JP2010539084A - 治療用細胞を動物の中枢神経系に投与するための方法、医薬組成物および製品 - Google Patents
治療用細胞を動物の中枢神経系に投与するための方法、医薬組成物および製品 Download PDFInfo
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Abstract
Description
本願は、「Intranasal Delivery of Therapeutic Cells to the Central Nervous System」との表題で2007年9月11日出願の仮出願番号60/971,284号に対する利益を主張する。この出願の内容は、本明細書中に参考として援用される。
(発明の分野)
本発明は、哺乳動物の鼻腔の上部3分の1に治療用細胞を投与することで、治療用細胞が血液脳関門を迂回して、哺乳動物の傷害を受けた、および/または変性中の、および/または損傷した中枢神経系(CNS)を予防および/または処置できるようにするための方法および医薬組成物に関する。
多くの神経学的状態(neurological condition)は、加齢、疾患または損傷による、中枢神経系のある種の細胞集団の傷害または喪失、すなわち、死によってもたらされる。このような状態で傷害を受けたまたは破壊された細胞は本質的に元に戻らないため、中枢神経系は傷害を受け、および/または変性し、結果として機能が喪失する。最近の知見から、細胞移植治療によりニューロンの置換およびニューロン回路網の部分再建が可能であることが明らかにされている。この分野の初期の研究の大半は、胎児細胞療法を用いていた。しかしながら、より近年では、発育中の哺乳動物神経系、さらには成体の哺乳動物神経系に未分化の多能性神経幹細胞集団が含まれており、この細胞集団が、上記の神経学的状態の多くに対する、より効果的な神経再生戦略の設計に好都合な可塑性を示すことが明らかになった。
上述の状況を踏まえれば、治療用細胞および/または医薬組成物を、傷害を受けたおよび/または変性中の中枢神経系へと効率的で非侵襲的に送達する方法が必要である。
(定義)
本明細書で使用する場合、「中枢神経系」(CNS)とは、脳および脊髄および関連する組織をいう。
嗅神経
本発明の様々な方法は、本発明の治療用細胞および/または医薬組成物(単数または複数)を、嗅神経により支配されて鼻腔の上部3分の1に存在する組織に投与することを含む。本発明の治療用細胞および/または医薬組成物(単数または複数)は、鼻腔の上部3分の1に適用することで嗅覚野に送達することができる。
本方法の実施形態は、哺乳動物被験体の鼻腔の上部3分の1に適用することにより、本発明の治療用細胞および/または医薬組成物(単数または複数)を被験体に投与することを含む。このように本発明の治療用細胞および/または医薬組成物(単数または複数)を適用すれば、全身喪失および全身曝露を抑えつつ、治療用細胞および/または医薬組成物(単数または複数)が神経路に沿ってCNS、脳および/または脊髄に輸送されるようになる。神経路には、ニューロン内またはニューロンに沿った輸送、ニューロンと伴走するリンパ管(lymphatics)を介するまたは経由する輸送、ニューロンまたは神経路と伴走する血管の血管周囲腔を介するまたは経由する輸送、ニューロンまたは神経路と伴走する血管の外膜を介するまたは経由する輸送、または血管リンパ系を介する輸送が含まれる。
本方法の一実施形態は、嗅覚神経路に沿って制御作用物質をCNS、例えば、脳および/または脊髄に輸送するような、制御作用物質の被験体への送達を含む。一般に、こうした実施形態は、嗅神経によって支配されている組織および鼻腔内部に制御作用物質を投与することを含む。上記のように、嗅覚神経路は主として、鼻腔の上部3分の1にある嗅上皮を支配している。制御作用物質を嗅神経によって支配されている組織に適用すれば、制御作用物質をCNS、脳および/または脊髄の傷害を受けたニューロンまたは細胞に送達することができる。嗅覚ニューロンは嗅覚におけるその役割によりこの組織を支配し、CNS、脳および/または脊髄と直接連絡することができると考えられる。
上記で論じた嗅神経経路に代わる経路として、鼻腔を支配する他の神経に沿った経路、例えば、当業者(the skilled artisanl)に公知の三叉神経路が挙げられる。
本発明の治療用細胞(単数または複数)は、任意の胎児または成体哺乳動物の骨髄などの組織から誘導されても、または海馬、嗅上皮、嗅球、脳室下帯、小脳、脊髄、皮質(すなわち、運動皮質または体性感覚皮質)、線条体、前脳基底部(コリン作動性(cholenergic)ニューロン)、腹側中脳(黒質の細胞)および青斑核(中枢神経系のニューロアドレナリン細胞)由来の組織などの神経組織から誘導されてもよい。さらに、治療用細胞(単数または複数)としては、以下に限定されるものではないが、神経および/または多能性幹細胞、神経前駆細胞、遺伝子改変細胞、T細胞および/または自家の細胞を挙げることができる。
