JP7094236B2 - 変異aav、及び、細胞、臓器並びに組織への遺伝子導入のための組成物、方法並びに使用法 - Google Patents
変異aav、及び、細胞、臓器並びに組織への遺伝子導入のための組成物、方法並びに使用法 Download PDFInfo
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Description
本出願は、2014年4月28日に出願された米国特許仮出願第61/985,365号、及び2013年7月22日に出願された米国特許仮出願第61/857,161号からの優先権を主張するものであり、これらの出願の全内容は参照ににより本明細書に組み入れられる。
序文
入遺伝子の発現を達成すること、及び、2)AAVに対する既存の液性免疫を有するためにAAV遺伝子導入ができない患者群に対する治療を、固有の血清陽性率を有する代替AAV血清型により可能とすること。本発明は、上記のような要望に対処し、更なる利点をもたらす。
AAV-Rh74変異体は、遺伝子コード配列のようなポリヌクレオチドを送達するのに使用することができ、所望の又は治療的な利点を提供できるタンパク質を発現させることができると共に、望ましくない又は欠陥を有する遺伝子の発現を低減する又は抑制する阻害ヌクレオチドについても使用できることから、様々な疾患を治療することができる。例えば、AAV-Rh74、及びAAV-Rh74カプシド変異体(例えば、RHM4-1)は、血友病A、B等を治療するべく治療遺伝子(例えば、FIX、FVIII)を細胞、組織、及び肝臓などの臓器に送達するためのベクターとして使用することができる。また、このようなAAV-Rh74、及びAAV-Rh74カプシド変異体(例えば、RHM4-1)ベクターは、その他の代謝異常又は血漿タンパク質欠乏等の幅広い疾患のために遺伝子を送達するのに使用することができる。又は、その他の治療目的で使用される遺伝子を送達するのに使用することができ、例えば、これに限定されないが、肝臓でゲノム編集を実行するのに使用されるジンクフィンガーヌクレアーゼ(zinc finger
nucleases)をコードする遺伝子、肝炎ウィルス感染を治療するためのアルファインターフェーロンのような免疫調整薬の局所的(肝臓)送達、又は、肝臓形質導入を必要とする若しくは血流に治療的導入遺伝子生成物を存在させること(肝臓で発現させるための導入遺伝子を標的とすることによって達成することができる)を必要とするあらゆる疾患に対する治療に使用することができる。
性線維性膜貫通調節因子(cystic fibrosis transmembrane regulator protein ; CFTR )、抗体、網膜色素上皮特異的 65 kDaタンパク質( retinal pigment epithelium-specific 65 kDa protein; RPE65)、エリスロポエチン(赤血球生成促進因子)、 LDL 受容体、リポタンパク質リパーゼ、 オルニチン・トランスカルバミラーゼ、βグロビン、αグロビン、スペクトリン、αアンチトリプシン、アデノシンデアミナーゼ(ADA)、金属輸送体(ATP7AまたはATP7)、スルファミダーゼ(sulfamidase)、リソソーム蓄積症に関わる酵素(ARSA)、 ヒポキサンチン・グアニン・ホスホリボシルトランスフェラーゼ、β-25グルコセレブロシダーゼ、スフィンゴミエリナーゼ、リソソーム・ヘキソサミニダーゼ、分枝鎖ケト酸脱水素酵素、成長因子(例えば、インスリン様成長因子1および2、血小板由来成長因子、上皮成長因子、神経成長因子、神経栄養因子3および4、脳由来神経栄養因子、グリア細胞由来成長因子、形質転換成長因子α 、β等)、サイトカイン(例えばαインターフェロン、βインターフェロン、インターフェロンγ、インターロイキン2、インターロイキン4、インターロイキン12、顆粒球マクロファージコロニー刺激因子、リンホトキシン等)、自殺遺伝子産物(例えば、単純ヘルペスウイルスチミジンキナーゼ、シトシンデアミナーゼ、ジフテリア毒素、チトクロームP450、デオキシシチジンキナーゼ、腫瘍壊死因子等)、薬剤耐性タンパク質(例えば癌治療に使われる薬剤に抵抗性を付与するタンパク質)、腫瘍抑制タンパク質(例えばp53、Rb、Wt-1、NF1、フォン・ヒッペル・リンドウ(Von Hippel-Lindau ; VHL)、大腸腺腫様ポリポーシス(APC))、免疫調節機能を有するペプチド、寛容原性もしくは免疫原性のペプチドまたはタンパク質Tregitopes(制御性T細胞エピトープ)、またはhCDR1、インスリン、グルコキナーゼ、グラニル酸シクラーゼ2D(LCA-GUCY2D)、Rabエスコートタンパク質1(先天性脈絡膜欠如)、LCA 5(LCA-レベルシリン)、オルニチンケト酸アミノ基転移酵素(脳回転状網膜脈絡膜萎縮)、レチノスキシン(Retinoschisin)1(X染色体連鎖性の網膜分離症)、USH1C(アッシャー症候群1C)、X染色体連鎖性の網膜色素変性症GTPアーゼ(XLRP)、MERTK(AR型の網膜色素変性症)、DFNB1(コネキシン26難聴)、ACHM 2、3および4(色覚異常)、PKD-1またはPKD-2(多発性嚢胞腎)、TPP1、CLN2、リソソーム蓄積症の原因となる遺伝的欠損(例えば、スルファターゼ、N-アセチルグルコサミン-1-リン酸トランスフェラーゼ、カテプシンA、GM2-AP、NPC1、VPC2、スフィンゴ脂質活性化タンパク等)、ゲノムエディティングに用いられる一つまたは複数のジンク・フィンガーヌクレアーゼ、またはゲノムエディティングで修復テンプレートとして用いられるドナー配列である。
