JP7134089B2 - 老化に関連した障害を処置するための方法及び組成物 - Google Patents
老化に関連した障害を処置するための方法及び組成物 Download PDFInfo
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Description
上述したように、本発明の態様は、成体哺乳類の老化に関連する障害を処置する方法を含んでいる。老化に関連する障害は、多くの異なる態様で、例えば老化に関連する認知障害及び/又は生理学的障害として、例えば細胞損傷、組織損傷、臓器機能不全、老化に関連する寿命の短縮及び発癌のような、しかしこれらに限定されない身体の中心の臓器又は末梢の臓器への損傷の形態(ここで、注目する特定の臓器及び組織は、皮膚、ニューロン、筋肉、膵臓、脳、腎臓、肺、胃、小腸、脾臓、心臓、脂肪組織、精巣、卵巣、子宮、肝臓及び骨が含まれるが、これらに限定されない)で、神経発生の減少の形態などで現れる場合がある。
本方法は、個体の認知能力の障害のような老化に関連する障害及びこのような障害に関連する状態を処置する、例えば予防する際に使用される。老化に関連する認知障害を患うか又は発症する危険性がある個体は、約50歳以上、例えば60歳以上、70歳以上、80歳以上、90歳以上であって、通常100 歳以下、つまり約50歳と100 歳との間の年齢、例えば50歳、55歳、60歳、65歳、70歳、75歳、80歳、85歳、90歳、95歳又は約100 歳であり、自然老化現象に関連した認知障害、例えば軽度認知障害(M.C.I.)を患う個体と、約50歳以上、例えば60歳以上、70歳以上、80歳以上、90歳以上であって、通常100 歳以下、つまり約50歳と90 歳との間の年齢、例えば50歳、55歳、60歳、65歳、70歳、75歳、80歳、85歳、90歳、95歳又は約100 歳であり、認知障害の症状をまだ示し始めていない個体とを含んでいる。自然老化による認知障害の例として、以下が含まれる。
アルツハイマー病は、b-アミロイドとタウタンパク質から成る神経原線維濃縮体とを更に含んでいる、大脳皮質及び皮質下灰白質内の過剰な数の老人斑に関連した認知機能の進行性の止められない消失である。一般的な形態は60歳を超える人に発症し、年齢が進むにつれてその発生率が上昇する。アルツハイマー病は、高齢者の認知症の65%を超える割合を占める。
パーキンソン病(PD)は、緩慢な動作、筋固縮、静止振戦及び姿勢の不安定によって特徴付けられる特発性で、緩徐進行性の中枢神経系の変性疾患である。当初は主に運動障害とみなされていたが、PDは現在、認知、行動、睡眠、自律神経機能及び感覚機能に更に影響を及ぼすと認識されている。最も一般的な認知障害として、注意、集中、作業記憶、実行機能、言語の生成及び視空間機能の障害が含まれる。
前頭側頭型認知症(FTD )は、脳の前頭葉の進行性悪化に起因する疾患である。変性は、側頭葉に経時的に進む場合がある。FTD は、有病率でアルツハイマー病(AD)に次いで2番目であり、初老期の認知症の症例の20%を占める。症状は、発症した前頭葉及び側頭葉の機能に基づき3つのグループ:一方で嗜眠及び自発性喪失を含み、他方で脱抑制を含む症状を有する行動異常型FTD (bvFTD );明瞭な発音の困難、音韻体系の誤り及び/又は構文誤りによる発語の流暢性の崩壊が観察されるが、言葉の理解は保持されている進行性非流暢性失語(PNFA);及び、患者は正常な音韻論及び構文で流暢なままであるが、呼称及び言葉の理解で困難さが増す意味性認知症(SD)に分類される。全てのFTD 患者に共通する他の認知症状として、実行機能及び集中力の障害が含まれる。知覚、空間能力、記憶及び練習を含む他の認知能力が典型的には損なわれないままである。FTD は、構造的MRI スキャンにおいて明らかになる前頭葉及び/又は前側頭葉の萎縮を観察することにより診断され得る。
ハンチントン病(HD)は、情緒異常、行動異常及び精神異常の発症と、知的機能又は認知機能の消失と、動作異常(運動障害)とにより特徴付けられる遺伝性の進行性神経変性障害である。HDの古典的な徴候として、顔、腕、脚又は体幹に影響を及ぼす場合がある付随性で急速且つ不規則な痙攣様運動である舞踏病の発症と、思考過程能力及び後天性の知的能力を徐々に消失する認知機能低下とが含まれる。記憶、抽象的思考及び判断の障害;時間、場所又はアイデンティティの不適切な知覚(失見当識);激越の増加;及び人格変化(人格の崩壊)がある場合がある。症状は典型的には30歳代又は40歳代の間に明らかになるが、発病の年齢は不定的であり、幼児期から成人後期(例えば70歳代又は80歳代)の範囲内である。
