JPWO2021067611A5 - - Google Patents
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- JPWO2021067611A5 JPWO2021067611A5 JP2022520192A JP2022520192A JPWO2021067611A5 JP WO2021067611 A5 JPWO2021067611 A5 JP WO2021067611A5 JP 2022520192 A JP2022520192 A JP 2022520192A JP 2022520192 A JP2022520192 A JP 2022520192A JP WO2021067611 A5 JPWO2021067611 A5 JP WO2021067611A5
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- Prior art keywords
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- composition
- trem2
- metallothionein
- promoter
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- 210000004027 cell Anatomy 0.000 claims description 39
- 229920001184 polypeptide Polymers 0.000 claims description 37
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 37
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 37
- 102000040430 polynucleotide Human genes 0.000 claims description 35
- 108091033319 polynucleotide Proteins 0.000 claims description 35
- 239000002157 polynucleotide Substances 0.000 claims description 35
- 108010060219 Apolipoprotein E2 Proteins 0.000 claims description 26
- 102100037512 Metallothionein-1G Human genes 0.000 claims description 24
- 101710196491 Metallothionein-1G Proteins 0.000 claims description 24
- 239000013604 expression vector Substances 0.000 claims description 23
- 101000795117 Homo sapiens Triggering receptor expressed on myeloid cells 2 Proteins 0.000 claims description 21
- 102100029678 Triggering receptor expressed on myeloid cells 2 Human genes 0.000 claims description 21
- 239000013598 vector Substances 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 18
- 210000000130 stem cell Anatomy 0.000 claims description 14
- DIGQNXIGRZPYDK-WKSCXVIASA-N (2R)-6-amino-2-[[2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[[(2R,3S)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[2-[(2-amino-1-hydroxyethylidene)amino]-3-carboxy-1-hydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1,5-dihydroxy-5-iminopentylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]hexanoic acid Chemical compound C[C@@H]([C@@H](C(=N[C@@H](CS)C(=N[C@@H](C)C(=N[C@@H](CO)C(=NCC(=N[C@@H](CCC(=N)O)C(=NC(CS)C(=N[C@H]([C@H](C)O)C(=N[C@H](CS)C(=N[C@H](CO)C(=NCC(=N[C@H](CS)C(=NCC(=N[C@H](CCCCN)C(=O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)N=C([C@H](CS)N=C([C@H](CO)N=C([C@H](CO)N=C([C@H](C)N=C(CN=C([C@H](CO)N=C([C@H](CS)N=C(CN=C(C(CS)N=C(C(CC(=O)O)N=C(CN)O)O)O)O)O)O)O)O)O)O)O)O DIGQNXIGRZPYDK-WKSCXVIASA-N 0.000 claims description 13
- 102000003792 Metallothionein Human genes 0.000 claims description 13
- 108090000157 Metallothionein Proteins 0.000 claims description 13
- 239000012634 fragment Substances 0.000 claims description 13
- 102000011755 Phosphoglycerate Kinase Human genes 0.000 claims description 8
