JP6884831B2 - C9orf72遺伝子座における破壊を有する非ヒト動物 - Google Patents
C9orf72遺伝子座における破壊を有する非ヒト動物 Download PDFInfo
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- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/072—Animals genetically altered by homologous recombination maintaining or altering function, i.e. knock in
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/0306—Animal model for genetic diseases
- A01K2267/0318—Animal model for neurodegenerative disease, e.g. non- Alzheimer's
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/035—Animal model for multifactorial diseases
- A01K2267/0381—Animal model for diseases of the hematopoietic system
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/0393—Animal model comprising a reporter system for screening tests
Description
本願は、2015年5月29日に出願された米国仮出願第62/168,171号、2015年9月25日に出願された米国仮出願第62/232,658号、および2015年10月23日に出願された米国仮出願第62/245,382号からの優先権の利益を主張し、これらの内容全体が本明細書中に参照によって組み込まれる。
32698_10152US01_SequenceListingと名付けられた、56kbの、ASCIIテキストファイルによる配列表であって、2016年5月19日に作成され、EFS−Webを介して米国特許商標庁へと提出された配列表は、参照により本明細書に組み込まれる。
特定の実施形態では、例えば以下の項目が提供される。
(項目1)
齧歯動物であって、そのゲノム内に、C9orf72遺伝子座における全コード配列の欠失を含む齧歯動物。
(項目2)
前記欠失が、少なくともエクソン2〜11の全体または部分的な欠失を含む、項目1に記載の齧歯動物。
(項目3)
前記C9orf72遺伝子座が、レポーター遺伝子を含む、前記項目のいずれか一項に記載の齧歯動物。
(項目4)
前記レポーター遺伝子が、C9orf72プロモーターに作動可能に連結している、項目3に記載の齧歯動物。
(項目5)
前記C9orf72プロモーターが、内因性プロモーターである、項目4に記載の齧歯動物。
(項目6)
前記C9orf72遺伝子座が、エクソン2のコード部分〜エクソン11のコード部分を含むC9orf72ゲノム配列を欠き、レポーター遺伝子を含む、項目3から5のいずれか一項に記載の齧歯動物。
(項目7)
前記レポーター遺伝子が、前記C9orf72遺伝子座のエクソン1に作動可能に連結している、項目6に記載の齧歯動物。
(項目8)
前記レポーター遺伝子が、lacZ、ルシフェラーゼ、緑色蛍光タンパク質(GFP)、増強型GFP(eGFP)、シアン蛍光タンパク質(CFP)、黄色蛍光タンパク質(YFP)、増強型黄色蛍光タンパク質(eYFP)、青色蛍光タンパク質(BFP)、増強型青色蛍光タンパク質(eBFP)、DsRed、およびMmGFPからなる群から選択される、項目3から7のいずれか一項に記載の齧歯動物。
(項目9)
ラットまたはマウスである、前記項目のいずれか一項に記載の齧歯動物。
(項目10)
前記欠失についてホモ接合性である、項目1に記載の齧歯動物。
(項目11)
前記欠失についてヘテロ接合性である、項目1に記載の齧歯動物。
(項目12)
発生の間、任意選択で、約36週齢となった後、または約40週齢となった後において、ALSおよび/またはFTDの1または複数の症状を発症する、項目1から11のいずれか一項に記載の齧歯動物。
(項目13)
約36週齢となった後において、進行性の運動欠損を発症し、約40週齢となった後において、下位運動ニューロン病変を発症し、かつ/または約36週齢となった後において、体重の減少をきたす、項目1から12のいずれか一項に記載の齧歯動物。
(項目14)
発生の間に、以下:
(i)運動ニューロンにおけるミトコンドリア機能不全であって、ミトコンドリア呼吸、基底呼吸、最大呼吸、予備呼吸能、ATP産生、およびプロトン漏出のうちの1もしくは複数の減少によって特徴付けられるか;または対照齧歯動物もしくは基準齧歯動物の運動ニューロンのミトコンドリアDNA対核DNA比と比較した、ミトコンドリアDNA対核DNA比の増加によって特徴付けられるミトコンドリア機能不全;
(ii)任意選択で、約35週齢となった後、または端点を含めて約35〜41週齢となった後の、糸球体腎炎の1または複数の症状;