筋萎縮性側索硬化症(ALS )は、運動ニューロンを攻撃する急速に進行して常に致死的な神経疾患である。筋力低下並びに前角細胞の萎縮及び機能障害の徴候は最初、ほとんどの場合手に認められ、足に認められることは少ない。発病の箇所はランダムであり、進行は非対称である。痙攣がよく見られ、衰弱より先に生じる場合がある。例外的に、患者は30年間生存し、50%が発病後3年以内に死亡し、20%が5年間生存し、10%が10年間生存する。診断上の特徴として、中年期又は成人後期中の発病、及び感覚異常のない進行性で全身性の運動障害が含まれる。この疾患の末期まで、神経伝達速度は正常である。最近の研究は、同様に認知障害の症状、特に即時性の言語記憶、視覚記憶、言語及び実行機能の低下を実証した。
多発性硬化症(MS)は、寛解及び再発性の悪化と共に、中枢神経系の機能障害の様々な症状及び徴候によって特徴付けられる。最も一般的な主症状は、一又は複数の四肢、体幹又は顔の一側における感覚異常;脚若しくは手の衰弱若しくは失調;又は、視覚障害、例えば部分盲及び一方の目の痛み(球後視神経炎)、視覚の薄暗さ若しくは暗点である。一般的な認知障害として、記憶(新しい情報の取得、保持及び検索)、注意及び集中(特に分割的注意)、情報処理、実行機能、視空間機能及び言語流暢性の障害が含まれる。一般的な初期症状は、眼筋麻痺による複視(double vision )(複視(diplopia))、一又は複数の四肢の一時的な衰弱、肢の僅かな硬直又は異常な疲労感、軽微な歩行障害、膀胱制御困難、回転性めまい、及び軽微な情緒障害であり、全ての症状は、散在性の中枢神経系障害を示し、疾患が認識される前の何ヶ月又は何年も前に生じることが多い。過剰な熱が症状及び徴候を際立たせる場合がある。
緑内障は、網膜神経節細胞(RGC )に影響を及ぼす一般的な神経変性疾患である。区画化された変性プログラムがRGC を含むシナプス及び樹状突起に存在することをサポートする証拠がある。最近の証拠は、高齢者の認知障害と緑内障との相関関係を更に示している(Yochim BP 等著,Prevalence of cognitive impairment, depression, and anxiety symptoms among older adults with glaucoma. J Glaucoma. 2012;21(4):250-254)。
筋強直性ジストロフィ(DM)は、ジストロフィ性筋力低下及び筋強直症によって特徴付けられる常染色体優性多系統障害である。分子欠損は、染色体19q の筋強直タンパク質キナーゼ遺伝子の3'非翻訳領域の伸長トリヌクレオチド(CTG )反復である。症状はあらゆる年齢で生じる場合があり、臨床重症度の範囲は広い。筋強直症は手の筋肉で顕著であり、軽度な症例でも眼瞼下垂が一般的である。重度な症例では、著しい末梢の筋低下が、多くの場合、白内障、早期の脱毛、斧状顔貌、不整脈、精巣萎縮及び内分泌異常(例えば糖尿病)と共に生じる。精神遅滞は重症先天性の形態で一般的である一方、前頭部及び側頭部の認知機能、特に言語機能及び実行機能の加齢性の低下は、障害のより軽症な成人の形態に観察される。重症の人は、50代前半までに死亡する。
認知症は、日常機能を妨げるほど重症な、思考能力及び社会能力に影響を及ぼす症状を有する障害のクラスのことである。上記に記載された老化に関連する障害の後期段階で観察される認知症に加えて、認知症の他の症例として、以下に述べる血管性認知症とレヴィ小体型認知症とが含まれる。
進行性核上性麻痺(PSP )は、複雑な目の動き及び思考の問題と共に、歩行及びバランスの制御に関する重大で進行性の問題を引き起こす脳障害である。この疾患の古典的な徴候の内の1つは、目を適切に向ける能力の欠如であり、目の動きを調整する脳の領域の病変のために生じる。一部の個体はこの影響をかすむと表現する。発症した個体は、抑うつ及び無感情並びに進行性の軽度認知症を含む、気分及び行動の変化を示すことが多い。この疾患の長い名前は、疾患がゆっくり始まり悪化し続け(進行性であり)、目の動きを制御する細胞核と称される豆粒大の構造の上方の脳のある部分(核上)を損傷することにより衰弱(麻痺)を引き起こすことを示している。3人の科学者がこの状態をパーキンソン病と区別する論文を発表した1964年に、PSP が別個の障害として最初に表現された。PSP は、この障害を定めた科学者の名前の組合せを反映して、スティール-リチャードソン-オルスゼフスキー症候群と称されることもある。PSP は次第に悪化するが、PSP 自体で死亡する人はいない。
運動失調を呈する人は、動き及びバランスを制御する神経系の部分に変調をきたすため、調整に関する問題を有する。運動失調は、指、手、腕、脚、身体、発語及び目の動きに影響を及ぼし得る。運動失調という言葉は、感染、損傷、他の疾患又は中枢神経系の変性変化と関連付けられ得る協調運動障害の症状を表現するために使用されることが多い。運動失調は更に、National Ataxia Foundationの主たる重点である遺伝性及び散発性の運動失調と称される神経系の特異的な変性疾患のグループを示すために用いられる。