- 101001099217 Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8) Triosephosphate isomerase Proteins 0.000 claims description 8
- 230000002025 microglial effect Effects 0.000 claims description 8
- 208000024827 Alzheimer disease Diseases 0.000 claims description 7
- 230000003394 haemopoietic effect Effects 0.000 claims description 7
- 210000003958 hematopoietic stem cell Anatomy 0.000 claims description 7
- 108090000835 CX3C Chemokine Receptor 1 Proteins 0.000 claims description 6
- 102100039196 CX3C chemokine receptor 1 Human genes 0.000 claims description 6
- 101000845237 Cereibacter sphaeroides Tryptophan-rich sensory protein Proteins 0.000 claims description 6
- 101000845206 Homo sapiens Putative peripheral benzodiazepine receptor-related protein Proteins 0.000 claims description 6
- 101000845233 Homo sapiens Translocator protein Proteins 0.000 claims description 6
- 102100031269 Putative peripheral benzodiazepine receptor-related protein Human genes 0.000 claims description 6
- 210000000274 microglia Anatomy 0.000 claims description 6
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 claims description 4
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 4
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 4
- 101150062345 CX3CR1 gene Proteins 0.000 claims description 4
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 claims description 4
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 claims description 4
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 claims description 4
- 101000800116 Homo sapiens Thy-1 membrane glycoprotein Proteins 0.000 claims description 4
- 102000043131 MHC class II family Human genes 0.000 claims description 4
- 108091054438 MHC class II family Proteins 0.000 claims description 4
- 102100033523 Thy-1 membrane glycoprotein Human genes 0.000 claims description 4
- 206010057249 Phagocytosis Diseases 0.000 claims description 2
- 230000008782 phagocytosis Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 101001105486 Homo sapiens Proteasome subunit alpha type-7 Proteins 0.000 claims 1
- 102100021201 Proteasome subunit alpha type-7 Human genes 0.000 claims 1
- 238000007913 intrathecal administration Methods 0.000 claims 1
- 238000001990 intravenous administration Methods 0.000 claims 1
- 238000007914 intraventricular administration Methods 0.000 claims 1
- 238000000034 method Methods 0.000 description 64
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 230000001066 destructive effect Effects 0.000 description 2
- 208000025688 early-onset autosomal dominant Alzheimer disease Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- NSMOZFXKTHCPTQ-UHFFFAOYSA-N 6-fluoro-n-[(5-fluoro-2-methoxypyridin-3-yl)methyl]-5-[(5-methyl-1h-pyrrolo[2,3-b]pyridin-3-yl)methyl]pyridin-2-amine Chemical compound COC1=NC=C(F)C=C1CNC(N=C1F)=CC=C1CC1=CNC2=NC=C(C)C=C12 NSMOZFXKTHCPTQ-UHFFFAOYSA-N 0.000 description 1