本発明では、ある種の化合物、すなわち、送達強化剤を用いて、治療用細胞を中枢神経系およびその傷害を受けた領域に送達するのを強化してもよい。好ましい送達強化剤は、ヒアルロニダーゼを含む。ヒアルロニダーゼは、本発明の治療用細胞を適用する前に有効量で投与する前処置剤として、または本発明の治療用細胞を含む医薬組成物の成分として、または治療用細胞および/または医薬組成物として実質的に同時に鼻腔の上部3分の1に鼻腔内投与する別の化合物として、鼻腔の上部3分の1に適用すると、治療用細胞のCNSへの送達を極めて顕著に増加させることが認められている。ヒアルロニダーゼは、細胞外マトリックスでヒアルロン酸に作用し、治療用細胞および/または治療用細胞を含む医薬組成物のCNSへの送達を強化すると考えられる。以下の実施例2は、こうした送達強化剤により治療用細胞のCNSへの送達の有効性が高まることを示す。
CNS内に送達される治療用細胞の、特に成長および分化を制御するある種の制御作用物質は本発明の範囲内であり、例えば、免疫および炎症反応を調節することによりドナー細胞の生存を促進する有効量の制御作用物質が挙げられる。こうした制御作用物質は、例えば、シクロスポリンおよびインターロイキン(すなわち、IL−1、IL−2、IL−3、IL−4、IL−5、IL−6、IL−7、IL−8、IL−9、IL−10)などの他の様々な免疫調節剤;腫瘍壊死因子(すなわち、TNF−αおよびTNF−β);およびインターフェロン(すなわち、IFN−α、IFN−β、INF−γ、IFN−ωおよびIFN−τ);およびこれらの任意の生物活性変異体を含む。本発明の方法によるこうした免疫調節作用物質の投与に関するさらなる詳細は、参照によって本明細書に援用する、「Methods for Administering a Cytokine to the Central Nervous System and the Lymphatic System」を発明の名称とする2000年12月9日に出願された米国特許出願第09/733,168号で確認することができる。
種々の実施形態では、本発明は、治療用細胞による治療を受けている患者を保護するため、有効量の少なくとも1種の抗生物質をさらに含んでもよいし、または代わりに、医薬組成物を鼻腔の上部3分の1に適用する前に投与する少なくとも1種の抗生物質(単数または複数)前処置剤またはその任意の組み合わせを用いてもよい。また、抗生物質(単数または複数)は、全身および/または鼻腔の上部3分の1への適用により前処置剤、併用処置剤および/または後処置剤として送達しても構わない。本発明内のこうした抗生物質要素の有用性は、治療用細胞(単数または複数)および/または医薬組成物の適用の過程で、鼻腔内に認められる細菌が鼻腔の上部3分の1の鼻組織に進入し、血液脳関門を通過してCNS内の他の組織に感染するかもしれないリスクを軽減することにある。懸念される具体的な組織として、脳組織、髄膜組織、血液組織、脊髄および他の末梢組織があるが、これに限定されるものではない。好ましい実施形態では、送達強化剤(単数または複数)、例えば、ヒアルロニダーゼを鼻腔の上部3分の1に適用する際、抗生物質(単数または複数)で患者を前処理および/または同時処置する。
本発明の別の実施形態は、宿主の免疫担当細胞の炎症反応および/または活性化から保護することで治療用細胞(単数または複数)の生存率を向上させる少なくとも1種の免疫抑制薬を有効量でさらに含んでもよい。免疫抑制薬(単数または複数)は、前処置剤として、治療用細胞(単数または複数)および/または医薬組成物と同時に、および/または治療用細胞(単数または複数)および/または医薬組成物の後処置剤として送達することができる。こうした免疫抑制療法剤と鼻腔の上部3分の1に適用される治療用細胞(単数または複数)および/または医薬組成物と組み合わせると、そうした細胞の生存が改善する。
哺乳動物の鼻腔上部3分の1に投与される有効量の少なくとも1種の治療用細胞に加えて、医薬組成物を鼻腔の上部3分の1に適用または投与してもよい。こうした医薬組成物は有効量の少なくとも1種の治療用細胞の他に含ませてもよく、例えば、その組成物は、上掲のような少なくとも1種の制御作用物質、上掲のような少なくとも1種の送達強化剤、少なくとも1種の抗生物質および/または少なくとも1種の免疫抑制薬、上記および以下に検討されるあらゆるものを含んでもよい。本発明の医薬組成物は、少なくとも1種の制御作用物質、送達強化剤、抗生物質および/または免疫抑制薬の全身および/または鼻腔の上部3分の1への適用と任意に組み合わせて前処置剤、併用処置剤および後処置剤と併用してもよい。