.1 P/Q 、TATA結合タンパク質、ATXN8OSとしても知られるアタキシン8逆鎖、脊髄小脳失調におけるセリン・スレオニンタンパク質ホスファターゼ2Aの55
kDa調節サブユニットBベータアイソフォーム(1,2,3,6,7,8,12,17型)、脆弱性X症候群におけるFMR1 (脆弱性X精神遅滞1)、脆弱X関連震戦/運動失調症候群におけるFMR1(脆弱性X精神遅滞1),脆弱性XE精神遅滞におけるFMR1(脆弱性X精神遅滞2)またはAF4/FMR2ファミリーメンバー2(AF4/FMR2 family member 2)、筋強直性ジストロフィー症におけるミオトニンタンパク質キナーゼ(Myotonin-protein kinase)(MT-PK)、フリートライヒ運動失調症におけるフラタキシン(Frataxin)、筋萎縮性側索硬化症における変異型スーパーオキシドディスムターゼ1(SOD1)遺伝子、パーキンソン病および/またはアルツハイマー病の発症機序に関与する遺伝子、アポリポタンパク質B(APOB) および前駆タンパク質変換酵素サブチリシン/ケキシンタイプ9(PCSK9)、高コレステロール血症、ヒト免疫不全ウイルス(HIV)感染におけるHIV転写トランス活性化因子遺伝子、HIV Tat、ヒト免疫不全ウイルス(HIV)感染におけるHIVトランス活性化因子応答配列遺伝子、HIV TAR、HIV感染におけるC-Cケモカイン受容体(CCR5)、ラウス肉腫ウイルス(RSV)感染におけるRSVヌクレオカプシドタンパク質、C型肝炎ウイルス感染における肝臓特異的マイクロRNA(miR-122)、p53、急性腎損傷または移植腎機能発現遅延または腎損傷急性腎不全、進行した再発性または転移性の固形悪性腫瘍におけるタンパク質キナーゼN3(PKN3)、転移性黒色腫におけるLMP2、LMP2はプロテアソームサブユニットベータ9型(PSMB 9)としても知られる、転移性黒色腫におけるLMP7、プロテアソームサブユニットベータ8型(PSMB 8)としても知られる、転移性黒色腫におけるプロテアソームサブユニットベータ10型(PSMB 10)としても知られるMECL1、固形腫瘍における血管内皮成長因子(VEGF)、固形腫瘍におけるキネシン紡錘タンパク質、慢性骨髄性白血病におけるアポトーシス抑制B細胞CLL/リンパ腫(BCL-2)、固形腫瘍におけるリボヌクレオチド還元酵素M2(RRM2)、固形腫瘍におけるフーリン(Furin)、肝臓がんにおけるpolo様キナーゼ1(PLK1)、C型肝炎感染におけるジアシルグリセロールアシルトランスフェラーゼ1(DGAT1)、家族性大腸腺腫症におけるベータカテニン、緑内障におけるベータアドレナリン受容体、糖尿病性黄斑浮腫(DME)または加齢に伴う黄斑変性症におけるDAN損傷誘導性転写物4タンパク質としても知られるRTP801/Redd1、加齢に伴う黄斑変性症または脈絡膜血管新生における血管内皮成長因子受容体I(VEGFR1)、非動脈炎性虚血性視神経症におけるカスパーゼ2、先天性爪肥厚症におけるケラチン6A N17K 変異型タンパク質、インフルエンザ感染におけるインフルエンザA型ウイルスのゲノム・遺伝子配列、重症急性呼吸器症候群(SARS)感染におけるコロナウイルのゲノム・遺伝子配列、呼吸器合胞体ウイルス感染における呼吸器合胞体ウイルスのゲノム・遺伝子配列、エボラ感染におけるエボラフィロウイルスのゲノム・遺伝子配列、B型およびC型肝炎感染におけるB型およびC型肝炎ウイルスのゲノム・遺伝子配列、単純ヘルペスウイルス(HSV)感染におけるHSVウイルスのゲノム・遺伝子配列、コクサッキーウイルスB3感染におけるコクサッキーウイルスB3のゲノム・遺伝子配列、原発性筋失調症におけるトルシンA(TOR1A)の様な遺伝子の病原性対立遺伝子のサイレンシング(対立遺伝子特異的サイレンシング)、移植における汎クラスIおよびHLA対立遺伝子特異的(サイレンシング)、常染色体優性遺伝性網膜色素変性症(adRP)における変異型ロドプシン遺伝子、または前記の遺伝子または配列のいずれかの転写物に結合する抑制性核酸の発現を阻害する。