(iii)約8週齢となった後の脾腫;
(iv)約8週齢となった後のリンパ節症であって、任意選択で、端点を含めて約12〜18週齢となった後の、触知可能であるリンパ節症;
(v)形質細胞、単球、顆粒球、およびF4/80+マクロファージのうちの1または複数の浸潤であって、任意選択で、約8週齢となった後の、かつ、60週齢までに検出可能である浸潤;
(vi)約35週齢となった後の、腎臓内のF4/80+マクロファージの浸潤;
(vii)約8週齢となった後の、IL−10、IL−12、IL−17、IFN−γ、TNF−α、およびMCP−1のうちの1または複数の血清サイトカインレベルの増加;
(viii)約8週齢となった後の、IL−12の血清レベルの増加であって、基準非ヒト動物または対照非ヒト動物と比較して、約6倍またはこれを超える増加;
(ix)端点を含めて約28〜35週齢となった後の、基底膜の肥厚、円柱形成、免疫複合体の沈着、膜増殖性糸球体腎炎、間質性単核球性炎症、糸球体硬化症、好塩基性尿細管、またはこれらの組合せによって特徴付けられる腎疾患;
(x)端点を含めて約28〜35週齢となった後の、脾臓、リンパ節、骨髄、腎臓、および血液のうちの1または複数における、骨髄系樹状細胞集団の増加であって、任意選択で、該骨髄系樹状細胞集団が、CD45+CD11b+CD11c+MHCII+として特徴付けられる増加;
(xi)約8週齢となった後の、1または複数の自己抗体の血清レベルの増加であって、任意選択で、1または複数の自己抗体が、抗リウマチ因子(抗RF)抗体、抗dsDNA抗体、抗核抗体(ANA)、抗スミス(抗Sm)抗体、抗カルジオリピン抗体、およびこれらの組合せから選択される増加;
(xii)端点を含めて約28〜35週齢となった後の、脾臓、リンパ節、骨髄、腎臓、および血液のうちの1または複数における、F4/80+マクロファージレベルの増加であって、任意選択で、該F4/80+マクロファージが、CD45+CD11b+F4/80+Ly6G−として特徴付けられる増加;
(xiii)端点を含めて約28〜35週齢となった後の、脾臓、リンパ節、骨髄、腎臓、および血液のうちの1または複数における、T細胞集団の増加であって、任意選択で、該T細胞集団が、CD8+CD44+、CD8+CD69+、CD8+PD1+、CD4+CD44+、CD4+CD69+またはCD4+PD1+として特徴付けられる増加;
(xiv)端点を含めて約28〜35週齢となった後の、脾臓および/もしくはリンパ節における、調節性T細胞集団の増加であって、該調節性T細胞集団が、CD4+FoxP3+として特徴付けられる増加;または約26週齢となった後の、脾臓、リンパ節、および/もしくは血液における、濾胞性ヘルパーT(Tfh)細胞の増加であって、該Tfh細胞集団が、CD4+CXCR5+CD44+ICOS+PD−1+Bcl−6+として特徴付けられる増加;
(xv)端点を含めて約8〜60週齢となった後の、脾臓、リンパ節、および骨髄のうちの1または複数における、形質細胞集団の増加であって、任意選択で、該形質細胞集団が、CD45+CD19−B220−CD138+またはCD45+CD19intB220intCD138+として特徴付けられる増加;
(xvi)自己免疫性リンパ増殖症候群(ALPS);あるいは
(xvii)発生の間におけるループス腎炎
のうちの1または複数を発症する、項目1から12のいずれか一項に記載の齧歯動物。
(項目15)
そのゲノムが、C9orf72遺伝子座における全コード配列の欠失を含む単離齧歯動物細胞または単離齧歯動物組織。
(項目16)
項目15に記載の単離齧歯動物細胞から作製された不死化細胞株。
(項目17)
齧歯動物胚性幹細胞であって、そのゲノムが、C9orf72遺伝子座における全コード配列の欠失を含む齧歯動物胚性幹細胞。
(項目18)
項目17に記載の胚性幹細胞から生み出された齧歯動物胚。
(項目19)
齧歯動物のゲノムが、C9orf72遺伝子座における全コード配列の欠失を含む齧歯動物を作製する方法であって、
齧歯動物の該ゲノムを、それが、C9orf72遺伝子座における全コード配列の欠失を含むように改変し、これにより、該齧歯動物を作製するステップ
を含む方法。
(項目20)
前記改変するステップを、
(a)C9orf72遺伝子座における全コード配列を欠失させるように、核酸配列を、齧歯動物胚性幹細胞へと導入するステップであって、核酸配列が、該C9orf72遺伝子座と相同なポリヌクレオチドを含むステップと;
(b)(a)から、遺伝子改変された齧歯動物胚性幹細胞を得るステップと;
(c)(b)の、該遺伝子改変された齧歯動物胚性幹細胞を使用して、齧歯動物を作り出すステップと
を含むプロセスにより達成する、項目19に記載の方法。
(項目21)
前記核酸配列が、1または複数の選択マーカーを含む、項目20に記載の方法。
(項目22)
前記核酸配列が、1または複数の部位特異的組換え部位を含む、項目20または21に記載の方法。
(項目23)
前記核酸配列が、切出しを導くように配向させたリコンビナーゼ認識部位に挟まれた、リコンビナーゼ遺伝子と選択マーカーとを含む、項目22に記載の方法。
(項目24)
前記核酸配列が、任意選択で前記選択マーカーの下流にあるレポーター遺伝子をさらに含む、項目23に記載の方法。
