JP2017502974A - 炎症関連疾患の治療と予防のためのp62/sqstm1に関する方法と組成物 - Google Patents
炎症関連疾患の治療と予防のためのp62/sqstm1に関する方法と組成物 Download PDFInfo
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Abstract
Description
多発性硬化症(MS)は、炎症、脱髄、およびCNSにおける軸索変性が特徴の異種(heterogenous)かつ複雑な自己免疫疾患である。この病変は髄鞘成分を対象とする免疫系統の最初の異常が原因で生じ、ニューロンに対して二次的な作用を生じる。MSはCNSにおける炎症性脱髄病変の存在により特徴付けられる免疫介在性疾患と考えられる。バクテリアあるいはウィルスによる感染またはその他の環境刺激物が、多発性硬化症(MS)における小膠細胞および星状膠細胞の活性化を誘発し、転写因子NFカッパBおよびAP-1の活性化による炎症性サイトカインの産生に至る(Luessi他、2012年、多発性硬化症における神経変性:最新治療ストラテジー、Expert Rev Neurother 12:1061-1076)。齧歯目がミエリン由来抗原およびアジュバントで免疫付与される、実験室的な自己免疫脳脊髄炎(EAE)が最も一般的なMSの動物モデルである。遺伝的背景および免疫プロトコルを変化させることで、EAEはヒトMSの主要な形態の症状を再現することが可能である。
肝臓におけるアルファフェトプロテイン遺伝子制領域(Krumlauf他、1985年、Mol. Cell. Biol., 5:1639-48;Hammer他、1987年、Science 235:53-58);肝臓におけるアルファ1−アンチトリプシン遺伝子制御領域(Kelsey他、1987年、Genes and Devel. 1:161-71);骨髄細胞のベータグロビン遺伝子制御領域(Mogram他、1985年、Nature 315:338-40;Kollias他、1986年、Cell 46:89-94);脳内乏突起膠細胞におけるミエリン塩基性タンパク質遺伝子制御領域(Readhead他、1987年、Cell 48:703-12);骨格筋におけるミオシン軽鎖-2遺伝子制御領域(Sani、1985年、Nature 314:283-86);視床下部における性腺刺激放出ホルモン遺伝子制御領域(Mason他、1986年、Science 234:1372-78)、および黒色腫細胞におけるチロシナーゼプロモーター(Hart, I. Semin Oncol 1996 February、23(1):154-8;Siders他、Cancer Gene Ther 1998年 Sep-Oct; 5(5):281-91)が挙げられる。また、例えば、ある分子の存在下、または光、熱、放射線、テトラサイクリンまたはヒートショックタンパク質などの条件下で活性化される誘導性プロモーターも使用できる(例えば、国際公開第00/10612号を参照)。当技術ではその他の好適なプロモーターが知られている。
それのもつ脂肪性肝炎(NASH)、線維症、肝硬変、および一部のケースでは肝細胞がんへの進行のための潜在力から生じる。NAFLDの罹患率は肥満の上昇率と並行して上昇しつつあり、この地球規模のトレンドは西洋式生活スタイルの食事に起因する。NAFLDの発病は十分に理解されていないが、「二撃」のプロセスであることが提案される。第1「撃」は脂質蓄積と脂肪症にむすびつく。この脂質蓄積の機序ははっきりしないが、ベータ酸化、ごく低密度リポタンパク質の分泌、デノボ脂質合成、ならびに脂質の輸送および貯蔵などの無調節な脂質恒常性にかかわっているようである。この肝臓脂肪症は、脂肪性肝炎の重要な病態生理学的特徴である炎症、および進行性の肝臓疾患につながる第2「撃」に対して肝臓を敏感にする(Renaud他、2014. 「マウスの脂質代謝、酸化によるストレス、および炎症に関係する遺伝子発現に対する食事効果-脂肪肝症の機構洞察」 PLoS ONE 9:e88584)。
材料および方法
ベクターの構築
p62をコードするcDNAのソースとして、全RNAをヒーラ細胞から抽出した。p62のより長いアイソフォームをコードする全長cDNA(転写変異体1、ジーンバンク参照番号NP_003891)をPCR(HotStar HiFidelity Polymerase Kit、キアゲン)により、プライマー、FW:5-CCCGCTAGCATGGCGTCGCTCACCGTG-3およびREV:5'-CCCAAGCTTTCACAACGGCGGGGGATGCTTTG-3'を用いて増幅した。PCR産物を精製し、NheI−Hind III消化フラグメントがpcDNA3.1に対応する核酸配列を有するDNAベクター内にクローニングされ、結果としてp62プラスミドを産生した。pcDNA3.1内にクローニングされた全長卵白アルブミン遺伝子(pOVA)を参照プラスミドとして採取した。内毒素をもたないプラスミドの大規模製造は、Endo Free Plasmid Kit(キアゲン)あるいはGen Elute HPSelect Plasmid Giga Prep columns(シグマ、番号NA0800)のいずれかを用いたアルカリ溶菌法により日常的に実施された。DNA構築物は配列決定により確認した。
3月齢の雌性FVBおよびBalb/cマウス(ハーランイタリー社(Harlan Italy SrL)、コッレツァーナミラノ、イタリア)を使用した。マウスは標準化環境条件下のラミナーフロー・ケージ内で飼育した。予防試験において、マウスをランダムに3グループ(G1〜G3)に分け、筋肉内注射を、食塩水(G1、n=12)のみと、pcDNA3.1(G2、n=12)またはhp62 DNA(G3、n=12)とで、0、1、2の各週に行った。最後の注射から45日後、各グループのマウスをランダムに2つのサブグループに分けて、擬似手術(SO; n=6)あるいは卵巣切除(OVX n=6)を行った。2か月後、「イタリア倫理委員会」の推奨に従ってマウスは、C02麻酔により犠牲死された。治療試験のため、マウスは卵巣切除(OVX)が行われ、2か月間未処置のまま放置した。その後、マウスは4つのサブグループにランダムに分けられ、上述と同様のプラスミド注射を行った。2か月後、マウスを解析のため犠牲死させた。