Rh74(カプシド)変異体(例えば、RHM4-1)粒子などの関連AAVは、以下をも有する。それらは、異種ポリヌクレオチド配列の5’末端または3’末端に隣接する一つ以上の逆方向末端反復(ITR)配列、異種ポリヌクレオチド配列の転写を駆動する発現制御配列(例えば、構成型の又は調整可能な制御要素などの、異種ポリヌクレオチド配列の転写に貢献するプロモータ又はエンハンサ、又は組織特異型の発現制御要素)、異種ポリヌクレオチド配列の3’に配置されるポリアデニン配列、選択可能なマーカー(例えば、カナマイシン耐性などの抗生物質に対する耐性を提供するタンパク質)、及び/又は複製基点、である。
たはスタッファーポリヌクレオチド配列の長さは4.7Kbを超えるものとし、約5.0~10.0Kbまたは約6.0~8.0Kbとする。
蓋内に、吸入により、腔内に、または粘膜に投与または送達される。
清型は、AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、およびRh10を含むが、これらに限定されるものではない。したがって、ベクターゲノムを含む本発明の組換えウイルス(例えばAAV)粒子は、AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、またはRh10血清型のVP1、VP2またはVP3カプシドタンパク質のように、異なる血清型、血清型の混合物、または異なる血清型からなるハイブリッドまたはキメラに由来するカプシドタンパク質を含み得る。さらに、本発明の組換えベクター(例えばAAV)、配列、プラスミド、ベクターゲノムは、任意の単一の血清型、血清型の混合物、または異なる血清型からなるハイブリッドまたはキメラに由来する要素を含んでよい。種々の実施形態において、組換えAAVベクターは、AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、Rh74またはRh10の血清型、または前記のAAV血清型のうち任意のものを含んでなる混合ハイブリッドまたはキメラに由来するCap、Repおよび/またはITRを含む。
変異体が提供される。
しないことを意味する。自然界に存在するウイルスのより多くの単離株が発見され、カプシドの突然変異体が作出されるにつれて、現存する血清型との間の差異は必ずしも存在しない可能性がある。従って、新しいウイルス(例えばAAV)に血清学的な差異が認められない場合、この新しいウイルス(例えばAAV)は、対応する血清型の亜群または変異体となる。多くの場合、カプシド配列が改変された突然変異ウイルスについては、血清型の従来の定義に基づいてそれらが他の血清型に属するか否かを決定するための、中和活性の血清学試験は行われていない。従って、便宜上、また重複を避けるため、「血清型」という用語は、血清学的に異なるウイルス(例えばAAV)および血清学的には差異が無くある血清型の亜群または変異体に属するウイルス(例えばAAV)の両者を幅広く指す。
と100%未満の一致率を呈するが、AAV1-AAV11、AAV-Rh10の遺伝子又はタンパク質のような周知のAAV遺伝子又はタンパク質とは異なる及び同一ではない。一実施形態では、AAV-Rh74ポリペプチド又はその部分配列は、任意の標準AAV-Rh74配列またはその部分配列(例えば、図3Aから図3Eに記載されるVP1、VP2及び/又はVP3配列)と少なくとも80%一致する又は80%を超えて最高で100%まで(例えば、85%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%)の一致する配列を含む又はそのような配列から構成される。特定の態様において、AAV-Rh74関連変異体は、AAV-Rh74(例えば、RHM4-1、RHM15-1、RHM15-2、RHM15-3/RHM15-5、RHM15-4、及びRHM15-6などのカプシド変異体)において述べた4つのアミノ酸置換のうちの1つ、2つ、3つ、又は4つを有する。
種ポリヌクレオチドを含むことを意図する。
胞成分)、脾臓、皮膚、胸腺、睾丸、肺、横隔膜、心臓(心臓細胞)、筋肉または腰筋、または腸(例えば内分泌細胞)、脂肪組織(白色、褐色またはベージュ脂肪細胞)、筋肉(例えば繊維芽細胞)、滑膜細胞、軟骨細胞、破骨細胞、上皮細胞、内皮細胞、唾液腺細胞、内耳の神経細胞、または造血細胞(例えば、血液細胞またはリンパ球)が挙げられる。更なる例としては、肝臓(例えば、肝細胞、類洞内皮細胞)、膵臓(例えば、膵島β細胞)、肺、脳(例えば、神経、グリアまたは上衣細胞)または脊髄の様な中枢または末梢神経系、腎臓、眼(例えば、網膜細胞成分)、脾臓、皮膚、胸腺、睾丸、肺、横隔膜、心臓(心臓細胞)、筋肉または腰筋、または腸(例えば内分泌細胞)、脂肪組織(白色、褐色またはベージュ脂肪細胞)、筋肉(例えば、繊維芽細胞)、滑膜細胞、軟骨細胞、破骨細胞、上皮細胞、内皮細胞、唾液腺細胞、内耳の神経細胞、または造血細胞(例えば血液細胞またはリンパ球)へと発達または分化する万能性または多能性前駆細胞の様な幹細胞が挙げられる。
