JP6141021B2 - パルボウイルスの形質導入を増強するための組成物および方法 - Google Patents
パルボウイルスの形質導入を増強するための組成物および方法 Download PDFInfo
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Description
本出願は、2010年2月5日出願の米国仮特許出願第61/301,998号の米国特許法第119条(e)による利益を請求し、その内容全体が本明細書に組み込まれる。
本発明の一部は、アメリカ国立衛生研究所から授与された、National Heart,Lung,and Blood Institute(NHLBI)Program Project Grant No.P01 HL66973から資金の供給を受けた。米国政府は、本発明の特定の権利を有する。
本明細書で使用する場合、「ある(a)」、「ある(an)」および「その(the)」は、使用されている文脈に応じて、1つまたは2つ以上を意味することができる。例えば、「ある(a)」細胞は、1つの細胞または複数の細胞を意味することができる。
AAVベクターを使用する、野生型アデノ随伴ウイルス(AAV)の4680ヌクレオチド長のゲノムよりも大きい遺伝子の送達は、効率が悪い。この研究では、AAV中にパッケージした5.6kbの第VIII因子の発現カセットを使用して、FDAの承認を得ているプロテアソーム阻害剤(ボルテゾミブ)をベクター送達と併用した場合の治療の効果を、in vivoにおいて試験した。血友病マウスにおいて、肝臓内へのベクター送達の結果、1年超の経過観察にわたり持続した第VIII因子の発現が生じた。AAV2の第VIII因子ベクターまたはAAV8の第VIII因子ベクターと共に与えた、単回用量のボルテゾミブはそれぞれ、発現を、平均して約600%および約300%増強した。さらに、血友病Aイヌ(n=4)における、AAV8.イヌFVIII(1×1013vg/kg)とボルテゾミブとの同時投与の結果、未治療の血友病Aイヌ(n=3)またはベクター単独を投与したイヌ(n=3)と比較して、全血凝固時間(WBCT)の完全な正常化および出血頻度の90%の低下も、最長32カ月にわたり生じた。FDAの承認を得ている薬物(ボルテゾミブ)と、過大な導入遺伝子を運ぶAAVベクターとの組合せ療法による、血友病Aイヌの表現型の2年超にわたる矯正の妥当性が確認されたことによって、ヒト遺伝子療法における治療対象の顕著な拡大が促進される。
これらの研究の主要な目標は、小型および大型の動物において、FDAの承認を得ている薬物ボルテゾミブと、AAV導入遺伝子用ベクターとを使用する「組合せ療法」の妥当性を確認することであった。提示する研究は、プロテアソーム阻害剤のボルテゾミブ(ベルケイド(登録商標)としてもまた公知である)の使用を記載する。これは、この薬物が、臨床における使用について現時点でFDAの承認を得ている唯一のプロテアソーム阻害剤であるからである。ボルテゾミブは、ほとんどの化学療法と同様、体表面積に基づいて投与される。大型動物の研究については全て、FDAの承認を得ている用量(1.3mg/m2)を使用した。しかし、マウスについては、前臨床毒性データから、0.5mg/キログラム体重のボルテゾミブの安全な用量が確立されている23。AAVベクターがない状態で、0.5mg/kgの用量を与えたマウスは、プロテアソーム阻害剤を忍容し、副作用も血液学的パラメータの変化も明らかに生じないことが確立された。追加のマウスを、より高い用量(1.0mg/kgのボルテゾミブ)を用いて試験したが、時折、この用量を与えたマウスは、活動および摂食の減少を示した。したがって、以前の前臨床における毒性の研究および解析に基づいて、プロテアソーム阻害剤ボルテゾミブを、マウスの研究全てにおいて、0.5mg/kgで、単回の門脈注射により、AAVベクターと同時投与して与えた。マウスにおける投与量は、臨床的に推奨されている体表面積ではなく、キログラム体重当たりに基づいて計算したにもかかわらず、マウスにおいて使用した総用量は、本明細書に記載するイヌの研究において使用した総用量とおおよそ同等である。