接着組織の切断された大腿骨を4%パラホルムアルデヒド(PFA)中に24時間固定し、14%EDTA溶液中で3日間石灰質を除去した上、30%蔗糖中で一晩浸漬した。Tissue-Tek OCT化合物に埋め込まれた試料を、回転式-30°Cミクロトーム低温槽(Ames Cryostat Miles)を使って切片化し(8μm厚薄片)、トルイジンブルーで染色した。その他の薄片は、0.3% Triton X-100で透過処理した後、ラビット抗p62希釈比1:800 (Enzo Life Sciences; Vinci-Biochem s.r.l. Firenze, Italy) 希釈比1:400で培養を行った。リンスした後、薄片をチキン抗-ラビットIgG Alexa Fluor 488コンジュゲート(Molecular Probes; Invitrogen, Milano Italy) 希釈比1:100で培養した。対照実験は然るべき一次抗体を省くことで、若しくは一次抗体を相対ブロッキングペプチドと複合化することで実施した。スライドをLeica DM 2500蛍光顕微鏡を用いて画像化した。蛍光分析を蛍光計Tecan Infinite [29]を使って実施した。
大腿骨を上述同様に切断し、固定した。骨密度(BMD)および骨含量(BMC)はPIXImus DEXAを使って測定した。
マウスグループからの長骨(大腿骨、脛骨および上腕骨)を切断して接着組織がない状態にした。端部は除去し骨髄空洞を洗い流した上、DMEM内で培養した。
BMSC上清のサイトカイン/ケモカインプロファイルはELISAに基づくサイトカインアレイによりMouse Cytokine Array Panel A kit (R&D Systems, Milano, Italy)を利用してメーカー使用説明書に従って評価した。免疫活性点はLiteAblot Turboルミノール試薬(Euroclone, Milano, Italy)ならびにHyperfilm-ECLフィルム(Euroclone, Milano, Italy)を用いて視覚化し、密度計測により定量化した。
骨髄空洞部を洗い流した直後に、Cell Lysis Buffer(Cell Signaling Euroclone, Milano, Italy)中に全骨髄細胞集団のタンパク質を抽出し、濃度をBCAタンパク質アッセイ試薬(Pierce, Euroclone Milano, Italy)で測定した。ウェスタンブロッティングは標準手法により行った。
インビトロおよびインビボ試験はすべて少なくとも3回は繰り返した。t-スチューデント検定を使用し、2グループ間の有意差を調べ、差*p<0.05で有意とみなした。
p62ワクチンはマウスモデルの骨粗鬆症を予防する
p62ワクチンが骨粗鬆症を予防できたか否かの評価のため、まず、マウスグループにp62DNAまたは参照プラスミド(pcDNA 3.1、pOVA)のいずれかを注射し、その後卵巣切除(OVX)を行った。試験毎に、擬似手術(SO)対照グループマウスを含めた。マウスは術後2か月でと殺され、長骨を回収して組織学的試験に付した。pcDNA3.1-OVX(対照)マウス由来の遠位大腿骨の骨幹端領域の骨喪失が多くなり、薄くなって脱臼した棒状組織構造が特徴の従来の骨粗鬆症特性を示した。一方、p62-OVX骨(処置マウス)はSOマウスで見られたものに対して本質的に区別ができないミクロ構造を示した。さらに、p62DNA-OVXマウスの横断面大腿骨骨端部試験は、(参照プラスミド処置マウスから得られたものとは相違し)、p62治療の同化作用を示唆する新たな皮質骨付加から明らかなように同化−骨芽細胞活性の増加を明らかにした。
p62ワクチンはマウスモデルにおける骨粗鬆症を後退させる
これらの試験では、マウスは卵巣切除を行い、その2か月後、p62-DNAあるいは参照プラスミドのいずれかを使って注射を行った(詳細にはM&Mを参照)。最終プラスミド注射の2か月後、骨を回収し組織学的に評価を受けさせた。OVX-p62処置マウスグループ(対照グループに照らして)は、遠位大腿骨の骨幹端領域における棒状組織マイクロ構造の回復と皮質骨の多孔性の減少を示した。また、p62-DNA処置は、DXA解析から判断された通り、骨密度(BMD)もその量(BMC)も、ともに増加させることが判明した(図6)。最終的に、骨芽細胞形成Runx2とOsterixの顕著な上方調節(図7、パネルA)とセットになって、OVX-p62マウスからのBMC中にTNFαおよびRANKLなどの2大骨吸収性因子の強力な抑制も観察された。RANKLは骨芽細胞前駆体上のその受容体RANKと結合することで、細胞内NF-kBシグナル伝達を介して骨芽細胞形成を育てる重要な炎症メディエーターである。また、OVX-p62 BMCにおけるNF-カッパ-Bの下方調節も観察された(図7、パネルB)。従って、p62投与はマウスモデルにおける骨粗鬆症を後退させた。
p62ワクチンはマウスモデルにおいて内因性p62を上方調節する
卵巣切除前にプラスミド注射を受けたマウスから回収したBMCにおけるp62の発現レベルを測定した。驚くべきことに、BMC内のp62発現は卵巣切除により下方調節されたが、p62DNAを事前注射されたマウスからのBMCはp62の上方調節を見せた(図8、パネルA)。上昇したp62免疫ラベリングはp62-OVXマウスの大腿骨の骨端領域にて一貫して観察された(図8、パネルB)。
マウスモデルにおける筋萎縮性側索硬化症(ALS)症状のp62投与による低減
図9はALSのマウスモデルに及ぼすp62の効果を示す。神経炎症はALSの患者の脊髄における顕著な病理学的特色であると同時に神経膠活性化とT細胞浸潤により特徴付けられる。類似の炎症性応答がALSマウスの脊髄にも存在する。これはSODのG93A突然変異形態を発現するALSの一番ありふれたマウスモデルであり、同一の突然変異がALSにかかったヒトにおいても発生し、このモデルはALSに対する薬物の試験に広く使用される。マウスは、75日齢からp62プラスミドまたはpcDNA 3.1プラスミドを用いて処置し(150 μg/ マウス、筋肉内投与、で週当たり6回)を用いて治療し(1グループにつき6匹)、ALS向けの標準試験(後肢伸展反射作用)を適用した。この反射作用は実験動物が尻尾で吊るされたときの後肢の完全な伸展を行う能力として評価された。ALSでない場合、対照もp62処置マウスも、ともに強力な反射能力を示し、ALSマウスにおいては生後60日後には低下し始め、100日後には100%からゼロまで低下した、しかし、p62を使っての治療では、顕著に反射能力の低下が遅れた。従って、p62プラスミドの投与はマウスモデルにおけるALS関連症状を低減した。
