JP2022160505A - ファンコニ貧血患者に対する遺伝子療法 - Google Patents
ファンコニ貧血患者に対する遺伝子療法 Download PDFInfo
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Abstract
Description
本願は、2016年9月8日に出願された米国仮出願番号62/385185および2016年10月24日に出願された米国仮出願62/412.028からの優先権および恩典を主張し、それらの内容の全体を参照により本明細書に組み入れる。
本発明は、概して、1つまたは複数のFANCAコードタンパク質からのタンパク質活性が減少または消失した細胞への遺伝子移入に関する。
本願に付属する配列表は、紙面の複製物に代えてテキスト形式で提供され、参照により本明細書に組み入れられる。配列を含むテキストファイルの名前は、ROPA_002_01WO_ST25.txtである。このテキストファイルは46KBであり、2017年9月8日に作成され、EFS-WEBを通じて電子的に提出される。
ファンコニ貧血(FA)は、患者の生存率の中央値がおよそ24歳である、常染色体劣性疾患である(X連鎖である相補群FA-Bを除く)(Butturini A, et al. (1994) Blood 84: 1650-1655(非特許文献1); Kutler DI, et al. (2003) Blood 101: 1249-1256(非特許文献2))。出生時、これらの患者の血球数は一般に正常である。大赤血球症が、多くの場合、これらの患者において検出される最初の血液学的異常である。これは通常、血小板減少症、貧血および汎血球減少症と共に発展する。通常、これらの患者において5~10歳以降に骨髄不全(BMF)が観察され、血液学的疾患発症の平均年齢は7歳である。FA患者の約80%は、その生涯の最初の10年でBMFの兆候を示すであろう。今日までの疫学的研究に基づき、形成不全前に悪性エピソードが現れない場合、実質的にすべてのFA患者が40歳までにBMFを発症すると考えられ(Butturini A, et al. (1994) Blood 84: 1650-1655(非特許文献1); Kutler DI, et al. (2003) Blood 101: 1249-1256(非特許文献2))、これはこれらの患者における一番の死因である。
5'から3'の順に以下:
(a)ヒトホスホグリセリン酸キナーゼ(PGK)プロモーター配列またはその機能的ホモログもしくは変種と、
(b)ヒトFANCAポリペプチドまたはその機能的フラグメントもしくは変種をコードする配列と、
(c)ウッドチャック肝炎ウイルス調節エレメント(WPRE)RNA輸送シグナル配列またはその機能的変種もしくはフラグメントと
を含むポリヌクレオチド配列を含む発現カセットであって、ヒトFANCAポリペプチドまたはその機能的フラグメントもしくは変種をコードする配列が、PGKプロモーター配列に機能的に連結されている、発現カセット。
[本発明1002]
FANCAポリペプチドまたはその機能的フラグメントもしくは変種が、SEQ ID NO:25に示される配列を含む、本発明1001の発現カセット。
[本発明1003]
FANCAポリペプチドまたはその機能的フラグメントもしくは変種をコードする配列が、SEQ ID NO:8に示される配列を含む、本発明1001の発現カセット。
[本発明1004]
PGKプロモーターが、SEQ ID NO:7のヌクレオチド配列を含む、本発明1001の発現カセット。
[本発明1005]
WPREエレメントが、SEQ ID NO:23のヌクレオチド配列を含む、本発明1001の発現カセット。
[本発明1006]
SEQ ID NO:24のヌクレオチド配列を含む、本発明1001の発現カセット。
[本発明1007]
1つまたは複数のエンハンサー配列をさらに含む、本発明1001~1008のいずれかの発現カセット。
[本発明1008]
(d)ポリプリントラクト(PPT)またはポリアデニル化(ポリA)シグナル配列
をさらに含む、本発明1001の発現カセット。
[本発明1009]
以下の配列:
(e)パッケージングシグナル配列、
(f)短縮型Gag配列、
(g)Rev応答エレメント(RRE)、
(h)セントラルポリプリントラクト(cPPT)、
(i)セントラルターミナル配列(CTS)、および
(j)上流配列エレメント(USE)、任意でサルウイルス40由来(SV40-USE)
のうちの1つまたは複数をさらに含む、本発明1001の発現カセット。
[本発明1010]
本発明1001~1009のいずれかの発現カセットを含む、組換え遺伝子送達ベクター。
[本発明1011]
ウイルスまたはウイルスベクターである、本発明1010の組換え遺伝子送達ベクター。
[本発明1012]
ウイルスまたはウイルスベクターが、レンチウイルス(LV)である、本発明1011の組換え遺伝子送達ベクター。
[本発明1013]
本発明1001の発現カセットまたは本発明1011もしくは本発明1012の組換え遺伝子送達ベクターを含む、細胞。
[本発明1014]
造血幹細胞である、本発明1013の細胞。
[本発明1015]
CD34+細胞である、本発明1013の細胞。
[本発明1016]
薬学的に許容される賦形剤および本発明1010~1012のいずれかの組換え遺伝子送達ベクターを含む、薬学的組成物。
[本発明1017]
薬学的に許容される賦形剤および本発明1013~1015のいずれかの細胞を含む、薬学的組成物。
[本発明1018]
その必要がある対象においてファンコニ貧血を処置する方法であって、本発明1017または本発明1017の薬学的組成物を該対象に提供する工程を含む、方法。
[本発明1019]
その必要がある対象においてファンコニ貧血を処置するための方法であって、発現カセットを含むCD34+細胞を該対象に提供する工程を含み、該発現カセットは、5’から3'の順に以下:
(a)ヒトホスホグリセリン酸キナーゼ(PGK)プロモーター配列またはその機能的ホモログもしくは変種と、
(b)ヒトFANCAポリペプチドまたはその機能的フラグメントもしくは変種をコードする配列と、
(c)ウッドチャック肝炎ウイルス調節エレメント(WPRE)RNA輸送シグナル配列またはその機能的変種もしくはフラグメントと
を含むポリヌクレオチド配列を含み、ヒトFANCAポリペプチドまたはその機能的フラグメントもしくは変種をコードする配列が、PGKプロモーター配列に機能的に連結されている、方法。
[本発明1020]
CD34+細胞が、前記対象から得られた、本発明1019の方法。
[本発明1021]
CD34+細胞が、前記対象を(i)G-CSFまたはフィルグラスチムおよび(ii)プレリキサホルの組み合わせで処置した後に該対象から得られた、本発明1020の方法。
[本発明1021]
CD34+細胞が、前記発現カセットを含む組換え遺伝子送達ベクターを用いて形質導入された、本発明1020の方法。
[本発明1022]
CD34+細胞が、該CD34+細胞と前記組換え遺伝子送達ベクターを約24時間接触させることによって形質導入された、本発明1021の方法。
[本発明1023]
その必要がある対象においてファンコニ貧血を処置するための方法であって、
(a)該対象においてCD34+細胞を動員するために、該対象に(i)G-CSFまたはフィルグラスチムおよび(ii)プレリキサホルの組み合わせを提供する工程、
(b)該対象からCD34+細胞を含む生物学的サンプルを入手する工程であって、該生物学的サンプルが任意で末梢血または骨髄である、工程、
(c)該生物学的サンプルから、CD34+細胞が濃縮された細胞集団を調製する工程、
(d)5'から3'の順に以下:
(i)プロモーター配列またはその機能的ホモログもしくは変種と、
(ii)ヒトFANCAポリペプチドまたはその機能的フラグメントもしくは変種をコードする配列と
を含むポリヌクレオチド配列を含む発現カセットを含む組換え遺伝子送達ベクターを用いて、CD34+細胞が濃縮された細胞集団に形質導入する工程であって、ヒトFANCAポリペプチドまたはその機能的フラグメントもしくは変種をコードする配列が、PGKプロモーター配列に機能的に連結されており、該形質導入が、該CD34+細胞が濃縮された細胞集団とレンチウイルスベクターを約24時間接触させることを含む、工程、ならびに
(e)工程(d)に起因するレンチウイルスベクターを用いて形質導入された細胞集団を該対象に提供する工程
を含む、方法。
[本発明1024]
前記細胞集団を調製する工程が、赤血球を除去する工程を含む、本発明1023の方法。
[本発明1025]
前記細胞集団を調製する工程が、陽性選択、陰性選択またはそれらの組み合わせによりCD34+細胞を濃縮する工程を含む、本発明1023の方法。
[本発明1026]
前記対象におけるファンコニ貧血の発症を阻害する、ファンコニ貧血の進行を停止させる、および/またはファンコニ貧血の血液学的症状の進行を逆転させる、本発明1023の方法。
[本発明1027]
ファンコニ貧血の血液学的症状が、BMF、血小板減少症、白血球減少症、汎血球減少症、好中球減少症および貧血のうちの1つまたは複数から選択される、本発明1026の方法。
本発明の他の特徴および利点は、以下の詳細な説明および特許請求の範囲から明らかとなり、かつそれらに包含される。
本発明は、概して、分子生物学およびウイルス学の分野、特に、遺伝子発現カセットならびに(例えば、ペプチド、ポリペプチド、リボザイムおよび触媒性RNA分子を含む)選択された治療用構築物をコードする核酸セグメントを脊椎動物の選択された細胞および組織に送達するのに有用なそれらを含むベクターに関する。特に、これらの遺伝子構築物は、FANCA遺伝子産物の機能不全に関連する哺乳動物、特にヒトの疾患、障害および機能不全を処置するための遺伝子療法に有用である。
それ以外の定義がなされていない限り、本明細書で使用される全ての技術および科学用語は、本発明の属する技術の分野における通常の知識を有する者によって一般に理解されているのと同じ意味を有する。本発明の実施には、本明細書に記載されているのと同様または同等の方法および材料が使用され得るが、以下では適当な方法および材料について記載する。本明細書中で言及されているすべての刊行物、特許出願、特許およびその他の参考文献は、明示的に、それらの全体が参照により組み入れられる。相反する場合、定義を含めて本明細書が優先される。加えて、本明細書に記載される材料、方法および実施例は例示にすぎず、限定を意図したものではない。
ファンコニ貧血(FA)は、主として骨髄不全(BMF)および癌体質により特徴づけられる稀な遺伝性染色体不安定症候群である(Butturini A et al. Blood. 1994; 84; 1650-1655; Kutler DI et al. Blood. 2003; 101: 1249-1256)。FAの有病率は、100万人あたり1~5人であり、ヘテロ接合型キャリアの頻度は、300人に1人と見積もられている(Tamary H et al. Eur J Haematol. 2004; 72: 330-335)。
本開示のいくつかの局面において、真核生物細胞内でのFANCAトランスジーンの発現のための組成物が提供される。ある態様において、真核生物細胞は、哺乳動物細胞である。1つの態様において、哺乳動物細胞は、造血幹細胞(HSC)である。1つの態様において、哺乳動物細胞は、造血前駆体である。1つの態様において、哺乳動物細胞は、CD34+である。1つの態様において、哺乳動物細胞は、ヒト細胞である。具体的な態様において、細胞は、本明細書に開示される遺伝子送達によって形質導入された後にそのCD34+細胞によって処置されるべきFAと診断された対象由来であり、開示される遺伝子発現カセットを含むヒトCD34+細胞である。
