JP7173548B2 - 非組み込みウイルス送達系およびその関連方法 - Google Patents
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Description
パピローマウイルス
エプスタイン・バーウイルス(EBV)
B型肝炎ウイルス(HBV)
レトロウイルス
ベクター・イン・ベクター系
方法
感染性疾患
創傷治癒
別の実施形態では、本発明は、創傷治癒に関連する状態、症候、または副作用を処置、予防、または最小にする方法に関する。開示される組成物は、全身に、または事故、損傷、もしくは外科手術後の創傷に直接投与され得る。外科手術のケースでは、VIV系は、治癒を促進するために予防的に投与され得る。事故、損傷、または外科手術による創傷のケースでは、VIV系は、創傷形成のある程度後に投与され得る。例えば、VIV系は、創傷形成の約1、約2、約3、約4、約5、約10、約12、約24、約36、約48、約60、約72、約84、約96、約108、約120、または約168時間以内に投与され得る。
一実施形態では、本発明は、骨損傷を有する対象を識別するステップ、および治療有効量の本発明に従ったウイルス送達系を対象に投与するステップを含む、骨の治癒を増強する方法に関する。ウイルス送達系は、ウイルス担体、異種ウイルスエピソーム複製起点、異種ウイルスエピソーム複製起点に特異的なイニシエータータンパク質をコードする配列、ならびに目的の少なくとも1つの遺伝子、遺伝子産物、shRNA、siRNA、miRNA、および/または他の遺伝子サイレンシングRNAを含み、ここで、ウイルス担体は欠陥のあるインテグラーゼ遺伝子を有し、異種ウイルスエピソームDNA複製起点に特異的なイニシエータータンパク質をコードする配列の発現は、誘導性プロモーターの制御下にある。骨損傷は、事故、損傷、または外科手術によるものであり得、骨の癒合不全または急性骨折または所要の脊椎固定術であり得る。一部の実施形態では、目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、および/または他の遺伝子抑制RNAは、骨形成タンパク質1~4またはシクロオキシゲナーゼ-2または血管内皮増殖因子またはそれらの断片をコードする。さらに、ある特定の実施形態では、上述の変異体は、骨損傷または関連疾患を処置するために好ましく、またそれらは本発明の範囲内である。
遺伝性遺伝子疾患
P-点突然変異、または全体が1つの遺伝子内にあるあらゆる挿入/欠失
D-1つまたは複数の遺伝子の欠失
C-全染色体の過剰、喪失、またはその両方(染色体異常を参照されたい)
T-トリヌクレオチド反復障害:遺伝子はその長さを伸長している
別の態様では、VIV系は、疾患の治療に使用される細胞または組織を改変するために使用され得る。細胞には、限定はしないが、リンパ球、幹細胞、上皮細胞、神経細胞などの一次細胞が含まれ得る。例えば、VIV系は、がん、感染性疾患、または自己免疫を含む特定疾患に再び向けられるリンパ球を改変するために、かつ遺伝子改変された細胞の長期的存在が健康上のリスクを有する場合に、使用され得る。例えば、VIV系は、高レベルの転写産物因子を要する多能性幹細胞を規定された間隔にわたりプログラムするために、そして組み込まれたウイルスベクターの長期的存在が望ましくない場合に、使用され得る。好適な上皮細胞は、合成皮膚または他の適用に使用され得る上皮細胞を含む。これらは、処置後の正常組織の機能に有害となり本明細書に開示されるVIV系によって最良に送達される栄養因子または増殖因子の、最初の処置の間の発現を要し得る。
開示されるVIV系は、目的の遺伝子または配列の短期、中期、または長期の発現、および開示されるベクターのエピソームでの維持を可能にする。したがって、投薬レジメンは、処置される状態および投与方法に基づいて変化し得る。
本明細書で具体的に定義されない語は、当業者によって理解される意味と同じ意味を有すると理解される。
感染性疾患を処置するためのVIV
この実施例は、感染性疾患を処置するための例示的なVIV構築物を実証する。
実施例2
感染性疾患を予防するためのVIV
実施例3
創傷治癒を増強するためのVIV
実施例4
骨損傷を処置するためのVIV
実施例5
遺伝性疾患を処置するためのVIV
実施例6
カーゴを発現するためのE1を含有するVIV
実施例7
カーゴを発現するためのE1およびE2を含有するVIV
実施例8
カーゴを発現するためのE1およびE2の導入
実施例9
VEGFの発現
実施例10