oschisin)1(X染色体連鎖性の網膜分離症)、USH1C(アッシャー症候群1C)、X染色体連鎖性の網膜色素変性症GTPアーゼ(XLRP)、MERTK(AR型の網膜色素変性症)、DFNB1(コネキシン26難聴)、ACHM2、3および4(色覚異常)、PKD-1またはPKD-2(多発性嚢胞腎)、TPP1、CLN2、リソソーム蓄積症の原因となる遺伝的欠損(例えば、スルファターゼ、N-アセチルグルコサミン-1-リン酸トランスフェラーゼ、カテプシンA、GM2-AP、NPC1、VPC2、スフィンゴ脂質活性化タンパク等)、ゲノムエディティングに用いられる一つまたは複数のジンク・フィンガーヌクレアーゼ、またはゲノムエディティングで修復テンプレートとして用いられるドナー配列を含む、またはコードする遺伝子を含むが、これらに限定されるものではない。
sease)、ハーラー病(Hurler’s disease)、アデノシ
ン・デアミナーゼ欠損症、グリコーゲン蓄積症および他の代謝障害、網膜変性疾患(眼の他の疾患)、および固形臓器(脳、肝臓、腎臓、心臓)の疾患を含む疾患や障害の治療に用いられる可能性のあるものを含むが、これらに限定されるものではない。
al.、1982年、Proc. Natl. Acad. Sci.USA 79:6461-6464;Jaye et al.、1983年、Nucl.Acids Res. 11:2325-2335;Anson et al.、1984年、EMBO
J.3:1053-1060;Wu et al.、1990年、Gene 86:275-278;Evans et al.、Proc Natl Acad Sci USA 86:10095(1989年)、Blood 74:207-212;Pendurthi et al.、1992年、Thromb.Res.65:177-186;Sakar et al.、1990年、Genomics 1990年、6:133-143;及び、Katayama et al.、1979年、Proc.Natl.Acad.Sci.USA 76:4990-4994に記載されている。
、二本鎖又は三本鎖ポリヌクレオチド及びペプチド核酸(PNA)を含む。標的遺伝子の転写開始部位、例えば、開始部位から-10から+10の間の位置、から得られたオリゴヌクレオチドは、別の具体例である。三重鎖構造(triplex forming)のアンチセンスは、二本鎖構造のDNAと結合して、遺伝子の転写を阻害することができる。“RNAi”は、遺伝子の発現を阻害するための一本鎖又は二本鎖のRNA配列の利用である(例えば、Kennerdell et al.、Cell 95:1017(1998年);及びFire et al.、Nature、391:806(1998年)参照)。したがって、本発明の方法及び利用において、標的遺伝子コード領域からの二本鎖RNA配列を、遺伝子発現/転写を阻害する又は防ぐのに使用してもよい。アンチセンスおよびRNAiは、標的遺伝子配列(例えばハンチンチンまたはHTT)をコードする核酸、例えば哺乳類およびヒトのHTTをコードする核酸に基づいて作成できる。例えば、一本鎖又は二本鎖核酸(例えば、RNA)は、HTT転写(例えば、mRNA)を標的とすることができる。
Cruachem(Glasgow, UK)がある。標的遺伝子のmRNAを阻害するための特異的siRNA構成物は、15~50ヌクレオチドの長さであってよく、より典型的には約20~30ヌクレオチドの長さであってよい。そのような核酸分子は、当業者に既知の従来法によって、本明細書に開示したウイルスベクター内に容易に組み込むことができる。
結合タンパク質、ATXN8OSとも称されるアタキシン8逆鎖、脊髄小脳失調症(1、2、3、6、7、8、12、17型)におけるセリン/スレオニンタンパク質ホスファターゼ2A 55 kDa調節サブユニットBベータイソ型(isoform)、脆弱X症候群 におけるFMR1(脆弱X精神遅滞1)、脆弱X関連振戦(tremor)/運動失調症におけるFMR1(脆弱X精神遅滞1)、脆弱XE精神遅滞におけるFMR1(脆弱X精神遅滞2)又はAF4/FMR2ファミリーメンバー;筋強直性ジストロフィーにおける筋強直性プロテインキナーゼ(Myotonin-protein kinase
:MT-PK);フリードライヒ失調症におけるフラタキシン(Frataxin)、筋萎縮性側索硬化症におけるスーパーオキシドジスムターゼ1(SOD1)遺伝子の変異体;パーキンソン病及び/又はアルツハイマー病の病因に関与する遺伝子;アポリポタンパクB(APOB)及びプロタンパク質転換酵素サブチリシン(proprotein convertase subtilisin)/ケキシン(kexin)9型(PCSK9)、高コレステロール血症(hypercoloesterolemia);HIV感染症におけるHIV Tat、転写遺伝子のヒト免疫不全ウイルストランス活性化因子(transactivator);HIV感染症におけるHIV