マウスモデルにおける多発性硬化症(MS)の症状のp62投与による減少
MSは、原因が分かっておらず、限られた治療選択肢しかない、中枢神経系(CNS)全体を通じて脱髄および軸索喪失を生じさせる慢性炎症疾患である(Noseworthy, J.H., C. Lucchinetti他、(2000)「多発性硬化症」、N Engl J Med 343(13): 938-52;Lassmann他、2001、「多発性硬化症病原の不均一性: 診断と治療の関わり合い」 Trends Mol Med 7(3):115-21)。MS研究用に一番普通に使用される実験動物モデルは、MOGポリペプチド投与によって誘導されるマウス実験用アレルギー性脳脊髄炎(EAE)である。このモデルは、ヒトの疾患で所見されるように、炎症段階の自動反応性ミエリン特有T細胞の発生、ならびに該疾病の神経変性段階の軸索周囲の髄鞘の破壊とその後続く軸索の喪失の両方ともに似ている(Steinman, 2001,「多発性硬化症: 2段階疾病」 Nat Immunol 2(9):762-4.)。図10はrMOG誘導EAEの臨床兆候を指摘した平均的臨床成績を示している。マウス(グループあたり4匹)はEAEの臨床兆候につき毎日試験を行い、結果は無疾患0;尻尾無力1;後肢虚弱2;後肢完全麻痺3;後肢プラス前肢麻痺4;そして活動停止または死亡5であった。MOGワクチン接種ゼロ日目。p62DNA(100μg/50μl)は、MOGワクチン接種後16日および22日に、赤色矢印にて表示されるとおり投与した。見て分かるように、対照マウスのEAEスコアは観察終了(31日目)まで高かったにも関わらず、p62プラスミドで治療したマウスではこのスコアが漸進的に低下した(31日目で約0.5に)。依って、p62プラスミドの投与はMSマウスモデルにおけるMS様症状を緩和した。
腫瘍成長およびマウスの生存に対するp62投与
慢性炎症は肉腫、特にカポジ肉腫の病原に関係している(Douglas JL、2010、「カポジ肉腫病因:ウィルス感染試験、腫瘍形成ならびに慢性炎症」 Transl Biomed 1(2))。腫瘍成長に及ぼすp62予防接種効果の調査にマウスの中で移植可能な肉腫37が使用された。マウス(グループ当たり6匹)に、p62プラスミドまたは空ベクター(マウス当たり250μg)の筋肉内注射を腫瘍接種14日前、7日前、1日後、8日後、14日後におこない、カリパスを使って腫瘍の成長をチェックした。p62プラスミドの注射がほぼ完全に肉腫37の成長を防止した。従って、p62プラスミドの投与はマウスS37肉腫の成長を減らした。
p62ポリヌクレオチド投与の腫瘍転移に及ぼす効果
LLCは転移肺がんの広く使用されるモデルである。マウス横腹への腫瘍細胞の皮下接種後、3週間以内に、簡単に数えられる肺の転移を形成する。p62ポリヌクレオチドでのマウスの治療は、大小転移の両方の形成を顕著に抑制するため、転移プロセスの阻止に効果を発揮する(図13)。依って、p62プラスミドの投与はマウスモデルにおける肺がんを抑制する。
肥満とメタボリック症候群
新生雄マウスの3グループに、グルタミン酸ナトリウム(MSG)のi)プラセボまたはii)およびiii)3mg/kgの皮下注射を10日間にわたり毎日受けさせた。その後、グループ3にp62コーディングプラスミド200μgの筋肉内注射を1週間に5回受けさせた。3グループすべての生命体体重を測定、比較した。MSGは対照グループと比べて両グループにおいて顕著に体重を増やした(p<0.01とp<0.05)。しかし、p62プラスミドを受けたグループにおける体重上昇はMSGだけを受けたグループにおけるよりもかなり少なかった。すなわち、p62コーディングプラスミド投与はマススモデルでの肥満を減少させた。
2型糖尿病
2型糖尿病標準モデル、Zucker Diabetic Fatty (ZDF)ラットの2グループに6.5%脂肪過多食餌を与えた。1グループは1回当たり200μgのp62プラスミド注射を週に5回受けさせた一方で、もう1グループは対照として使用した。対照グループでは、高血糖症が8〜10週齢の間に所見された一方で、プラスミド治療グループでは高血糖症は平均して3週間遅れで所見された。従って、p62プラスミドの投与はラットモデルの2型糖尿病発生を遅延させた。
脂肪肝
2グループのマウスにMCD食餌(10%脂肪、40%蔗糖、コリン無し、メチオニン無し)を与えた。各グループには15匹のマウスを入れた。アラニンアミノトランスフェラーゼ(ALT)の血清レベルのチェックを給餌10週後から開始した。試験グループは1回当たりp62コーディングプラスミド200μgを週に5回筋肉内注射を受けた。プラセボグループにはプラスミド介入なしでMCD食餌を受けさせた。対照グループには全調査期間を通じてプラスミド無しの普通の食事を受けさせた。MCD給餌中の両グループの示したALTレベルが、対照グループと比較して上昇した(両グループともp<0.01)。しかし、p62治療はプラセボグループに比べてALTレベルを下げた(p<0.05)。従って、p62プラスミド投与はマウスモデルの脂肪肝臓疾患の発生を減らした。
クローン病
マウスに8%デキストラン硫酸ナトリウム(DSS)含有の飲み水を2週間与えた。平行して、マウスの1グループは、週に5回、p62コーディングプラスミドの200μgの注射を行った一方で、別のグループは対照にした(各グループ当たり10実験動物)。p62治療実験動物は血便と下痢の減少を示した。また、各実験動物の体重を個別に週1回チェックした。p62は体重ロスを抑制した(p<0.05)ものの、完全には止まらなかった。従って、p62プラスミドの投与はマウスモデルにおけるクローン病関連症状を低減した。
膵臓炎
マウスは、膵臓炎を誘導するため、LPSを4mg/実験動物およびセルレインを1μg/実験動物で、10週間、週2回、処置した。対照グループとして3匹のマウスを使用し、3匹に週5回、p62ワクチンを1回当たり200μgで筋肉内注射を行った。15週後、マウスをと殺し、組織学的解析を行った。p62プラスミド治療は慢性膵臓炎の所見の程度を減らした。従って、p62プラスミドの投与はマウスモデルにおいて膵臓炎を軽減した。
喘息