E1およびE2含有ベクターの開発
3’LTRフォワード CTAATTCACTCCCAACGAAG(配列番号11);および
5’LTRリバース GCCGAGTCCTGCGTCGAGAG(配列番号12)。
実施例11
LCR断片および関連ベクターの開発
実施例12
LCR断片およびE1/E2バリアントを含有するベクターの試験
実施例13
抗体発現
実施例14
マイクロRNA発現およびノックダウン
実施例15
EBVに基づくイニシエータータンパク質
実施例16
LCR断片の組合せおよび分析
配列
以下の配列が、本明細書で参照される。
本発明は、例えば、以下の項目を提供する。
(項目1)
(a)欠陥のあるインテグラーゼ遺伝子を含有するウイルス担体、
(b)異種ウイルスエピソームDNA複製起点、
(c)前記異種ウイルスエピソームDNA複製起点に特異的な少なくとも1つのイニシエータータンパク質をコードする配列であって、前記異種ウイルスエピソームDNA複製起点に特異的な前記少なくとも1つのイニシエータータンパク質をコードする配列の発現が誘導性である、配列、および
(d)少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNA
を含む、非組み込みウイルス送達系。
(項目2)
前記ウイルス担体がレンチウイルスである、項目1に記載の非組み込みウイルス送達系。
(項目3)
前記異種ウイルスエピソームDNA複製起点がパピローマウイルスに由来する、項目1に記載の非組み込みウイルス送達系。
(項目4)
前記異種ウイルスエピソームDNA複製起点がヒトパピローマウイルスまたはウシパピローマウイルスに由来する、項目3に記載の非組み込みウイルス送達系。
(項目5)
前記異種ウイルスエピソームDNA複製起点がヒトパピローマウイルス16型(HPV16)に由来する、項目4に記載の非組み込みウイルス送達系。
(項目6)
前記異種ウイルスエピソームDNA複製起点がHPV16の長制御領域(LCR)に由来する、項目5に記載の非組み込みウイルス送達系。
(項目7)
前記異種ウイルスエピソームDNA複製起点が配列番号1を含む、項目6に記載の非組み込みウイルス送達系。
(項目8)
前記異種ウイルスエピソームDNA複製起点が配列番号1の5’トランケーションを含む、項目6に記載の非組み込みウイルス送達系。
(項目9)
前記異種ウイルスエピソームDNA複製起点が、配列番号1の少なくとも約200ヌクレオチド、または少なくとも約300ヌクレオチド、または少なくとも約400ヌクレオチド、または少なくとも約500ヌクレオチド、または少なくとも約600ヌクレオチド、または少なくとも約700ヌクレオチドの5’トランケーションを含む、項目6に記載の非組み込みウイルス送達系。
(項目10)
前記異種ウイルスエピソームDNA複製起点が、HPV16の前記LCRのFrag1(配列番号2)、Frag2(配列番号3)、Frag3(配列番号4)、またはFrag4(配列番号5)と少なくとも約80%の配列同一性、または少なくとも約85%の配列同一性、または少なくとも約90%の配列同一性、または少なくとも約95%の配列同一性、または少なくとも約98%の配列同一性を含む、項目6に記載の非組み込みウイルス送達系。
(項目11)
前記異種ウイルスエピソームDNA複製起点が、HPV16の前記LCRのFrag1(配列番号2)、Frag2(配列番号3)、Frag3(配列番号4)、またはFrag4(配列番号5)を含む、項目6に記載の非組み込みウイルス送達系。
(項目12)
前記異種ウイルスエピソームDNA複製起点に特異的な前記少なくとも1つのイニシエータータンパク質がE1またはその作動可能な断片を含む、項目1に記載の非組み込みウイルス送達系。
(項目13)
前記異種ウイルスエピソームDNA複製起点に特異的な前記少なくとも1つのイニシエータータンパク質がE2またはその作動可能な断片を含む、項目1に記載の非組み込みウイルス送達系。
(項目14)
前記異種ウイルスエピソームDNA複製起点に特異的な前記少なくとも1つのイニシエータータンパク質がEBNA-1またはその作動可能な断片を含む、項目1に記載の非組み込みウイルス送達系。
(項目15)
前記異種ウイルスエピソームDNA複製起点に特異的な少なくとも2つのイニシエータータンパク質を含む、項目1に記載の非組み込みウイルス送達系。
(項目16)
前記異種ウイルスエピソームDNA複製起点に特異的な少なくとも2つのイニシエータータンパク質がE1およびE2またはそれらの作動可能な断片である、項目15に記載の非組み込みウイルス送達系。
(項目17)