TAR,ヒト免疫不全ウイルストランス活性化活性化因子応答エレメント遺伝子;HIV感染症におけるCCケモカイン(chemokine)受容体(CCR5);ラウス肉腫ウイルス(RSV)感染症におけるRSVヌクレオカプシドタンパク質、C型肝炎ウイルス感染症における肝臓固有のマイクロRNA(miR-122);p53の、急性腎障害又は腎臓移植後臓器機能障害又は腎臓障害による急性腎不全;進行性、再発性又は転移性の固形悪性腫瘍におけるプロテインキナーゼN3(PKN3);LMP2、これは、プロテアソーム(proteasome)サブユニットベータ型9(PSMB9)転移性黒色腫としても知られる;LMP7、これは、プロテアソームサブユニットベータ型8(PSMB8)転移性黒色腫としても知られる;MECL1、これは、プロテアソームサブユニットベータ型10(PSMB 10)転移性黒色腫としても知られる;固形腫瘍における血管内皮成長因子(VEGF);固形腫瘍におけるキネシンスピンドル(kinesin spindle)タンパク質、慢性骨髄性白血病におけるアポトーシス抑制B-細胞CLL/リンパ腫(BCL-2);固形腫瘍におけるリボヌクレオチドレダクターゼM2(ribonucleotide reductase M2:RRM2);固形腫瘍におけるフーリン(Furin);肝腫瘍におけるポロ様キナーゼ(polo-like kinase)1(PLK1)、C型肝炎感染におけるジアシルグリセロールアシルトランスフェラーゼ(diacylglycerol acyltransferase)1(DGAT1),家族性大腸腺腫症におけるベータカテニン;ベータ2アドレナリン受容体、緑内障;糖尿病性黄斑浮腫(DME)や加齢黄斑変性におけるRTP801/Redd1として知られるDAN損傷誘導性転写産物4タンパク質;加齢性黄斑変性症又は脈絡膜血管新生(choroidal neivascularization)における血管内皮増殖因子受容体I(VEGFR1);非動脈炎性虚血性視神経症におけるカスパーゼ2;先天性爪肥厚症におけるケラチン6AN17K変異タンパク質;インフルエンザ感染症におけるインフルエンザAウイルスゲノム/遺伝子配列;重症急性呼吸器症候群(SARS)感染におけるコロナウイルスゲノム/遺伝子配列;呼吸器合胞体ウイルス(RS)感染症におけるRSウイルスゲノム/遺伝子配列;エボラ感染症におけるエボラフィロウイルスゲノム/遺伝子配列;B型肝炎及びC型肝炎感染におけるB型及びC型肝炎ウイルスゲノム/遺伝子配列;単純ヘルペスウイルス(HSV)感染症における単純ヘルペスウイルス(HSV)ゲノム/遺伝子配列、コクサッキーウイルス(coxsackievirus)B3感染におけるコクサッキーウイルスB3ゲノム/遺伝子配列;原発性ジストニアにおけるトーシン(torsin)A(TOR1A)、pan-classI及び移植において特定のHLA対立遺伝子のような遺伝子の病原性対立遺伝子のサイレンシング(対立遺伝子を狙ったサイレンシング);又は、遺伝子常染色体優性遺伝網膜色素変性(adRP)における変異ロドプシン遺伝子(RHO)。
チロシン。“保存的置換”はまた、非置換型の親アミノ酸に代えて、置換型アミノ酸を使用することを含む。
ミノ酸である。更なる別の特定の態様において、一致する配列の長さは、50又は50を超える連続したポリヌクレオチド又はアミノ酸であり、例えば、50-55、55-60、60-65、65-70、75-80、80-85、85-90、90-95、95-100、100-110等の連続したポリヌクレオチド又はアミノ酸である。
extension)2。ポリペプチド配列の比較には、一般的にBLASTPアルゴリズムを、PAM100、PAM 250、BLOSUM 62 または BLOSUM
50の様なスコアマトリクス(scoring matrix)と組み合わせて用いる。一致の程度を定量化するのに、FASTA(例えば、FASTA2及びFASTA3)及びSSEARCH配列比較プログラムも使用されている(Pearson et al.、Proc.Natl.Acad.Sci.USA 85:2444(1988年);Pearson、Methods Mol Biol.132:185(2000年);及びSmith et al.、J.Mol.Biol.147:195(1981年))。ドロネー(Delaunay)ベースの位相マッピングを使用して、タンパク質構造類似性を定量化するプログラムも開発されている(Bostick et al.、Biochem Biophys Res Commun.304:320(2003年))。
AAV)ベクターの様なパルボウイルスベクターが含まれる。
制御要素は通常、特定の細胞または組織(例えば肝臓、脳、中枢神経系、脊髄、眼、網膜、骨、筋肉、肺、すい臓、心臓、腎臓の細胞等)で活性である。発現制御要素は、特定の種類の細胞、組織又は臓器に固有の転写活性化タンパク質又はその他の転写制御因子によって認識されるので、通常は、このような細胞、組織又は臓器内で活性を有する。