(項目25)
前記リコンビナーゼ遺伝子が、分化細胞内の該リコンビナーゼ遺伝子の発現は駆動するが、未分化細胞内の該リコンビナーゼ遺伝子の発現は駆動しないプロモーターに作動可能に連結している、項目24に記載の方法。
(項目26)
前記リコンビナーゼ遺伝子が、転写的にコンピテントであり、発生的に調節されたプロモーターに作動可能に連結している、項目24に記載の方法。
(項目27)
前記プロモーターが、配列番号5、配列番号6、または配列番号7であるかまたはこれを含む、項目26に記載の方法。
(項目28)
前記欠失についてホモ接合性の齧歯動物を作り出すように、(c)において生み出された前記齧歯動物を交配させるステップをさらに含む、項目20から27のいずれか一項に記載の方法。
(項目29)
前記欠失が、少なくともエクソン2〜11の全体または部分的な欠失を含む、項目19または20に記載の方法。
(項目30)
前記欠失が、エクソン2のコード部分〜エクソン11のコード部分を含む、項目29に記載の方法。
(項目31)
前記C9orf72遺伝子座が、レポーター遺伝子を含む、項目29または30に記載の方法。
(項目32)
前記レポーター遺伝子が、C9orf72プロモーターに作動可能に連結している、項目31に記載の方法。
(項目33)
前記C9orf72プロモーターが、内因性プロモーターである、項目32に記載の方法。
(項目34)
前記C9orf72遺伝子座が、エクソン2〜10を欠き、レポーター遺伝子を含む、項目31から33のいずれか一項に記載の方法。
(項目35)
前記レポーター遺伝子が、前記C9orf72遺伝子座のエクソン1に作動可能に連結している、項目34に記載の方法。
(項目36)
前記レポーター遺伝子が、lacZ、ルシフェラーゼ、GFP、eGFP、CFP、YFP、eYFP、BFP、eBFP、DsRed、およびMmGFPからなる群から選択される、項目32から35のいずれか一項に記載の方法。
(項目37)
前記齧歯動物が、ラットまたはマウスである、項目19から36のいずれか一項に記載の方法。
(項目38)
項目19から37のいずれか一項に記載の方法により得ることができる齧歯動物。
(項目39)
齧歯動物における疾患または状態を処置するための、治療剤候補を同定する方法であって、
(a)候補薬剤を、項目1から14のいずれか一項に記載の齧歯動物へと投与するステップと;
(b)1または複数のアッセイを実施して、該候補薬剤が、該疾患または状態と関連する1または複数の徴候、症状、および/または状態に対して効果を有するのかどうかを決定するステップと;
(c)該疾患または状態と関連する、該1または複数の徴候、症状、および/または状態に対して効果を有する該候補薬剤を、該治療剤候補として同定するステップと
を含む方法。
(項目40)
前記疾患または状態が、神経変性疾患または神経変性状態、炎症性疾患または炎症性状態、自己免疫疾患または自己免疫状態、全身性エリテマトーデス(SLE)、自己免疫性リンパ増殖症候群(ALPS)、およびループス腎炎からなる群から選択される、項目39に記載の方法。
(項目41)
ALPSが、IL−10、抗リウマチ因子(抗RF)抗体、抗核抗体(ANA)、またはこれらの組合せの血清レベルの増加によって特徴付けられ;ループス腎炎が、メサンギウムの増殖および/もしくは拡大、または1もしくは複数の尿細管異常によって特徴付けられる、項目40に記載の方法。
(項目42)
前記神経変性疾患もしくは神経変性状態が、筋萎縮性側索硬化症(ALS)もしくは前頭側頭型認知症(FTD)であるか、前記炎症性疾患もしくは炎症性状態が、糸球体腎炎であるか、または前記自己免疫疾患もしくは自己免疫状態が、糸球体腎炎である、項目40に記載の方法。
本発明は、本明細書で記載される特定の方法および実験条件に限定されるものではない。なぜなら、そのような方法および条件は変化しうるからである。本発明の範囲は、特許請求の範囲により規定されるので、本明細書で使用される用語法は、特定の実施形態について記載することだけを目的とするものであり、限定的であることを意図するものではないこともまた理解されたい。
C9ORF72遺伝子座における破壊を有する非ヒト動物が提供される。特に、本明細書で記載される非ヒト動物は、C9ORF72遺伝子座における全コード配列の欠失、すなわち、全てのC9ORF72アイソフォームをコードするゲノムセグメントの欠失(例えば、アイソフォームV1の、エクソン2のコード部分〜エクソン11のコード部分の欠失)を有する。本明細書で記載される非ヒト動物は、体重減少と、例えば、運動の不活発化および歩行機能障害などのALS様運動異常とを示す。本明細書で記載される非ヒト動物はまた、約8週齢において、脾腫および/またはリンパ節症も示す。さらに、本明細書で記載される非ヒト動物は、約35週齢において、糸球体腎炎を示す。したがって、神経変性疾患、神経変性障害、および神経変性状態を処置および/または改善するための治療剤候補を開発および同定するのに特に有用な非ヒト動物、一部の実施形態では、自己免疫疾患および/または炎症性疾患、自己免疫障害および/または炎症性障害、ならびに自己免疫状態および/または炎症性状態を処置および/または改善するための治療剤候補を開発および同定するのに特に有用な非ヒト動物が提供される。特に、本明細書で記載される非ヒト動物は、レポーター遺伝子の、内因性C9ORF72遺伝子座への導入であって、非ヒト動物の神経系および免疫系におけるレポーター遺伝子(すなわち、レポーターポリペプチド)の発現を結果としてもたらす導入を包含する。このようなトランスジェニック非ヒト動物は、治療剤候補が、ALSおよび/またはFTDを改善する有効性を決定するための細胞の供給源を提供する。さらに、このようなトランスジェニック非ヒト動物は、神経変性疾患、自己免疫疾患、および/または炎症性疾患、神経変性障害、自己免疫障害、および/または炎症性障害、ならびに神経変性状態、自己免疫状態、および/または炎症性状態を処置するための治療剤を開発するのに有用な動物モデル系を提供する。
