JP2022519345A - 癌、アテローム硬化症、糖尿病およびcnsの疾患の将来の発症に対する早期マーカーとしてならびにこれらの疾患の治療および予防のための標的としてのcmi配列 - Google Patents
癌、アテローム硬化症、糖尿病およびcnsの疾患の将来の発症に対する早期マーカーとしてならびにこれらの疾患の治療および予防のための標的としてのcmi配列 Download PDFInfo
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Abstract
Description
新規のウイルスおよびファージのゲノムの多数のセットは過去数年間に同定されている。これらは、ヒトマイクロバイオーム(Kowarsky et al., 2017; Fernandes et al., 2018)または他の供給物由来の試料の分析を通じて同定された。メタゲノミック(metagenomic)分析が一般的に適用される(Rosario et al., 2012; Gronenborn et al., 2018; Wang et al., 2018; Kazlauskas et al., 2018; Kraberger et al., 2015; Varsani et al., 2018)が、より伝統的な技術の適用も、いくつかの新規の感染性因子の同定をもたらした(de Villiers et al., 2009; Peretti et al., 2015; zur Hausen and de Villiers, 2015)。分析はほとんど、他の公知の薬剤との比較または集合したゲノム中の複製遺伝子の同定に頼った。不運にも、いくつかの試験は、まだ未知であるかまたは推定の新規の感染性因子を同定するためにはより少ない注意を払いながら、公知の感染性実体の存在のみに集中した(Moustafa et al., 2017; Sadeghi et al., 2017; Legoff et al., 2017)。キメラゲノムの発見は、感染性因子の特定の種類または群の間の厳密な境界を弱め、その系統発生的な起源を調べる試験をもたらした(Kurpovic, 2013; Krupovic et al., 2015; Roux et al., 2013; Wawrzyniak et al., 2017; Kazlauskas et al., 2017)。
前記の技術的な課題の解決は、特許請求の範囲において特徴付けられる態様を提供することにより達成される。
細菌性プラスミドは、それらのレプリカーゼ遺伝子のヌクレオチド相同性に基づいて分類される(Bertini et al., 2010)。本発明者らは、全てのBMMF2およびBMMF1単離物の推定Repタンパク質を比較した。系統発生的分析においてコア保存領域(329aa)を使用した。BMMF2 repタンパク質は2つのクレード(AおよびB)にグループ分けされたが、BMMF1 repタンパク質は第3のクレード(C)を形成した。クレードAおよびBは60~65%の類似性を共有した。クレードAにおけるrepタンパク質は、クレード内で69~90%の類似性を共有し、p4ABAYE repに対して70~82%を共有した。同様に、クレードB repタンパク質は、クレード内で80~90%を共有し、p4ABAYE repに対して59~62%を共有した。BMMF1のrepタンパク質(クレードC)は、より多様であり、クレードAおよびBに対して類似性をほとんど共有しなかった(10~12%)。
略語:
Rep=複製タンパク質;
CMI:畜牛乳単離物
C2MI:BMMF2群に属する畜牛乳単離物
HCBI:健常な畜牛血液単離物
Sphinx:可変(X)潜伏期の遅進行性隠れ感染(slow progressive hidden infection of variable (X) latency)
本願において、CNSの疾患(例えば多発性硬化症MS、筋萎縮性側索硬化症、伝染性海綿状脳症/プリオン関連疾患、パーキンソン病、アルツハイマー病)、糖尿病、アテローム硬化症ならびに結腸癌、乳癌および前立腺癌の病因についての新しい概念が提示される。