(i)ホスホグリセリン酸キナーゼ(PGK)プロモーター配列またはその機能的変種もしくはフラグメント、
(ii)ヒトFANCAタンパク質またはその機能的フラグメントもしくは変種をコードする配列、および
(iii)ウッドチャック肝炎ウイルス配列の転写後調節エレメント(WPRE)
を含む。
(i)ヒトホスホグリセリン酸キナーゼ(PGK)プロモーター配列、
(ii)ヒトFANCAタンパク質をコードする配列、および
(iii)変異WPRE配列
を含む。
a)5'LTR、任意で改変5'LTR、
b)cPPT配列、
c)PGKプロモーター配列、任意でヒトPGKプロモーター配列、
d)ヒトFANCAタンパク質をコードする配列、任意でcDNA配列またはコドン最適化配列、
e)変異wPRE配列、および
f)3'LTR、任意で改変3'LTR
を含む。
;または
SEQ ID NO:24のヌクレオチド2649~2882を含むかもしくはそれからなる配列。
;または
SEQ ID NO:24のポリヌクレオチド2031~2156を含むかもしくはそれからなる配列。
;または
SEQ ID NO:24のポリヌクレオチド1586~9495を含むかもしくはそれからなる配列。
;または
SEQ ID NO:24のポリヌクレオチド9262~9495を含むかもしくはそれからなる配列。
;または
SEQ ID NO:24のポリヌクレオチド1586~1789を含むかもしくはそれからなる配列。
;または
SEQ ID NO:24のヌクレオチド3378~3495を含むかもしくはそれからなる配列。
;または
SEQ ID NO:24のヌクレオチド3541~4051を含むかもしくはそれからなる配列。
。
。
。
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(i)初期pCCLsin-cppt-hPGK-eGFP-WPRE由来のレンチウイルスベクターの骨格(Dull et al, 1998; J. Virol 72(11), 9873-9880)。pCCL骨格は、プロデューサー細胞において高レベルのウイルスRNA転写を行うために異種CMV-HIV 5'LTRを利用する。そのような異種LTRは、rHIV粒子の産生のためにHIV Tatタンパク質を使用する必要性から構築物を解放し、したがってそれは安全な特徴である。3'LTRのU3領域は、そのベクターに自己不活性化特性を付与する(Zufferey et al J Virol, 1998)に記載される400 bp欠失を含む;
(ii)ヒトPGKプロモーターの制御下でFANCAタンパク質(1455 AA)をコードする(4368 bp GeneBankアクセッション番号:X_99226または本明細書に開示される)ヒトFANCA遺伝子のcDNA。このプロモーターは、遺伝子療法においてすでに使用されている他のプロモーターとの比較で、インビボでのその安定的な活性によっておよび改善された安全面の特性によってすでに特徴づけられている;および
(iii)Schambachら(Gene therapy, 2006; 13, 641-645)によって記載されるXタンパク質をコードする配列の3'領域および任意の残留するORFを含まない変異版のウッドチャック肝炎ウイルス転写後調節エレメント(WPRE)またはWPRE*。
以下でより詳細に述べるように、本明細書中で集合的に「本発明の組成物」と呼ばれる本発明のポリヌクレオチドカセットおよび遺伝子送達ベクターは、動物、例えば哺乳動物またはヒトの細胞におけるトランスジーン、例えばFANCAの発現において、有用である。例えば、本発明の組成物は、研究において、例えば、細胞の生存度および/または機能に対して遺伝子が及ぼす効果を決定するために使用され得る。もう一つの例として、本発明の組成物は、医療において、例えば、FAなどの障害を処置するために使用され得る。従って、本発明のいくつかの局面において、細胞を本開示の組成物と接触させる工程を含む、細胞における遺伝子の発現の方法が提供される。いくつかの態様において、接触は、インビトロで行われる。いくつかの態様において、接触は、インビボで行われる、即ち、本発明の組成物が対象へ投与される。
FANCAレンチウイルスベクター
RVと比較してLVの組み込みパターンがより高い安全性を有することから(Gonzalez-Murillo et al., 2008; Modlich et al., 2009; Montini et al., 2006; Mitchell RS, Beitzel BF, Schroder AR et al. Plos Biol. 2004; 2: E234; Montini E et al. J Clin Invest. 2009; 119: 964-975; Schroder AR et al. Cell. 2002; 110-521-529)、FA細胞の表現型を矯正する治療用ベクターとしてLVを開発することを目的とした(Gonzalez-Murillo et al., 2009)。さらに、最近の研究は、強力な内部プロモーターを有するLVが隣接遺伝子もトランス活性化し得ることを示している(Modlich et al., 2009)。LVは、治療効果と隣接遺伝子のトランス活性化の危険の間の妥協の産物として臨床での使用を考慮されていた。したがって、目的は、治療遺伝子の発現を誘導するエンハンサー/プロモーターによる遺伝子のトランス活性化の危険を抑制するために、治療的であり得るFANCA発現のしきいレベルを定義することであった。FANCA LVの効果を、最初にFA-A LCLにおいてインビトロで、その後にFA-A患者由来の初代BMサンプルにおいて、最後にFA-Aのマウスモデルにおいてインビボで、検証した。
*FANCAコピーあたりのFANCA mRNAおよびFANCAタンパク質のレベルを推定するため、健常ドナーLCLにおいてはゲノムFANCAが2コピーであるとみなした。
遺伝的に矯正されたまたはされていないいずれかのFA患者由来のBMサンプルの複製性を評価するため、複数のグループが、FA患者由来のBM細胞を免疫不全マウスに移植した。しかし、いずれの例においても、おそらくこれらの患者のBMに存在する造血前駆体およびHSCの数の少なさから、有意な生着が報告されなかった。
FA凍結保存造血幹細胞(HSC)の形質導入は新鮮な移植片の形質導入と比較して低効率であることが以前に示されているので(Jacome et al., 2009)、凍結保存FA BMサンプルの形質導入効率を最適化する試みを行った。図7に示されるように、3回の形質導入サイクルの実施が、1回の形質導入サイクル後に得られる値と比較して、FA CFCの形質導入効率を有意に増加させた(それぞれ、45.7±4.2%対13.5±5.1%)。サンプルを、2時間の静的な事前ローディングの後の1回の形質導入サイクル(16時間)からなる標準的な形質導入(白色バー;1xS)またはレンチウイルスベクターを用いた3回の形質導入サイクル(2時間+2時間+12時間)からなる改善された形質導入(灰色バー;3xD)に供した。
FANCAをPGKプロモーターによって誘導するLVの有効性から、ならびにPGKプロモーターを有するLVの安定性(Follenzi A et al. Nat Genet. 2000; 25: 217-222)および低い遺伝毒性(Modlich et al., 2009, Montini et al., 2006, Montini et al., 2009)を示す以前の研究に基づき、いかなるWPREエレメントも含まないまたはWPREもしくはWPRE*配列を有するPGK-FANCA LVを用いて、LCLにおいて、およびFA-A患者由来の骨髄細胞においても、さらなる実験を行った。図8Aに示されるように、これら3つのベクターはすべて、MMCに対するFA-A LCLの感受性をを同様に逆転させた。
LVはGALV-TRおよびVSV-Gの両方のエンベロープを用いて偽型化することができるので、2つのエンベロープで偽型化されたEGFP-LVを用いて至適条件下でFA患者由来の非選択骨髄細胞に形質導入する新しい実験を実施した。
図10Aに示されるレンチウイルスベクターの形質転換能を、コピー数あたりの再プレーティング回数で測定した。図10Bに示されるように、PGK-FANCA-WPRE* LV(PGK由来レンチウイルスベクター)に対応するレンチウイルスベクター骨格の形質転換能は、X1-SCIDおよびCGD臨床試験においてすでに使用されているウイルスプロモーターを有するベクターの形質転換能と比較して著しく低い。
FANCAレンチウイルスベクターは、ヒトPGKプロモーターの制御下でヒトFANCA cDNAをコードし、Xタンパク質ORFを欠く変異WPREにより転写後レベルで調節される第3世代自己不活性化rHIV1由来ベクターである(図1、図41およびSEQ ID NO:24を参照のこと)。そのようなFANCAレンチウイルスベクターは、FA遺伝子療法において以前から使用されているガンマレトロウイルスベクターを凌ぐ様々な利点、特に、造血幹細胞の多分化能を保存するのに有利である、短い事前活性化プロトコルにもかかわらず細胞に形質導入する能力を示す。
米国内で、FA-AおよびFA-C患者において2つの遺伝子療法試験が実施されたが、これらは臨床効果を示さなかった(Liu, J.M., et al.(1999). Engraftment of hematopoietic progenitor cells transduced with the Fanconi anaemia group C gene (FANCC). Hum. Gene Ther. 10: 2337-2346; Kelly, P.F., et al. (2007). Stem cell collection and gene transfer in fanconi anaemia. Mol Ther 15: 211-219)。上記試験の効果は、様々な最適化を通じて大きく改善され得る。2つの臨床試験は、将来の臨床利用のために十分数のCD34+細胞を収集および精製するプロセスの実現可能性を決定するため(FANCOSTEM)に前後して、ならびにFA相補群A(FA-A)を有する患者における遺伝子療法の安全性および効果を評価するため(FANCOLEN)に並行して実施された。図11を参照のこと。
第2の並行して行われる臨床試験(FANCOLEN)は、FA相補群A(FA-A)を有する患者における遺伝子療法の安全性および効果を評価することを目的とするものであった(FANCOLEN)。遺伝子矯正自己HSCを輸注することによってFA患者の造血能を回復させるために、最適化されたベクターおよび形質導入プロトコルを構築した。詳細に、これは、ファンコニ貧血サブタイプAを有する患者に対するFANCA遺伝子を有するレンチウイルスベクター(希少疾病用医薬品)を用いて形質導入された自己CD34+細胞の輸注の安全性および効果を評価するための第I/II相臨床試験であった。
G-CSF/プレリキサホル法で処置された患者由来の少量の動員末梢血(mPB)CD34+サンプルの治療用ベクターを用いた短期間形質導入は、17~45%の形質導入効率を示した(図35)。少量のこれらのサンプルを、1.5 Gyで調整したNSGマウスに移植した。移植されたサンプルの大部分がNSGマウスに生着した(BM細胞の1~10%がhCD45+/mCD45-であった)(図36)。さらに、生着したマウスにおいて、矯正されたCD34+ FA-A細胞の明白な選択優位性が観察された(図37)。
SEQUENCE LISTING
<110> CENTRO DE INVESTIGACIONES ENERGETICAS, MEDIOAMBIENTALES Y
TECNOLOGICAS, O.A., M.P.
