JP2023529686A - グルタル酸尿症治療用組成物及びこの投与方法 - Google Patents
グルタル酸尿症治療用組成物及びこの投与方法 Download PDFInfo
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- JP2023529686A JP2023529686A JP2022575842A JP2022575842A JP2023529686A JP 2023529686 A JP2023529686 A JP 2023529686A JP 2022575842 A JP2022575842 A JP 2022575842A JP 2022575842 A JP2022575842 A JP 2022575842A JP 2023529686 A JP2023529686 A JP 2023529686A
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- glutaric aciduria
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Abstract
Description
(特許文献1)国際特許公開公報WO 2013133691 A1
(特許文献2)国際特許公開公報WO 2013133711 A1
(非特許文献1)Kolker et al., “Diagnosis and management of glutaric aciduria type I - revised recommendations”;Journal of Inherited Metabolic Disease, Published online Mar 23, 2011;34(3):pp 677-694.
実施例1.組換えヒトグルタリル-CoA脱水素酵素(GCDH)の製造及び精製
組換えヒトグルタリル-CoA脱水素酵素(Glutaryl-CoA Dehydrogenase;GCDH)を生産するために、pcDNA3.4-TOPOをバックボーンにしたプラスミドからCHO細胞(Cricetulus griseus;Chinese Hamster細胞)でのGCDH発現に適切になり得るように最適化プラスミドを製作した。これにより、配列番号1のアミノ酸配列を含むGCDH蛋白質を発現するプラスミドを製作した(p18AFUOQC_GCDH_pcDNA3.4-TOPO)。本実施では、発現及び収得の最適化のためにシグナル配列である配列番号2のアミノ酸配列をN末端付近に付加したGCDH蛋白質を発現して得た。
グルタル酸尿症疾患モデルマウスとして用いられるGCDH KOマウスは、既に広く商用化されたマウスstrainである(例えば、Cyagen社、strain name:KO-C57BL/6J-Gcdhem1cyagen;Conditional KO-C57BL/6J-Gcdhem1.1cyagen)。一方、本開示では、各発明者が別途にクリスパー(Clustered Regularly Interspaced Short Palindromic Repeats;CRISPR)遺伝子ハサミ技術を用いてGCDH KOマウスを製作した。マウスGCDHのExon 2部分をターゲッティングしてKOマウスを製作し、具体的な製作はマクロジェン(社)に依頼した。製造したグルタル酸尿症疾患モデルマウス(GCDH KOマウス)のノックアウト(Knock-out;KO)の有無を確認するT7エンドヌクレアーゼI反応を通じた遺伝子型検査(Genotyping)を行った。Genotypingを通じてKOされたマウスを一次的に同定した(表1)。
前記実施例1で生産した組換えヒトグルタリル-CoA脱水素酵素(GCDH)を、前記実施例2で生産/確認したグルタル酸尿症1型動物モデルに投与して、治療効果を2回にわたって確認した。
5週齢GCDH KOマウスに尻尾静脈を通じて組換えヒトGCDHを単回投与する実験を行った。具体的には、rhGCDHを50及び100μgを単回投与し、小便内のグルタル酸(GA)数値をLC-MS/MS方法で測定した。GA数値はrhGCDH投与1週間前、及び投与2日後に各実験群別に小便を採取して測定した。1次動物実験の概ねの概要は図4の通りであり、各実験群及び個体の数は下記の表3の通りである。
5~6週齢GCDH KOマウスに組換えヒトGCDHを尻尾静脈(i.v.)または皮下(s.c.)に単回投与する実験を行った。具体的には、尻尾静脈はrhGCDHを50及び100μg単回投与し、皮下にはrhGCDHを50、150及び250μg単回投与した。一般に、皮下投与用量は、静脈投与に比べて生体利用率(bioavailability;BA)が20%であるので(大韓民国公開特許第2017-0004814号参考)、静脈投与50μgに比べて1、3及び5倍に用量設定した。
Claims (14)
- 組換えヒトグルタリル-CoA脱水素酵素(recombinant human Glutaryl-CoA dehydrogenase;rhGCDH)を含むグルタル酸尿症治療用薬剤学的組成物。
- 前記rhGCDHが配列番号1のアミノ酸を含むものである、請求項1に記載のグルタル酸尿症治療用薬剤学的組成物。