ルー・ゲーリック病ともまた称する、筋萎縮性側索硬化症(ALS)とは、上位運動ニューロンおよび/または下位運動ニューロンの喪失によって特徴付けられる、最も高頻度な成人発症型麻痺性障害である。ALSは、米国全体で、20,000人もの個体において生じ、毎年約5,000例の新たな症例が生じている。医師であるアーノルド・ピックにちなんで、もとはピック病と称した、前頭側頭型認知症(FTD)とは、脳の前頭葉または側頭葉における、進行性の細胞変性により引き起こされる障害群である。FTDは、全ての認知症症例のうちの10〜15%を占めることが報告されている。C9ORF72の2つの非コードエクソンの間の、GGGGCCヘキサヌクレオチドリピート拡張は、ALSおよびFTDのいずれとも関係付けられている(DeJesus-Hernandez, M.ら、2011年、Neuron、72巻:245〜256頁;Renton, A.E.ら、2011年、Neuron、72巻:257〜268頁;Majounie, E.ら、2012年、Lancet Neurol.、11巻:323〜330頁;Waite, A.J.ら、2014年、Neurobiol. Aging、35巻:1779.e5〜1779.e13頁)。しかし、このようなリピート変異が、疾患を引き起こす機構は、毒性による機能喪失を介するか、毒性による機能獲得を介するかどうかは、依然として不明なままである。例えば、ターゲティングされた低減またはノックダウンにより、C9ORF72の発現が低減されたゼブラフィッシュは、軸索障害と、自発運動機能の欠損とを示す(Ciura, S.ら、2013年、Ann. Neurol.、74巻(42号):180〜187頁)が、C9ORF72の発現が低減されたマウスは、ALS疾患と関連する、いかなる行動学的または病理学的特色もを示さない(Lagier-Tourenne, C.ら、2013年、Proc. Nat. Acad. Sci. U.S.A.、E4530〜E4539頁)。さらに、C9ORF72内に66回のリピート拡張を含有するように生み出されたノックインマウスは、それらのニューロン内に、RNA凝集体(RNA foci)およびジペプチドタンパク質凝集物を呈する。これらのマウスは、皮質ニューロンの喪失を示し、6カ月齢において、行動障害および運動欠損を呈した(Chew, J.ら、2015年、Science、5月14日、Pii:aaa9344)。
マウスC9ORF72転写物バリアントについては、当技術分野で報告されており(例えば、Koppersら、Ann Neurol(2015年);78巻:426〜438頁;Atkinsonら、Acta Neuropathologica Communications(2015年)、3巻:59頁)、また、図1Aでも描示されている。報告されている3つのマウスC9ORF72転写物バリアントについてのゲノム情報はまた、ENSMUST00000108127(V1)、ENSMUST00000108126(V2)、およびENSMUST00000084724(V3)の呼称の下、Ensemblウェブサイトでも入手可能である。例示的な非ヒト(例えば、齧歯動物)C9ORF72のmRNA配列およびアミノ酸配列を、表1に明示する。mRNA配列については、括弧内に示される太字体は、コード配列を表示し、表示される場合の連続するエクソンは、交互の小文字と大文字により分けられている。アミノ酸配列については、表示される場合の成熟ポリペプチド配列を太字体としている。
本明細書では、本明細書で記載されるC9ORF72遺伝子座における破壊を有する非ヒト動物を作製するための、ターゲティングベクターまたはターゲティング構築物が提示される。
本明細書で記載される非ヒト動物は、神経変性疾患、神経変性障害、および神経変性状態についての改善された動物モデルを提供する。特に、本明細書で記載される非ヒト動物は、上位運動ニューロンの症状および/または非運動ニューロンの喪失によってを特徴付けられる、例えば、ALSおよび/またはFTDなどのヒト疾患への置き換える(translate)改善された動物モデルを提供する。
非ヒトC9ORF72遺伝子座における破壊の作出