FUNDACION INSTITUTO DE INVESTIGACION SANITARIA FUNDACION
JIMENEZ DIAZ
CONSORCIO CENTRO DE INVESTIGACION BIOMEDICA EN RED, M.P.
FUNDACION PARA LA INVESTIGACION BIOMEDICA DEL HOSPITAL INFANTIL
UNIVERSITARIO NINO JESUS
<120> GENE THERAPY FOR PATIENTS WITH FANCONI ANEMIA
<150> US 62/385,185
<151> 2016-09-08
<150> US 62/412,028
<151> 2016-10-24
<160> 25
<170> PatentIn version 3.5
<210> 1
<211> 234
<212> DNA
<213> Human immunodeficiency virus 1 (HIV-1)
<400> 1
aggagctttg ttccttgggt tcttgggagc agcaggaagc actatgggcg cagcgtcaat 60
gacgctgacg gtacaggcca gacaattatt gtctggtata gtgcagcagc agaacaattt 120
gctgagggct attgaggcgc aacagcatct gttgcaactc acagtctggg gcatcaagca 180
gctccaggca agaatcctgg ctgtggaaag atacctaaag gatcaacagc tcct 234
<210> 2
<211> 126
<212> DNA
<213> Human immunodeficiency virus 1 (HIV-1)
<400> 2
ctctctcgac gcaggactcg gcttgctgaa gcgcgcacgg caagaggcga ggggcggcga 60
ctggtgagta cgccaaaaat tttgactagc ggaggctaga aggagagaga tgggtgcgag 120
agcgtc 126
<210> 3
<211> 181
<212> DNA
<213> Human immunodeficiency virus 1 (HIV-1)
<400> 3
gggtctctct ggttagacca gatctgagcc tgggagctct ctggctaact agggaaccca 60
ctgcttaagc ctcaataaag cttgccttga gtgcttcaag tagtgtgtgc ccgtctgttg 120
tgtgactctg gtaactagag atccctcaga cccttttagt cagtgtggaa aatctctagc 180
a 181
<210> 4
<211> 234
<212> DNA
<213> Human immunodeficiency virus 1 (HIV-1)
<400> 4
tggaagggct aattcactcc caacgaagac aagatctgct ttttgcttgt actgggtctc 60
tctggttaga ccagatctga gcctgggagc tctctggcta actagggaac ccactgctta 120
agcctcaata aagcttgcct tgagtgcttc aagtagtgtg tgcccgtctg ttgtgtgact 180
ctggtaacta gagatccctc agaccctttt agtcagtgtg gaaaatctct agca 234
<210> 5
<211> 204
<212> DNA
<213> Human herpesvirus-5
<400> 5
gtgatgcggt tttggcagta catcaatggg cgtggatagc ggtttgactc acggggattt 60
ccaagtctcc accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac 120
tttccaaaat gtcgtaacaa ctccgcccca ttgacgcaaa tgggcggtag gcgtgtacgg 180
tgggaggtct atataagcag agct 204
<210> 6
<211> 118
<212> DNA
<213> Human immunodeficiency virus 1 (HIV-1)
<400> 6
ttttaaaaga aaagggggga ttggggggta cagtgcaggg gaaagaatag tagacataat 60
agcaacagac atacaaacta aagaattaca aaaacaaatt acaaaaattc aaaatttt 118
<210> 7
<211> 511
<212> DNA
<213> Homo sapiens
<400> 7
ggggttgggg ttgcgccttt tccaaggcag ccctgggttt gcgcagggac gcggctgctc 60
tgggcgtggt tccgggaaac gcagcggcgc cgaccctggg tctcgcacat tcttcacgtc 120
cgttcgcagc gtcacccgga tcttcgccgc tacccttgtg ggccccccgg cgacgcttcc 180
tgctccgccc ctaagtcggg aaggttcctt gcggttcgcg gcgtgccgga cgtgacaaac 240
ggaagccgca cgtctcacta gtaccctcgc agacggacag cgccagggag caatggcagc 300
gcgccgaccg cgatgggctg tggccaatag cggctgctca gcagggcgcg ccgagagcag 360
cggccgggaa ggggcggtgc gggaggcggg gtgtggggcg gtagtgtggg ccctgttcct 420
gcccgcgcgg tgttccgcat tctgcaagcc tccggagcgc acgtcggcag tcggctccct 480
cgttgaccga atcaccgacc tctctcccca g 511
<210> 8
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<212> DNA
<213> Homo sapiens
<400> 8
atgtccgact cgtgggtccc gaactccgcc tcgggccagg acccaggggg ccgccggagg 60
gcctgggccg agctgctggc gggaagggtc aagagggaaa aatataatcc tgaaagggca 120
cagaaattaa aggaatcagc tgtgcgcctc ctgcgaagcc atcaggacct gaatgccctt 180
ttgcttgagg tagaaggtcc actgtgtaaa aaattgtctc tcagcaaagt gattgactgt 240
gacagttctg aggcctatgc taatcattct agttcattta taggctctgc tttgcaggat 300
caagcctcaa ggctgggggt tcccgtgggt attctctcag ccgggatggt tgcctctagc 360
gtgggacaga tctgcacggc tccagcggag accagtcacc ctgtgctgct gactgtggag 420
cagagaaaga agctgtcttc cctgttagag tttgctcagt atttattggc acacagtatg 480
ttctcccgtc tttccttctg tcaagaatta tggaaaatac agagttcttt gttgcttgaa 540
gcggtgtggc atcttcacgt acaaggcatt gtgagcctgc aagagctgct ggaaagccat 600
cccgacatgc atgctgtggg atcgtggctc ttcaggaatc tgtgctgcct ttgtgaacag 660
atggaagcat cctgccagca tgctgacgtc gccagggcca tgctttctga ttttgttcaa 720
atgtttgttt tgaggggatt tcagaaaaac tcagatctga gaagaactgt ggagcctgaa 780
aaaatgccgc aggtcacggt tgatgtactg cagagaatgc tgatttttgc acttgacgct 840
ttggctgctg gagtacagga ggagtcctcc actcacaaga tcgtgaggtg ctggttcgga 900
gtgttcagtg gacacacgct tggcagtgta atttccacag atcctctgaa gaggttcttc 960
agtcataccc tgactcagat actcactcac agccctgtgc tgaaagcatc tgatgctgtt 1020
cagatgcaga gagagtggag ctttgcgcgg acacaccctc tgctcacctc actgtaccgc 1080
aggctctttg tgatgctgag tgcagaggag ttggttggcc atttgcaaga agttctggaa 1140
acgcaggagg ttcactggca gagagtgctc tcctttgtgt ctgccctggt tgtctgcttt 1200
ccagaagcgc agcagctgct tgaagactgg gtggcgcgtt tgatggccca ggcattcgag 1260
agctgccagc tggacagcat ggtcactgcg ttcctggttg tgcgccaggc agcactggag 1320
ggcccctctg cgttcctgtc atatgcagac tggttcaagg cctcctttgg gagcacacga 1380
ggctaccatg gctgcagcaa gaaggccctg gtcttcctgt ttacgttctt gtcagaactc 1440
gtgccttttg agtctccccg gtacctgcag gtgcacattc tccacccacc cctggttccc 1500
agcaagtacc gctccctcct cacagactac atctcattgg ccaagacacg gctggccgac 1560
ctcaaggttt ctatagaaaa catgggactc tacgaggatt tgtcatcagc tggggacatt 1620
actgagcccc acagccaagc tcttcaggat gttgaaaagg ccatcatggt gtttgagcat 1680
acggggaaca tcccagtcac cgtcatggag gccagcatat tcaggaggcc ttactacgtg 1740
tcccacttcc tccccgccct gctcacacct cgagtgctcc ccaaagtccc tgactcccgt 1800
gtggcgttta tagagtctct gaagagagca gataaaatcc ccccatctct gtactccacc 1860
tactgccagg cctgctctgc tgctgaagag aagccagaag atgcagccct gggagtgagg 1920
gcagaaccca actctgctga ggagcccctg ggacagctca cagctgcact gggagagctg 1980
agagcctcca tgacagaccc cagccagcgt gatgttatat cggcacaggt ggcagtgatt 2040
tctgaaagac tgagggctgt cctgggccac aatgaggatg acagcagcgt tgagatatca 2100
aagattcagc tcagcatcaa cacgccgaga ctggagccac gggaacacat tgctgtggac 2160
ctcctgctga cgtctttctg tcagaacctg atggctgcct ccagtgtcgc tcccccggag 2220
aggcagggtc cctgggctgc cctcttcgtg aggaccatgt gtggacgtgt gctccctgca 2280
gtgctcaccc ggctctgcca gctgctccgt caccagggcc cgagcctgag tgccccacat 2340
gtgctggggt tggctgccct ggccgtgcac ctgggtgagt ccaggtctgc gctcccagag 2400
gtggatgtgg gtcctcctgc acctggtgct ggccttcctg tccctgcgct ctttgacagc 2460
ctcctgacct gtaggacgag ggattccttg ttcttctgcc tgaaattttg tacagcagca 2520
atttcttact ctctctgcaa gttttcttcc cagtcacgag atactttgtg cagctgctta 2580
tctccaggcc ttattaaaaa gtttcagttc ctcatgttca gattgttctc agaggcccga 2640
cagcctcttt ctgaggagga cgtagccagc ctttcctgga gacccttgca ccttccttct 2700
gcagactggc agagagctgc cctctctctc tggacacaca gaaccttccg agaggtgttg 2760