マウスに1%卵白アルブミン溶液の腹腔内注射を3回行った。注射は14日の間隔で行った。3回目の注射の1週間後、喘息様疾患を誘導するため、実験動物を3日間毎日1%卵白アルブミンエアロゾルに30分間ばく露を行った。この5週の間に、1グループのマウスに週に5回、p62プラスミド200μgの筋肉内注射を行った一方で、もう一方は対照として飼育した。最終のばく露の2日後、気道過敏性(AHR)を測定して、対照と治療グループで比較した。冷気あるいは換気亢進のいずれかによりAHRを誘導した。AHR症状がp62治療グループで大きく低減された。依って、p62プラスミドの投与はマウスモデルにおける喘息症状を減らした。
関節炎、骨関節症
2グループのマウス(グループ当たり10実験動物)にコラーゲンII(CII)と完全フロイントアジュバントを投与し、コラーゲン誘導関節炎を誘導した。実験動物は6週齢とし、これより年長の実験動物で観察され得る自然発生関節炎を回避した。また、実験グループに週に5回、p62コーディングプラスミド200μfの注射を行った。対照グループはCII投与後、30〜33週で最初の関節炎の兆候を見せた。p62治療グループには、CII注射後、38〜43週でコラーゲン誘導関節炎が現れた。依って、p62プラスミドの投与はマウスモデルにおけるコラーゲン誘導関節炎の発症を遅らせた。
アテローム性動脈硬化症
ApoE(-/-)マウスを高脂肪食餌状態に8週間維持した。対照グループにはワクチン接種を行わなかったが、実験グループには週に5回、p62コーディングプラスミド200μgの注射を行った。プラスミド治療はアテローム性動脈硬化症プラーク区域とプラーク新生血管密度を低下させた。プラスミド治療はプラークコラーゲンとエラスチン含有量を増やすと同時に、プラスマアンジオテンシンIIレベルとプラークマクロファージ浸潤物とカテプシンS(Cats)タンパク質とを減少させた。また、p62投与は、大動脈根においてAT1R、gp91phox、TLR2、単核白血球走化性タンパク質-1のレベルを減少させた。従って、p62プラスミドの投与はマウスモデル内のアテローム性動脈硬化症を軽減した。
パーキンソン病
雄のWistarラットは週5回、1回当たり200μgのp62コーディングプラスミドの注射で事前治療するか若しくは対照グループとして採用した。その後、片側線条体注射により6−ヒドロキシドーパミン、6-OHDA(正規食塩水中0.1%アスコルビン酸中に10マイクログラム)を実験と対照のグループのラットに投与してパーキンソン病を刺激した。6-OHDA注入後3週間、ラットを神経行動活動に関して試験を行った(オープンフィールドテストおよびロータロッド筋肉協調テスト)。プラスミドも6-OHDAも受けなかった対照グループを利用して6-OHDAの効果の評価を行った。p62プラスミドでの事前治療はラットモデルにて6-OHDAによる誘導されたパーキンソン様の症状を顕著に減少させた。
実施例18
ハンティントン病とアルツハイマー病
実験はすべて実験室動物の保護と使用に関する欧州共同体審議会指令(86/609/EEC)に従って明期中に行った。
視覚位置認識反射神経
視覚系統機能評価のために視覚による位置認識反射神経テストを行った。この位置認識応答実績についてマウスを尻尾で中吊にして濃い黒色面の方に向け下げた。前肢の完全な伸展をポジティブな応答と見なした。3回のテストの応答平均で評価した(Baeza他、2010)。
後肢伸展反射能力
この方法は5秒のトレーニングテスト2回ならびに60秒のテスト試験での筋肉活力、運動協調および牽引力を試験することにより老化するマウスのバイタリティー喪失の評価に使用される(MiquelおよびBlasco、Ex p Gerontol. 1978;13(6):389-96ならびにBaeza他、2010)。マウスは水平なタイトロープを真ん中で持ち上げ前肢で宙づりにした(高さ40cm、長さ60cmで10cmのセグメントに分割した)。筋肉活力はロープから落下するマウスのパーセンテージおよび落下するまでの待ち時間(秒)として評価した。運動協調は少なくとも1セグメントを歩くマウスのパーセンテージ(判定基準1)ならびにテストを成功させるマウスのパーセンテージ(判定基準2)を含めた。牽引力は宙づりのままとどまるのに使われる体の複数部分(前肢、後肢および尻尾)の分析により評価して、それ以降、引き続き、最大(前肢、後肢および尻尾)および最小(前肢のみ)の牽引能力を示すマウスのパーセンテージを各グループの範囲内で評価した。
このグループには実験動物におけるうつ状態と不安状態行動を調査するFST、オープンフィールド、明暗ならびにEPMテストの複数テストを含めた。
強制水泳テストは齧歯目での抗うつ状活動の評価用にベストの認知薬理学モデルテストである(Porsolt他、1977a Arch Int Pharmacodyn Ther 229:327-336、Porsolt他、1977b Nature 266:730-732; Willner、 1990 Pharmacol Ther 45:425-455; Al-Rahbi他、Biomed Res Int. 2013; 2013:493643. doi: 10.1155/2013/493643)。マウスが逃げることの不可能な水を張ったシリンダー内に置かれたとき、不動時間が増えることにより粘り強い逃亡志向行動の中止を反映させて学習性無気力症候の発達が分かる(Lucki, 1997 Behav Pharmacol 8:523-532)。不動の減少は抗うつ様行動と一致した一つの行動プロファイルと見なされる(Cryan他、2002 Trends Pharmacol Sci 23:238-245; Waif and Frye、 2010 Physiol Behav. 2010 Feb 9;99(2):169-74; Al-Rahbi他、2013)。簡単にいえば、水(23±1℃)を深さ15cmまで満たしたカラス性シリンダー(高さ20cm、直径14cm)内にマウスを個別に入れた。この水深さにて、マウスは尻尾がジャーの底に触れる可能性があるものの、後肢で自立することはできない。それぞれのマウスに6分間の水泳テストを与え、最初の2分間は実験動物が環境に慣れるために使われるため、テストの残りの4分間の間の不動時間を記録にとった。水泳試験セッションはすべてシリンダー上部に直接位置するビデオカメラで記録した。治療条件を知らない2名の熟練観察者がビデオテープ内容の評価点数をつけた。マウスがもがくことなく頭部を水面上部に保つ必要のあるごく僅かの動作しかしない間水中に浮いて費やした時間を不動時間と見なした。これらの水泳セッションの後、マウスをタオルで乾かし収容ケースに戻した。各実験動物は1回だけテストした。