- 101150053137 AIF1 gene Proteins 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical group CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 102100039289 Glial fibrillary acidic protein Human genes 0.000 description 1
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 1
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 1
- 101710150918 Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 1
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 208000015756 familial Alzheimer disease Diseases 0.000 description 1
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006724 microglial activation Effects 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- JGWRKYUXBBNENE-UHFFFAOYSA-N pexidartinib Chemical group C1=NC(C(F)(F)F)=CC=C1CNC(N=C1)=CC=C1CC1=CNC2=NC=C(Cl)C=C12 JGWRKYUXBBNENE-UHFFFAOYSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000003936 working memory Effects 0.000 description 1
Description
本明細書で提供される任意の組成物または方法は、本明細書で提供される他の組成物および方法のいずれか1つまたは複数と組み合わせることができる。
[本発明1001]
アルツハイマー病を有するか、またはアルツハイマー病を発症する傾向がある対象を治療する方法であって、該対象に、ApoE2ポリペプチドおよびTrem2ポリペプチドをコードする1つまたは複数のポリヌクレオチドを含む発現ベクターまたは発現カセットを含む細胞の有効量を投与することを含む、該方法。
[本発明1002]
ApoE2とメタロチオネイン1G、TREM2とメタロチオネイン1G、ApoE2とTREM2、またはApoE2とTREM2とメタロチオネイン1G（MT1G）をコードするポリヌクレオチドを含む、発現ベクターまたは発現カセット。
[本発明1003]
TREM2ポリペプチドおよびApoE2ポリペプチドまたはそれらの断片をコードするポリヌクレオチドを含む、発現ベクターまたは発現カセット。
[本発明1004]
前記ベクターまたはカセットが、2コピー以上のメタロチオネインを含む、本発明1001の方法、または本発明1002もしくは本発明1003の発現ベクターもしくは発現カセット。
[本発明1005]
前記ベクターが少なくとも4コピーのMT1Gをコードするポリヌクレオチドを含む、本発明1001もしくは本発明1004の方法、または本発明1002～1004のいずれかの発現ベクターもしくは発現カセット。
[本発明1006]
前記ベクターが、前記ポリヌクレオチドの発現を駆動するプロモーターを含む、本発明1001および1004～1005のいずれかの方法、または本発明1002～1005のいずれかの発現ベクターもしくは発現カセット。
[本発明1007]
前記プロモーターがヒトホスホグリセリン酸キナーゼプロモーターである、本発明1006の方法、または本発明1006の発現ベクターもしくは発現カセット。
[本発明1008]
前記プロモーターがミクログリア特異的プロモーターである、本発明1006の方法、または本発明1006の発現ベクターもしくは発現カセット。
[本発明1009]
前記プロモーターがTSPOプロモーター、MHCクラスIIプロモーター、またはCX3CR1プロモーターである、本発明1008の方法、または本発明1008の発現ベクターもしくは発現カセット。
[本発明1010]
本発明1002～1009のいずれかの発現カセットを含む、発現ベクター。
[本発明1011]
前記ベクターがレンチウイルスベクターである、本発明1001および1004～1009のいずれかの方法、または本発明1001～1009のいずれかの発現ベクターもしくは発現カセット、または本発明1010のベクター。
[本発明1012]
TREM2ポリペプチドおよびApoE2ポリペプチドまたはそれらの断片をコードするポリヌクレオチドの発現を駆動するホスホグリセリン酸キナーゼ（PGK）プロモーターを含む、レンチウイルスベクター。
[本発明1013]
TREM2ポリペプチドおよびApoE2ポリペプチドまたはそれらの断片をコードするポリヌクレオチドの発現を駆動するミクログリア特異的プロモーターを含む、レンチウイルスベクター。
[本発明1014]
メタロチオネインをコードするポリヌクレオチドを1コピー以上さらに含む、本発明1012または1013のレンチウイルスベクター。
[本発明1015]
本発明1002～1014のいずれかのベクターまたは本発明1002～1009および1011のいずれかのカセットを含む、細胞。
[本発明1016]
前記カセットがCX3CR1またはTSPO遺伝子座に挿入されている、本発明1015の細胞。
[本発明1017]
ミクログリア細胞もしくはその前駆細胞、造血幹細胞、造血幹前駆細胞（HSPC）、または造血幹細胞もしくは造血幹前駆細胞の子孫細胞である、本発明1015または本発明1016の細胞。
[本発明1018]
前記HSPCがCD34