本実施例は、齧歯動物のC9orf72遺伝子座における標的破壊について例示する。特に、本実施例は、マウスC9orf72プロモーターとの作動可能な連結下に置かれたlacZレポーター構築物を使用する、マウスC9orf72遺伝子座の全コード配列の欠失について具体的に記載する。内因性マウスC9orf72遺伝子座における破壊を作り出すための、C9orf72−lacZターゲティングベクターは、既に記載されている通りに作製した(例えば、米国特許第6,586,251号;Valenzuelaら、2003年、Nature、Biotech.、21巻(6号):652〜659頁;ならびにAdams, N.C.およびN.W. Gale、Mammalian and Avian Transgeneis-New Approaches、Lois, S.P.a.C.編、Springer Verlag、Berlin Heidelberg、2006年を参照されたい)。結果として得られる改変C9orf72遺伝子座を、図1A(下ボックス)に描示する。
C9orf72遺伝子座における破壊を有する非ヒト動物についての行動解析
本実施例は、とりわけ、本明細書で記載される非ヒト動物(例えば、齧歯動物)が、実施例1で記載した、齧歯動物(例えば、マウス)C9orf72遺伝子座における破壊から生じるALS様症状、例えば、体重の減少および有意な運動異常などを発症することを裏付ける。
C9orf72遺伝子座における破壊を有する非ヒト動物についての免疫表現型解析
本実施例は、実施例1に従い作製された非ヒト動物が、一部の実施形態では、多様な免疫細胞集団の浸潤から生じる、脾腫およびリンパ節症によって特徴付けられる、免疫学的表現型を示すことを裏付ける。さらに、本実施例は、このような非ヒト動物が、腎臓における免疫細胞集団の浸潤によって特徴付けられる糸球体腎炎を発症することを具体的に裏付ける。いかなる特定の理論にも束縛されることを望まずに述べると、本発明者らは、C9ORF72遺伝子座の産物が、免疫機能において、極めて重要な役割を果たし、本明細書で記載される非ヒト動物における、C9ORF72ポリペプチドの喪失が、ALS疾患および/またはFTD疾患の顕著な機構ではないことを提起する。多様な組織を、解析のために、C9orf72−/−マウスおよび野生型マウス(雌については、8、18、および37週齢であり、雄については、9〜10、18、および57〜60週齢の、遺伝子型1つ当たりn=4〜6匹の動物)から採取した。
C9orf72遺伝子座における破壊を有する非ヒト動物への、神経毒素の投与
この実験は、本明細書で記載される非ヒト動物への多様な毒素の投与が、観察されるALS様表現型の側面を増悪しうることを裏付ける。特に、本実施例は、C9orf72−/−マウスへの多様な毒素の投与が、ALS様運動表現型を軽微に増悪させ、運動ニューロンに対する酸化ストレスを増加させるが、これらのマウスの不活発化および歩行異常の増大に影響を及ぼさないことを具体的に裏付ける。本実施例はまた、C9orf72−/−マウスの運動ニューロンが、有意なミトコンドリア機能不全を発症することも裏付ける。
こうして、本発明の少なくとも1つの実施形態の、いくつかの態様について記載してきたが、当業者には多様な変更、改変、および改善にたやすく想到されることを、当業者であれば十分に理解されたい。このような変更、改変、および改善は、本開示の一部であることを意図し、本発明の精神および範囲内にあることを意図するものである。したがって、上掲の記載および図面は、例だけを目的とするものであり、本発明は、以下の特許請求の範囲により詳細に記載される。
Claims (14)
- 単離された運動ニューロンであって、そのゲノム内に、内因性C9orf72遺伝子座のエクソン2のコード部分〜エクソン11のコード部分の欠失を含む、運動ニューロン。
- 前記C9orf72遺伝子座が、レポーター遺伝子を含む、請求項1に記載の運動ニューロン。
- 前記レポーター遺伝子が、C9orf72プロモーターに作動可能に連結している、請求項2に記載の運動ニューロン。
- 前記C9orf72プロモーターが、内因性プロモーターである、請求項3に記載の運動ニューロン。
- 内因性C9orf72遺伝子座のエクソン2のコード部分〜エクソン11のコード部分の欠失を含む運動ニューロンを作製する方法であって、
齧歯動物胚性幹(ES)細胞を培養し、運動ニューロンへと分化させるステップ
を含み、前記ES細胞は、内因性C9orf72遺伝子座のエクソン2のコード部分〜エクソン11のコード部分の欠失を含む、方法。 - 前記ES細胞から胚様体が形成され、前記胚様体が前記運動ニューロンへと分化させられる、請求項5に記載の方法。
- 前記運動ニューロンが、野生型運動ニューロンと比較して、ミトコンドリア機能不全および/または酸化ストレスを示す、請求項5または6のいずれかに記載の方法。
- 前記C9orf72遺伝子座がレポーター遺伝子を含む、請求項5〜7のいずれか一項に記載の方法。
- 前記レポーター遺伝子が、C9orf72プロモーターに作動可能に連結している、請求項8に記載の方法。
- 前記C9orf72プロモーターが、内因性プロモーターである、請求項9に記載の方法。
- 前記齧歯動物ES細胞がラットES細胞である、請求項5〜10のいずれか一項に記載の方法。
- 前記齧歯動物ES細胞がマウスES細胞である、請求項5〜10のいずれか一項に記載の方法。
- 前記齧歯動物ES細胞が、前記欠失についてホモ接合性またはヘテロ接合性である、請求項5〜12のいずれか一項に記載の方法。
- 運動ニューロンにおけるミトコンドリア機能不全および/または酸化ストレスを低減するための候補薬剤をスクリーニングする方法であって、