移動活動は、水平および垂直方向の活動を測定する16個の光電池2系統を備える四角い広場(43.2cm×43.2cm)から構成されるオープンフィールド器具により測定した。該広場を1個の赤色ランプ(25W)で照明を行い、部屋内のホワイトノイズジェネレーターで70dB.の周辺バックグラウンドノイズを発生させた。データはすべて隣接する制御室内のパソコン(MED-PCオープンフィールド活動ソフトウェア)に記録した。マウスは器具の中央に置きテストを5分間行った。多数の従来のそして動物行動学のパラメーター(Choleris他、2001 Neurosci Biobehav Rev 25:353-360; PerfumiおよびMattioli、Phytother Res. 2007 1月;21(1):37-43)をセッション中に収集した。中央および周辺区域での水平活動(すなわち、走行距離、歩行時間、休息時間)および垂直活動(すなわち、棒立ち)を自動的に記録した。中央区域で費やす時間、この区域での歩行時間および垂直活動、ならびに出発中央地点を離れるまでの時間および周辺部に到達する(「凍結挙動」)までの時間をマウスの情緒的反応のインジケーターとして測定した(Baeza他、2010)。さらに、老化は排便行動の減少および尿失禁の増加に関係する。従って、複数の世代グループの中の丸薬糞便数および尿の存在にも注意を払った(成熟した実験動物の卵巣切除が老化した実験動物中で観察されるものにより類似した行動を引き起こしたのか否かを調査しようとして)。
マウスにおける不安関連行動を検知する適切なテストシステムが明/暗探検テストであって、このテストは齧歯目が光輝き照らされた広い空間を嫌がる性質を利用するものである(Hascoet他、2001 Prog Neuropsychopharmacol Biol Psychiatry 25:141-166; BourinおよびHascoet、2003 Eur J Pharmacol 463: 55-65)。明/暗装置は小区画(18×30cm)と大区画(27×30cm)とに分割した床レベルで間仕切りの中央に位置する開口部扉(7.5×7.5cm)付きの上面が開放した(45×30×30cm; l×b×h)の長方形のプレキシガラスボックスで構成した。小区画では黒色塗装で暗闇を保った一方、大区画は白色塗装を行い60W(400 lx)の光源で明るく照らした。つまりは、実験動物はそれぞれ暗闇の区域の1面に面して照らされた区画の中央に置いた。明るい区画から暗闇の区画までの最初の通行までの時間、各区画に入る回数、照明が行われた区画で費やされる時間、ならびに、明るい空間でマウスが後足で立ち上がる(棒立ちになる)回数を5分間記録した(WaifおよびFrye. 2010)。
高架十字迷路は不安様行動を評価すると同時に、2本の開いたアーム付きの黒色プレクシグラス(30×3.5cm)と同一サイズの2本の閉じたアーム(高さ14cmの壁)で構成された。4本のアームは中央広場(6×6cm四方)に接合され、地上よりおおよそ74cmの高さに持ち上げられた。つまり、マウスは閉じたアームの1本に面する中央広場に置かれ、その行動を5分間記録した。アームの範囲内に4本のすべての足が入る回数とアーム内で費やされた時間を開いたアームと閉じたアームにつき別々に記録した。明るく照明された高架十字迷路の開いたアーム上で費やされた、生の時間の長い方およびより長い方の時間割合(%)を不安様行動の指標と見なした(Kolosova他、老化(Albany NY). 2013 6月;5(6):474-84; WaifおよびFrye、2010)。
Claims (27)
- 対象における炎症性サイトカインの発現を調節する方法であって、
a.p62/SQSTM1ポリペプチドまたはその変異体の少なくとも30個のアミノ酸;または
b.p62/SQSTM1ポリペプチドまたはその変異体の少なくとも30個のアミノ酸をコードするp62/SQSTM1コーディング核酸
を含む薬剤を対象に投与することを含む方法。 - 炎症促進性サイトカインがTNFα、IL-6、IL-lb、RANTES、IL-17、IL-23、CCL-1、MCP-5、およびCXCL2からなる群より選択される請求項1記載の方法。
-
対象における骨形成転写因子の発現を調節するための方法であって、
a.p62/SQSTM1ポリペプチドまたはその変異体の少なくとも30個のアミノ酸;または
b.p62/SQSTM1ポリペプチドまたはその変異体の少なくとも30個のアミノ酸をコードするp62/SQSTM1コーディング核酸
を含む薬剤を対象に投与することを含む方法。 - 骨形成性転写因子がオステリックスおよびrunx2の群から選択される請求項3記載の方法。
- 対象における骨吸収因子の発現を調節するための方法であって、
a.p62/SQSTM1ポリペプチドまたはその変異体の少なくとも30個のアミノ酸;または
b.p62/SQSTM1ポリペプチドまたはその変異体の少なくとも30個のアミノ酸をコードするp62/SQSTM1コーディング核酸
を含む薬剤を対象に投与することを含む方法。 - 骨吸収因子がTNFαおよびRANKLの群から選択される請求項5記載の方法。
- 対象における内因性p62/SQSTM1の発現を調節するための方法であって、
a. p62/SQSTM1ポリペプチドまたはその変異体の少なくとも30個のアミノ酸;または
b.p62/SQSTM1ポリペプチドまたはその変異体の少なくとも30個のアミノ酸をコードするp62/SQSTM1コーディング核酸
を含む薬剤を対象に投与することを含む方法。 - 対象における非がん関連慢性炎症性疾患の1つ以上の症状の治療、緩和、改善、軽減、発症の遅延、進行の抑制、重症度の軽減、または発生率の低減のための方法であって、
a.p62/SQSTM1ポリペプチドまたはその変異体の少なくとも30個のアミノ酸;または
b.p62/SQSTM1ポリペプチドまたはその変異体の少なくとも30個のアミノ酸をコードするp62/SQSTM1コーディング核酸
を含む薬剤を対象に投与することを含む方法。 - 前記変異体が、配列番号2に、80%以上、85%以上、90%以上、91%以上、92%以上、93%以上、94%以上、95%以上、96%以上、97%以上、98%以上、99%以上相同である請求項1〜8のいずれか1項に記載の方法。
- 前記変異体が、配列番号2に、80%以上、85%以上、90%以上、91%以上、92%以上、93%以上、94%以上、95%以上、96%以上、97%以上、98%以上、99%以上配列相同である請求項1〜8のいずれか1項に記載の方法。