Miner. Res. 11 :654-64 (1996))、リンパ球についてはCD2(Hansalら、J. Immunol., 161:1063-8 (1998))、免疫グロブリン重鎖、T細胞受容体a鎖、神経については神経細胞特異的エノラーゼ(NSE)プロモーター(Andersenら、Cell. Mol. Neurobiol., 13:503-15 (1993))、ニューロフィラメント軽鎖遺伝子(Piccioliら、Proc. Natl. Acad. Sci. USA, 88:5611-5 (1991)、神経細胞特異的vgf遺伝子(Piccioli,
et al., Neuron, 15:373-84 (1995))が特に挙げられる。
ター、T7ポリメラーゼプロモーターシステム(WO 98/10088)、テトラサイクリン抑制性システム(Gossenら、 Proc. Natl. Acad. Sci. USA, 89:5547-5551 (1992))、テトラサイクリン誘導性システム(Gossenら、Science. 268:1766-1769 (1995); Harveyら、Curr. Opin. Chem. Biol. 2:512-518 (1998)も参照のこと)、RU486誘導性システム(Wangら、Nat. Biotech. 15:239-243 (1997) およびWangら、Gene Ther. 4:432-441 (1997))、およびラパマイシン誘導性システム(Magariら、J. Clin. Invest. 100:2865-2872 (1997); Riveraら、Nat. Medicine. 2:1028-1032 (1996))が挙げられる。このような背景において有用な可能性のある他の制御可能な調節因子は、例えば温度や急性期のような特定の生理的状態によって制御を受けるものである。
。フィラーまたはスタッファーポリヌクレオチド配列として機能するイントロンおよびイントロン断片(例えばFIXのイントロンIの一部)もまた、発現を向上させることができる。例えば、イントロンを含めることで、イントロンが不在の場合に比べて発現を向上させる可能性がある(Kurachiら、1995、上記参照)。
、糖鎖付加または脂質付加)、または誘導体の様な組成物の別の物理的形態、または人の手によって作出された宿主細胞で発現される形態を除外するものではない。
、グリコーゲン蓄積症および他の代謝障害、ポンペ病、鬱血性心不全、網膜変性疾患(先
天性脈絡膜欠如、レーバー先天性黒内障および眼の他の疾患)、および固形臓器(脳、肝臓、腎臓、心臓)の疾患等を含むが、これらに限定されるものではない。
物または哺乳動物の細胞に投与し、以て異種ポリヌクレオチド配列を哺乳動物または哺乳動物の細胞内に送達または移入することによる。
の体重の1kgあたり(vg/kg)又はこれを超える範囲であり、例えば、1×109
、1×1010、1×1011、1×1012、1×1013、1×1014又はこれを超える範囲である。
効量又は十分な量とは、グループ又は一般集団における有効性又は十分であることを意味するのではなく、特定の対象(患者)において有効又は十分であることを意味する。このような方法においては典型的であるが、所与の治療方法又は使用法に対して、ある対象は大きな反応を示すが、別の対象は、反応が少ない又は全く反応を示さないといった場合がある。したがって、適切な量というのは、治療すべき状態、望まれる治療効果、及び、個々の対象(例えば、対象の生物学的利用能(bioavailability)、性別、年齢等)に依存する。
ター又はカプシド変異体(例えば、RHM4-1)などのAAV-Rh74変異体などの関連AAVベクター)の投与の前に、実質的に同時に、または後に被験体に投与することができる。組み合わせの実施形態の非制限的な具体例としては、上記の又はその他の化合物、作用物質、薬物、治療レジメン、治療プロトコル、プロセス、治療薬又は組成物を含む。
伝子産物(タンパク質)のスクリーニングにより陽性と発見された被験体が含まれる。
acceptable)”及び“生理学的に許容される(physiologically acceptable)”という言葉は、生体内送達又は接触において、一の又は複数の投与経路に適した、生物学的に許容される製剤、気体、液体又は固体又はこれらの組み合わせを意味する。「医薬品として許容できる」または「生理学的に許容できる」成分は、生物学的または他の側面で有害でない物質で、例えば著しい望ましくない生物学的影響を引き起こすことなく被験体に投与され得る物質である。従って、その様な医薬組成物は、例えばウイルスベクター、ウイルス粒子(例えば、AAV-Rh74又はカプシド変異体(例えば、RHM4-1)などのAAV-Rh74変異体などの関連AAV)または形質転換細胞を被験体に投与する際に用いられ得る。
of Solid Dosage Forms (1993), Technonic
Publishing Co., Inc., Lancaster, Pa.; Ansel and Stoklosa, Pharmaceutical Calculations (2001) 第11版, Lippincott Williams