＋
および/またはCD38
－
および/またはCD90
＋
である、本発明1017の細胞。
[本発明1019]
CX3CR1遺伝子についてヘミ接合性である、本発明1015～1018のいずれかの細胞。
[本発明1020]
細胞または組織におけるアミロイドβのレベルを低減させる方法であって、該細胞に、ApoE2ポリペプチド、Trem2ポリペプチド、およびメタロチオネインポリペプチド、またはそれらの断片のうちの2つ以上をコードするポリヌクレオチドを接触させることを含む、該方法。
[本発明1021]
細胞によるβアミロイドの貪食を増加させる方法であって、該細胞に、ApoE2ポリペプチド、Trem2ポリペプチド、およびメタロチオネインポリペプチド、またはそれらの断片のうちの2つ以上をコードするポリヌクレオチドを接触させることを含む、該方法。
[本発明1022]
前記ポリヌクレオチドが発現ベクターに含まれる、本発明1020または1021の方法。
[本発明1023]
前記発現ベクターがレンチウイルスベクターである、本発明1022の方法。
[本発明1024]
前記ポリヌクレオチドが発現カセットを含む、本発明1020～1023のいずれかの方法。
[本発明1025]
前記ポリヌクレオチドが、ApoE2とTREM2、ApoE2とメタロチオネイン1G、TREM2とメタロチオネイン1G、またはApoE2とTREM2とメタロチオネイン1G（MT1G）をコードする、本発明1020～1024のいずれかの方法。
[本発明1026]
前記ポリヌクレオチドが1コピー以上のメタロチオネインをコードする、本発明1020～1025のいずれかの方法。
[本発明1027]
前記ポリヌクレオチドが少なくとも4コピーのMT1Gをコードする、本発明1026の方法。
[本発明1028]
前記ポリヌクレオチドがプロモーターを含む、本発明1020～1027のいずれかの方法。
[本発明1029]
前記プロモーターがホスホグリセリン酸キナーゼプロモーターである、本発明1028の方法。
[本発明1030]
前記プロモーターがミクログリア特異的プロモーターである、本発明1028の方法。
[本発明1031]
前記プロモーターがTSPOプロモーター、MHCクラスIIプロモーター、またはCX3CR1プロモーターである、本発明1030の方法。
[本発明1032]
前記細胞がミクログリア細胞、造血幹細胞、造血幹前駆細胞（HSPC）、またはその子孫細胞である、本発明1020～1031のいずれかの方法。
[本発明1033]
インビトロまたはインビボで実施される、本発明1020～1032のいずれかの方法。
[本発明1034]
アルツハイマー病を有するか、またはアルツハイマー病を発症する傾向がある対象を治療する方法であって、該対象に、ApoE2ポリペプチド、Trem2ポリペプチド、およびメタロチオネインポリペプチド、またはそれらの断片のうちの2つ以上をコードするポリヌクレオチドを含む細胞の有効量を投与することを含む、該方法。
[本発明1035]
神経炎症を有するか、または神経炎症を発症する傾向がある対象を治療する方法であって、該対象に、ApoE2ポリペプチド、Trem2ポリペプチド、およびメタロチオネインポリペプチド、またはそれらの断片のうちの2つ以上をコードするポリヌクレオチドを含む細胞の有効量を投与することを含む、該方法。
[本発明1036]
前記ポリヌクレオチドが発現ベクターに含まれる、本発明1034または1035の方法。
[本発明1037]
前記発現ベクターがレンチウイルスベクターである、本発明1036の方法。
[本発明1038]
前記ポリヌクレオチドが発現カセットを含む、本発明1034～1037のいずれかの方法。
[本発明1039]
前記細胞が脳室内、静脈内、または髄腔内に投与される、本発明1034～1038のいずれかの方法。
[本発明1040]
前記ポリヌクレオチドが、ApoE2とTREM2、ApoE2とメタロチオネイン1G、TREM2とメタロチオネイン1G、またはApoE2とTREM2とメタロチオネイン1G（MT1G）をコードする、本発明1034～1039のいずれかの方法。
[本発明1041]
前記ポリヌクレオチドが、TREM2ポリペプチドおよびApoE2ポリペプチド、またはそれらの断片をコードする、本発明1034～1040のいずれかの方法。
[本発明1042]
前記ポリヌクレオチドが1コピー以上のMT1Gをさらにコードする、本発明1041の方法。
[本発明1043]
前記ポリヌクレオチドがプロモーターを含む、本発明1034～1042のいずれかの方法。
[本発明1044]
前記プロモーターがヒトホスホグリセリン酸キナーゼプロモーターである、本発明1043の方法。
[本発明1045]
前記プロモーターがミクログリア特異的プロモーターである、本発明1043の方法。
[本発明1046]
前記プロモーターがTSPOプロモーター、MHCクラスIIプロモーター、またはCX3CR1プロモーターである、本発明1045の方法。
[本発明1047]
前記細胞が、ミクログリア細胞またはその前駆細胞、造血幹細胞、造血幹前駆細胞（HSPC）またはその子孫細胞である、本発明1034～1046のいずれかの方法。
[本発明1048]
前記細胞が造血幹前駆細胞（HSPC）である、本発明1047の方法。
[本発明1049]
前記HSPCがLin
－
、CD34
＋
、CD38
－
、および/またはCD90
＋
である、本発明1048の方法。
[本発明1050]
前記HSPCが、移植後にミクログリア前駆細胞と機能的に同等である、本発明1047～1049のいずれかの方法。
[本発明1051]
前記HSPCが脳内に生着する、本発明1047～1050のいずれかの方法。
[本発明1052]
生着したHSPCが、ミクログリア前駆細胞と機能的に同等であるか、またはミクログリア前駆細胞に特徴的なマーカーを発現する、本発明1051の方法。
[本発明1053]
前記対象が、前記方法に先立って破壊的前処置を受ける、本発明1034～1052のいずれかの方法。
[本発明1054]
破壊的前処置が前記対象にアルキル化剤を投与することを含む、本発明1053の方法。
[本発明1055]
アルキル化剤がブスルファンである、本発明1054の方法。
[本発明1056]
前記前処置がCSF-1R阻害剤を投与することを含む、本発明1053の方法。
[本発明1057]