- 静脈内投与または皮下投与されるものである、請求項1に記載のグルタル酸尿症治療用薬剤学的組成物。
- 前記グルタル酸尿症はグルタル酸尿症第1型であるものである、請求項1に記載のグルタル酸尿症治療用薬剤学的組成物。
- 週1回、月2回、または、月1回投与されるものである、請求項1に記載のグルタル酸尿症治療用薬剤学的組成物。
- グルタル酸尿症のための食餌調節とともに投与される、請求項1に記載のグルタル酸尿症治療用薬剤学的組成物。
- 前記グルタル酸尿症のための食餌調節は、低蛋白食餌、低-リシン食餌、リシン除去食餌、アルギニン、カルニチン、クロフィブラート(clofibrate)及び/又はリボフラビン補充療法またはこの組合わせであるものである、請求項6に記載のグルタル酸尿症治療用薬剤学的組成物。
- 組換えヒトグルタリル-CoA脱水素酵素(recombinant human Glutaryl-CoA dehydrogenase;rhGCDH)を含むグルタル酸尿症治療用薬剤学的組成物を投与する段階を含む、グルタル酸尿症治療方法。
- 前記rhGCDHが配列番号1のアミノ酸を含むものである、請求項8に記載のグルタル酸尿症治療方法。
- 前記投与が静脈内投与または皮下投与である、請求項8に記載のグルタル酸尿症治療方法。
- 前記グルタル酸尿症はグルタル酸尿症第1型であるものである、請求項8に記載のグルタル酸尿症治療方法。
- 週1回、月2回、または、月1回投与されるものである、請求項8に記載のグルタル酸尿症治療方法。
- グルタル酸尿症のための食餌調節と並行して患者に投与される、請求項8に記載のグルタル酸尿症治療方法。
- 前記グルタル酸尿症のための食餌調節は、低蛋白食餌、低-リシン食餌、リシン除去食餌、アルギニン、カルニチン、クロフィブラート(clofibrate)及び/又はリボフラビン補充療法またはこの組合わせであるものである、請求項13に記載のグルタル酸尿症治療方法。
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JP2004524814A (ja) * | 2000-09-29 | 2004-08-19 | インサイト・ゲノミックス・インコーポレイテッド | 酸化還元酵素 |
JP2005522517A (ja) * | 2002-04-16 | 2005-07-28 | 敬也 小澤 | 組み換えアデノ随伴ウイルスビリオンを使用したアミノ酸代謝に関与する酵素を搬送するための組成物、およびそのようなアデノ随伴ウイルスビリオンを用いてアミノ酸代謝疾患を治療するための使用方法 |
WO2020014209A1 (en) * | 2018-07-09 | 2020-01-16 | Flagship Pioneering Innovations V, Inc. | Fusosome compositions and uses thereof |
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CN1331304A (zh) * | 2000-06-30 | 2002-01-16 | 上海博德基因开发有限公司 | 一种新的多肽——人戊二酰辅酶a脱氢酶16.17和编码这种多肽的多核苷酸 |
WO2013133691A1 (en) | 2012-03-09 | 2013-09-12 | N.V. Nutricia | Liquid nutritional composition comprising free amino acids |
KR20170004814A (ko) | 2015-07-02 | 2017-01-11 | 주식회사 녹십자 | 헌터증후군 치료제 |
KR102547253B1 (ko) * | 2016-07-20 | 2023-06-26 | 주식회사 지씨지놈 | 유전성 대사질환 진단용 조성물 및 이의 용도 |
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JP2004524814A (ja) * | 2000-09-29 | 2004-08-19 | インサイト・ゲノミックス・インコーポレイテッド | 酸化還元酵素 |
JP2005522517A (ja) * | 2002-04-16 | 2005-07-28 | 敬也 小澤 | 組み換えアデノ随伴ウイルスビリオンを使用したアミノ酸代謝に関与する酵素を搬送するための組成物、およびそのようなアデノ随伴ウイルスビリオンを用いてアミノ酸代謝疾患を治療するための使用方法 |
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WO2021256579A1 (ko) | 2021-12-23 |
CA3180563A1 (en) | 2021-12-23 |
CN115916244A (zh) | 2023-04-04 |
US20230210959A1 (en) | 2023-07-06 |
AU2020454140A1 (en) | 2023-01-19 |
EP4166157A1 (en) | 2023-04-19 |
EP4166157A4 (en) | 2024-03-06 |
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