前記少なくとも1つのイニシエータータンパク質をコードする配列が単一の別個のプラスミドまたは非組み込みウイルスベクターに存在する、項目1に記載の非組み込みウイルス送達系。
(項目18)
前記系が、前記異種ウイルスエピソームDNA複製起点に特異的な少なくとも2つのイニシエータータンパク質を含み、前記少なくとも2つのイニシエータータンパク質をコードする配列が、単一の別個のプラスミドまたは非組み込みウイルスベクターに存在する、項目1に記載の非組み込みウイルス送達系。
(項目19)
前記系が、前記異種ウイルスエピソームDNA複製起点に特異的な少なくとも2つのイニシエータータンパク質を含み、ここで、第1のイニシエータータンパク質のための配列および第2のイニシエータータンパク質のための配列が、別個のプラスミドまたは非組み込みウイルスベクターに存在する、項目1に記載の非組み込みウイルス送達系。
(項目20)
前記少なくとも1つの遺伝子産物が、抗体、抗体断片、または増殖因子を含む、項目1に記載の非組み込みウイルス送達系。
(項目21)
前記抗体が、抗HER2抗体またはその断片を含む、項目20に記載の非組み込みウイルス送達系。
(項目22)
前記増殖因子が、血管内皮増殖因子(VEGF)またはそのバリアントを含む、項目20に記載の非組み込みウイルス送達系。
(項目23)
前記miRNAが、CCR5 miRNAを含む、項目1に記載の非組み込みウイルス送達系。
(項目24)
項目1に記載の前記非組み込みウイルス送達系および少なくとも1つの薬学的に許容される担体を含む医薬組成物。
(項目25)
少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAを細胞中で発現させる方法であって、
前記細胞を、有効量の非組み込みウイルス送達系に接触させること
を含み、ここで、前記系が、
i.欠陥のあるインテグラーゼ遺伝子を含有するウイルス担体、
ii.異種ウイルスエピソームDNA複製起点、
iii.前記異種ウイルスエピソームDNA複製起点に特異的な少なくとも1つのイニシエータータンパク質をコードする配列であって、前記異種ウイルスエピソームDNA複製起点に特異的な前記少なくとも1つのイニシエータータンパク質をコードする配列の発現が誘導性である、配列、および
iv.少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNA
を含む、方法。
(項目26)
少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAを、それを必要とする対象中で発現させる方法であって、
前記対象に、有効量の非組み込みウイルス送達系を投与することを含み、ここで、前記系が、
i.欠陥のあるインテグラーゼ遺伝子を含有するウイルス担体、
ii.異種ウイルスエピソーム複製起点、
iii.異種ウイルスエピソームDNA複製起点に特異的な少なくとも1つのイニシエータータンパク質をコードする配列であって、前記異種ウイルスエピソームDNA複製起点に特異的な前記少なくとも1つのイニシエータータンパク質をコードする配列の発現が誘導性である、配列、および
iv.少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNA
を含む、方法。
(項目27)
前記少なくとも1つのイニシエータータンパク質をコードする配列が、単一の別個のプラスミドに存在し、前記少なくとも1つのイニシエータータンパク質が、E1またはE2である、項目26に記載の方法。
(項目28)
前記少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAの第1の発現レベルを開始させるための第1の量の前記単一の別個のプラスミドを、それを必要とする前記対象に投与することをさらに含む、項目27に記載の方法。
(項目29)
前記少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAの第2の発現レベルを開始させるための第2の量の前記単一の別個のプラスミドを、それを必要とする前記対象に投与することをさらに含む、項目28に記載の方法。
(項目30)
前記第2の量が前記第1の量より低いとき、前記少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAの発現レベルが減少する、項目29に記載の方法。
(項目31)