- 前記p62コーディング核酸が配列番号1の配列を含む請求項1〜8のいずれか1項に記載の方法。
- 前記p62ポリペプチドまたはその変異体が少なくとも1つのドメイン欠失を有する請求項1〜8のいずれか1項に記載の方法。
- 前記ドメイン欠失が、PB1、ZZ、NLS2、TB、NLS1、NES、LIR、KIR、およびUBAからなる群より選択される請求項12記載の方法。
- 前記薬剤が、p62コーディング核酸を含み、前記p62コーディング核酸が配列番号2と95%以上同一であるポリペプチドをコードし、かつ前記p62コーディング核酸が、さらにプラスミド、RNAまたはウィルスベクターを含む請求項1〜8のいずれか1項に記載の方法。
- 前記p62/SQSTM1ポリペプチドまたはp62/SQSTM1コーディング核酸が、さらに融合ポリペプチドまたは融合ポリペプチドをコードする核酸それぞれ含む請求項1〜14のいずれか1項に記載の方法。
- 前記p62/SQSTM1ポリペプチドまたはp62/SQSTM1コーディング核酸がワクチンを含み、さらに前記対象にアジュバントを投与することを含む請求項1〜14のいずれか1項に記載の方法。
- 前記アジュバントが、ゲルタイプアジュバント、微生物アジュバント、微粒子アジュバント、油状乳剤アジュバント、界面活性剤ベースのアジュバントおよび合成アジュバントからなる群より選択される請求項17記載の方法。
- 前記非がん慢性炎症性疾患が、肥満、メタボリック症候群、2型糖尿病、脂肪肝、クローン病、膵臓炎、喘息、慢性閉そく性肺炎、関節炎、骨粗鬆症、変形性関節症、多発性硬化症、乾癬、うつ血性心不全、アテローム性動脈硬化症、神経変性疾患、うつ病、統合失調症、痛風、石綿症および珪肺症からなる群より選択される請求項8記載の方法。
- 前記神経変性疾患が、筋萎縮性側索硬化症、パーキンソン病、ハンティントン病およびアルツハイマー病からなる群より選択される請求項18記載の方法。
- さらに、前記対象に抗炎症性治療を施すことを含む請求項1〜8のいずれか1項に記載の方法。
- 前記対象が、炎症性疾患と診断される対象、過去に炎症性疾患の治療を受けた対象、炎症性疾患の家族歴をもつ対象および炎症性疾患に罹患しやすい対象からなる群より選択される請求項1〜8のいずれか1項に記載の方法。
- 前記薬剤が、p62コーディング核酸であり、さらに、対象におけるp62の核酸にもとづく発現効率の改善のためのストラテジーを含む請求項1〜8のいずれか1項に記載の方法。
- 前記ストラテジーが、自己複製ウィルス・レプリコンを含めること、コドンの最適化、インビボエレクトロポーレーション、CpG刺激モチーフの組込み、エンドサイトーシスまたはユビキチン処理経路のターゲティング用配列を含めること、マレック病ウィルス1型VP22配列を含めること、プライム・ブースト投与計画、粘膜送達ベクターおよび核酸送達システムからなる群より選択される請求項22記載の方法。
- 前記核酸送達システムが、ポリマー遺伝子送達システム、リポソーム送達システムおよび細胞透過ペプチド遺伝子送達システムからなる群より選択される請求項23記載の方法。
- さらに、抗炎症性の化学療法薬剤または生物学的薬剤を投与することを含む請求項1〜8のいずれか1項に記載の方法。
- 前記化学療法薬剤が、非ステロイド系抗炎症薬、糖質コルチコイド、メトトレキサート、シクロスポリンおよびラパマイシンからなる群より選択される請求項25記載の方法。
- 前記抗炎症性の生物学的薬剤が、抗TNF抗体、抗IL1抗体、抗IL6抗体、抗IL6受容体抗体、抗IL12/23抗体、抗IL17抗体、抗IL1R抗体、抗IL1受容体拮抗剤および可溶性IL-1受容体からなる群より選択される請求項26記載の方法。
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SG11201605316VA (en) | 2013-12-29 | 2016-07-28 | Curelab Oncology Inc | Methods and compositions relating to p62/sqstm1 for the treatment and prevention of inflammation-associated diseases |
WO2020028923A2 (en) * | 2018-08-02 | 2020-02-06 | Curelab Oncology, Inc. | Compositions and methods relating to p62 for the treatment and prophylaxis of age-related macular degeneration |
US20220065875A1 (en) * | 2019-02-08 | 2022-03-03 | Ajou University Industry-Academic Cooperation Foundation | Biomarker composition for diagnosis of degenerative brain disease |
WO2021231652A1 (en) * | 2020-05-14 | 2021-11-18 | Curelab Oncology, Inc. | Using the p62 plasmid to treat or reduce the severity of coronavirus infections |
WO2022129180A1 (en) * | 2020-12-15 | 2022-06-23 | Centre National De La Recherche Scientifique | Sqstm1 and its use in cancer therapy |
WO2023156807A2 (en) * | 2021-09-27 | 2023-08-24 | Curelab Oncology, Inc. | Prevention and treatment of diseases by modulating activity of mesenchymal stem cells with p62 (sqstm1)-encoding vector and pharmaceutical formulations containing p62 (sqstm1) proteins |