明らかに全てのヘルペスウイルス型は、以下の議論に関連があると思われる2つの特性を共有する:
潜伏期におけるそれらの残存の間、特定の遺伝子機能により、また部分的に後成的な機構によっても部分的に制御される自発的な再活性化が起こり得る。再活性化はまた、トランスホーミング成長因子βなどの細胞外サイトカインとの相互作用により引き起こされ得る。
低温殺菌されていない牛乳の消費とMS発症の間の相関は、特に低温殺菌されていない牛乳を人生の初期に消費した場合に観察される(zur Hausen, 2017; zur Hausen, 2018)。
ビタミンD欠乏の役割は、MSの開始について繰り返し影響を与えている。
・2つの異なる感染性因子による同じ細胞の潜伏的な感染、ここでそのうちの1つはヘルペス型ウイルス(特に、EBV、HHV-6、VZV、さらにHSV、HHV-7)が最も可能性があり、他の1つは第1の事象として牛乳消費(牛乳因子(bovine milk factor)-BMF)により獲得される。それらのそれぞれは、潜在的に個々の細胞に感染するが、場合によっては両方の因子のゲノムが同じ細胞内に生じる。
・第2の前提条件として、最も頻繁にはヘルペス型ウイルスであるがそれだけではなくエプスタインバーウイルス(EBV)の、溶解サイクルへの再活性。EBVについて、これはおそらくは、活性化されたビタミンD受容体により負に制御されるトランスホーミング成長因子β(TGFβ)のレベルの増加に関連がある;
・第3の事象として、ヘルペス型DNA合成の部分的な抑制およびBMF粒子の形成またはその核酸の神経相互連結を介した隣接する細胞への拡散を生じるBMMFの増幅;
・この後に、隣接する細胞の、BMMFタンパク質の発現による感染が続く;
・最終的に、BMMFに対するT細胞応答は、罹患した細胞の破壊およびMSの場合はプラーク形成をもたらす。これは、一般的に早期の病変において中心静脈および強い局在化した免疫応答から始まる、病変の病巣出現の臨床的な観察を支持する。
(a)図1(A)~22(A)のいずれかに示されるヌクレオチド配列;
(b) (a)のヌクレオチド配列に対して少なくとも93%の同一性を有するヌクレオチド配列;
(c) (a)もしくは(b)のヌクレオチド配列の断片;
(d) (a)、(b)もしくは(c)のヌクレオチド配列に相補的なヌクレオチド配列;または
(e)上述のヌクレオチド配列のいずれかと比較して遺伝子コードの縮重の結果として重複するヌクレオチド配列
を含む、C2MIポリ核酸に関する。
>LSconAfwd
aaggcagatcaacacagg
>LSconArev
agcagattgcaaagcctg
プライマーペアB:
>LSconBfwd
caacacagggatagaataac
>LSconBrev
atctgccttagcagattgc
材料
市販のアッセイ
-NucleoSpin(登録商標)ゲルおよびPCRクリーンアップ(Clean up) Macherey-Nagel
-InvitrogenTM TA CloningTMキット、pCRTM 2.1ベクター有り、コンピテント細胞無し Invitrogen
-InvitrogenTM TA CloningTMキット、pCRTM2.1ベクターおよびOne ShotTM TOP10F' 化学的にコンピテントな大腸菌有り Invitrogen
-InvitrogenTM One ShotTM TOP10F' 化学的にコンピテントな大腸菌 Invitrogen
-AccuPrepプラスミドミニ抽出キット Bioneer
-JeneJetプラスミドMiniprepキット Thermo Scientific
-プラスミドmaxiキット Qiagen
-TaKaRa LA Taq(登録商標)DNAポリメラーゼ、GCバッファ有り TaKaRa
-塩化ナトリウム Sigma-Aldrich
-酵母抽出物 Gerbu
-カゼイン由来のトリプトン/ペプトン Roth
-phi29 DNAポリメラーゼ New England Biolabs M02695
-dNTP Takara '4030