これらの研究で使用した第VIII因子発現ベクターは、これまでに記載されている6。このベクターは、合成的に誘導した短い肝臓特異的プロモーター/エンハンサーにより推進される、イヌのBドメイン欠失(BDD)FVIII(cFVIII)cDNA、およびそれに続く、キメラのイントロン(IGBP/enh/イントロン)を含有する。第IX因子ベクターは、これまでに記載されており、CMVエンハンサー/ニワトリβ−アクチンプロモーターの転写制御下にあるhFIX cDNA(1.4kb)を包含する4.2kbの発現カセットを含有する(rAAV−CBA−hFIX)22。全てのベクターを、以前の記載に従って39、UNC Virus Vector Core Facilityにおいて生成し、力価を測定した。これらのベクターは、緑色蛍光タンパク質(GFP)をコードし、CMVプロモーターにより推進される、一本鎖のかつ自己相補的なAAV2(総サイズ:約1.5kb);CBAプロモーターにより推進される、AAV8のキャプシドを用いてキャプシド形成したホタルルシフェラーゼ;ならびにヒト第IX因子(hFIX)を発現するAAV2およびAAV8を包含した。ボルテゾミブ(Millennium Pharmaceutical Co、Cambridge、MA)を、注射のために、リン酸緩衝生理食塩水(PBS)中で希釈した。MG132(Calbiochem、La Jolla、CA)を、70%エタノールを用いて溶解させて、保存液としての20mMとした。デキサメタゾンを、Sicor Pharmaceuticals Inc、Irvine、CAから、注射用液剤として購入した。
293T細胞を、9%ウシ胎仔血清および1%ペニシリン/ストレプトマイシン溶液を補充したダルベッコ変法イーグル培地(Mediatech、Herndon、VA)中で増殖し、1の感染効率で形質導入を行った。形質導入後の第3〜5日に、細胞を、収集し、2%ホルムアルデヒド/0.2%グルタルアルデヒドを含有するリン酸緩衝生理食塩水(PBS)中に固定し、以前の記載に従って40FACScanにより解析した。
FVIII欠損マウス(FVIII−/−)は、FVIIII遺伝子のエクソン16の標的欠失を有する。C57Bl/6 FIX−/−マウスは、FIX遺伝子の第3エクソンからのプロモーターの標的欠失を有する。FVIII−/−マウスおよびFIX−/−マウスは、組織内で繁殖させた。野生型C57B6マウスは、7〜8週齢におけるルシフェラーゼベクターの送達のために、Jackson Laboratory(Bar Harbor、ME)から購入した。血友病マウスに、麻酔を、全ての手順について2.5%アベルチン(Avertin)を使用して施した。全ての血漿試料を、後眼窩神経叢から、3.2%クエン酸ナトリウム中に収集し、−80℃で保存した。後眼窩からの血液の収集およびバイオルミネセンスの撮像は、イソフルラン麻酔下で実施した。
血友病Aイヌは、最初はScott−Ritchey Research Center、Auburn Universityで飼育されていたが、現在はUAB Medical Schoolで飼育されている血友病Aコロニーに由来する雑種のイヌであった。全ての動物を、AAALAC公認の施設において飼育した。治療したイヌは、重度血友病Aを有する雄(n=4)または雌(n=3)であった。7匹のイヌ全てに、出生の3〜4週間後に、AAV8.cFVIIIを腸間膜静脈投与により投与した41。また、4匹のイヌ(2匹の雌/2匹の雄)には、ベクターの投与時に、ボルテゾミブ(1.3mg/m2)も投与した。1匹の雄イヌおよび1匹の雌イヌには、ベクターおよびボルテゾミブの投与の時に、IVデキサメタゾン(1.0mg/kg)を投与した。