前記第2の量が前記第1の量より高いとき、前記少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAの発現レベルは増加する、項目29に記載の方法。
(項目32)
前記系が、前記少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAの低レベルの基底発現を生じるように最適化されており、ここで、前記異種ウイルスエピソームDNA複製起点が、配列番号1またはHPV16のLCRのFrag1(配列番号2)と少なくとも約80%の配列同一性、または少なくとも約85%の配列同一性、または少なくとも約90%の配列同一性、または少なくとも約95%の配列同一性、または少なくとも約98%の配列同一性を含む、項目1に記載の非組み込みウイルス送達系。
(項目33)
前記系が、前記少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAの低レベルの基底発現を生じるように最適化されており、前記異種ウイルスエピソームDNA複製起点が、配列番号1またはHPV16のLCRのFrag1(配列番号2)を含む、項目1に記載の非組み込みウイルス送達系。
(項目34)
前記系が、前記少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAの中等度レベルの基底発現を生じるように最適化されており、ここで、前記異種ウイルスエピソームDNA複製起点が、HPV16のLCRのFrag2(配列番号3)、Frag3(配列番号4)、またはFrag4(配列番号5)と少なくとも約80%の配列同一性、または少なくとも約85%の配列同一性、または少なくとも約90%の配列同一性、または少なくとも約95%の配列同一性、または少なくとも約98%の配列同一性を含む、項目1に記載の非組み込みウイルス送達系。
(項目35)
前記系が、前記少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAの中等度レベルの基底発現を生じるように最適化されており、前記異種ウイルスエピソームDNA複製起点が、HPV16のLCRのFrag2(配列番号3)、Frag3(配列番号4)、またはFrag4(配列番号5)を含む、項目1に記載の非組み込みウイルス送達系。
(項目36)
最適化された非組み込みウイルス送達系を選択する方法であって、
基底発現レベルを選択すること
を含み、ここで、レベルXが選択されるとき、対応するYが選択され、ここでYは、前記非組み込みウイルス送達系に組み入れられるように選択される異種ウイルスエピソームDNA複製起点に対応し、
X=低の場合、Yは、配列番号1またはFrag1(配列番号2)を含み、
X=中等度の場合、Yは、HPV16のLCRのFrag2(配列番号3)、Frag3(配列番号4)、またはFrag4(配列番号5)を含む、方法。
Claims (22)
- (a)欠陥のあるインテグラーゼ遺伝子を含有するウイルス担体、
(b)異種ウイルスエピソームDNA複製起点、
(c)前記異種ウイルスエピソームDNA複製起点に特異的な少なくとも1つのイニシエータータンパク質をコードする第1の配列であって、前記第1の配列の発現が誘導性である、配列、および
(d)少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAをコードする第2の配列
を含み、
前記少なくとも1つのイニシエータータンパク質の発現は、前記第2の配列の発現を調節するように機能し、
前記ウイルス担体がレンチウイルスであり、
前記異種ウイルスエピソームDNA複製起点が5’トランケーションを伴うHPV16長制御領域(LCR)を含み、
トランケートされたHPV16 LCRがE1結合部位と2つのE2結合部位とを含み、
前記異種ウイルスエピソームDNA複製起点に特異的な少なくとも1つのイニシエータータンパク質が、E1またはその作動可能な断片、E1-C、E2またはその作動可能な断片、E1-T2A-E2、あるいは、EBNA-1またはその作動可能な断片のうち少なくとも1つを含む、
非組み込みウイルス送達系。 - 前記トランケートされたHPV16 LCRが、2つのさらなるE2結合部位、3つのAP1結合部位およびYY1結合部位のいずれか、あるいは、少なくとも1つのさらなるE2結合部位および2つのAP1結合部位のいずれか、あるいは、少なくとも1つのさらなるE2結合部位をさらに含む、請求項1に記載の非組み込みウイルス送達系。