複合神経系萎縮(MSA )は変性神経疾患である。MSA は、脳の特定の領域の神経細胞の変性と関連付けられる。この細胞変性は、動き、バランス、及び膀胱の制御又は血圧の調節のような身体の他の自律神経機能に関する問題を引き起こす。MSA の原因は分かっておらず、特異的な危険因子が識別されていない。症例の約55%が男性で生じ、発症する典型的な年齢は50代後半から60代前半である。MSA は、パーキンソン病と同じ症状の一部を示すことが多い。しかしながら、MSA 患者は、パーキンソン病に使用されるドーパミン剤に反応するにしても、一般にごく僅かしか反応しない。
更に、上記の方法の内の一又は複数を実施するための試薬、デバイス及びキットを提供する。本試薬、本デバイス及び本キットは大幅に異なってもよい。注目する試薬及びデバイスは、成体哺乳類のB2M レベルを下げる方法に関して上記に記載されているものを含んでいる。
以下の実施例は、本発明をどのように作製して使用するかについての完全な開示及び説明を当業者に提供するために記載されるのであって、本発明者らが自身の発明であるとみなすものの範囲を限定することを意図するものではなく、以下の実験が、行われた全ての又は唯一の実験であると表すことを意図するものでもない。使用された数値(例えば、量、温度等)に関して正確性を確保するために努力がなされたが、ある程度の実験誤差及び偏差は考慮に入れられるべきである。別途記載のない限り、部は重量部であり、分子量は重量平均分子量であり、温度は摂氏であり、圧力は大気圧であるか又は大気圧に近い圧力である。
A.動物モデル
C57BL/6 (The Jackson Laboratory)、C57BL/6 老齢マウス(National Institutes of Aging)、β2ミクログロブリン(B2M-/-)変異マウス及び抗原ペプチド輸送体1(Tap1 -/-)変異マウス(The Jackson Laboratory)のマウス系統を使用した。全ての研究はオスのマウスで行った。統計的な有意差をもたらすために使用されたマウスの数を、α=0.05及び0.8 の検出力での標準的な検出力計算を使用して計算した。本発明者らはオンラインツール(http://www.stat.uiowa.edu/~rlenth/Power/index.html)を使用して、夫々の試験での経験、分析の変動性及びグループ内の個体差に基づき検出力及びサンプルサイズを計算した。マウスを特定病原体未感染の状態で12時間の明暗サイクルで収容し、全ての動物の取り扱い及び使用については、the University of California San Francisco IACUC及びthe VA Palo Alto Committee on Animal Researchによって承認された組織的ガイドラインに従った。
並体結合の手術は既に述べた手順に従った(Villeda, S.A. 等著,「The ageing systemic milieu negatively regulates neurogenesis and cognitive function」,Nature (2011) 477: 90-94)、(Villeda, S.A. 等著,「Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice」,Nature medicine (2014) 20:659-663)。左側腹部及び右側腹部の鏡像切開を皮膚を通して行い、より小さい切開を腹壁を通して行った。隣接した並体結合体の腹膜の開口部を共に縫合した。各並体結合体の肘及び膝関節を共に縫合し、各マウスの皮膚を、隣接した並体結合体の皮膚にステープルで留めた(9mm Autoclip ,Clay Adams)。痛みを管理するように各マウスにBaytril の抗生物質及びBuprenexを皮下注射して回復中に監視した。健康全般及び維持行動に関して、対の重量及び身繕い行動を含む複数の回復特性を手術後の様々な時点で分析した。
動物を定位フレームに置き、麻酔ノーズコーンを通して運ばれた2%のイソフルラン(2L/分の酸素流速)で麻酔した。手術中の乾燥を防ぐために眼軟膏(Puralube Vet Ointment, Dechra)を角膜に塗布した。切開の周りの領域を切り取った。背側海馬のDGの両側に(ブレグマから)前方=-2mm、側方=1.5 mm、(頭蓋表面から)高さ=-2.1 mmの座標を用いて溶液を注射した。2μlの溶液を5μl26s ゲージハミルトン注射器を使用して(注射速度:0.20μl/分で)10分間に亘って定位で注射した。注射の跡に沿った逆流を制限するために、針を原位置で8分間維持して途中まで徐々に引き抜き、更に2分間所定の位置で維持した。皮膚を絹縫合で閉じた。各マウスに鎮痛性のBuprenexを皮下注射した。マウスを単独で収容して回復中に監視した。