CN117603982B (zh) * | 2024-01-22 | 2024-04-19 | 中国医学科学院北京协和医院 | 肌萎缩侧索硬化症的SQSTM1的p.P374TfsTer18突变致病基因及其应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005050170A2 (en) * | 2003-11-17 | 2005-06-02 | Auburn University | Methods and compositions for inhibiting intracellular aggregate formation |
US20060035823A1 (en) * | 2000-08-17 | 2006-02-16 | Seth Lederman | Isolated fragments of p62 nucleoporin and uses thereof |
WO2007044522A1 (en) * | 2005-10-05 | 2007-04-19 | Auburn University | P62 as a risk determinant for metabolic syndrome |
WO2013022991A2 (en) * | 2011-08-08 | 2013-02-14 | Curelab Oncology, Inc. | Methods and compositions relating to p62 for the treatment and prophylaxis of cancer |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5364773A (en) | 1991-03-07 | 1994-11-15 | Virogenetics Corporation | Genetically engineered vaccine strain |
EP0681026A1 (en) | 1987-03-02 | 1995-11-08 | Whitehead Institute For Biomedical Research | Recombinant mycobacterial vaccine |
US5504005A (en) | 1987-03-02 | 1996-04-02 | Albert Einstein College Of Medicine Of Yeshiva University | Recombinant mycobacterial vaccine |
AU648505B2 (en) | 1989-05-19 | 1994-04-28 | Amgen, Inc. | Metalloproteinase inhibitor |
EP0517751A4 (en) | 1990-02-26 | 1993-03-31 | Commonwealth Scientific & Industrial Research Organisation ( C.S.I.R.O. ) | Shuttle plasmid for escherichia coli and mycobacteria |
GB9015888D0 (en) | 1990-07-19 | 1990-09-05 | Smithkline Biolog | Vectors |
WO1992015672A1 (en) | 1991-03-07 | 1992-09-17 | Virogenetics Corporation | Genetically engineered vaccine strain |
AU2185592A (en) | 1991-06-06 | 1993-01-08 | Med Immune, Inc. | Induction of ctl responses to foreign antigens expressed in mycobacteria |
US5962224A (en) * | 1995-12-19 | 1999-10-05 | Dana-Farber Cancer Institute | Isolated DNA encoding p62 polypeptides and uses therefor |
US5990091A (en) | 1997-03-12 | 1999-11-23 | Virogenetics Corporation | Vectors having enhanced expression, and methods of making and uses thereof |
US5977311A (en) * | 1997-09-23 | 1999-11-02 | Curagen Corporation | 53BP2 complexes |
NZ509966A (en) | 1998-08-18 | 2003-07-25 | Res Dev Foundation | Recombinant vector comprising a cassette with TET-ON under the control of a heat shock promoter, a cassette with a cloning site for a therapeutic gene, a cassette comprising antisense TET-ON and cassette with a dominative negative TET-ON and its use for metastatic prostate, breast and ovarian cancer |
CN1322730A (zh) * | 2000-05-09 | 2001-11-21 | 上海博德基因开发有限公司 | 一种新的多肽——p62cdc6蛋白24和编码这种多肽的多核苷酸 |
AU2001280767A1 (en) | 2000-07-31 | 2002-02-13 | Active Motif | Peptide-mediated delivery of molecules into cells |
EP1372720A4 (en) * | 2001-03-02 | 2006-07-26 | Medimmune Inc | PREVENTING OR TREATING INFLAMMATORY OR AUTOIMMUNE DISORDERS BY ADMINISTERING ANTAGONISTS OF INTEGRIN ALPHA V BETA 3 |