& Wilkins, Baltimore, MD; and Poznanskyら, Drug Delivery Systems (1980), R. L. Juliano編、Oxford, N.Y., pp. 253-315を参照)。
予定がある又は有している場合に、有害な副作用や合併症が発生することがあるため、説明書には、このような不適合性に関する情報を含めることができる。
86%、 87%、 88%、 89%、 90%、 91%等、 および81.1%、 81.2%、 81.3%、 81.4%、 81.5%等、また 82.1%、 82.2%、 82.3%、 82.4%、 82.5%等を含む。
のような値の分数部分、及び、このような範囲内の整数値、並びに、このような範囲内の整数値の分数部分を含む。従って、例えば、パーセンテージの範囲の様な数的範囲に言及する際、1~10の範囲は、1、2、3、4、5、6、7、8、9、10、および1.1、1.2、1.3、1.4、1.5等を含む。1~50の範囲に言及する際には、従って、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20等、50を含めて50に至るまで、および1.1、 1.2、 1.3、 1.4、 1.5等、2.1、 2.2、 2.3、 2.4、 2.5等を含む。
以下の実施例は、様々な材料及び方法の説明を含む。
マウス:オスのC57BL / 6J(WT)マウス8~10週齢で、実験群当たりn
= 5。犬は、ノースカロライナ州チャペルヒル大学のFIX遺伝子におけるミスセンス変異を有するコロニーのからのHB犬である(Evans et al., Proc
Natl Acad Sci USA 86:10095 (1989年))。
ogicalsからのものである。犬においても、Haurigot et al. (Mol Ther 18:1318 (2010年))に記載されるように、Affinity Biologicalsからの抗体対が使用された。
濃度で、細胞を96ウェルプレートに播種し、1:1000希釈のポナステロンA(Invitrogen)を培地に添加して、E4発現を引き起こした。測定の日に、熱不活性化テスト血清の3.2倍希釈列(serial half-log dilutions)を、ウイルスを含む培地と混合した。ssAAV-LacZベクターに対しては、測定で使用されたウイルス濃度は、AAV2の場合には約1x1010vg/ml、及び、AAV5,6又は8の場合には約5.5x1010vg/mlであった。scAAV-Lucベクターの場合、測定におけるウイルス濃度は、約50から約150倍低かった。レポーター導入遺伝子の残存活性は、比色分析法 (ssAAV-LacZ)又はルミノメータ(scAAV-Luc)を使用して測定された。
Ther 17:503 (2010年))に詳細に記載されている。
実施例2
本例は、ヒトFIX遺伝子導入動物(マウス)の研究及び遺伝子導入の後のFIX発現の説明が含まれている。
実施例3
本例には、血友病の犬における治療レベルのFIXの効果的なAAV-Rh74の調整による送達を実証する動物実験及びデータの記述が含まれる。
実施例4
本例は、ヒトにおける抗AAV中和抗体(NAb)の存在を示す研究の説明を含む。
本例では、AAV-Rh74を含む様々なAAV血清型の生成量を示すデータの説明が含まれる。
この例では、肝臓特異的プロモーターの制御下で、ヒト第IX因子(FIX)を発現するAAVrh74ベクターをアカゲザルに投与し、同じ量のAAV8ベクター投与した場合よりも高いレベルでの、動物におけるFIXの生産量につながったことを示すデータの詳細が含まれる。
実施例7
以下の実施例は、いくつかのRh74カプシド変異体の説明を含む。
た。さらに、これらの変異体は、種々の位置にアルギニンを置換したリジンを複数有していた。
本例は、Rh74カプシド変異体を用いてRh74及びAAV8と比較したヒト第IX因子発現研究の説明を含む。
た。
実施例9
この例では、肝臓特異的プロモーターの制御下で、ヒト第IX因子(FIX)を発現するAAVrh74変異体RHM4-1ベクターをカニクイザル(マカクザル)に投与し、同じ量のAAV8ベクター投与した場合よりも高い濃度での、動物におけるFIXの生産量につながったことを示すデータの詳細が含まれる。
Claims (30)
- 配列ID番号:5に示すAAVカプシド配列を含む組換えAAV粒子であって、前記組換えAAV粒子のゲノムが、AAV逆方向末端反復(ITR)と、リソソーム蓄積症に関わる酵素をコードする異種ポリヌクレオチド配列とを含み、前記異種ポリヌクレオチド配列は発現制御要素に作動可能に連結されており、前記異種ポリヌクレオチド配列は、5’又は3’のAAV逆方向末端反復(ITR)に隣接している、組換えAAV粒子。
- 前記発現制御要素が構成的または制御可能な制御要素を含む、請求項1に記載の組換えAAV粒子。
- 前記発現制御要素が組織特異的発現制御要素またはプロモーターを含む、請求項1に記載の組換えAAV粒子。