aaagaggaag atgttcactt aacttaccaa gactggttac acctggagct ggaaattcaa 2820
cctgaagctg atgctctttc agatactgaa cggcaggact tccaccagtg ggcgatccat 2880
gagcactttc tccctgagtc ctcggcttca gggggctgtg acggagacct gcaggctgcg 2940
tgtaccattc ttgtcaacgc actgatggat ttccaccaaa gctcaaggag ttatgaccac 3000
tcagaaaatt ctgatttggt ctttggtggc cgcacaggaa atgaggatat tatttccaga 3060
ttgcaggaga tggtagctga cctggagctg cagcaagacc tcatagtgcc tctcggccac 3120
accccttccc aggagcactt cctctttgag attttccgca gacggctcca ggctctgaca 3180
agcgggtgga gcgtggctgc cagccttcag agacagaggg agctgctaat gtacaaacgg 3240
atcctcctcc gcctgccttc gtctgtcctc tgcggcagca gcttccaggc agaacagccc 3300
atcactgcca gatgcgagca gttcttccac ttggtcaact ctgagatgag aaacttctgc 3360
tcccacggag gtgccctgac acaggacatc actgcccact tcttcagggg cctcctgaac 3420
gcctgtctgc ggagcagaga cccctccctg atggtcgact tcatactggc caagtgccag 3480
acgaaatgcc ccttaatttt gacctctgct ctggtgtggt ggccgagcct ggagcctgtg 3540
ctgctctgcc ggtggaggag acactgccag agcccgctgc cccgggaact gcagaagcta 3600
caagaaggcc ggcagtttgc cagcgatttc ctctcccctg aggctgcctc cccagcaccc 3660
aacccggact ggctctcagc tgctgcactg cactttgcga ttcaacaagt cagggaagaa 3720
aacatcagga agcagctaaa gaagctggac tgcgagagag aggagctatt ggttttcctt 3780
ttcttcttct ccttgatggg cctgctgtcg tcacatctga cctcaaatag caccacagac 3840
ctgccaaagg ctttccacgt ttgtgcagca atcctcgagt gtttagagaa gaggaagata 3900
tcctggctgg cactctttca gttgacagag agtgacctca ggctggggcg gctcctcctc 3960
cgtgtggccc cggatcagca caccaggctg ctgcctttcg ctttttacag tcttctctcc 4020
tacttccatg aagacgcggc catcagggaa gaggccttcc tgcatgttgc tgtggacatg 4080
tacttgaagc tggtccagct cttcgtggct ggggatacaa gcacagtttc acctccagct 4140
ggcaggagcc tggagctcaa gggtcagggc aaccccgtgg aactgataac aaaagctcgt 4200
ctttttctgc tgcagttaat acctcggtgc ccgaaaaaga gcttctcaca cgtggcagag 4260
ctgctggctg atcgtgggga ctgcgaccca gaggtgagcg ccgccctcca gagcagacag 4320
caggctgccc ctgacgctga cctgtcccag gagcctcatc tcttctga 4368
<210> 9
<211> 380
<212> DNA
<213> Human herpesvirus-5
<400> 9
gacattgatt attgactagt tattaatagt aatcaattac ggggtcatta gttcatagcc 60
catatatgga gttccgcgtt acataactta cggtaaatgg cccgcctggc tgaccgccca 120
acgacccccg cccattgacg tcaataatga cgtatgttcc catagtaacg ccaataggga 180
ctttccattg acgtcaatgg gtggagtatt tacggtaaac tgcccacttg gcagtacatc 240
aagtgtatca tatgccaagt acgcccccta ttgacgtcaa tgacggtaaa tggcccgcct 300
ggcattatgc ccagtacatg accttatggg actttcctac ttggcagtac atctacgtat 360
tagtcatcgc tattaccatg 380
<210> 10
<211> 122
<212> DNA
<213> Simian virus 40
<400> 10
aacttgttta ttgcagctta taatggttac aaataaagca atagcatcac aaatttcaca 60
aataaagcat ttttttcact gcattctagt tgtggtttgt ccaaactcat caatgtatct 120
ta 122
<210> 11
<211> 136
<212> DNA
<213> Simian virus 40
<400> 11
atcccgcccc taactccgcc cagttccgcc cattctccgc cccatggctg actaattttt 60
tttatttatg cagaggccga ggccgcctcg gcctctgagc tattccagaa gtagtgagga 120
ggcttttttg gaggcc 136
<210> 12
<211> 28
<212> DNA
<213> Human immunodeficiency virus 1 (HIV-1)
<400> 12
tttaaaagaa aaggggggat tggggggt 28
<210> 13
<211> 83
<212> DNA
<213> Human immunodeficiency virus 1 (HIV-1)
<400> 13
gaattcgagc tcggtacctt taagaccaat gacttacaag gcagctgtag atcttagcca 60
ctttttaaaa gaaaaggggg gac 83
<210> 14
<211> 795
<212> DNA
<213> Escherichia coli
<400> 14
atgattgaac aagatggatt gcacgcaggt tctccggcgg cttgggtgga gaggctattc 60
ggctatgact gggcacaaca gacaatcggc tgctctgatg ccgccgtgtt ccggctgtca 120
gcgcaggggc gtccggttct ttttgtcaag accgacctgt ccggtgccct gaatgaactg 180
caagacgagg cagcgcggct atcgtggctg gcgacgacgg gcgttccttg cgcggctgtg 240
ctcgacgttg tcactgaagc gggaagggac tggctgctat tgggcgaagt gccggggcag 300
gatctcctgt catctcacct tgctcctgcc gagaaagtat ccatcatggc tgatgcaatg 360
cggcggctgc atacgcttga tccggctacc tgcccattcg accaccaagc gaaacatcgc 420
atcgagcgag cacgtactcg gatggaagcc ggtcttgtcg atcaggatga tctggacgaa 480
gagcatcagg ggctcgcgcc agccgaactg ttcgccaggc tcaaggcgtc tatgcccgac 540
ggcgaggatc tcgtcgtgac ccacggcgat gcctgcttgc cgaatatcat ggtggaaaat 600
ggccgctttt ctggattcat cgactgtggc cgtctgggtg tggcggaccg ctatcaggac 660
atagcgttgg ctacccgtga tattgctgaa gagcttggcg gcgaatgggc tgaccgcttc 720
cttgtgcttt acggtatcgc cgcgcccgat tcgcagcgca tcgccttcta tcgccttctt 780
gacgagttct tctga 795
<210> 15
<211> 137
<212> DNA
<213> Escherichia coli
<400> 15
gcattggcgc agaaaaaaat gcctgatgcg acgctgcgcg tcttatactc ccacatatgc 60
cagattcagc aacggatacg gcttccccaa cttgcccact tccatacgtg tcctccttac 120
cagaaattta tccttaa 137
<210> 16
<211> 589
<212> DNA
<213> unknown
<220>
<223> ColE1/pMB1/pBR322/pUC origin of replication plasmid sequence
<400> 16
ttgagatcct ttttttctgc gcgtaatctg ctgcttgcaa acaaaaaaac caccgctacc 60
agcggtggtt tgtttgccgg atcaagagct accaactctt tttccgaagg taactggctt 120
cagcagagcg cagataccaa atactgttct tctagtgtag ccgtagttag gccaccactt 180
caagaactct gtagcaccgc ctacatacct cgctctgcta atcctgttac cagtggctgc 240
tgccagtggc gataagtcgt gtcttaccgg gttggactca agacgatagt taccggataa 300
ggcgcagcgg tcgggctgaa cggggggttc gtgcacacag cccagcttgg agcgaacgac 360
ctacaccgaa ctgagatacc tacagcgtga gctatgagaa agcgccacgc ttcccgaagg 420
gagaaaggcg gacaggtatc cggtaagcgg cagggtcgga acaggagagc gcacgaggga 480
gcttccaggg ggaaacgcct ggtatcttta tagtcctgtc gggtttcgcc acctctgact 540
tgagcgtcga tttttgtgat gctcgtcagg ggggcggagc ctatggaaa 589
<210> 17
<211> 22
<212> DNA
<213> Escherichia coli
<400> 17
taatgtgagt tagctcactc at 22
<210> 18
<211> 31
<212> DNA
<213> Escherichia coli
<400> 18
tttacacttt atgcttccgg ctcgtatgtt g 31
<210> 19
<211> 17
<212> DNA
<213> Escherichia coli
<400> 19
ttgtgagcgg ataacaa 17
<210> 20
<211> 19
<212> DNA
<213> Bacteriophage T3
<400> 20
aattaaccct cactaaagg 19
<210> 21
<211> 19
<212> DNA
<213> Bacteriophage T7
<400> 21
cctatagtga gtcgtatta 19
<210> 22
<211> 428
<212> DNA
<213> F1 bacteriophage
<400> 22
acgcgccctg tagcggcgca ttaagcgcgg cgggtgtggt ggttacgcgc agcgtgaccg 60
ctacacttgc cagcgcccta gcgcccgctc ctttcgcttt cttcccttcc tttctcgcca 120
cgttcgccgg ctttccccgt caagctctaa atcgggggct ccctttaggg ttccgattta 180
gtgctttacg gcacctcgac cccaaaaaac ttgattaggg tgatggttca cgtagtgggc 240
catcgccctg atagacggtt tttcgccctt tgacgttgga gtccacgttc tttaatagtg 300
gactcttgtt ccaaactgga acaacactca accctatctc ggtctattct tttgatttat 360
aagggatttt gccgatttcg gcctattggt taaaaaatga gctgatttaa caaaaattta 420
