JP2012210228A - アンジオゲニンおよびその変異体による治療 - Google Patents
アンジオゲニンおよびその変異体による治療 Download PDFInfo
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Abstract
【解決手段】本発明は、神経細胞損傷もしくは神経細胞死、または軸索変性、特に筋萎縮性側索硬化症(ALS)などの神経変性疾患によって特徴付けられる疾患または状態を治療するための使用、またはその断片もしくは変種に関する。本発明はまた、神経変性疾患表現型、特にALS表現型に関連したヒトアンジオゲニン遺伝子における複数の変異について記載する。個体が神経損傷もしくは神経細胞死、または軸索変性によって特徴付けられる疾患または状態に罹患したかどうか、または発症することが遺伝的に予測されるかどうかを評価する方法もまた記載する。
【選択図】 図1
Description
− 個体から得られた試料中の循環アンジオゲニンの血清レベルを決定するステップと、
− 個体の循環アンジオゲニンの血清レベルと対照アンジオゲニンレベルの予め決定された範囲とを比較するステップの比較ステップを含み、
予め決定された対照範囲と比較して個体におけるアンジオゲニンの血清レベルの減少が、その個体が神経細胞損傷もしくは神経細胞死、または軸索変性によって特徴付けられる疾患または状態に罹患しているか、または発症する遺伝的素因があることを示唆する方法に関する。典型的には、予め測定された対照範囲は、神経細胞損傷もしくは神経細胞死、または軸索変性によって特徴付けられる疾患または状態に罹患していないか、または発症する遺伝的素因がない個体群から得られる。好ましい実施形態では、この診断または予後方法は、神経変性疾患、特にALSまたは運動ニューロン疾患、または原発性側索硬化症および脊髄性筋萎縮症を含むその変種の診断または予後を特に指向する。この診断/予後方法は、循環アンジオゲニンの血清レベルの測定によって明確に定められるが、全血、リンパ液、脳脊髄液、尿、唾液、精液などのその他の生体液中のアンジオゲニンレベルの測定によっても具体化され得ることは理解されよう。
・ ミニ浸透圧ポンプによるクモ膜下腔内への輸送(例えば、非特許文献3参照)。
・ 筋肉内−シリンジまたはミニ浸透圧ポンプによる筋肉内へのAng直接輸送(例えば、非特許文献4参照)。
・ 腹腔内−Angの全身投与用。シリンジまたはミニ浸透圧ポンプによる腹膜への直接投与(例えば、非特許文献5参照)。
・ 皮下−Angの全身投与用。シリンジによる皮下への直接投与(例えば、非特許文献6参照)。
・ 脳室内−注射による、または浸透圧ポンプに装着された小カテーテルを使用した、脳室への直接投与(例えば、非特許文献7参照)。
・ 移植−angを放出する移植片(例えば、小シリコン移植片)内にangを調製することができる。移植片は、筋肉または脊髄上に配置することができる(例えば、非特許文献8参照)。
本出願人は、アイルランド人およびスコットランド人集団における筋萎縮性側索硬化症の候補領域として染色体14q11.2を先に同定し(例えば、非特許文献28、29参照)、アイルランド人のALS集団において、ALSとrs11701一塩基多形との関係を報告した(例えば、非特許文献28)。独立した5種の集団のALSの個体1629人および対照1264人におけるrs11701SNPの遺伝子型解析(表2)によって、米国、英国またはスウェーデン人集団には関連性が認められなかったが、アイルランド人とスコットランド人のALS集団には関連性が確認された。rs11701SNPは、ANG、即ち1エキソン遺伝子であって、その産物が運動ニューロンで発現し、RNアーゼA活性を備えた血管新生因子であるもの、における同義の置換である。
方法
運動ニューロン変性のin vitroモデルとして、in vitroにおける7日目の運動ニューロン初代培養物を培地中においてAMPA 50μMに24時間曝露した(例えば、非特許文献44参照)。アンジオゲニンの可能性のある神経保護効果を調べるために、培地中で、アンジオゲニン(R&D systems)によるi)予備処理およびii)共処理の効果を25ng/ml、50ng/ml、100ng/ml、200ng/mlおよび500ng/mlの濃度で調べた。対照として、アンジオゲニンに曝露していないか、または(前述と同濃度で)曝露した、またはBSA(ウシ血清アルブミン、Sigma)に曝露した姉妹培養物を使用した。