- 前記組織特異的発現制御要素またはプロモーターが肝臓特異的である、請求項3に記載の組換えAAV粒子。
- 前記発現制御要素が肝臓特異的エンハンサー・プロモーターを含む、請求項1に記載の組換えAAV粒子。
- 前記発現制御要素がApoE-hAATエンハンサー・プロモーターである、請求項1に記載の組換えAAV粒子。
- 前記異種ポリヌクレオチド配列がポリA配列に連結された、請求項1から6のいずれか1項に記載の組換えAAV粒子。
- 前記組換えAAV粒子のゲノムが非翻訳領域をさらに含む、請求項1から7のいずれか1項に記載の組換えAAV粒子。
- 前記異種ポリヌクレオチド配列が5’及び3’のAAV逆方向末端反復(ITR)に隣接している、請求項1から7のいずれか1項に記載の組換えAAV粒子。
- 前記AAV逆方向末端反復(ITR)がAAV2に由来する、請求項1から9のいずれか1項に記載の組換えAAV粒子。
- 配列ID番号:5のアミノ酸配列を有するVP1カプシドタンパクを含む組換えAAV粒子であって、前記組換えAAV粒子のゲノムが、5’から3’の順で、
(a)第1のAAV逆方向末端反復(ITR)と、
(b)肝臓特異的エンハンサー・プロモーターと、
(c)前記肝臓特異的エンハンサー・プロモーターに作動可能に連結されたリソソーム蓄積症に関わる酵素をコードするポリヌクレオチド配列と、
(d)ポリA配列と、
(e)第2のAAV逆方向末端反復(ITR)と
を含む、組換えAAV粒子。 - 前記第1及び第2のAAV逆方向末端反復(ITR)がAAV2に由来する、請求項11に記載の組換えAAV粒子。
- 前記肝臓特異的エンハンサー・プロモーターがApoE-hAATエンハンサー・プロモーターである、請求項11又は12に記載の組換えAAV粒子。
- 前記組換えAAV粒子のゲノムが非翻訳領域をさらに含む、請求項11から13のいずれか1項に記載の組換えAAV粒子。
- 請求項1から14のいずれか1項に記載の組換えAAV粒子と薬学的に許容される担体とを含む医薬組成物。
- 空のカプシドAAVをさらに含む請求項15に記載の医薬組成物。
- 空のカプシドAAV-Rh74、又は配列ID番号:5のAAVカプシド配列を含む空のカプシドをさらに含む、請求項15に記載の医薬組成物。
- 請求項1から14のいずれか1項に記載の組換えAAV粒子を製造する方法であって、
請求項1から14のいずれか1項に記載の組換えAAV粒子のゲノムを含む組換えプラスミドを含むヘルパー細胞を培養する工程を備える、方法。 - 請求項1から14のいずれか1項に記載の組換えAAV粒子を治療有効量含む、ポンペ病を治療するための医薬組成物。
- ポンペ病に関わる酵素に欠陥のある哺乳動物を治療するための医薬組成物であって、
配列ID番号:5のAAVカプシド配列を含む組換えAAV粒子であって、前記組換えAAV粒子のゲノムは、前記欠陥のある酵素の発現又は機能を修正することができる酵素をコードする異種ポリヌクレオチド配列を含み、前記異種ポリヌクレオチド配列は、当該異種ポリヌクレオチド配列の転写を付与する発現制御要素に作動可能に連結されている、
前記組換えAAV粒子を備える、医薬組成物。 - 前記異種ポリヌクレオチド配列は、前記異種ポリヌクレオチド配列の転写を付与する発現制御要素に作動可能に連結されている、請求項19に記載の医薬組成物。
- ポンペ病に関わる前記酵素が、前記哺乳動物に対して治療的効果を有する、請求項19又は20に記載の医薬組成物。
- 前記哺乳動物がポンペ病に関わる前記酵素、又はポンペ病に関わる欠陥若しくは異常を有する酵素を不十分な量だけ産生する、請求項20から22のいずれか1項に記載の医薬組成物。
- 前記組換えAAV粒子は、静脈内への投与、動脈内への投与、筋肉内への投与、皮下への投与、挿管による投与、カテーテルを介する投与、又は、体腔内への投与のために配合される、請求項20から23のいずれか1項に記載の医薬組成物。
- 前記哺乳動物はヒトである、請求項20から24のいずれか1項に記載の医薬組成物。
- 前記哺乳動物は、AAV-Rh74以外のAAV血清型に対して血清学的に陽性である、請求項20から25のいずれか1項に記載の医薬組成物。
- 前記哺乳動物は、AAV血清型AAV1、AAV2、AAV3、AAV4、AAV5、
AAV6、AAV7、AAV8、AAV9、AAV10又はAAV11に対して血清学的に陽性である、請求項20から26のいずれか1項に記載の医薬組成物。 - 前記哺乳動物はAAV-Rh74に対して血清学的に陰性又は血清学的に陽性である、
請求項20から25のいずれか1項に記載の医薬組成物。 - 空のカプシドAAVをさらに備える、請求項20から28のいずれか1項に記載の医薬組成物。
- 前記医薬組成物が、空のカプシドAAV-Rh74、又は配列ID番号:5の配列を含む空のカプシドをさらに備える、請求項20から28のいずれか1項に記載の医薬組成物。
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