acgcgaat 428
<210> 23
<211> 677
<212> DNA
<213> Woodchuck hepatitis virus
<400> 23
cgagcatctt accgccattt attcccatat ttgttctgtt tttcttgatt tgggtataca 60
tttaaatgtt aataaaacaa aatggtgggg caatcattta catttttagg gatatgtaat 120
tactagttca ggtgtattgc cacaagacaa acatgttaag aaactttccc gttatttacg 180
ctctgttcct gttaatcaac ctctggatta caaaatttgt gaaagattga ctgatattct 240
taactatgtt gctcctttta cgctgtgtgg atatgctgct ttaatgcctc tgtatcatgc 300
tattgcttcc cgtacggctt tcgttttctc ctccttgtat aaatcctggt tgctgtctct 360
ttatgaggag ttgtggcccg ttgtccgtca acgtggcgtg gtgtgctctg tgtttgctga 420
cgcaaccccc actggctggg gcattgccac cacctgtcaa ctcctttctg ggactttcgc 480
tttccccctc ccgatcgcca cggcagaact catcgccgcc tgccttgccc gctgctggac 540
aggggctagg ttgctgggca ctgataattc cgtggtgttg tcggggaagg gcctgctgcc 600
ggctctgcgg cctcttccgc gtcttcgcct tcgccctcag acgagtcgga tctccctttg 660
ggccgcctcc ccgcctg 677
<210> 24
<211> 11433
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in lab transfer cassette pCCL-SIN-cPPT/CTS -hPGK-hFANCA-WPRE
<400> 24
catgaccaaa atcccttaac gtgagttttc gttccactga gcgtcagacc ccgtagaaaa 60
gatcaaagga tcttcttgag atcctttttt tctgcgcgta atctgctgct tgcaaacaaa 120
aaaaccaccg ctaccagcgg tggtttgttt gccggatcaa gagctaccaa ctctttttcc 180
gaaggtaact ggcttcagca gagcgcagat accaaatact gttcttctag tgtagccgta 240
gttaggccac cacttcaaga actctgtagc accgcctaca tacctcgctc tgctaatcct 300
gttaccagtg gctgctgcca gtggcgataa gtcgtgtctt accgggttgg actcaagacg 360
atagttaccg gataaggcgc agcggtcggg ctgaacgggg ggttcgtgca cacagcccag 420
cttggagcga acgacctaca ccgaactgag atacctacag cgtgagctat gagaaagcgc 480
cacgcttccc gaagggagaa aggcggacag gtatccggta agcggcaggg tcggaacagg 540
agagcgcacg agggagcttc cagggggaaa cgcctggtat ctttatagtc ctgtcgggtt 600
tcgccacctc tgacttgagc gtcgattttt gtgatgctcg tcaggggggc ggagcctatg 660
gaaaaacgcc agcaacgcgg cctttttacg gttcctggcc ttttgctggc cttttgctca 720
catgttcttt cctgcgttat cccctgattc tgtggataac cgtattaccg cctttgagtg 780
agctgatacc gctcgccgca gccgaacgac cgagcgcagc gagtcagtga gcgaggaagc 840
ggaagagcgc ccaatacgca aaccgcctct ccccgcgcgt tggccgattc attaatgcag 900
ctggcacgac aggtttcccg actggaaagc gggcagtgag cgcaacgcaa ttaatgtgag 960
ttagctcact cattaggcac cccaggcttt acactttatg cttccggctc gtatgttgtg 1020
tggaattgtg agcggataac aatttcacac aggaaacagc tatgaccatg attacgccaa 1080
gcgcgcaatt aaccctcact aaagggaaca aaagctggag ctgcaagctt ggccattgca 1140
tacgttgtat ccatatcata atatgtacat ttatattggc tcatgtccaa cattaccgcc 1200
atgttgacat tgattattga ctagttatta atagtaatca attacggggt cattagttca 1260
tagcccatat atggagttcc gcgttacata acttacggta aatggcccgc ctggctgacc 1320
gcccaacgac ccccgcccat tgacgtcaat aatgacgtat gttcccatag taacgccaat 1380
agggactttc cattgacgtc aatgggtgga gtatttacgg taaactgccc acttggcagt 1440
acatcaagtg tatcatatgc caagtacgcc ccctattgac gtcaatgacg gtaaatggcc 1500
cgcctggcat tatgcccagt acatgacctt atgggacttt cctacttggc agtacatcta 1560
cgtattagtc atcgctatta ccatggtgat gcggttttgg cagtacatca atgggcgtgg 1620
atagcggttt gactcacggg gatttccaag tctccacccc attgacgtca atgggagttt 1680
gttttggcac caaaatcaac gggactttcc aaaatgtcgt aacaactccg ccccattgac 1740
gcaaatgggc ggtaggcgtg tacggtggga ggtctatata agcagagctc gtttagtgaa 1800
ccggggtctc tctggttaga ccagatctga gcctgggagc tctctggcta actagggaac 1860
ccactgctta agcctcaata aagcttgcct tgagtgcttc aagtagtgtg tgcccgtctg 1920
ttgtgtgact ctggtaacta gagatccctc agaccctttt agtcagtgtg gaaaatctct 1980
agcagtggcg cccgaacagg gacttgaaag cgaaagggaa accagaggag ctctctcgac 2040
gcaggactcg gcttgctgaa gcgcgcacgg caagaggcga ggggcggcga ctggtgagta 2100
cgccaaaaat tttgactagc ggaggctaga aggagagaga tgggtgcgag agcgtcagta 2160
ttaagcgggg gagaattaga tcgcgatggg aaaaaattcg gttaaggcca gggggaaaga 2220
aaaaatataa attaaaacat atagtatggg caagcaggga gctagaacga ttcgcagtta 2280
atcctggcct gttagaaaca tcagaaggct gtagacaaat actgggacag ctacaaccat 2340
cccttcagac aggatcagaa gaacttagat cattatataa tacagtagca accctctatt 2400
gtgtgcatca aaggatagag ataaaagaca ccaaggaagc tttagacaag atagaggaag 2460
agcaaaacaa aagtaagacc accgcacagc aagcggccgc tgatcttcag acctggagga 2520
ggagatatga gggacaattg gagaagtgaa ttatataaat ataaagtagt aaaaattgaa 2580
ccattaggag tagcacccac caaggcaaag agaagagtgg tgcagagaga aaaaagagca 2640
gtgggaatag gagctttgtt ccttgggttc ttgggagcag caggaagcac tatgggcgca 2700
gcgtcaatga cgctgacggt acaggccaga caattattgt ctggtatagt gcagcagcag 2760
aacaatttgc tgagggctat tgaggcgcaa cagcatctgt tgcaactcac agtctggggc 2820
atcaagcagc tccaggcaag aatcctggct gtggaaagat acctaaagga tcaacagctc 2880
ctggggattt ggggttgctc tggaaaactc atttgcacca ctgctgtgcc ttggaatgct 2940
agttggagta ataaatctct ggaacagatt tggaatcaca cgacctggat ggagtgggac 3000
agagaaatta acaattacac aagcttaata cactccttaa ttgaagaatc gcaaaaccag 3060
caagaaaaga atgaacaaga attattggaa ttagataaat gggcaagttt gtggaattgg 3120
tttaacataa caaattggct gtggtatata aaattattca taatgatagt aggaggcttg 3180
gtaggtttaa gaatagtttt tgctgtactt tctatagtga atagagttag gcagggatat 3240
tcaccattat cgtttcagac ccacctccca accccgaggg gacccgacag gcccgaagga 3300
atagaagaag aaggtggaga gagagacaga gacagatcca ttcgattagt gaacggatct 3360
cgacggtatc ggttaacttt taaaagaaaa ggggggattg gggggtacag tgcaggggaa 3420
agaatagtag acataatagc aacagacata caaactaaag aattacaaaa acaaattaca 3480
aaaattcaaa attttatcga tcacgagact agcctcgaga agcttgatat cgaattccac 3540
ggggttgggg ttgcgccttt tccaaggcag ccctgggttt gcgcagggac gcggctgctc 3600
tgggcgtggt tccgggaaac gcagcggcgc cgaccctggg tctcgcacat tcttcacgtc 3660
cgttcgcagc gtcacccgga tcttcgccgc tacccttgtg ggccccccgg cgacgcttcc 3720
tgctccgccc ctaagtcggg aaggttcctt gcggttcgcg gcgtgccgga cgtgacaaac 3780
ggaagccgca cgtctcacta gtaccctcgc agacggacag cgccagggag caatggcagc 3840
gcgccgaccg cgatgggctg tggccaatag cggctgctca gcagggcgcg ccgagagcag 3900
cggccgggaa ggggcggtgc gggaggcggg gtgtggggcg gtagtgtggg ccctgttcct 3960
gcccgcgcgg tgttccgcat tctgcaagcc tccggagcgc acgtcggcag tcggctccct 4020
cgttgaccga atcaccgacc tctctcccca gggggatccc ccgggctgca ggaattcatg 4080
tccgactcgt gggtcccgaa ctccgcctcg ggccaggacc cagggggccg ccggagggcc 4140
tgggccgagc tgctggcggg aagggtcaag agggaaaaat ataatcctga aagggcacag 4200
aaattaaagg aatcagctgt gcgcctcctg cgaagccatc aggacctgaa tgcccttttg 4260
cttgaggtag aaggtccact gtgtaaaaaa ttgtctctca gcaaagtgat tgactgtgac 4320