本発明の方法による治療用細胞の投与は、治療用細胞の単独での適用、あるいは、治療用細胞を医薬組成物として上述した化合物の1種または複数種と製剤化し、その医薬組成物をヒト患者などの動物被験体または宿主の鼻腔の上部3分の1に鼻腔内投与することを含んでもよい。治療用細胞および/、例えば、送達強化剤、制御作用物質、抗生物質および/または免疫抑制薬などのその医薬組成物の他の成分については、治療用細胞および/または医薬組成物の成分の所望の作用点で有効量となるのに十分な種々の用量のうちの1つで投与すればよい。ヒトおよび他の哺乳動物の用量は、約0.001mg/kg〜約100mg/kg、好ましくは約0.01mg/kg〜約10mg/kg、好ましくは約0.1mg/kg〜約1〜10mg/kgの幅があってもよい。上述のように、送達強化剤(単数または複数)、制御作用物質(単数または複数)、抗生物質(単数または複数)および/または免疫抑制薬(単数または複数)は、単独または医薬組成物の成分として治療用細胞(単数または複数)および/または医薬組成物とともに、前処置剤、併用処置剤および/または後処置剤として送達しても構わないが、医薬組成物中に含まれていない場合は、全身送達しても、あるいは鼻腔の上部3分の1に送達してもよい。
さらに、本発明の治療用細胞および/または治療用細胞を含む医薬組成物および/または医薬組成物の成分は、粉末または液体鼻スプレー、懸濁剤、点鼻薬、ゲル、薄膜または軟膏として、チューブまたはカテーテル、シリンジ、パックテイル、綿球(小型で平たい吸水パッド)、鼻タンポンまたは粘膜下注入により、小分けして鼻腔の上部3分の1に鼻腔内適用してもよい。本発明のいくつかの態様では、この方法は、治療用細胞および/またはその医薬組成物を送達装置により個体の鼻腔の上部3分の1に投与することを含む。経鼻薬物送達については、以下に限定されるものではないが、単一用量容器、ポンプ式スプレー、スポイト、スクイーズボトル、防腐剤を含まないエアレススプレー、ネブライザー(液体薬物をエアロゾル粒子に変えるのに使用する装置)、定量吸入器および加圧式定量吸入器などの装置を用いて行えばよい。いくつかの態様では、正確な効果的投薬量を、鼻腔の上部3分の1内およびその表面に直接設置する生体接着パッチ内に含ませる。
本発明の種々の実施形態では、治療用細胞および/または有効量の治療用細胞を含む医薬組成物および/または医薬組成物の成分を単回および1回投与として投与してもよいし、または代わりに、治療用細胞および/または医薬組成物の成分を繰り返し間歇的に投与してもよい。「間歇的投与」とは、有効量の治療用細胞および/または医薬組成物の成分を投与し、次いで一定期間中断し、その後続けて有効量でさらに投与を行い、以下同様に行うことを意味する。有効量の治療用細胞および/または医薬組成物の成分の投与については、例えば、徐放性製剤のように持続的に行ってもよいし、または、例えば、1日1回、2回、3回またはそれ以上の投与のように所望の1日投与レジメンに従って行ってもよい。「一定期間の中断」とは、治療用細胞および/または医薬組成物の成分の持続的な徐放性投与または連日投与を中断することを意味する。一定期間の中断は、持続的な徐放性投与または連日投与の期間より長くても短くても構わない。一定期間の中断の間、関連する組織中の治療用細胞および/または医薬組成物の成分のレベルは、処置中に認められる最大レベルを実質的に下回る。中断期間の好ましい長さは、使用する有効用量の濃度および治療用細胞および/または医薬組成物の成分の形態によって異なる。中断期間は少なくとも2日間としてもよいが、好ましくは少なくとも4日間、一層好ましくは少なくとも1週間であり、通常4週間を超えない。徐放性製剤を用いる場合は、損傷部位での制御作用物質の滞留時間が長くなることを考慮して中断期間を延ばす必要がある。あるいは、有効用量の徐放性製剤の投与頻度を必要に応じて減らしても構わない。治療用細胞および/または医薬組成物の成分の間歇的投与スケジュールは、疾患または障害の所望の治療効果が得られ、最終的な処置が実施されるまで継続してもよい。
本発明はまた、鼻腔の上部3分の1に鼻腔内投与し、その後血液脳関門を迂回してCNSに輸送するための本発明の治療用細胞および/または治療用細胞を含む医薬組成物および/または医薬組成物の成分を提供する製品を含む。この製品は、本方法に好適な組成物とともに乾燥形態または液体形態の任意のキャリアを含むバイアルまたは他の容器を含む。この製品はさらに、容器上のラベルとして、および/または容器が収められた箱に入っている添付文書として本発明の方法を実施するための説明書が付いている。また、説明書は、バイアルが収められた箱に印刷されていてもよい。説明書には、被験体または当業者が本発明の治療用細胞および/または治療用細胞を含む医薬組成物および/または医薬組成物の成分を投与できるよう投薬量および投与に関する十分な情報などの情報が記載されている。当業者には任意の医師、看護師、技術者、配偶者または本発明の治療用細胞および/または治療用細胞を含む医薬組成物および/または医薬組成物の成分を投与し得る他の介護者が包含されると思われる。治療用細胞および/または医薬組成物の成分は、被験体により自己投与されてもよい。