-Exo-耐性ランダムプライマー Thermo Fisher Scientific S0181
DNA(牛乳および牛乳生成物由来の16試料)を、以前に記載されるように(Whitley et al., 2014)フェノール/クロロホルムで抽出した。試料を、プロテイナーゼKバッファ(0.2M Tris-HCL、pH7.5、25mM EDTA、0.3M NaCl、2%SDS)で1:1に希釈し、プロテイナーゼK(終濃度1mg/ml、Sigma-Aldrich P6556)を用いて37℃で一晩消化した。フェノール/クロロホルム抽出の後にエタノール沈殿を続けた。その後、試料5~16を、製造業者のプロトコル(Machery and Nagel, 740.609.250)に従ってNucleospin GelおよびPCRクリーンアップキットを使用したさらなる精製に供した。最終的にDNAを、5mM Tris-HCl、pH8.0に溶出した。
ローリングサークル増幅を、Funk et al, 2014に記載されるように行った。鋳型DNA(50ng)を、10μlの総体積(1x phi29 DNAポリメラーゼバッファ)中、25μM Exo-耐性ランダムプライマーと共に95℃で3分インキュベートし、次いで氷上で冷却した。BSA(0.4mg/ml)、0.75mM dNTPそれぞれおよび1x phi29 DNAポリメラーゼバッファ中10U phi29 DNAポリメラーゼを添加して、この試料を20μlに希釈した。30℃で18時間および65℃で10分のインキュベーション後、15℃で反応を停止した。
RCA増幅されたDNA由来の3μlの鋳型を、TAKARA Taq酵素および添付の溶液を使用して、製造業者のプロトコル(LA TAKARA RR02AG)に従ってポリメラーゼ連鎖反応(PCR)に使用した。それぞれの隣接するプライマーを、それぞれ0.2mMの終濃度で添加した。プライマーは、BMMF2群についてHCBI1、HCBI2およびHCBI7を整列した後に保存された領域に基づいて、ならびにBMMF1群については複製遺伝子の保存された領域に基づいて設計された。
PCRは、それぞれのプライマーペア:
BMMF1群についてMBB2プライマー:
Mbb2(MSBI1.176bbF296フォワード)-5'-TGCAGAAATTGCCCCTCGACT-3'および
Mbb2(MSBI1.176bbR295リバース)-5'-AACAATGGGGAAGAAGTCAAAGG-3'
に特異的なタッチダウン(touchdown)プロトコルを使用して行った。
BMMF2群について使用される隣接するプライマーペアは:
LSConA5p(フォワード)-5'-AAGGCAGATCAACACAGG-3'およびLSconA3p(リバース)-5'-AGCAGATTGCAAAGCCTG-3'、
LSconB5p(フォワード)-5'-CAACACAGGGATAGAATAAC-3'およびLSconB3p(リバース)-5'-ATCTGCCTTAGCAGATTGC-3'
であった。
GATCにより全てのクローンの配列決定を行った。
得られた全ての配列をGenbankにおいて利用可能な配列と比較して、推定タンパク質配列をswissprotおよびswissprot_splicevarと比較した。
Claims (15)
- (a)牛乳試料由来のDNAのフェノール-クロロホルム抽出、その後エタノール沈殿、
(b)工程(a)で抽出されたDNAを用いてローリングサークル増幅(RCA)を行う工程、
(c)プライマーペアA:
>LSconAfwd:
aaggcagatcaacacagg
>LSconArev:
Agcagattgcaaagcctg
プライマーペアB:
>LSconBfwd:
caacacagggatagaataac
>LSconBrev:
atctgccttagcagattgc
から選択される2つの隣接するプライマーペアAおよびBを用いた逆(inverted)PCR
の工程を含む、牛乳試料からDNAを単離するための方法。 - (a)図1(A)~22(A)のいずれかに示されるヌクレオチド配列;
(b)(a)のヌクレオチド配列に対して少なくとも93%の同一性を有するヌクレオチド配列;