(a)薬剤の存在下または非存在下で、請求項1〜4のいずれか一項に記載の運動ニューロン、または、請求項5〜13のいずれか一項に記載の方法に従って作製された運動ニューロンを培養するステップと;
(b)前記薬剤が、前記薬剤の非存在下で培養された運動ニューロンの対照集団と比較して、運動ニューロンの集団におけるミトコンドリア機能不全および/または酸化ストレスを防止、阻害、および/または、低減するかどうかを決定するステップと
を含み、前記運動ニューロンにおける酸化ストレスの防止、阻害および/または低減が、運動ニューロンにおけるミトコンドリア機能不全および/または酸化ストレスを低減する候補薬剤の指標となる、方法。
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Family Cites Families (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5523226A (en) | 1993-05-14 | 1996-06-04 | Biotechnology Research And Development Corp. | Transgenic swine compositions and methods |
US5670356A (en) | 1994-12-12 | 1997-09-23 | Promega Corporation | Modified luciferase |
US5874304A (en) | 1996-01-18 | 1999-02-23 | University Of Florida Research Foundation, Inc. | Humanized green fluorescent protein genes and methods |
WO1999005266A2 (en) | 1997-07-26 | 1999-02-04 | Wisconsin Alumni Research Foundation | Trans-species nuclear transfer |
US6586251B2 (en) | 2000-10-31 | 2003-07-01 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
US20050144655A1 (en) | 2000-10-31 | 2005-06-30 | Economides Aris N. | Methods of modifying eukaryotic cells |
US6596541B2 (en) | 2000-10-31 | 2003-07-22 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
US7105348B2 (en) | 2000-10-31 | 2006-09-12 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
AUPR451401A0 (en) | 2001-04-20 | 2001-05-24 | Monash University | A method of nuclear transfer |
US7612250B2 (en) | 2002-07-29 | 2009-11-03 | Trustees Of Tufts College | Nuclear transfer embryo formation method |
SI1802193T1 (sl) | 2004-10-19 | 2014-08-29 | Regeneron Pharmaceuticals, Inc. | Postopek za generiranje miši, homozigotne za genetsko modifikacijo |
CN101117633B (zh) | 2006-08-03 | 2011-07-20 | 上海交通大学附属儿童医院 | 一种细胞核移植方法 |
JP2008307007A (ja) * | 2007-06-15 | 2008-12-25 | Bayer Schering Pharma Ag | 出生後のヒト組織由来未分化幹細胞から誘導したヒト多能性幹細胞 |
DK3064599T3 (en) | 2008-02-15 | 2019-04-08 | Synthetic Genomics Inc | METHODS IN VITRO FOR COMBINING AND COMBINATORY CONSTRUCTION OF NUCLEIC ACID MOLECULES |
US8470594B2 (en) * | 2008-04-15 | 2013-06-25 | President And Fellows Of Harvard College | Methods for identifying agents that affect the survival of motor neurons |
RU2425880C2 (ru) * | 2009-07-30 | 2011-08-10 | Учреждение Российской академии наук Институт общей генетики им. Н.И. Вавилова РАН | Способ получения трансгенных мышей |
