へと注射する前に、トロピカミドおよびフェニレフリン塩酸塩(Mydrin−P(登録商標), Santen Pharmaceutical Co., Ltd.)で瞳孔を開かせた。30ゲージ針を付けたHamiltonシリンジを使用して注射を行った。コントロールコホートには、ビヒクル(PBS)を注射したか、または未処置のまま(ナイーブ)であった。実験デザインを表1に示す。
SB623細胞を、実施例1に記載されるとおりに調製し、密度3×104 細胞/μlへとPBS中に懸濁した。RCSラットの免疫抑制、全身麻酔および局所麻酔、ならびに瞳孔拡大を、全て実施例2に記載されるとおりに行った。SB623細胞の移植を、30ゲージ針を付けたHamiltonシリンジを使用して、網膜下腔へと硝子体内に5μlのSB623細胞懸濁物を注射することによって生後4週間で行った。コントロールコホートにはビヒクル(PBS)を注射したか、または注射しないまま(ナイーブ)であった。実験デザインを表2に示す。この実験では、処置後より長期間にわたって分析を継続した:網膜電図記録法およびアジド応答測定を、24週間にわたって継続し、処置後27週間で得た標本に対して組織学および免疫組織化学法を行った。
実施形態1。網膜変性を処置する必要性のある被験体における網膜変性を処置するための方法であって、該方法は、SB623細胞を該被験体に投与する工程を包含する、方法。
実施形態2。SB623細胞は、前記被験体の眼に移植される、実施形態1に記載の方法。
実施形態3。前記移植は、硝子体中である、実施形態2に記載の方法。
実施形態4。前記移植は、網膜下である、実施形態2に記載の方法。
実施形態5。前記網膜変性は、網膜色素変性で起こる、実施形態1〜4のいずれかに記載の方法。
実施形態6。前記網膜変性は、加齢黄斑変性(AMD)で起こる、実施形態1〜4のいずれかに記載の方法。
特定の実施形態では、例えば以下が提供される:
(項目1)
網膜変性を処置する必要性のある被験体における網膜変性を処置するための方法であって、該方法は、SB623細胞を該被験体に投与する工程を包含する、方法。
(項目2)
SB623細胞は、前記被験体の眼に移植される、項目1に記載の方法。
(項目3)
前記移植は、硝子体中である、項目2に記載の方法。
(項目4)
前記移植は、網膜下である、項目2に記載の方法。
(項目5)
前記網膜変性は、網膜色素変性で起こる、項目1〜4のいずれかに記載の方法。
(項目6)
前記網膜変性は、加齢黄斑変性(AMD)で起こる、項目1〜4のいずれかに記載の方法。
Claims (6)
- 網膜変性を処置する必要性のある被験体における網膜変性を処置するための方法であって、該方法は、SB623細胞を該被験体に投与する工程を包含する、方法。
- SB623細胞は、前記被験体の眼に移植される、請求項1に記載の方法。
- 前記移植は、硝子体中である、請求項2に記載の方法。
- 前記移植は、網膜下である、請求項2に記載の方法。
- 前記網膜変性は、網膜色素変性で起こる、請求項1〜4のいずれかに記載の方法。
- 前記網膜変性は、加齢黄斑変性(AMD)で起こる、請求項1〜4のいずれかに記載の方法。
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PCT/US2013/030983 WO2014058464A1 (en) | 2012-10-09 | 2013-03-13 | Methods and compositions for treatment of retinal degeneration |
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US10519237B2 (en) | 2014-03-12 | 2019-12-31 | Yeda Research And Development Co. Ltd | Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS |
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US20160271181A1 (en) | 2016-09-22 |
HK1208371A1 (en) | 2016-03-04 |
AU2016213752B2 (en) | 2017-11-23 |
CN104797264A (zh) | 2015-07-22 |
IL237772A0 (en) | 2015-05-31 |
EP2906293B1 (en) | 2018-12-12 |
KR20170133515A (ko) | 2017-12-05 |
SG11201502753YA (en) | 2015-05-28 |
SG10201607176TA (en) | 2016-10-28 |
WO2014058464A1 (en) | 2014-04-17 |
AU2013330433B2 (en) | 2016-06-16 |
CA2885414C (en) | 2018-05-01 |
CA2885414A1 (en) | 2014-04-17 |
JP6267713B2 (ja) | 2018-01-24 |
AU2013330433A1 (en) | 2015-04-02 |
JP6297648B2 (ja) | 2018-03-20 |
AU2016213752A1 (en) | 2016-08-25 |
US20140099291A1 (en) | 2014-04-10 |
KR20150075082A (ko) | 2015-07-02 |
US9855299B2 (en) | 2018-01-02 |
JP2016210813A (ja) | 2016-12-15 |
IL237772B (en) | 2019-10-31 |
US9326999B2 (en) | 2016-05-03 |
KR101906756B1 (ko) | 2018-12-05 |
EP2906293A1 (en) | 2015-08-19 |
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