無担体の精製されたヒトβ2ミクログロブリン(Lee Biosolutions)をPBS に溶解して、若齢(3ヶ月)野生型動物に眼窩内を通って全身に(100 μg/kgで)投与するか、又は、若齢(3ヶ月)野生型且つTap1-/- 変異体の海馬のDGに(0.50μl;0.1 μg/μlで)定位に投与した。組織学的分析のために、B2M 及び媒体を同一の動物の対側性のDGに投与した。行動分析のために、B2M 又は媒体をDGの両側に投与し、認知機能試験前に6日間又は30日間マウスを回復させた。
短期間のBrduの標識のために、屠殺前に50 mg/kgのBrdUを毎日、3日間又は6日間マウスの腹腔内に注射した。長期間のBrduの標識のために、50 mg/kgのBrdUを6日間1日に1回マウスに注射し、第1回目の投与から28日後に動物を屠殺した。脳のBrdU陽性細胞の総数を推定するために、本発明者らは、合計6つの切片に関して6個の半脳切片毎にBrdUのDAB 染色を行った。DGの顆粒細胞及び顆粒下細胞層のBrdU陽性細胞の数を合計して12を掛けて、DG全体のBrdU陽性細胞の総数を推定した。分裂細胞の運命を決定するために、マウス当たり4~6個の切片で合計200 個のBrdU陽性細胞を、NeuN及びGFAPを用いた同時発現に関して共焦点顕微鏡検査によって分析した。二重陽性細胞の数をBrdU陽性細胞の百分率として表現した。
組織処理及び免疫組織化学法を、標準的な公開された技術の後に浮遊性切片に関して行った(Villeda, S.A. 等著,「The ageing systemic milieu negatively regulates neurogenesis and cognitive function」,Nature (2011) 477: 90-94)。一時的に、マウスを400 mg/kg の抱水クロラール(Sigma-Aldrich)で麻酔して0.9 %の生理食塩水で経心的に潅流した。脳を取り除いて、4%のリン酸緩衝のパラホルムアルデヒド(pH 7.4)に4°Cで48時間固定し、その後、凍結保護のために30%のスクロースに浸透させた。その後、脳をクライオミクロトーム(Leica Camera, Inc.)を用いて40μmで冠状に薄片に切り分けて凍結保護媒体に保管した。一次抗体は、ヤギ抗-Dcx(1:500; Santa Cruz Biotechnology; sc-8066, clone: C-18)、ラット抗-BrdU(1:5000, Accurate Chemical and Scientific Corp.; ab6326, clone: BU1/75)、マウス抗-Nestin(1:500; Millipore; MAB353; clone: rat-401)、MCM2(1:500, BD Biosciences; 610700; clone: 46/BM28)、ニワトリ抗-Tbr2(1:500; Millipore; AB15894)、マウス抗-NeuN(1:1000; Millipore; MAB377; clone: A60)、ウサギ抗-GFAP(1:500; DAKO; Z0334)である。一晩培養した後、一次抗体染色を、ジアミノベンジジン(DAB, Sigma-Aldrich)又は蛍光性結合二次抗体(Life Technologies)と共にビオチン化二次抗体(Vector)及びABC キット(Vector)を用いて示した。BrdUの標識のために、脳の切片を2N HClで30分間37℃で予め処置し、一次抗体と共に培養する前にTris-Buffered Saline with Tween (TBST)を用いて3回洗浄した。Nestin及びTbr2の標識のために、脳の切片を0.1 M クエン酸塩で5分間95℃で3回予め処置し、一次抗体と共に培養する前にTris-Buffered Saline with Tween(TBST)を用いて3回洗浄した。DG当たりのDcx 陽性細胞の総数を推定するために、DGの顆粒細胞及び顆粒下細胞層の免疫陽性細胞を、合計6個の切片に関して海馬の6個の冠状半脳切片毎に合計して12を掛けた。
マウスの海馬を動物の潅流後に解剖して急速冷凍し、RIPA溶解緩衝液(500 mM Tris,pH 7.4,150 mM NaCl ,0.5 %デオキシコール酸ナトリウム,1%NP40,0.1 %SDS 及び完全プロテアーゼ阻害剤;Roche )で溶解した。組織溶解物を4×NuPage LDSローディング緩衝液(Invitrogen)と混合して4~12%のSDS ポリアクリルアミド勾配ゲル(Invitrogen)上にロードし、その後、ニトロセルロース膜に移した。ブロットをTris-Buffered Saline with Tween (TBST)中の5%の乳にブロックして、ウサギ抗アクチン(1:5000,Sigma ;A5060 )及びウサギ抗B2M(1:2500,Abcam ;ab75853 ;クローン:EP2978Y )で培養した。