マウス血漿中のイヌFVIII活性を、Coatest SP4キット(Chromogenix、DiPharma、West Chester、OH)により、製造元の指示に改変を加えて従って測定した。正常イヌ血漿(100パーセント活性=1IU/mlとみなす)を、プールしたFVIII−/−マウス血漿中に段階希釈して、検量線を生成した。マウス中のイヌFVIIIに対する中和抗体を、記載に従って42、ベセスダアッセイにより、START4 Coagulation Analyzer(Diagnostica Stago、Asnieres、フランス)を使用して測定した。ヒト第IX因子を、以前の記載に従って、一段階第IX因子活性アッセイ(FIX特異的aPTT)に基づいて、START4 Coagulation Analyzer(Diagnostica Stago、Asnieres、フランス)を使用して測定した43。
血液試料を、記載に従って44、正常対照、未治療のFVIII対照、および治療した血友病Aイヌから得た。全血凝固時間(WBCT)およびベセスダ力価を、以前の記載に従って測定した。WBCTアッセイを、凝血塊を形成するに至らない場合には、第20分時に止めた。
核および細胞質の画分を、記載45に、軽微な改変を加えて従って単離した。マウス肝臓を、リン酸緩衝生理食塩水(PBS)を用いて灌流し、氷上で刻み、加圧型細胞破砕装置を使用してホモジナイズした(緩衝液:250mMスクロース、50mM Tris−HCl(pH7.5)、25mM KCl、5mM MgCl2、0.5%NP−40、1mMフッ化フェニルメチルスルホニル(PMSF))。核およびその他のオルガネラを、Sorvall臨床用遠心分離機中、3,000rpmで10分間遠心分離することにより収集した。上清を、40μmのポアサイズのフィルターを使用してろ過し、細胞質として使用した。多層化ペレットをさらに処理して、蒸留水中に溶解させた核の抽出物を得た。
AAV8.ルシフェラーゼベクターの注射の1週後、マウスに、150μg/gのD−ルシフェリン(Biotium、Hayward、CA)/PBSを腹腔内注射した。バイオルミネセンスの撮像を、CCDカメラ(IVIS、Xenogen)を用いて、注射のぴったり15分後に開始した。生きている全身の撮像から得られたシグナル強度を、総光子束(光子/秒/cm2)として表す。
cFVIIIのDNAのQ−PCRを、第VIII因子ベクター送達の2週間後に、マウス肝臓から単離したゲノムDNAに対して、Bio−Rad(Hercules、CA)製のiQ SYBR Greenキットを使用して実施した11。cFVIIIのDNAのコピー数を、イヌBDD−FVIIIのDNAをコードする直線化されたプラスミドを用いて生成し、プールしたナイーブC57マウス由来のゲノムDNA中に1×107〜1個のコピー/反応物に段階希釈した標準に対して定量化し、マウスβ−アクチンについて正規化した。イヌFVIIIについて使用したプライマー配列は、以前に記載された配列と同一であった11,17。ルシフェラーゼDNAについてのQ−PCRを、ルシフェラーゼベクターの送達の1週間後に実施した。バイオルミネセンスの撮像に続いて、マウスを屠殺し、ゲノムDNAを、肝臓、脳、心臓、肺、脾臓、胃、腎臓、回腸、筋肉および精巣から抽出した。ルシフェラーゼおよびベータアクチンのQ−PCRを、Bio−Rad(Hercules、CA)製のiQ SYBR Greenキットを使用して、単離したゲノムDNAに対して実施した。ルシフェラーゼ遺伝子産物およびイヌFVIII遺伝子産物のコピー数を、定量化し、マウスβ−アクチンについて正規化し、細胞当たりのベクターのコピー数として表した。全てのQ−PCR反応を、iCycler(Bio−Rad Laboratories、Hercules、CA)上で実施した。