本発明者らは、健康な齧歯動物(マウスおよびラット)と、パーキンソン病のモデルを作製するため6−OHDA(6−hydroxydopamine)で処置したラットとを用いて、治療用細胞が血液脳関門を迂回することが実際に可能であるという仮説を試験した。この実施例では、健康な成体マウスの鼻腔の上部3分の1、およびパーキンソン病患者の傷害を受けたおよび/または変性中のCNSのモデルとなる、6−ヒドロキシドーパミン(6−OHDA)片側性病変のラットに間葉系幹細胞、すなわち、真核細胞を鼻腔内投与した。加えて、神経膠腫細胞を健康な若年ラットの鼻腔の上部3分の1に鼻腔内投与した。投与/適用から1時間以内にどちらの細胞型も、健康な動物の嗅球、皮質、海馬、線条体および小脳に到達した。パーキンソン病の6−OHDAラットモデルの場合、投与から4時間後に細胞を検出した。どちらの症例も、1時間未満で細胞が脳に到達していた可能性があると考えられる。細胞が篩板を通過した後、2つの移動経路が観察された:(1)嗅球、さらに皮質および線条体などの脳の他の部分への移動;および(2)皮質の表面に沿って移動して脳脊髄液に進入し、その後脳実質に進入する移動。
CFDAまたはHoechst色素で標識したラット間葉系幹細胞(MSC:mesenchymal stem cell)を7週齢のC57 bl/6マウスの鼻腔の上部3分の1に鼻腔内適用して、治療用細胞の投与および適用および輸送において血液脳関門を迂回して治療用細胞を脳へ鼻腔内送達することの有効性を評価した。
実施例2から得られ上述した結果は、鼻腔内適用した治療用細胞が皮質、嗅球および小脳に加えて線条体領域にも認められたことを示すため、成体ラットの6−OHDAによる片側性病変モデルを用いて、神経変性により、適用した細胞が病変側に向かい得るかどうかを調査することとした。
この研究では、鼻腔内投与後に治療用幹細胞だけでなく腫瘍細胞も脳に送達することができるか否かを検討する。ヒトPhi−YellowおよびCFDA標識T406神経膠腫細胞を10日齢のラット(n=5)の鼻腔の上部3分の1に鼻腔内投与した。投与から1時間後、動物を屠殺した。動物の全頭(頭蓋および脳を含む)の矢状切片(20μm)を蛍光顕微鏡で観察した。CFDA標識神経膠腫細胞は、鼻腔、篩板、嗅球、前頭皮質および海馬領域で確認された。
Claims (30)
- 動物の傷害を受けた、または変性中の、または損傷した中枢神経系に治療用細胞を輸送するための方法であって、該傷害または変性は中枢神経系細胞の喪失または死を引き起こす神経学的な疾患または状態によって引き起こされ、該方法は:
少なくとも1種の治療用細胞を該哺乳動物の鼻腔の上部3分の1に適用すること;および
該治療用細胞が血液脳関門を迂回して、該傷害を受けた中枢神経系に到達できるようにすること
を含む、方法。 - 前記少なくとも1種の治療用細胞を嗅神経によって支配されている組織に投与し、該少なくとも1種の治療用細胞が前記血液脳関門を迂回して前記傷害を受けた中枢神経系に到達すること、および
該中枢神経系の外側での該治療用細胞の全身送達を最小限に押さえること
をさらに含む、請求項1に記載の方法。 - 神経路に沿って前記傷害を受けた中枢神経系に移動することにより、前記血液脳関門を迂回する前記少なくとも1種の治療用細胞をさらに含む、請求項2に記載の方法。
- 前記中枢神経系内の傷害領域に優先的に移動する前記少なくとも1種の治療用細胞をさらに含む、請求項3に記載の方法。
- 前記動物の鼻腔の上部3分の1に有効量でヒアルロニダーゼを鼻腔内適用することをさらに含む、請求項1に記載の方法。
- 前記少なくとも1種の治療用細胞を前記動物の鼻腔の上部3分の1に適用する前に有効量でヒアルロニダーゼを適用することをさらに含む、請求項1に記載の方法。
- 前記少なくとも1種の治療用細胞および有効量のヒアルロニダーゼを含む医薬組成物を提供すること;および有効量の該医薬組成物を前記動物の鼻腔の上部3分の1に適用することをさらに含む、請求項1に記載の方法。
- 前記治療用細胞は真核細胞を含む、請求項1に記載の方法。
- 前記治療用細胞は幹細胞を含む、請求項1に記載の方法。
- 前記治療用細胞は治療作用を発揮できる腫瘍細胞を含む、請求項1に記載の方法。
- 前記少なくとも1種の治療用細胞を生理学的有効量で前記動物の鼻腔の上部3分の1に適用して、前記傷害を受けた中枢神経系の失われた細胞および/または死につつある細胞を置換することを含む治療作用を提供することをさらに含む、請求項1に記載の方法。