WO2011020005A1 (en) | 2009-08-14 | 2011-02-17 | Regeneron Pharmaceuticals, Inc. | miRNA-REGULATED DIFFERENTIATION-DEPENDENT SELF-DELETING CASSETTE |
KR20120050485A (ko) | 2009-08-14 | 2012-05-18 | 레비비코르 인코포레이션 | 당뇨병 치료를 위한 복수 형질전환 돼지 |
EP3202914B2 (en) * | 2011-08-31 | 2023-06-28 | The University of Manchester | Method for treating a neurodegenerative disease |
WO2013041577A1 (en) * | 2011-09-20 | 2013-03-28 | Vib Vzw | Methods for the diagnosis of amyotrophic lateral sclerosis and frontotemporal lobar degeneration |
DK2847335T3 (en) | 2012-04-25 | 2018-08-13 | Regeneron Pharma | NUCLEASED MEDIUM TARGETING WITH LARGE TARGET VECTORS |
EP2906697A4 (en) | 2012-10-15 | 2016-06-22 | Ionis Pharmaceuticals Inc | METHODS OF MONITORING C9ORF72 EXPRESSION |
FI2906696T4 (fi) | 2012-10-15 | 2023-03-18 | Menetelmiä c9orf72:n ilmentymisen moduloimiseksi | |
US8697359B1 (en) | 2012-12-12 | 2014-04-15 | The Broad Institute, Inc. | CRISPR-Cas systems and methods for altering expression of gene products |
EP3561050B1 (en) | 2013-02-20 | 2021-12-08 | Regeneron Pharmaceuticals, Inc. | Genetic modification of rats |
ES2888250T3 (es) | 2013-04-16 | 2022-01-03 | Regeneron Pharma | Modificación direccionada del genoma de rata |
KR102251168B1 (ko) | 2013-10-25 | 2021-05-13 | 셀렉티스 | 고 반복 모티프를 포함하는 dna 서열에 대한 효율적이고 특이적인 표적화를 위한 희소-절단 엔도뉴클레아제의 설계 |
AU2014362248A1 (en) | 2013-12-12 | 2016-06-16 | Massachusetts Institute Of Technology | Compositions and methods of use of CRISPR-Cas systems in nucleotide repeat disorders |
EP3750907A3 (en) | 2014-03-18 | 2021-04-28 | University of Massachusetts | Raav-based compositions and methods for treating amyotrophic lateral sclerosis |
WO2015153760A2 (en) | 2014-04-01 | 2015-10-08 | Sangamo Biosciences, Inc. | Methods and compositions for prevention or treatment of a nervous system disorder |
CA2953499C (en) | 2014-06-23 | 2023-10-24 | Regeneron Pharmaceuticals, Inc. | Nuclease-mediated dna assembly |
HUE041584T2 (hu) | 2014-06-26 | 2019-05-28 | Regeneron Pharma | Célzott genetikai módosítások és alkalmazási módszerek és készítmények |
AU2015349692B2 (en) | 2014-11-21 | 2021-10-28 | Regeneron Pharmaceuticals, Inc. | Methods and compositions for targeted genetic modification using paired guide RNAs |