agttctgagg cctatgctaa tcattctagt tcatttatag gctctgcttt gcaggatcaa 4380
gcctcaaggc tgggggttcc cgtgggtatt ctctcagccg ggatggttgc ctctagcgtg 4440
ggacagatct gcacggctcc agcggagacc agtcaccctg tgctgctgac tgtggagcag 4500
agaaagaagc tgtcttccct gttagagttt gctcagtatt tattggcaca cagtatgttc 4560
tcccgtcttt ccttctgtca agaattatgg aaaatacaga gttctttgtt gcttgaagcg 4620
gtgtggcatc ttcacgtaca aggcattgtg agcctgcaag agctgctgga aagccatccc 4680
gacatgcatg ctgtgggatc gtggctcttc aggaatctgt gctgcctttg tgaacagatg 4740
gaagcatcct gccagcatgc tgacgtcgcc agggccatgc tttctgattt tgttcaaatg 4800
tttgttttga ggggatttca gaaaaactca gatctgagaa gaactgtgga gcctgaaaaa 4860
atgccgcagg tcacggttga tgtactgcag agaatgctga tttttgcact tgacgctttg 4920
gctgctggag tacaggagga gtcctccact cacaagatcg tgaggtgctg gttcggagtg 4980
ttcagtggac acacgcttgg cagtgtaatt tccacagatc ctctgaagag gttcttcagt 5040
cataccctga ctcagatact cactcacagc cctgtgctga aagcatctga tgctgttcag 5100
atgcagagag agtggagctt tgcgcggaca caccctctgc tcacctcact gtaccgcagg 5160
ctctttgtga tgctgagtgc agaggagttg gttggccatt tgcaagaagt tctggaaacg 5220
caggaggttc actggcagag agtgctctcc tttgtgtctg ccctggttgt ctgctttcca 5280
gaagcgcagc agctgcttga agactgggtg gcgcgtttga tggcccaggc attcgagagc 5340
tgccagctgg acagcatggt cactgcgttc ctggttgtgc gccaggcagc actggagggc 5400
ccctctgcgt tcctgtcata tgcagactgg ttcaaggcct cctttgggag cacacgaggc 5460
taccatggct gcagcaagaa ggccctggtc ttcctgttta cgttcttgtc agaactcgtg 5520
ccttttgagt ctccccggta cctgcaggtg cacattctcc acccacccct ggttcccagc 5580
aagtaccgct ccctcctcac agactacatc tcattggcca agacacggct ggccgacctc 5640
aaggtttcta tagaaaacat gggactctac gaggatttgt catcagctgg ggacattact 5700
gagccccaca gccaagctct tcaggatgtt gaaaaggcca tcatggtgtt tgagcatacg 5760
gggaacatcc cagtcaccgt catggaggcc agcatattca ggaggcctta ctacgtgtcc 5820
cacttcctcc ccgccctgct cacacctcga gtgctcccca aagtccctga ctcccgtgtg 5880
gcgtttatag agtctctgaa gagagcagat aaaatccccc catctctgta ctccacctac 5940
tgccaggcct gctctgctgc tgaagagaag ccagaagatg cagccctggg agtgagggca 6000
gaacccaact ctgctgagga gcccctggga cagctcacag ctgcactggg agagctgaga 6060
gcctccatga cagaccccag ccagcgtgat gttatatcgg cacaggtggc agtgatttct 6120
gaaagactga gggctgtcct gggccacaat gaggatgaca gcagcgttga gatatcaaag 6180
attcagctca gcatcaacac gccgagactg gagccacggg aacacattgc tgtggacctc 6240
ctgctgacgt ctttctgtca gaacctgatg gctgcctcca gtgtcgctcc cccggagagg 6300
cagggtccct gggctgccct cttcgtgagg accatgtgtg gacgtgtgct ccctgcagtg 6360
ctcacccggc tctgccagct gctccgtcac cagggcccga gcctgagtgc cccacatgtg 6420
ctggggttgg ctgccctggc cgtgcacctg ggtgagtcca ggtctgcgct cccagaggtg 6480
gatgtgggtc ctcctgcacc tggtgctggc cttcctgtcc ctgcgctctt tgacagcctc 6540
ctgacctgta ggacgaggga ttccttgttc ttctgcctga aattttgtac agcagcaatt 6600
tcttactctc tctgcaagtt ttcttcccag tcacgagata ctttgtgcag ctgcttatct 6660
ccaggcctta ttaaaaagtt tcagttcctc atgttcagat tgttctcaga ggcccgacag 6720
cctctttctg aggaggacgt agccagcctt tcctggagac ccttgcacct tccttctgca 6780
gactggcaga gagctgccct ctctctctgg acacacagaa ccttccgaga ggtgttgaaa 6840
gaggaagatg ttcacttaac ttaccaagac tggttacacc tggagctgga aattcaacct 6900
gaagctgatg ctctttcaga tactgaacgg caggacttcc accagtgggc gatccatgag 6960
cactttctcc ctgagtcctc ggcttcaggg ggctgtgacg gagacctgca ggctgcgtgt 7020
accattcttg tcaacgcact gatggatttc caccaaagct caaggagtta tgaccactca 7080
gaaaattctg atttggtctt tggtggccgc acaggaaatg aggatattat ttccagattg 7140
caggagatgg tagctgacct ggagctgcag caagacctca tagtgcctct cggccacacc 7200
ccttcccagg agcacttcct ctttgagatt ttccgcagac ggctccaggc tctgacaagc 7260
gggtggagcg tggctgccag ccttcagaga cagagggagc tgctaatgta caaacggatc 7320
ctcctccgcc tgccttcgtc tgtcctctgc ggcagcagct tccaggcaga acagcccatc 7380
actgccagat gcgagcagtt cttccacttg gtcaactctg agatgagaaa cttctgctcc 7440
cacggaggtg ccctgacaca ggacatcact gcccacttct tcaggggcct cctgaacgcc 7500
tgtctgcgga gcagagaccc ctccctgatg gtcgacttca tactggccaa gtgccagacg 7560
aaatgcccct taattttgac ctctgctctg gtgtggtggc cgagcctgga gcctgtgctg 7620
ctctgccggt ggaggagaca ctgccagagc ccgctgcccc gggaactgca gaagctacaa 7680
gaaggccggc agtttgccag cgatttcctc tcccctgagg ctgcctcccc agcacccaac 7740
ccggactggc tctcagctgc tgcactgcac tttgcgattc aacaagtcag ggaagaaaac 7800
atcaggaagc agctaaagaa gctggactgc gagagagagg agctattggt tttccttttc 7860
ttcttctcct tgatgggcct gctgtcgtca catctgacct caaatagcac cacagacctg 7920
ccaaaggctt tccacgtttg tgcagcaatc ctcgagtgtt tagagaagag gaagatatcc 7980
tggctggcac tctttcagtt gacagagagt gacctcaggc tggggcggct cctcctccgt 8040
gtggccccgg atcagcacac caggctgctg cctttcgctt tttacagtct tctctcctac 8100
ttccatgaag acgcggccat cagggaagag gccttcctgc atgttgctgt ggacatgtac 8160
ttgaagctgg tccagctctt cgtggctggg gatacaagca cagtttcacc tccagctggc 8220
aggagcctgg agctcaaggg tcagggcaac cccgtggaac tgataacaaa agctcgtctt 8280
tttctgctgc agttaatacc tcggtgcccg aaaaagagct tctcacacgt ggcagagctg 8340
ctggctgatc gtggggactg cgacccagag gtgagcgccg ccctccagag cagacagcag 8400
gctgcccctg acgctgacct gtcccaggag cctcatctct tctgatgaga attcgatatc 8460
aagcttatcg ataccgtcga atcccccggg ctgcaggaat tcgagcatct taccgccatt 8520
tattcccata tttgttctgt ttttcttgat ttgggtatac atttaaatgt taataaaaca 8580
aaatggtggg gcaatcattt acatttttag ggatatgtaa ttactagttc aggtgtattg 8640
ccacaagaca aacatgttaa gaaactttcc cgttatttac gctctgttcc tgttaatcaa 8700
cctctggatt acaaaatttg tgaaagattg actgatattc ttaactatgt tgctcctttt 8760
acgctgtgtg gatatgctgc tttaatgcct ctgtatcatg ctattgcttc ccgtacggct 8820
ttcgttttct cctccttgta taaatcctgg ttgctgtctc tttatgagga gttgtggccc 8880
gttgtccgtc aacgtggcgt ggtgtgctct gtgtttgctg acgcaacccc cactggctgg 8940
ggcattgcca ccacctgtca actcctttct gggactttcg ctttccccct cccgatcgcc 9000
acggcagaac tcatcgccgc ctgccttgcc cgctgctgga caggggctag gttgctgggc 9060
actgataatt ccgtggtgtt gtcggggaag ggcctgctgc cggctctgcg gcctcttccg 9120
cgtcttcgcc ttcgccctca gacgagtcgg atctcccttt gggccgcctc cccgcctgga 9180
attcgagctc ggtaccttta agaccaatga cttacaaggc agctgtagat cttagccact 9240
ttttaaaaga aaagggggga ctggaagggc taattcactc ccaacgaaga caagatctgc 9300
tttttgcttg tactgggtct ctctggttag accagatctg agcctgggag ctctctggct 9360
aactagggaa cccactgctt aagcctcaat aaagcttgcc ttgagtgctt caagtagtgt 9420
gtgcccgtct gttgtgtgac tctggtaact agagatccct cagacccttt tagtcagtgt 9480