- 前記異種ウイルスエピソームDNA複製起点が、HPV16の前記LCRのFrag1(配列番号2)、Frag2(配列番号3)、Frag3(配列番号4)、またはFrag4(配列番号5)と少なくとも約90%の配列同一性、または少なくとも約95%の配列同一性、または少なくとも約98%の配列同一性を含む、請求項1に記載の非組み込みウイルス送達系。
- 前記異種ウイルスエピソームDNA複製起点が、HPV16の前記LCRのFrag1(配列番号2)、Frag2(配列番号3)、Frag3(配列番号4)、またはFrag4(配列番号5)を含む、請求項1に記載の非組み込みウイルス送達系。
- 前記異種ウイルスエピソームDNA複製起点に特異的な前記少なくとも1つのイニシエータータンパク質がE1またはその作動可能な断片を含む、請求項1に記載の非組み込みウイルス送達系。
- 前記異種ウイルスエピソームDNA複製起点に特異的な前記少なくとも1つのイニシエータータンパク質がE2またはその作動可能な断片を含む、請求項1に記載の非組み込みウイルス送達系。
- 前記異種ウイルスエピソームDNA複製起点に特異的な前記少なくとも1つのイニシエータータンパク質がEBNA-1またはその作動可能な断片を含む、請求項1に記載の非組み込みウイルス送達系。
- 前記異種ウイルスエピソームDNA複製起点に特異的な少なくとも2つのイニシエータータンパク質を含む、請求項1に記載の非組み込みウイルス送達系。
- 前記異種ウイルスエピソームDNA複製起点に特異的な少なくとも2つのイニシエータータンパク質がE1およびE2またはそれらの作動可能な断片である、請求項8に記載の非組み込みウイルス送達系。
- 前記少なくとも1つのイニシエータータンパク質をコードする配列が単一の別個のプラスミドまたは非組み込みウイルスベクターに存在する、請求項1に記載の非組み込みウイルス送達系。
- 前記系が、前記異種ウイルスエピソームDNA複製起点に特異的な少なくとも2つのイニシエータータンパク質を含み、前記少なくとも2つのイニシエータータンパク質をコードする配列が、単一の別個のプラスミドまたは非組み込みウイルスベクターに存在する、請求項1に記載の非組み込みウイルス送達系。
- 前記系が、前記異種ウイルスエピソームDNA複製起点に特異的な少なくとも2つのイニシエータータンパク質を含み、ここで、第1のイニシエータータンパク質のための配列および第2のイニシエータータンパク質のための配列が、別個のプラスミドまたは非組み込みウイルスベクターに存在する、請求項1に記載の非組み込みウイルス送達系。
- 前記少なくとも1つの遺伝子産物が、抗体、抗体断片、または増殖因子を含む、請求項1に記載の非組み込みウイルス送達系。
- 前記miRNAが、CCR5 miRNAを含む、請求項1に記載の非組み込みウイルス送達系。
- 請求項1に記載の前記非組み込みウイルス送達系および少なくとも1つの薬学的に許容される担体を含む医薬組成物。
- 少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAを培養された細胞中で発現させる方法であって、
前記培養された細胞を、有効量の非組み込みウイルス送達系に接触させること
を含み、ここで、前記系が、
i.欠陥のあるインテグラーゼ遺伝子を含有するウイルス担体、
ii.異種ウイルスエピソームDNA複製起点、
iii.前記異種ウイルスエピソームDNA複製起点に特異的な少なくとも1つのイニシエータータンパク質をコードする第1の配列であって、前記第1の配列の発現が誘導性である、配列、および
iv.少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAをコードする第2の配列
を含み、
前記少なくとも1つのイニシエータータンパク質の発現は、前記第2の配列の発現を調節するように機能し、
前記ウイルス担体がレンチウイルスであり、
前記異種ウイルスエピソームDNA複製起点が5’トランケーションを伴うHPV16長制御領域(LCR)を含み、
トランケートされたHPV16 LCRがE1結合部位と2つのE2結合部位とを含み、
前記異種ウイルスエピソームDNA複製起点に特異的な少なくとも1つのイニシエータータンパク質が、E1またはその作動可能な断片、E1-C、E2またはその作動可能な断片、E1-T2A-E2、あるいは、EBNA-1またはその作動可能な断片のうち少なくとも1つを含む、
方法。 - 少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAを、それを必要とする対象中で発現させる方法において使用するための非組み込みウイルス送達系であって、前記方法は、