(c) (a)もしくは(b)のヌクレオチド配列の断片;
(d) (a)、(b)もしくは(c)のヌクレオチド配列に相補的なヌクレオチド配列;または
(e)上記のヌクレオチド配列のいずれかと比較した遺伝コードの縮重の結果として重複している(redundant)ヌクレオチド配列
を含む、請求項1記載の方法により入手可能なC2MIポリ核酸。 - 請求項2記載のC2MIポリ核酸の一部を含むオリゴヌクレオチドプローブであって、該プローブが、請求項2記載のヌクレオチド配列を含む特定のC2MI単離物の核酸の特異的検出のためのハイブリダイゼーションプローブとして働き得る、オリゴヌクレオチドプローブ。
- 原核生物、真核生物またはウイルスの転写および翻訳制御因子に操作可能に連結される請求項2または3記載のC2MIポリ核酸を含む、発現ベクター。
- 請求項4記載の発現ベクターで形質転換されるかまたは改変される宿主細胞。
- 請求項2記載のC2MIポリ核酸によりコードされるポリペプチド。
- 請求項6記載のポリペプチドに特異的に結合する抗体またはその抗原結合断片。
- 癌、CNSの疾患、アテローム硬化症または糖尿病の素因または初期段階の診断のための診断組成物の調製のための、請求項3記載のプローブ、請求項6記載のポリペプチドまたは請求項7記載の抗体もしくはその断片の使用。
- 癌が、乳癌、卵巣癌、肺癌、前立腺癌、結腸直腸癌または結腸癌であり、CNSの疾患が、多発性硬化症MS、筋萎縮性側索硬化症、伝染性海綿状脳症(spongiforme encephalopathies)/プリオン関連疾患、パーキンソン病またはアルツハイマー病である、請求項8記載の使用。
- (a)任意に試料ポリ核酸を抽出する工程、(b)上述のポリ核酸と、少なくとも1つの請求項3記載のプローブ、任意に標識されたプローブをハイブリダイズさせる工程、および(c)ハイブリダイズしたポリ核酸を検出する工程を含む、生物学的試料における請求項2記載のC2MIポリ核酸の検出のための方法。
- 生物学的試料中に存在する請求項6記載のポリペプチドまたは請求項7記載の抗体を検出するための方法であって、(a)上で定義されるかかるポリペプチドまたは抗体の存在および/または濃度について生物学的試料を接触させる工程、ならびに(b)該抗体および/または該ポリペプチドの間で形成される免疫学的複合体を検出する工程を含む、方法。
- 請求項2記載のC2MIポリ核酸の発現を低減もしくは阻害するアンチセンスオリゴヌクレオチドまたは該アンチセンスオリゴヌクレオチドを含むベクター。
- 請求項7記載の抗体もしくはその抗原結合断片または請求項12記載のアンチセンスオリゴヌクレオチドおよび適切な薬学的担体を含む、医薬組成物。
- 請求項2記載のC2MIポリ核酸または請求項6記載のポリペプチドを含むワクチンであって、好ましくは該ワクチンが、VLPまたはタンパク質/DNAもしくはポリペプチド/DNAの複合体または特異的タンパク質または弱められた感染性因子を含む、ワクチン。
- 癌、CNSの疾患、アテローム硬化症または糖尿病の予防または治療のための医薬の開発のためのリード構成要素としての請求項2記載のC2MIポリ核酸の使用であって、好ましくは癌が、乳癌、卵巣癌、肺癌、前立腺癌、結腸直腸癌または結腸癌であり、CNSの疾患が、多発性硬化症MS、筋萎縮性側索硬化症、伝染性海綿状脳症(spongiforme encephalopathies)/プリオン関連疾患、パーキンソン病またはアルツハイマー病である、使用。
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JP2017522869A (ja) * | 2014-07-10 | 2017-08-17 | ドイチェス クレブスフォルシュンクスツェントルム | 癌およびcnsの疾患の将来の発症のための早期マーカー、ならびにこれらの疾患の治療および予防のための標的としてのhcbi、msbi、mssiおよびcmi配列 |
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