ggaaaatctc tagcagtagt agttcatgtc atcttattat tcagtattta taacttgcaa 9540
agaaatgaat atcagagagt gagaggaact tgtttattgc agcttataat ggttacaaat 9600
aaagcaatag catcacaaat ttcacaaata aagcattttt ttcactgcat tctagttgtg 9660
gtttgtccaa actcatcaat gtatcttatc atgtctggct ctagctatcc cgcccctaac 9720
tccgcccatc ccgcccctaa ctccgcccag ttccgcccat tctccgcccc atggctgact 9780
aatttttttt atttatgcag aggccgaggc cgcctcggcc tctgagctat tccagaagta 9840
gtgaggaggc ttttttggag gcctagggac gtacccaatt cgccctatag tgagtcgtat 9900
tacgcgcgct cactggccgt cgttttacaa cgtcgtgact gggaaaaccc tggcgttacc 9960
caacttaatc gccttgcagc acatccccct ttcgccagct ggcgtaatag cgaagaggcc 10020
cgcaccgatc gcccttccca acagttgcgc agcctgaatg gcgaatggga cgcgccctgt 10080
agcggcgcat taagcgcggc gggtgtggtg gttacgcgca gcgtgaccgc tacacttgcc 10140
agcgccctag cgcccgctcc tttcgctttc ttcccttcct ttctcgccac gttcgccggc 10200
tttccccgtc aagctctaaa tcgggggctc cctttagggt tccgatttag tgctttacgg 10260
cacctcgacc ccaaaaaact tgattagggt gatggttcac gtagtgggcc atcgccctga 10320
tagacggttt ttcgcccttt gacgttggag tccacgttct ttaatagtgg actcttgttc 10380
caaactggaa caacactcaa ccctatctcg gtctattctt ttgatttata agggattttg 10440
ccgatttcgg cctattggtt aaaaaatgag ctgatttaac aaaaatttaa cgcgaatttt 10500
aacaaaatat taacgcttac aatttaggtg gcacttttcg gggaaatgtg cgcggaaccc 10560
ctatttgttt atttttctaa atacattcaa atatgtatcc gctcatgaga caataaccct 10620
gataaatgct tcaataatag cacctagatc aagagacagg atgaggatcg tttcgcatga 10680
ttgaacaaga tggattgcac gcaggttctc cggccgcttg ggtggagagg ctattcggct 10740
atgactgggc acaacagaca atcggctgct ctgatgccgc cgtgttccgg ctgtcagcgc 10800
aggggcgccc ggttcttttt gtcaagaccg acctgtccgg tgccctgaat gaactgcaag 10860
acgaggcagc gcggctatcg tggctggcca cgacgggcgt tccttgcgca gctgtgctcg 10920
acgttgtcac tgaagcggga agggactggc tgctattggg cgaagtgccg gggcaggatc 10980
tcctgtcatc tcaccttgct cctgccgaga aagtatccat catggctgat gcaatgcggc 11040
ggctgcatac gcttgatccg gctacctgcc cattcgacca ccaagcgaaa catcgcatcg 11100
agcgagcacg tactcggatg gaagccggtc ttgtcgatca ggatgatctg gacgaagagc 11160
atcaggggct cgcgccagcc gaactgttcg ccaggctcaa ggcgagcatg cccgacggcg 11220
aggatctcgt cgtgacccat ggcgatgcct gcttgccgaa tatcatggtg gaaaatggcc 11280
gcttttctgg attcatcgac tgtggccggc tgggtgtggc ggaccgctat caggacatag 11340
cgttggctac ccgtgatatt gctgaagagc ttggcggcga atgggctgac cgcttcctcg 11400
tgctttacgg tatcgccgct cccgattcgc agc 11433
<210> 25
<211> 1455
<212> PRT
<213> Homo sapiens
<400> 25
Met Ser Asp Ser Trp Val Pro Asn Ser Ala Ser Gly Gln Asp Pro Gly
1 5 10 15
Gly Arg Arg Arg Ala Trp Ala Glu Leu Leu Ala Gly Arg Val Lys Arg
20 25 30
Glu Lys Tyr Asn Pro Glu Arg Ala Gln Lys Leu Lys Glu Ser Ala Val
35 40 45
Arg Leu Leu Arg Ser His Gln Asp Leu Asn Ala Leu Leu Leu Glu Val
50 55 60
Glu Gly Pro Leu Cys Lys Lys Leu Ser Leu Ser Lys Val Ile Asp Cys
65 70 75 80
Asp Ser Ser Glu Ala Tyr Ala Asn His Ser Ser Ser Phe Ile Gly Ser
85 90 95
Ala Leu Gln Asp Gln Ala Ser Arg Leu Gly Val Pro Val Gly Ile Leu
100 105 110
Ser Ala Gly Met Val Ala Ser Ser Val Gly Gln Ile Cys Thr Ala Pro
115 120 125
Ala Glu Thr Ser His Pro Val Leu Leu Thr Val Glu Gln Arg Lys Lys
130 135 140
Leu Ser Ser Leu Leu Glu Phe Ala Gln Tyr Leu Leu Ala His Ser Met
145 150 155 160
Phe Ser Arg Leu Ser Phe Cys Gln Glu Leu Trp Lys Ile Gln Ser Ser
165 170 175
Leu Leu Leu Glu Ala Val Trp His Leu His Val Gln Gly Ile Val Ser
180 185 190
Leu Gln Glu Leu Leu Glu Ser His Pro Asp Met His Ala Val Gly Ser
195 200 205
Trp Leu Phe Arg Asn Leu Cys Cys Leu Cys Glu Gln Met Glu Ala Ser
210 215 220
Cys Gln His Ala Asp Val Ala Arg Ala Met Leu Ser Asp Phe Val Gln
225 230 235 240
Met Phe Val Leu Arg Gly Phe Gln Lys Asn Ser Asp Leu Arg Arg Thr
245 250 255
Val Glu Pro Glu Lys Met Pro Gln Val Thr Val Asp Val Leu Gln Arg
260 265 270
Met Leu Ile Phe Ala Leu Asp Ala Leu Ala Ala Gly Val Gln Glu Glu
275 280 285
Ser Ser Thr His Lys Ile Val Arg Cys Trp Phe Gly Val Phe Ser Gly
290 295 300
His Thr Leu Gly Ser Val Ile Ser Thr Asp Pro Leu Lys Arg Phe Phe
305 310 315 320
Ser His Thr Leu Thr Gln Ile Leu Thr His Ser Pro Val Leu Lys Ala
325 330 335
Ser Asp Ala Val Gln Met Gln Arg Glu Trp Ser Phe Ala Arg Thr His
340 345 350
Pro Leu Leu Thr Ser Leu Tyr Arg Arg Leu Phe Val Met Leu Ser Ala
355 360 365
Glu Glu Leu Val Gly His Leu Gln Glu Val Leu Glu Thr Gln Glu Val
370 375 380
His Trp Gln Arg Val Leu Ser Phe Val Ser Ala Leu Val Val Cys Phe
385 390 395 400
Pro Glu Ala Gln Gln Leu Leu Glu Asp Trp Val Ala Arg Leu Met Ala
405 410 415
Gln Ala Phe Glu Ser Cys Gln Leu Asp Ser Met Val Thr Ala Phe Leu
420 425 430
Val Val Arg Gln Ala Ala Leu Glu Gly Pro Ser Ala Phe Leu Ser Tyr
435 440 445
Ala Asp Trp Phe Lys Ala Ser Phe Gly Ser Thr Arg Gly Tyr His Gly
450 455 460
Cys Ser Lys Lys Ala Leu Val Phe Leu Phe Thr Phe Leu Ser Glu Leu
465 470 475 480
Val Pro Phe Glu Ser Pro Arg Tyr Leu Gln Val His Ile Leu His Pro
485 490 495
Pro Leu Val Pro Ser Lys Tyr Arg Ser Leu Leu Thr Asp Tyr Ile Ser
500 505 510
Leu Ala Lys Thr Arg Leu Ala Asp Leu Lys Val Ser Ile Glu Asn Met
515 520 525
Gly Leu Tyr Glu Asp Leu Ser Ser Ala Gly Asp Ile Thr Glu Pro His
530 535 540
Ser Gln Ala Leu Gln Asp Val Glu Lys Ala Ile Met Val Phe Glu His
545 550 555 560
Thr Gly Asn Ile Pro Val Thr Val Met Glu Ala Ser Ile Phe Arg Arg
565 570 575
Pro Tyr Tyr Val Ser His Phe Leu Pro Ala Leu Leu Thr Pro Arg Val
580 585 590
Leu Pro Lys Val Pro Asp Ser Arg Val Ala Phe Ile Glu Ser Leu Lys
595 600 605
Arg Ala Asp Lys Ile Pro Pro Ser Leu Tyr Ser Thr Tyr Cys Gln Ala
610 615 620
Cys Ser Ala Ala Glu Glu Lys Pro Glu Asp Ala Ala Leu Gly Val Arg
625 630 635 640
Ala Glu Pro Asn Ser Ala Glu Glu Pro Leu Gly Gln Leu Thr Ala Ala
645 650 655
Leu Gly Glu Leu Arg Ala Ser Met Thr Asp Pro Ser Gln Arg Asp Val
660 665 670
Ile Ser Ala Gln Val Ala Val Ile Ser Glu Arg Leu Arg Ala Val Leu
675 680 685
Gly His Asn Glu Asp Asp Ser Ser Val Glu Ile Ser Lys Ile Gln Leu
690 695 700
Ser Ile Asn Thr Pro Arg Leu Glu Pro Arg Glu His Ile Ala Val Asp
705 710 715 720
Leu Leu Leu Thr Ser Phe Cys Gln Asn Leu Met Ala Ala Ser Ser Val
725 730 735
Ala Pro Pro Glu Arg Gln Gly Pro Trp Ala Ala Leu Phe Val Arg Thr
740 745 750
Met Cys Gly Arg Val Leu Pro Ala Val Leu Thr Arg Leu Cys Gln Leu
755 760 765
Leu Arg His Gln Gly Pro Ser Leu Ser Ala Pro His Val Leu Gly Leu
770 775 780