それを必要とする前記対象に、有効量の前記非組み込みウイルス送達系を投与することを含み、ここで、前記系が、
i.欠陥のあるインテグラーゼ遺伝子を含有するウイルス担体、
ii.異種ウイルスエピソーム複製起点、
iii.異種ウイルスエピソームDNA複製起点に特異的な少なくとも1つのイニシエータータンパク質をコードする第1の配列であって、前記第1の配列の発現が誘導性である、配列、および
iv.少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAをコードする第2の配列
を含み、
前記少なくとも1つのイニシエータータンパク質の発現は、前記第2の配列の発現を調節するように機能し、
前記ウイルス担体がレンチウイルスであり、
前記異種ウイルスエピソームDNA複製起点が5’トランケーションを伴うHPV16長制御領域(LCR)を含み、
トランケートされたHPV16 LCRがE1結合部位と2つのE2結合部位とを含み、
前記異種ウイルスエピソームDNA複製起点に特異的な少なくとも1つのイニシエータータンパク質が、E1またはその作動可能な断片、E1-C、E2またはその作動可能な断片、E1-T2A-E2、あるいは、EBNA-1またはその作動可能な断片のうち少なくとも1つを含む、
非組み込みウイルス送達系。 - 前記少なくとも1つのイニシエータータンパク質をコードする配列が、単一の別個のプラスミドに存在し、前記少なくとも1つのイニシエータータンパク質が、E1またはE2である、請求項17に記載の非組み込みウイルス送達系。
- 前記方法が、前記少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAの第1の発現レベルを開始させるための第1の量の前記単一の別個のプラスミドを、それを必要とする前記対象に投与することをさらに含む、請求項18に記載の非組み込みウイルス送達系。
- 前記方法が、前記少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAの第2の発現レベルを開始させるための第2の量の前記単一の別個のプラスミドを、それを必要とする前記対象に投与することをさらに含む、請求項19に記載の非組み込みウイルス送達系。
- 前記第2の量が前記第1の量より低いとき、前記少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAの発現レベルが減少する、請求項20に記載の非組み込みウイルス送達系。
- 前記第2の量が前記第1の量より高いとき、前記少なくとも1つの目的の遺伝子、遺伝子産物、shRNA、siRNA、miRNA、または他のRNAの発現レベルは増加する、請求項20に記載の非組み込みウイルス送達系。
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JP2019523767A (ja) | 2019-08-29 |
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CA3025247A1 (en) | 2017-12-14 |
US20190264226A1 (en) | 2019-08-29 |
WO2017213697A1 (en) | 2017-12-14 |
WO2017214327A3 (en) | 2018-02-15 |
US20190255190A1 (en) | 2019-08-22 |
JP2023120412A (ja) | 2023-08-29 |
BR112018075399A2 (pt) | 2019-03-19 |
KR20190023065A (ko) | 2019-03-07 |
CN109641064A (zh) | 2019-04-16 |
IL263402A (en) | 2018-12-31 |
EP3468618A4 (en) | 2020-01-22 |
JP2019520814A (ja) | 2019-07-25 |
EP3468617A1 (en) | 2019-04-17 |
EP3468618A2 (en) | 2019-04-17 |
AU2017279542A1 (en) | 2018-12-06 |
WO2017214327A2 (en) | 2017-12-14 |
US11976292B2 (en) | 2024-05-07 |
KR102609667B1 (ko) | 2023-12-05 |
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