西洋ワサビペルオキシダーゼ結合二次抗体(1:5000, GE Healthcare; NA934)及びECL キット(GE Healthcare/Amersham Pharmacia Biotech)を用いてタンパク質信号を検出した。露出を多数回行い、ダイナミックレンジのフィルム(GE Healthcare Amersham HyperfilmTM ECL)内の画像を選択した。選択したフィルムを(300dpiで)スキャンしてImageJソフトウェア(バージョン 1.46k)を使用して定量化した。アクチンのバンドを正規化のために使用した。
上述したように(Villeda, S.A. 等著,「The ageing systemic milieu negatively regulates neurogenesis and cognitive function」,Nature (2011) 477: 90-94)、(Mosher KI 等著,「Neural progenitor cells regulate microglia functions and activity」,Nature neuroscience. 2012; 15:1485-1487)、C57BL/6 マウス又はDcx-レポータマウス(Couillard-Despres S 等著,「In vivo optical imaging of neurogenesis: watching new neurons in the intact brain」,Molecular imaging. 2008; 7:28-34.)からマウスの神経前駆細胞を分離した。出生後の動物(1日齢)からの脳を解剖して嗅球、皮質、小脳及び脳幹を取り除いた。表在血管を取り除いた後、海馬を最終的にメスで切り刻み、2.5 U/mlパパイン(Worthington Biochemicals)、1U/mlディスパーゼII(Boeringher Mannheim)及び250 U/ml DNase I(Worthington Biochemicals)を含むDMEMB 媒体で30分間37℃で消化して機械的に分離した。NSC /前駆体を65%のパーコール勾配を使用して精製して、覆われていない組織培養皿に105 細胞/cm2 の密度で播いた。NPC を、ペニシリン(100 U/ml)、ストレプトマイシン(100 mg/ml)、2mMのL-グルタミン、ビタミンA無しの無血清B27 補給剤(Sigma-Aldrich )、bFGF(20 ng/ml)及びEGF (20 ng/ml)が補われたNeuroBasal A媒体に48時間標準状態下で培養した。無担体形態のヒト組換えB2M (Vendor)をPBS で溶解して、細胞を播いた後、1日おきに自己再生条件下で細胞培養物に追加した。増殖のために、BrdUの取込みを、検出用色基質(Fisher)と共にペルオキシダーゼ結合抗BrdU抗体を使用する細胞増殖分析システムを用いて測定した。生物発光分析のためにDcx-ルシフェラーゼ活性をルシフェラーゼ分析システム(Promega )を使用して測定した。マウス抗MAP2(1:1000,Sigma ;M9942 ;クローン:HM-2)抗体及びウサギ抗GFAP(1:500 ,DAKO;Z0334 )抗体を使用して免疫組織化学法によって分化を評価した。Pierce LDH細胞毒性分析システム(Life Technologies )を使用して乳酸脱水素酵素(LDH )検出により細胞毒性を測定した。
このタスクでは、マウスは、海馬に依存する文脈的恐怖条件付けに関する試験を可能にする嫌悪刺激(軽度なフットショック;無条件刺激(US))と環境的文脈(恐怖条件付けチャンバ)とを関連付けることを学習した。文脈的恐怖条件付けは海馬及び扁桃体に依存しているため、扁桃体に依存する手がかりの恐怖条件付けを更に評価すべく、軽度なフットショックを光及び音の手がかり(条件刺激(CS))と対にした。条件付け恐怖をフリージング行動として表示した。具体的な訓練パラメータは、音の継続時間30秒;レベル70dB,2kHz ;ショックの継続時間2秒;強度0.6 mAである。この強度は痛みがなく、容易に耐えることができるが、不快感を生じさせる。より具体的には、1日目、各マウスを恐怖条件付けチャンバに置いて2分間散策させた後、2秒のフットショック(0.6 mA)で終わる30秒の音(70dB)を与えた。2分後、2回目のCS-US対を与えた。2日目、全く同一の文脈を含むが、CS又はフットショックを与えない恐怖条件付けチャンバに各マウスをまず置いた。フリージングを1~3分間分析した。1時間後、異なる臭気、洗浄液、床の質感、チャンバの壁及び形状を含む新たな文脈にマウスを置いた。動物を、CSに再度曝す前に2分間散策させた。フリージングを1~3分間分析した。FreezeScanビデオ追跡システム及びソフトウェア(Cleversys, Inc)を使用してフリージングを測定した。
