JP6805174B2 - 神経成長因子シグナルペプチド及び副甲状腺ホルモンを含むaav分離株及び融合タンパク質 - Google Patents
神経成長因子シグナルペプチド及び副甲状腺ホルモンを含むaav分離株及び融合タンパク質 Download PDFInfo
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- C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
Description
本特許出願は、2015年5月12日出願の米国仮特許出願第62/160,522号及び2016年5月4日出願の米国仮特許出願第62,331,699号(参照により組み込まれる)の利益を主張する。
本明細書と同時提出されるヌクレオチド/アミノ酸の配列表が、参照により、本明細書中にその全体が組み込まれる。
AAVはパルボウイルス科(Parvoviridae family)のメンバーであり、約5,000ヌクレオチド未満の、直鎖状の一本鎖DNAゲノムを含む。AAVは、効率的な複製のために、ヘルパーウイルス(即ち、アデノウイルス又はヘルペスウイルス)との共感染、又はヘルパー遺伝子の発現を必要とする。治療用核酸の投与のために用いられるAAVベクターは、典型的には、DNA複製及びパッケージングのための認識シグナルを含有する末端反復配列(terminal repeats)(ITR)のみが残るように、およそ96%の親ゲノムが欠失されている。これにより、ウイルス遺伝子の発現に起因する免疫学的な又は毒性の副作用が無くされる。更に、所望であれば、産生細胞に、特定のAAVタンパク質を送達することにより、AAV ITRを含むAAVベクターを、細胞ゲノムの特定領域に組み込むことが可能になる(例、米国特許第6,342,390号及び第6,821,511号を参照)。組み込まれたAAVゲノムを含む宿主細胞は、細胞増殖の変化や形態の変化を示さない(例えば、米国特許第4,797,368号参照)。
本発明は、配列番号4又は配列番号9のアミノ酸配列を含むキャプシドを含むアデノ随伴ウイルス(AAV)ベクターであって、異種核酸配列を更に含む、AAVベクターを提供する。一態様においては、異種核酸配列は、NGF−PTH融合ポリペプチド又はメチルマロニルCoAムターゼ酵素をコードする。
本発明者らは、「44−9」と名付けられたAAV分離株を生成し、特性解析した。AAV44.9は、唾液腺細胞、肝細胞、及び神経細胞(例、皮質、嗅球、及び脳幹の細胞及び小脳のプルキンエ細胞)を含む多くの細胞種において高い遺伝子導入活性を有する。
本実施例は、AAV44.9分離株の生成を説明する。
本実施例は、目下遺伝子導入のために効率的に標的化されていない細胞への、遺伝子導入ベクターとしての、AAV44.9分離株の使用を実例で示す。
本実施例は、配列番号3のCMV NGF−PTH遺伝子カセットを含有するAAVベクターの、単回耳下唾液腺カニューレ注入後の、NGF−PTH融合ポリペプチドの内分泌放出を実証する。
本実施例は、AAV44.9ベクターが肝臓への送達に用いられ得ることを実証する。
Claims (11)
- 配列番号4又は配列番号9のアミノ酸配列を含むキャプシドをコードする核酸を含む、アデノ随伴ウイルス(AAV)ベクターであって、異種核酸配列を更に含む、AAVベクター。
- 異種核酸配列が、宿主細胞におけるその発現を指令する調節配列に作動可能に連結される、請求項1のAAVベクター。
- 異種核酸配列に、1つ以上の逆位末端反復(ITR)配列が隣接する、請求項1又は2のAAVベクター。
- キャプシドが、配列番号5の核酸配列によってコードされる、請求項1〜3のいずれか1項のAAVベクター。
- 異種核酸配列が、メチルマロニルCoAムターゼ酵素をコードする、請求項1〜4のいずれか1項のAAVベクター。
- 異種核酸配列が、神経成長因子(NGF)シグナルペプチド及び副甲状腺ホルモン(PTH)を含むポリペプチドをコードする、請求項1〜4のいずれか1項のAAVベクター。
- ポリペプチドが、配列番号1及び配列番号2のアミノ酸配列を含む、請求項6のAAVベクター。
- 配列番号3の核酸配列を含む、請求項6又は7のAAVベクター。
- 請求項1〜8のいずれか1項のAAVベクター及び医薬的に許容可能な担体を含む、組成物。
- 哺乳動物の唾液腺への投与用に製剤化された、請求項6〜8のいずれか1項のベクターを含む、哺乳動物における副甲状腺機能低下症の治療剤。
- 請求項5のベクターを含む、哺乳動物におけるメチルマロン酸血症(MMA)の治療剤。
Applications Claiming Priority (5)
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US201562160552P | 2015-05-12 | 2015-05-12 | |
US62/160,552 | 2015-05-12 | ||
US201662331699P | 2016-05-04 | 2016-05-04 | |
US62/331,699 | 2016-05-04 | ||
PCT/US2016/032047 WO2016183297A1 (en) | 2015-05-12 | 2016-05-12 | Aav isolate and fusion protein comprising nerve growth factor signal peptide and parathyroid hormone |
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JP2018515096A JP2018515096A (ja) | 2018-06-14 |
JP2018515096A5 JP2018515096A5 (ja) | 2019-06-20 |
JP6805174B2 true JP6805174B2 (ja) | 2020-12-23 |
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EP (1) | EP3294894B8 (ja) |
JP (1) | JP6805174B2 (ja) |
CA (1) | CA2985786A1 (ja) |
WO (1) | WO2016183297A1 (ja) |
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PL3356390T3 (pl) | 2015-09-28 | 2021-07-05 | The University Of North Carolina At Chapel Hill | Sposoby i kompozycje dla wektorów wirusowych unikających przeciwciał |
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EP3294894B1 (en) | 2019-08-14 |
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