KR102313073B1 (ko) | 2014-12-05 | 2021-10-18 | 리제너론 파마슈티칼스 인코포레이티드 | 인간화 분화 클러스터 47 유전자를 가진 비인간 동물 |
BR112017013104A2 (pt) | 2014-12-19 | 2018-05-15 | Regeneron Pharma | métodos para modificar um locus genômico alvo em uma célula, para intensificar a recombinação homóloga em um locus genômico alvo em uma célula e para produzir uma geração f0 de um animal não humano. |
US10793855B2 (en) | 2015-01-06 | 2020-10-06 | Ionis Pharmaceuticals, Inc. | Compositions for modulating expression of C9ORF72 antisense transcript |
WO2016174056A1 (en) | 2015-04-27 | 2016-11-03 | Genethon | Compositions and methods for the treatment of nucleotide repeat expansion disorders |
DK3289076T3 (da) | 2015-05-01 | 2022-01-17 | Prec Biosciences Inc | Præcis sletning af kromosomale sekvenser in vivo |
CA3035810A1 (en) | 2015-09-02 | 2017-03-09 | University Of Massachusetts | Detection of gene loci with crispr arrayed repeats and/or polychromatic single guide ribonucleic acids |
MX2018007840A (es) | 2015-12-23 | 2019-05-02 | Crispr Therapeutics Ag | Materiales y metodos para el tratamiento de la esclerosis lateral amiotrofica y/o la degeneracion lobar frontotemporal. |
WO2017178590A1 (en) | 2016-04-14 | 2017-10-19 | Université de Lausanne | Treatment and/or prevention of dna-triplet repeat diseases or disorders |
WO2018022480A1 (en) | 2016-07-25 | 2018-02-01 | Mayo Foundation For Medical Education And Research | Treating cancer |
JP7026678B2 (ja) | 2016-09-30 | 2022-02-28 | リジェネロン・ファーマシューティカルズ・インコーポレイテッド | C9orf72座位中にヘキサヌクレオチドリピート伸長を有する非ヒト動物 |
WO2018078134A1 (en) | 2016-10-28 | 2018-05-03 | Genethon | Compositions and methods for the treatment of myotonic dystrophy |
WO2018078131A1 (en) | 2016-10-28 | 2018-05-03 | Genethon | Compositions and methods for the treatment of myotonic dystrophy |
EP3592365A4 (en) | 2017-03-10 | 2021-01-13 | The Board Of Regents Of The University Of Texas System | TREATMENT OF ENDOTHELIAL CORNEAL DYSTROPHY OF FUCHS |
JP7327803B2 (ja) | 2017-05-09 | 2023-08-16 | ユニバーシティ オブ マサチューセッツ | 筋萎縮性側索硬化症(als)を処置する方法 |
AU2018355343A1 (en) | 2017-10-24 | 2020-05-07 | Sangamo Therapeutics, Inc. | Methods and compositions for the treatment of rare diseases |
BR112020025306A2 (pt) * | 2018-06-18 | 2021-03-09 | Denali Therapeutics Inc. | Proteínas de fusão compreendendo progranulina |
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