Alamed等著,Nat. Protocols (2006) 1: 1671-1679に記載されているプロトコルの後、放射状枝水迷路(RAWM)パラダイムを使用して空間的な学習及び記憶を評価した。このタスクでは、プラットフォームを含むゴールのアーム位置は訓練段階及び試験段階を通して一定のままであるが、スタートのアームは各試験中に変わっている。訓練段階の1日目、マウスを15の試験に関して訓練し、試験は目視可能なプラットフォーム及び隠したプラットフォームに関して交互に行う。試験段階の2日目、マウスを、隠したプラットフォームについて15の試験に関して試験する。正しくないアームへのエントリをエラーとして採点し、エラーを訓練ブロック(3回の連続した試験)について平均する。研究者らは、採点するときに遺伝子型及び処置を知らされていなかった。
マウスの血液を、屠殺の際に尾静脈の出血、下顎静脈の出血又は心臓内の出血によってEDTAで覆った管に収集した。1000 gの新たに収集された血液で遠心分離によってEDTA血漿を生成し、アリコートを使用まで-80℃で保管した。University of Washington School of Medicine、Veterans Affairs Northwest Network Mental Illness Research, Education, and Clinical Center、Oregon Health Science University及びUniversity of California San Diegoからヒト血漿及びCSF サンプルを得た。上述したように(Villeda, S.A. 等著,「The ageing systemic milieu negatively regulates neurogenesis and cognitive function」,Nature (2011) 477: 90-94)、(Zhang, J. 等著,「CSF multianalyte profile distinguishes Alzheimer and Parkinson diseases」,American journal of clinical pathology (2008) 129: 526-529)、(Li, G.等著,「Cerebrospinal fluid concentration of brain-derived neurotrophic factor and cognitive function in non-demented subjects」,PloS one (2009) 4: e5424)、標準化された選択基準と除外基準に基づいて被験者を選択し、以下の補足表である表2にまとめた。夫々のセンターで施設内審査委員会ガイドラインに従ってヒトの被験者からインフォームドコンセントを得た。
全ての実験を、遺伝子マウスモデルの薬理的処置又は評価の前に独立した研究者によって無作為化して盲検化した。研究者は、組織学的評価、生化学的評価及び行動的評価全体に亘って盲検化を維持した。グループを統計解析の際、各実験の終わりに非盲検とした。データを平均±SEM として表現する。実験の各組のデータの分布を、ダゴスティーノ・パーソンオムニバス検定又はシャピロ・ウイルク検定を使用して正規性に関して試験した。グループ間の分散の有意差がF検定を使用して検出されなかった。Prism 5.0 ソフトウェア(GraphPad Software)を用いて統計解析を行った。2つのグループの平均を、両側不対Student のt検定と比較した。複数のグループからの平均の相互比較、又は1つの対照グループとの比較を、(図の説明に示されている)1-way ANOVA 検定、その後の適切な事後検定を用いて解析した。
老化は、依然として、アルツハイマー病のような認知症に関連する神経変性疾患に関する単一の最も支配的な危険因子である(Hedden & Gabrieli 著,「Insights into the ageing mind: a view from cognitive neuroscience」,Nature reviews. Neuroscience (2004) 5:87-96;Mattson & Magnus著,「Ageing and neuronal vulnerability」,Nature reviews. Neuroscience (2006) 7:278-294;Small 等著,「A pathophysiological framework of hippocampal dysfunction in ageing and disease」,Nature reviews. Neuroscience (2011) 12:585-601)。