ATE389015T1 (de) | 2001-07-30 | 2008-03-15 | G R M O Groupe De Rech En Mala | Paget knochenkrankheit |
ATE421532T1 (de) | 2002-05-14 | 2009-02-15 | Jaekyoon Shin | Die rolle von p62 bei altersbedingten erkrankungen |
EP1578367A4 (en) * | 2002-11-01 | 2012-05-02 | Genentech Inc | COMPOSITIONS AND METHODS FOR THE TREATMENT OF IMMUNE DISEASES |
WO2005073164A1 (en) * | 2004-01-30 | 2005-08-11 | Peplin Biolipids Pty Ltd | Therapeutic and carrier molecules |
GB0412301D0 (en) * | 2004-06-02 | 2004-07-07 | Diagenic As | Product and method |
WO2011039734A2 (en) * | 2009-10-02 | 2011-04-07 | Enzo Medico | Use of genes involved in anchorage independence for the optimization of diagnosis and treatment of human cancer |
US8945847B2 (en) | 2010-05-24 | 2015-02-03 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Methods and kits for ascertaining biosafety of an agent |
KR20150038915A (ko) | 2013-10-01 | 2015-04-09 | 코닝정밀소재 주식회사 | 전기 이중층 캐패시터의 전극 소재용 그래핀 플레이크 제조방법, 이에 의해 제조된 그래핀 플레이크 및 이를 전극 소재로 포함하는 전기 이중층 캐패시터 |
KR101594168B1 (ko) | 2013-10-02 | 2016-02-15 | 서울대학교산학협력단 | p62의 ZZ 영역에 의해 매개되는 자가포식 조절 방법 및 그 용도 |
SG11201605316VA (en) | 2013-12-29 | 2016-07-28 | Curelab Oncology Inc | Methods and compositions relating to p62/sqstm1 for the treatment and prevention of inflammation-associated diseases |
WO2020028923A2 (en) * | 2018-08-02 | 2020-02-06 | Curelab Oncology, Inc. | Compositions and methods relating to p62 for the treatment and prophylaxis of age-related macular degeneration |
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2014
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060035823A1 (en) * | 2000-08-17 | 2006-02-16 | Seth Lederman | Isolated fragments of p62 nucleoporin and uses thereof |
WO2005050170A2 (en) * | 2003-11-17 | 2005-06-02 | Auburn University | Methods and compositions for inhibiting intracellular aggregate formation |
WO2007044522A1 (en) * | 2005-10-05 | 2007-04-19 | Auburn University | P62 as a risk determinant for metabolic syndrome |
WO2013022991A2 (en) * | 2011-08-08 | 2013-02-14 | Curelab Oncology, Inc. | Methods and compositions relating to p62 for the treatment and prophylaxis of cancer |
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US20220009985A1 (en) | 2022-01-13 |
SG11201605316VA (en) | 2016-07-28 |
JP6498210B2 (ja) | 2019-04-10 |
US20190153056A1 (en) | 2019-05-23 |
EP3089753B8 (en) | 2020-10-28 |
CA2935232A1 (en) | 2015-07-02 |
EP3089753A4 (en) | 2017-08-09 |
KR20170016314A (ko) | 2017-02-13 |
WO2015100446A1 (en) | 2015-07-02 |
AU2014369861A1 (en) | 2016-06-23 |
KR102422580B1 (ko) | 2022-07-20 |
AU2014369861B2 (en) | 2018-09-13 |
US20160324944A1 (en) | 2016-11-10 |
EP3089753A1 (en) | 2016-11-09 |
CN106061501A (zh) | 2016-10-26 |
US11098098B2 (en) | 2021-08-24 |
RU2016128557A (ru) | 2018-02-01 |
EP3089753B1 (en) | 2020-08-26 |
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