ボルテゾミブを使用する組合せ療法の、血友病動物のin vivoにおける矯正に対する効果を試験するための研究を実施した。最初に、野生型AAVとおよそ同じサイズのゲノムを運ぶベクターを、マウスモデルにおける血友病Bの矯正のために使用した。以前に記載された22CMVエンハンサー/ニワトリβ−アクチンプロモーターにより推進されるヒト第IX因子発現カセットを運ぶAAVベクターを、ベクターの送達時に単回用量のボルテゾミブを加えてまたは加えずに、門脈を介して血友病Bマウスに注入した。図2Aに示すように、ssAAV2.FIX治療マウスは、20週間の観察にわたり、平均して2.4%の第IX因子の活性を示した。ボルテゾミブによる治療の結果、同じ期間にわたり、平均して4.3%の第IX因子の発現が生じた。このことは、第IX因子の発現の83%の増加に相当する。AAV8を使用する、肝臓に方向付けた第IX因子の発現は、AAV2よりも効率的であり、ベクター単独を与えたマウスは、20週間にわたり、平均して40%の第IX因子の活性を発現した。20週間にわたる第IX因子の発現は、単回用量のボルテゾミブを、AAV8ベクターと同時投与して与えたマウスにおいては中程度に増大し、平均して約24%高い第IX因子の活性を示した(図2B)。
大型の導入遺伝子カセットFVIIIを使用する組合せ療法の、同じ遺伝的背景(C57B1/6)を使用する血友病Aマウスにおける効果を解析するための研究を実施した。第VIII因子のcDNA(〜7.1kb)は、血液凝固に寄与しない大型のBドメイン(約2.7kb)を含有する。Bドメインをコードする大半の配列を除去したら、4.5kbのcFVIIIのcDNA配列を、AAVベクター中に組み込むことができる。にもかかわらず、プロモーターおよびその他の必要な転写調節エレメントを付加すると、これらのベクターは、5.6kbの過大なAAV発現カセットとなる。AAV2ベクターおよびAAV8ベクターは、5.6kbのFVIII発現プラスミドを使用して生成した。ウイルスを、qPCRによる総粒子数、電子顕微鏡法によるウイルス粒子の完全性、銀染色によるキャプシドの比、およびアルカリゲル電気泳動によるDNAゲノムのサイズについて特徴付けた。ベクターのパラメータは全て、マウスおよびイヌの両方の研究のための複数生成工程間において、以前の研究を用いて一貫性をもたせた。FVIII研究のために、プロテアソーム阻害剤であるMG−132(Z−LLLともまた呼ばれる)およびボルテゾミブを選び、したがって、MG−132を、臨床的に承認を得ているが未試験の薬剤であるボルテゾミブと比較することができた。
次に、血友病Aマウスを、第VIII因子ベクターとプロテアソーム阻害剤との組合せ療法を用いて治療し、ベクター配列の存在量を、細胞質中と核コンパートメント中とで比較した。ベクターの投与の2週間後に、ボルテゾミブを加えた場合または加えなかった場合の、AAV8.FVIII治療マウスに由来する肝臓細胞の細胞質総画分および核総画分を、ベクターのゲノムが細胞内で蓄積する場所を決定するために、精製し、調べた。細胞質ではなく核中に持続するゲノムの比が、単回用量のボルテゾミブにより増加し、このことは、ウイルスの感染に影響する役割を支持している。これらの結果は、過大なベクターのゲノムを、細胞質から核構造へ差し向け、それに続く、ベクターの脱コートおよび/またはゲノムの補完のステップが生じ得る経路を示唆しており、こうした経路は、最近の報告によっても示唆されている(表1)。