そのため、高齢者の認知的完全性を維持し、従って神経変性疾患の脆弱性を打ち消すために、脳の老化表現型を促進するものに対する機械論的な洞察を得ることは必須である。本発明者らなどは、(若齢動物及び老齢動物の循環系が結合されている)異年齢並体結合のような全身性操作、又は若齢の血漿の投与が老化脳の認知能力及び再生能力の加齢性の消失を部分的に反転し得ることを最近示した(Katsimpardi 等著,「Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors」,Science (2014) 344:630-634;Villeda 等著,「The ageing systemic milieu negatively regulates neurogenesis and cognitive function」,Nature (2011) 477:90-94;Villeda 等著,「Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice」,Nature medicine (2014) 20:659-663)。興味深いことに、異年齢並体結合の研究は、若齢の血液の不老促進因子が若返りを引き出す一方、老齢の血液の老化促進因子が老化を促すことを示す全身環境の影響下で年齢依存の双方向性を明らかにした(Katsimpardi 等著,「Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors」,Science (2014) 344:630-634;Villeda 等著,「The ageing systemic milieu negatively regulates neurogenesis and cognitive function」,Nature (2011) 477: 90-94;Ruckh 等著,「Rejuvenation of regeneration in the aging central nervous system」,Cell stem cell (2012) 10:96-103;Conboy等著,「Rejuvenation of aged progenitor cells by exposure to a young systemic environment」,Nature (2005) 433:760-764;Brack 等著,「Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis」,Science (2007) 317: 807-810)。老化促進因子の影響を緩和することにより、老化の表現型を若返らせるための効果的な手法が提案されている(Villeda 等著,「Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice」,Nature medicine (2014) 20:659-663;Laviano 著,「Young blood」,The New England journal of medicine (2014) 371:573-575;Bouchard及びVilleda 著,「Aging and brain rejuvenation as systemic events」,Journal of neurochemistry (2014))。
β2ミクログロブリンの相対的レベルを、SomaScan Proteomic Assay(Somalogic, Inc, Boulder, CO)によって18歳、30歳、45歳、55歳及び66歳の健康な男性のヒトのドナーの血漿サンプルで決定した。年齢グループ毎に、40人の個人からの血漿を1つのプール当たり5人の個人で8つのプールとして分析した。対数変換値の両側Student のt検定、及びヨンクヒール・タプストラ検定を使用した未変換データの傾向分析によって統計解析を行った。観察された変化が、1.1 ×10-4のt-検定のp-値(66歳対18歳)及び1.3 ×10-7のJT検定のp-値(全ての年齢グループ)で非常に重要であると分かった。(RFU はSomaScan Proteomic Assayによって「相対蛍光単位」を指す)。結果が図13のグラフに示されている。
老化に関連する障害のために成体哺乳類を処置するのに十分なように成体哺乳類のβ2ミクログロブリン(B2M )レベルを下げることを特徴とする方法。
Claims (8)
- 成体哺乳類の老化に関連する認知障害の処置のための血液製剤を調製する際に使用するためのβ2ミクログロブリン(B2M )結合剤であって、
成体哺乳類の老化に関連する認知障害の処置のために成体哺乳類の血液から成体哺乳類の全身のB2M を体外で取り除くべく使用されることを特徴とするB2M 結合剤。 - 前記B2M 結合剤は抗体又は前記抗体の結合断片を有していることを特徴とする請求項1に記載のB2M 結合剤。