Ala Ala Leu Ala Val His Leu Gly Glu Ser Arg Ser Ala Leu Pro Glu
785 790 795 800
Val Asp Val Gly Pro Pro Ala Pro Gly Ala Gly Leu Pro Val Pro Ala
805 810 815
Leu Phe Asp Ser Leu Leu Thr Cys Arg Thr Arg Asp Ser Leu Phe Phe
820 825 830
Cys Leu Lys Phe Cys Thr Ala Ala Ile Ser Tyr Ser Leu Cys Lys Phe
835 840 845
Ser Ser Gln Ser Arg Asp Thr Leu Cys Ser Cys Leu Ser Pro Gly Leu
850 855 860
Ile Lys Lys Phe Gln Phe Leu Met Phe Arg Leu Phe Ser Glu Ala Arg
865 870 875 880
Gln Pro Leu Ser Glu Glu Asp Val Ala Ser Leu Ser Trp Arg Pro Leu
885 890 895
His Leu Pro Ser Ala Asp Trp Gln Arg Ala Ala Leu Ser Leu Trp Thr
900 905 910
His Arg Thr Phe Arg Glu Val Leu Lys Glu Glu Asp Val His Leu Thr
915 920 925
Tyr Gln Asp Trp Leu His Leu Glu Leu Glu Ile Gln Pro Glu Ala Asp
930 935 940
Ala Leu Ser Asp Thr Glu Arg Gln Asp Phe His Gln Trp Ala Ile His
945 950 955 960
Glu His Phe Leu Pro Glu Ser Ser Ala Ser Gly Gly Cys Asp Gly Asp
965 970 975
Leu Gln Ala Ala Cys Thr Ile Leu Val Asn Ala Leu Met Asp Phe His
980 985 990
Gln Ser Ser Arg Ser Tyr Asp His Ser Glu Asn Ser Asp Leu Val Phe
995 1000 1005
Gly Gly Arg Thr Gly Asn Glu Asp Ile Ile Ser Arg Leu Gln Glu
1010 1015 1020
Met Val Ala Asp Leu Glu Leu Gln Gln Asp Leu Ile Val Pro Leu
1025 1030 1035
Gly His Thr Pro Ser Gln Glu His Phe Leu Phe Glu Ile Phe Arg
1040 1045 1050
Arg Arg Leu Gln Ala Leu Thr Ser Gly Trp Ser Val Ala Ala Ser
1055 1060 1065
Leu Gln Arg Gln Arg Glu Leu Leu Met Tyr Lys Arg Ile Leu Leu
1070 1075 1080
Arg Leu Pro Ser Ser Val Leu Cys Gly Ser Ser Phe Gln Ala Glu
1085 1090 1095
Gln Pro Ile Thr Ala Arg Cys Glu Gln Phe Phe His Leu Val Asn
1100 1105 1110
Ser Glu Met Arg Asn Phe Cys Ser His Gly Gly Ala Leu Thr Gln
1115 1120 1125
Asp Ile Thr Ala His Phe Phe Arg Gly Leu Leu Asn Ala Cys Leu
1130 1135 1140
Arg Ser Arg Asp Pro Ser Leu Met Val Asp Phe Ile Leu Ala Lys
1145 1150 1155
Cys Gln Thr Lys Cys Pro Leu Ile Leu Thr Ser Ala Leu Val Trp
1160 1165 1170
Trp Pro Ser Leu Glu Pro Val Leu Leu Cys Arg Trp Arg Arg His
1175 1180 1185
Cys Gln Ser Pro Leu Pro Arg Glu Leu Gln Lys Leu Gln Glu Gly
1190 1195 1200
Arg Gln Phe Ala Ser Asp Phe Leu Ser Pro Glu Ala Ala Ser Pro
1205 1210 1215
Ala Pro Asn Pro Asp Trp Leu Ser Ala Ala Ala Leu His Phe Ala
1220 1225 1230
Ile Gln Gln Val Arg Glu Glu Asn Ile Arg Lys Gln Leu Lys Lys
1235 1240 1245
Leu Asp Cys Glu Arg Glu Glu Leu Leu Val Phe Leu Phe Phe Phe
1250 1255 1260
Ser Leu Met Gly Leu Leu Ser Ser His Leu Thr Ser Asn Ser Thr
1265 1270 1275
Thr Asp Leu Pro Lys Ala Phe His Val Cys Ala Ala Ile Leu Glu
1280 1285 1290
Cys Leu Glu Lys Arg Lys Ile Ser Trp Leu Ala Leu Phe Gln Leu
1295 1300 1305
Thr Glu Ser Asp Leu Arg Leu Gly Arg Leu Leu Leu Arg Val Ala
1310 1315 1320
Pro Asp Gln His Thr Arg Leu Leu Pro Phe Ala Phe Tyr Ser Leu
1325 1330 1335
Leu Ser Tyr Phe His Glu Asp Ala Ala Ile Arg Glu Glu Ala Phe
1340 1345 1350
Leu His Val Ala Val Asp Met Tyr Leu Lys Leu Val Gln Leu Phe
1355 1360 1365
Val Ala Gly Asp Thr Ser Thr Val Ser Pro Pro Ala Gly Arg Ser
1370 1375 1380
Leu Glu Leu Lys Gly Gln Gly Asn Pro Val Glu Leu Ile Thr Lys
1385 1390 1395
Ala Arg Leu Phe Leu Leu Gln Leu Ile Pro Arg Cys Pro Lys Lys
1400 1405 1410
Ser Phe Ser His Val Ala Glu Leu Leu Ala Asp Arg Gly Asp Cys
1415 1420 1425
Asp Pro Glu Val Ser Ala Ala Leu Gln Ser Arg Gln Gln Ala Ala
1430 1435 1440
Pro Asp Ala Asp Leu Ser Gln Glu Pro His Leu Phe
1445 1450 1455
Claims (28)
- 5'から3'の順に以下:
(a)ヒトホスホグリセリン酸キナーゼ(PGK)プロモーター配列またはその機能的ホモログもしくは変種と、
(b)ヒトFANCAポリペプチドまたはその機能的フラグメントもしくは変種をコードする配列と、
(c)ウッドチャック肝炎ウイルス調節エレメント(WPRE)RNA輸送シグナル配列またはその機能的変種もしくはフラグメントと
を含むポリヌクレオチド配列を含む発現カセットであって、ヒトFANCAポリペプチドまたはその機能的フラグメントもしくは変種をコードする配列が、PGKプロモーター配列に機能的に連結されている、発現カセット。 - FANCAポリペプチドまたはその機能的フラグメントもしくは変種が、SEQ ID NO:25に示される配列を含む、請求項1記載の発現カセット。
- FANCAポリペプチドまたはその機能的フラグメントもしくは変種をコードする配列が、SEQ ID NO:8に示される配列を含む、請求項1記載の発現カセット。
- PGKプロモーターが、SEQ ID NO:7のヌクレオチド配列を含む、請求項1記載の発現カセット。
- WPREエレメントが、SEQ ID NO:23のヌクレオチド配列を含む、請求項1記載の発現カセット。
- SEQ ID NO:24のヌクレオチド配列を含む、請求項1記載の発現カセット。
- 1つまたは複数のエンハンサー配列をさらに含む、請求項1~8のいずれか一項記載の発現カセット。
- (d)ポリプリントラクト(PPT)またはポリアデニル化(ポリA)シグナル配列
をさらに含む、請求項1記載の発現カセット。 - 以下の配列:
(e)パッケージングシグナル配列、
(f)短縮型Gag配列、
(g)Rev応答エレメント(RRE)、
(h)セントラルポリプリントラクト(cPPT)、
(i)セントラルターミナル配列(CTS)、および
(j)上流配列エレメント(USE)、任意でサルウイルス40由来(SV40-USE)
のうちの1つまたは複数をさらに含む、請求項1記載の発現カセット。 - 請求項1~9のいずれか一項記載の発現カセットを含む、組換え遺伝子送達ベクター。
- ウイルスまたはウイルスベクターである、請求項10記載の組換え遺伝子送達ベクター。
- ウイルスまたはウイルスベクターが、レンチウイルス(LV)である、請求項11記載の組換え遺伝子送達ベクター。
- 請求項1記載の発現カセットまたは請求項11もしくは請求項12記載の組換え遺伝子送達ベクターを含む、細胞。
- 造血幹細胞である、請求項13記載の細胞。
- CD34+細胞である、請求項13記載の細胞。
- 薬学的に許容される賦形剤および請求項10~12のいずれか一項記載の組換え遺伝子送達ベクターを含む、薬学的組成物。
- 薬学的に許容される賦形剤および請求項13~15のいずれか一項記載の細胞を含む、薬学的組成物。
- その必要がある対象においてファンコニ貧血を処置する方法であって、請求項17または請求項17記載の薬学的組成物を該対象に提供する工程を含む、方法。
- その必要がある対象においてファンコニ貧血を処置するための方法であって、発現カセットを含むCD34+細胞を該対象に提供する工程を含み、該発現カセットは、5’から3'の順に以下:
(a)ヒトホスホグリセリン酸キナーゼ(PGK)プロモーター配列またはその機能的ホモログもしくは変種と、
(b)ヒトFANCAポリペプチドまたはその機能的フラグメントもしくは変種をコードする配列と、
(c)ウッドチャック肝炎ウイルス調節エレメント(WPRE)RNA輸送シグナル配列またはその機能的変種もしくはフラグメントと
を含むポリヌクレオチド配列を含み、ヒトFANCAポリペプチドまたはその機能的フラグメントもしくは変種をコードする配列が、PGKプロモーター配列に機能的に連結されている、方法。 - CD34+細胞が、前記対象から得られた、請求項19記載の方法。
- CD34+細胞が、前記対象を(i)G-CSFまたはフィルグラスチムおよび(ii)プレリキサホルの組み合わせで処置した後に該対象から得られた、請求項20記載の方法。
- CD34+細胞が、前記発現カセットを含む組換え遺伝子送達ベクターを用いて形質導入された、請求項20記載の方法。
- CD34+細胞が、該CD34+細胞と前記組換え遺伝子送達ベクターを約24時間接触させることによって形質導入された、請求項21記載の方法。
- その必要がある対象においてファンコニ貧血を処置するための方法であって、
(a)該対象においてCD34+細胞を動員するために、該対象に(i)G-CSFまたはフィルグラスチムおよび(ii)プレリキサホルの組み合わせを提供する工程、
(b)該対象からCD34+細胞を含む生物学的サンプルを入手する工程であって、該生物学的サンプルが任意で末梢血または骨髄である、工程、
(c)該生物学的サンプルから、CD34+細胞が濃縮された細胞集団を調製する工程、
(d)5'から3'の順に以下:
(i)プロモーター配列またはその機能的ホモログもしくは変種と、
(ii)ヒトFANCAポリペプチドまたはその機能的フラグメントもしくは変種をコードする配列と
を含むポリヌクレオチド配列を含む発現カセットを含む組換え遺伝子送達ベクターを用いて、CD34+細胞が濃縮された細胞集団に形質導入する工程であって、ヒトFANCAポリペプチドまたはその機能的フラグメントもしくは変種をコードする配列が、PGKプロモーター配列に機能的に連結されており、該形質導入が、該CD34+細胞が濃縮された細胞集団とレンチウイルスベクターを約24時間接触させることを含む、工程、ならびに
(e)工程(d)に起因するレンチウイルスベクターを用いて形質導入された細胞集団を該対象に提供する工程
を含む、方法。 - 前記細胞集団を調製する工程が、赤血球を除去する工程を含む、請求項23記載の方法。
- 前記細胞集団を調製する工程が、陽性選択、陰性選択またはそれらの組み合わせによりCD34+細胞を濃縮する工程を含む、請求項23記載の方法。
- 前記対象におけるファンコニ貧血の発症を阻害する、ファンコニ貧血の進行を停止させる、および/またはファンコニ貧血の血液学的症状の進行を逆転させる、請求項23記載の方法。
- ファンコニ貧血の血液学的症状が、BMF、血小板減少症、白血球減少症、汎血球減少症、好中球減少症および貧血のうちの1つまたは複数から選択される、請求項26記載の方法。
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