ボルテゾミブおよびデキサメタゾンは一般に、臨床における腫瘍学的療法において一緒に使用されている。ボルテゾミブ療法単独と比較して、デキサメタゾンとボルテゾミブとの組合せが、ボルテゾミブ単独療法に対する不完全な臨床応答の状況におけるデキサメタゾンの追加と同様に、有効性を増加させている24、25、26。また、この臨床パラメータは、過大な導入遺伝子カセットのベクターの形質導入を増強するのにも重要であるかどうかを決定するために、多剤組合せ療法におけるベクターの形質導入の成果を評価した。以前の研究は、肝臓に方向付けた遺伝子療法の間に、レポーター遺伝子を発現するAAVベクターの異所部位における取込みを減少させることを目指して、いくつかの追加の、薬理作用を示す物質を調べるために実施された。これらの早期の研究の間に、デキサメタゾンをベクターと同時投与した場合に、異所性のベクターの散乱を減少させる傾向が観察された。このことは、心臓、脾臓および膵臓を含めた、いくつかの臓器におけるより低い遺伝子の発現およびゲノムの持続に反映され、肝臓への送達は、中程度の増加を示した(図3および表2)。デキサメタゾンのボルテゾミブとの臨床における使用、およびこれらの結果に基づいて、研究を実施し、この場合、AAV8.cFVIII/ボルテゾミブマウスの追加の群を、単回用量の副腎皮質ステロイドのデキサメタゾンを同時に用いて治療し、持続性の導入遺伝子の発現に対する効果を調べた。
ボルテゾミブが第VIII因子の発現を増強する可能性を確立するに至り、追加のマウスを、AAV2ベクターおよびAAV8ベクターを用いて治療して、ボルテゾミブの増強の持続期間を決定した。AAV2単独を与えたマウス中の、循環している第VIII因子の活性は、最初に、第8週に検出可能となり、1年の観察全体を通して、このアッセイの検出の下限値(約1%の活性=0.01IU/ml)付近で変動した(図4)。しかし、ボルテゾミブの同時投与の結果、ほとんどのマウスにおいて、第1週に、検出可能な第VIII因子の活性が生じ、活性は、第8週にピーク(0.11±0.06IU/ml)に達し、3%超で1年間維持された。AAV8ベクターからのcFVIIIの発現は、第8週にピーク(0.51±0.38IU/ml)に達してから、徐々に減少して、正常なヒトの第VIII因子の活性の約10%のプラトーに達し、この状態は、第52週まで維持された(最後の観察、0.10±0.019IU/ml)。対照的に、AAV8.cFVIIIと単回用量のボルテゾミブとを用いて治療したマウスは、図4に示すように、最初の時点(第1週)でさえ、ベクターのみの群のピーク値を超え、1年の観察全体を通して、正常の>50%のcFVIII活性を維持した(第52週におけるcFVIII活性、0.67±0.58IU/ml)。これらの研究では、ボルテゾミブ治療マウスにおける全体的な発現パターンは、デキサメタゾンの追加の有無にかかわらず類似した。
表3に示すように、各治療群中の数匹のマウスが、Sarkarらが概要を述べているスケジュール6に従って、シクロホスファミドの投与を実施したにもかかわらず、ベクターへの暴露後の第2〜20週の種々の時間において、FVIII中和抗体を発生させた。インヒビター力価は、抗体を発生させたそれら数匹のAAV2.cFVIII治療マウスにおいては、検出の下限値付近であり、これらのボーダーラインの力価の意義は、不明確である。Jiangらが以前に報告したように16、インヒビターは、AAV2.cFVIIIに関してよりも、AAV8.cFVIIIに関して頻繁に発生し、インヒビターが、プロテアソーム阻害剤なしで、AAV8.cFVIIIを与えた6匹/10匹のマウスにおいて見られた。ボルテゾミブの同時投与は、AAV8血清型を用いて治療した動物におけるインヒビターの形成の発生率を減少させるように見えた(5匹/15匹のマウス、33.3%)。副腎皮質ステロイドとボルテゾミブとの組合せには、インヒビターの形成の最も低い率を伴い(AAV8.cFVIII/ボルテゾミブ/デキサメタゾンマウスの20%対ベクターのみのマウスの60%)、このことは、この組合せ療法から利益が得られる可能性があることを示唆している。