- 前記医薬組成物を生理学的有効量で前記動物の鼻腔の上部3分の1に適用して、前記傷害を受けた中枢神経系の失われた細胞および/または死につつある細胞を置換することを含む治療作用を提供することをさらに含む、請求項7に記載の方法。
- 前記神経学的な疾患または状態はパーキンソン病を含む、請求項1に記載の方法。
- 前記神経学的な疾患または状態はアルツハイマー病を含む、請求項1に記載の方法。
- 前記神経学的な疾患または状態は虚血を含む、請求項1に記載の方法。
- 動物の傷害を受けた、または変性中の中枢神経系に治療用細胞を輸送するための方法であって、該傷害または変性は中枢神経系細胞の失われたかまたは死を引き起こす神経学的な疾患または状態によって引き起こされ、該方法は:
少なくとも1種の治療用細胞および少なくとも1種の送達強化剤を含む医薬組成物を提供すること;
該医薬組成物を該哺乳動物の鼻腔の上部3分の1に適用すること;および
該治療用細胞が血液脳関門を迂回して、該傷害を受けた中枢神経系に到達できるようにすることを含む、方法。 - 前記少なくとも1種の送達強化剤はヒアルロニダーゼを含む、請求項16に記載の方法。
- 前記少なくとも1種の送達強化剤はヒアルロニダーゼ、遊走誘導活性およびニューレグリンからなる群のうちの1つをさらに含む、請求項17に記載の方法。
- 前記医薬組成物を適用する前に有効量の少なくとも1種の抗生物質で鼻腔の上部3分の1を前処置することをさらに含む、請求項17に記載の方法。
- 前記医薬組成物中に有効量の少なくとも1種の抗生物質を提供することをさらに含む、請求項17に記載の方法。
- 前記医薬組成物を適用する前に有効量の少なくとも1種の抗生物質で鼻腔の上部3分の1を前処置することをさらに含む、請求項20に記載の方法。
- 前記医薬組成物中に有効量の少なくとも1種の制御作用物質を提供することをさらに含む、請求項20に記載の方法。
- 前記医薬組成物中に有効量の少なくとも1種の免疫抑制薬を提供することをさらに含む、請求項20に記載の方法。
- 哺乳動物の傷害を受けた、または変性中の、または損傷した中枢神経系を処置するための鼻腔内送達される医薬組成物であって:
少なくとも1種の治療用細胞;および
該少なくとも1種の治療用細胞が血液脳関門を通過するのを補助する少なくとも1種の送達強化剤
を含み、該医薬組成物は該哺乳動物の鼻腔の上部3分の1に投与される、医薬組成物。 - 前記少なくとも1種の送達強化剤はヒアルロニダーゼを含む、請求項24に記載の医薬組成物。
- 前記少なくとも1種の送達強化剤はニューレグリンおよび遊走誘導活性をさらに含む、請求項25に記載の医薬組成物。
- 少なくとも1種の抗生物質をさらに含む、請求項25に記載の医薬組成物。
- 少なくとも1種の免疫抑制薬をさらに含む、請求項27に記載の医薬組成物。
- 少なくとも1種の制御作用物質をさらに含む、請求項24に記載の医薬組成物。
- 少なくとも1種の制御作用物質をさらに含む、請求項28に記載の医薬組成物。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US97128407P | 2007-09-11 | 2007-09-11 | |
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Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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KR20220005900A (ko) * | 2020-07-07 | 2022-01-14 | 가톨릭대학교 산학협력단 | 뇌신경계질환 예방 또는 치료용 약학적 조성물 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002531489A (ja) * | 1998-12-09 | 2002-09-24 | カイロン コーポレイション | 中枢神経系への神経栄養剤の投与 |
US20020169102A1 (en) * | 2001-04-03 | 2002-11-14 | Frey William H. | Intranasal delivery of agents for regulating development of implanted cells in the CNS |