1.運動ニューロン変性および脳卒中のin vitroモデルにおけるアンジオゲニンの神経保護効果。
ウェスタンブロッティングを使用して、アンジオゲニンの神経保護効果の媒介に関与する細胞生存経路を調べた。特に、PI3K/Akt細胞生存経路の活性化は、Aktの活性型(リン酸化Akt)の発現を調べることによって調査した。図4に示すように、活性化Akt(リン酸化Akt)のレベルは、AMPA単独またはアンジオゲニン単独で処理した培養物と比較して、アンジオゲニンで共処理したAMPA曝露培養物では増加していた。このAktの活性型の増加は、運動ニューロン変性のこのin−vitroモデルにおけるアンジオゲニンの神経保護効果にはPI3K/Akt経路の活性化が関与することを示している。
処理計画:
アンジオゲニン(ang)(R&D Systems Inc.、Minneapolis、USA、カタログ番号265−AN−250)を、ALS/MNDのマウスモデルである変異SOD1(mSOD1)マウスに投与する(例えば、非特許文献45参照)。これらのマウスは、Jackson Laboratory、Maine、USAから入手することができる。これらのマウスは、臨床症状が非常によく似ている進行型運動ニューロン変性および後肢麻痺のALS様表現型を発症する。この疾患は、これらのマウスで迅速に進行し、約125日の寿命を非常に縮める(例えば、非特許文献46)。異なる疾患段階でのang処理開始の効果を調べる。これらの段階は、i)症候前段階(35日から)、ii)症候初期段階(70日から)、iii)症候後期段階(90日から、患者は中後期、すなわち、麻痺が歴然としてから患者は神経科医とのみ会うので、この時点で臨床状況は最もよく似ている。)である。結果を混乱させる性差を回避するために、アンジオゲニンは、いくつかの同腹子の同性の動物に投与される。
1.クモ膜下腔内−脊髄へのangの直接送達
動物のクモ膜下腔内に、シリンジでangを投与する。これには、麻酔した動物の脊髄を、上に重なる椎骨に「穴」を創出するために椎弓切除を実施することによって露出し、次にこの穴を通して髄膜から脊髄周辺の空間にシリンジを挿入することが必要である。このシリンジは脊髄に貫通させない。
ang処理がmSOD1マウスで効果的かどうかを決定するために、処理したmSOD1マウスの疾患進行および寿命を未処理mSOD1同腹子と比較する。疾患進行のモニターには、歩行運動能力および筋肉機能の機能的評価、ならびに体重、一般的外見および運動ニューロン生存率(例えば、非特許文献48、44参照)が含まれる。寿命は、動物が生存する日数の尺度である。
Claims (9)
- 個体が神経変性疾患に罹患しているかどうか、または発症する遺伝的素因があるかどうかを評価する方法であって、個体からの生物学的試料を、表1に示したANG変異のいずれかの存在について検定するステップを含むことを特徴とする方法。
- 前記神経変性疾患は、筋萎縮性側索硬化症(ALS)または運動ニューロン疾患、または原発性側索硬化症および脊髄性筋萎縮症を含むその変種であることを特徴とする請求項1に記載の方法。
- 前記ANG変異がアミノ酸の変化であることを特徴とする請求項1または2に記載の方法。
- 前記アミノ酸の変化が、K40I、Q12L、K17I、K17E、R31K、C39WおよびI46Vからなる群から選択されることを特徴とする請求項3記載の方法。
- 前記ANG変異がヌクレオチドの変化であることを特徴とする請求項1または2に記載の方法。
- 前記ヌクレオチドの変化が、A191T、A107T、A122T、A121G、G164A、C189GおよびA208Gからなる群から選択されることを特徴とする請求項5に記載の方法。
- 表1に示されるANG変異のいずれかの存在について、個体からの生物学的試料を検定する手段が、表1のヌクレオチド変異の少なくとも1つを含むアンジオゲニン遺伝子の配列に相補的なオリゴヌクレオチドプローブ若しくはプライマーを含むことを特徴とする請求項5または6に記載の方法。
- 前記オリゴヌクレオチドプライマーが、PCR増幅用のプライマーであり、前記アンジオゲニン遺伝子の増幅が表1のヌクレオチド変異の1つが存在したときにのみ起こることを特徴とする請求項7に記載の方法。
- 前記オリゴヌクレオチドプローブ若しくはプライマーが、少なくとも14の連続的ヌクレオチドよりなることを特徴とする請求項7または8に記載の方法。
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