同一のAAV−cFVIIIベクターカセットを使用して、研究を実施して、プロテアソーム阻害剤による大型の導入遺伝子の発現の増大が、イヌ血友病Aモデルを変えるかどうかを決定した。表4に示すように、総数7匹の血友病Aイヌを、AAV8.cFVIIIを用いて治療し、経過観察を少なくとも10カ月間行った(最も長い経過観察=32カ月間)。3匹の血友病Aの仔イヌに、1×1013vg/kgの限界用量のAAV8.cFVIII(AAV8)を、門脈を介して与えた。4匹の血友病Aの仔イヌに、同じAAV療法を与え、FDAの承認を得ている用量(1.3mg/m2)のプロテアソーム阻害剤ボルテゾミブの単回I.V.投与も与えた。ベクターおよびプロテアソーム阻害剤は、忍容性良好であった。具体的には、肝臓トランスアミナーゼの上昇、神経学的症状、または血液学的パラメータの変化は観察されなかった。
第VIII因子−/−マウスに、3×1010vg/動物の、過大な第VIII因子導入遺伝子をコードする一本鎖AAV血清型8ベクターを与えた(n=5マウス/治療群)。ベクター中に組み込まれているイヌ第VIII因子のcDNA配列を工学的に作製して、最適な哺乳動物のコドンの使用およびGCヌクレオチド含有量を得た。マウスに、門脈へのベクターの注入を、単独で、または0.5mgのプロテアソーム阻害剤ボルテゾミブ(PI)/kgと組み合わせて与えた。コドン最適化が、凝固第VIII因子ベクターおよび凝固第IX因子ベクターからの発現を増加させることが確立されているが、PIが、より効率的なコドン最適化ベクターをさらに増大させることができるかどうかは確立されていなかった。ボルテゾミブの単回投与に続く、コドン最適化第VIII因子の発現の増大が、研究の長さ(12週間)全体を通して持続した(図6、上部の直線)。
Claims (11)
- (a)第VIII因子(FVIII)、ジストロフィン、ミニ−ジストロフィンおよび膜貫通制御因子タンパク質(CFTR)からなる群から選択されるタンパク質をコードする異種核酸を含むアデノ随伴ウイルス(AAV)ベクターゲノムを含むAAVベクターであって、前記AAVベクターのゲノムが、野生型AAVゲノムに比して過大であるベクターと、
(b)ボルテゾミブ(ベルケイド(登録商標))と
を含む組成物。 - 前記AAVベクターのゲノムのサイズが、5.2kb超である、請求項1に記載の組成物。
- 前記AAVベクターが、二本鎖AAVベクターのゲノムを含む、請求項1または2に記載の組成物。
- 前記AAVベクターが、分断された導入遺伝子のAAVベクターである、請求項1から3のいずれか1項に記載の組成物。
- 前記異種の核酸が、野生型ヌクレオチド配列に比して最適化されたコード配列を含む、請求項1から4のいずれか1項に記載の組成物。
- 前記異種の核酸が、野生型ヌクレオチド配列に比して最適化された非コード配列を含む、請求項1から5のいずれか1項に記載の組成物。
- 前記AAVベクターのゲノムが、野生型AAVゲノムに比して最適化された、請求項1から6のいずれか1項に記載の組成物。
- 薬学的に許容される担体中に、請求項1から7のいずれかに記載の組成物を含む医薬製剤。
- 請求項1から7のいずれかに記載の組成物を含む、第VIII因子(FVIII)、ジストロフィン、ミニ−ジストロフィンおよび膜貫通制御因子タンパク質(CFTR)からなる群から選択されるタンパク質をコードする異種核酸を細胞に送達するための医薬製剤。
- 前記細胞が、筋肉細胞、肝臓細胞、関節の部位の細胞または骨軟骨の部位の細胞である、請求項9に記載の医薬製剤。
- (a)第VIII因子(FVIII)、ジストロフィン、ミニ−ジストロフィンおよび膜貫通制御因子タンパク質(CFTR)からなる群から選択されるタンパク質をコードする異種核酸を含むアデノ随伴ウイルス(AAV)ベクターゲノムを含むAAVベクターであって、前記AAVベクターのゲノムが、野生型AAVゲノムに比して過大であるベクターと、
(b)ボルテゾミブ(ベルケイド(登録商標))と
を含む、異種核酸を対象に送達するためのキットであって、前記AAVベクターを、ボルテゾミブの前に、および/または、ボルテゾミブの後に、および/または、ボルテゾミブと同時に投与する、キット。
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