JP2006516558A (ja) * | 2003-01-17 | 2006-07-06 | シエーリング オサケユイチア | 耳科学的送達装置 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5624898A (en) * | 1989-12-05 | 1997-04-29 | Ramsey Foundation | Method for administering neurologic agents to the brain |
US20040266715A1 (en) | 1999-03-31 | 2004-12-30 | Wong Liang Fong | Neurite regeneration |
US6667176B1 (en) * | 2000-01-11 | 2003-12-23 | Geron Corporation | cDNA libraries reflecting gene expression during growth and differentiation of human pluripotent stem cells |
CN100425287C (zh) | 1999-02-09 | 2008-10-15 | 理化学研究所 | 肿瘤疫苗 |
US6749850B1 (en) * | 1999-08-18 | 2004-06-15 | The General Hospital Corporation | Methods, compositions and kits for promoting recovery from damage to the central nervous system |
JP3886346B2 (ja) | 2001-06-22 | 2007-02-28 | サンバイオ,インコーポレイティド | 骨髄間質細胞由来Schwann細胞を含む神経再生用医薬組成物 |
WO2005056755A2 (en) | 2003-12-02 | 2005-06-23 | Catholic Healthcare West | Compositions and methods for propagation of neural progenitor cells |
US20070122392A1 (en) * | 2005-06-22 | 2007-05-31 | Sharon Gerecht-Nir | Propagation of undifferentiated embryonic stem cells in hyaluronic acid hydrogel |
US9456979B2 (en) | 2006-04-27 | 2016-10-04 | Sri International | Adminstration of intact mammalian cells to the brain by the intranasal route |
US8168169B2 (en) * | 2006-08-09 | 2012-05-01 | Mclean Hospital Corporation | Methods and compositions for the treatment of medical disorders |
US8283160B2 (en) | 2007-09-11 | 2012-10-09 | Frey Ii William H | Methods, pharmaceutical compositions and articles of manufacture for administering therapeutic cells to the animal central nervous system |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002531489A (ja) * | 1998-12-09 | 2002-09-24 | カイロン コーポレイション | 中枢神経系への神経栄養剤の投与 |
US20020169102A1 (en) * | 2001-04-03 | 2002-11-14 | Frey William H. | Intranasal delivery of agents for regulating development of implanted cells in the CNS |
JP2006516558A (ja) * | 2003-01-17 | 2006-07-06 | シエーリング オサケユイチア | 耳科学的送達装置 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017522144A (ja) * | 2014-07-29 | 2017-08-10 | ピーター・エデンホッファー | 薬剤送達用陽圧吸入装置 |
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