- 前記B2M 結合剤は小分子を有していることを特徴とする請求項1に記載のB2M 結合剤。
- 前記B2M 結合剤はB2M 吸収要素を有していることを特徴とする請求項1に記載のB2M 結合剤。
- 前記成体哺乳類は霊長類であることを特徴とする請求項1~4のいずれかに記載のB2M 結合剤。
- 前記霊長類はヒトであることを特徴とする請求項5に記載のB2M 結合剤。
- 前記成体哺乳類は高齢の哺乳類であることを特徴とする請求項1~6のいずれかに記載のB2M 結合剤。
- 前記高齢の哺乳類は60歳以上のヒトであることを特徴とする請求項7に記載のB2M 結合剤。
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US10487148B2 (en) | 2010-01-28 | 2019-11-26 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and compositions for treating aging-associated impairments |
US20160208011A1 (en) | 2010-01-28 | 2016-07-21 | The Board Of Trustees Of The Leland Stanford Junior University | Ccr3 modulation in the treatment of aging-associated impairments, and compositions for practicing the same |
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DK3390367T3 (da) * | 2015-12-15 | 2020-10-26 | Univ Leland Stanford Junior | Fremgangsmåde til forebyggelse og/eller behandling af aldersrelateret kognitiv funktionsnedsættelse og neuroinflammation |
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NZ738184A (en) | 2019-09-27 |
AU2016265948A1 (en) | 2018-01-04 |
HK1248153A1 (zh) | 2018-10-12 |
IL255319B (en) | 2022-11-01 |
EA201792437A1 (ru) | 2018-04-30 |
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EP3297702A4 (en) | 2019-01-16 |
CN107921188A (zh) | 2018-04-17 |
EP3892315A1 (en) | 2021-10-13 |
JP7323561B2 (ja) | 2023-08-08 |
AU2022221494A1 (en) | 2022-09-29 |
CA2984645A1 (en) | 2016-11-24 |
EA202091057A2 (ru) | 2020-12-30 |
IL255319B2 (en) | 2023-03-01 |
EA035799B1 (ru) | 2020-08-12 |
AU2020210181B2 (en) | 2022-05-26 |
EP3297702A2 (en) | 2018-03-28 |
JP2021073264A (ja) | 2021-05-13 |
WO2016187217A3 (en) | 2017-01-05 |
AU2020210181A1 (en) | 2020-08-13 |
CA2984645C (en) | 2023-01-10 |
JP2018518530A (ja) | 2018-07-12 |
WO2016187217A2 (en) | 2016-11-24 |
AU2019201337A1 (en) | 2019-03-21 |
AU2019201337B2 (en) | 2020-05-14 |
EA202091057A3 (ru) | 2021-03-31 |
IL255319A0 (en) | 2017-12-31 |
AU2019201337B9 (en) | 2020-05-21 |
CN116687969A (zh) | 2023-09-05 |
KR20180030965A (ko) | 2018-03-27 |
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