前記阻害剤が、PLX3397、PLX5622、またはリポソーム化クロドロン酸である、本発明1056の方法。
[本発明1058]
前記HSPCが同種細胞または自己細胞である、本発明1047～1052のいずれかの方法。
[本発明1059]
前記細胞がCX3CR1遺伝子についてヘミ接合性である、本発明1034～1058のいずれかの方法。
[本発明1060]
アルツハイマー病が家族性アルツハイマー病または早期発症型アルツハイマー病である、本発明1034の方法。
[本発明1061]
不安を軽減し、認知機能を向上させ、または短期作業記憶を増加させる、本発明1034～1060のいずれかの方法。
[本発明1062]
ミクログリアの活性化および/またはアストロサイトの応答を低減する、本発明1034～1061のいずれかの方法。
[本発明1063]
Iba1および/またはGFAPのレベルを低下させる、本発明1034～1062のいずれかの方法。
[本発明1064]
本発明1017または本発明1018のHSPCを含有する薬学的組成物。
[本発明1065]
本発明1017または本発明1018のHSPCと、それを対象に送達するための説明書を含む、キット。
Any composition or method provided herein can be combined with any one or more of the other compositions and methods provided herein.
[Invention 1001]
A method of treating a subject having or predisposed to developing Alzheimer's disease, the method comprising: treating the subject with an expression vector comprising one or more polynucleotides encoding an ApoE2 polypeptide and a Trem2 polypeptide; The method comprises administering an effective amount of cells containing the expression cassette.
[Present invention 1002]
An expression vector or expression cassette comprising a polynucleotide encoding ApoE2 and metallothionein 1G, TREM2 and metallothionein 1G, ApoE2 and TREM2, or ApoE2 and TREM2 and metallothionein 1G (MT1G).
[Present invention 1003]
An expression vector or expression cassette comprising a polynucleotide encoding a TREM2 polypeptide and an ApoE2 polypeptide or a fragment thereof.
[Present invention 1004]
The method of the present invention 1001, or the expression vector or expression cassette of the present invention 1002 or the present invention 1003, wherein the vector or cassette contains two or more copies of metallothionein.
[Present invention 1005]
The method of invention 1001 or invention 1004, or the expression vector or expression cassette of any of inventions 1002-1004, wherein said vector comprises at least 4 copies of a polynucleotide encoding MT1G.
[Present invention 1006]
The method of any of inventions 1001 and 1004-1005, or the expression vector or expression cassette of any of inventions 1002-1005, wherein said vector comprises a promoter that drives expression of said polynucleotide.
[Present invention 1007]
The method of the invention 1006, or the expression vector or expression cassette of the invention 1006, wherein said promoter is a human phosphoglycerate kinase promoter.
[Present invention 1008]
The method of the invention 1006, or the expression vector or expression cassette of the invention 1006, wherein said promoter is a microglia-specific promoter.
[Present invention 1009]
The method of the present invention 1008, or the expression vector or expression cassette of the present invention 1008, wherein the promoter is a TSPO promoter, an MHC class II promoter, or a CX3CR1 promoter.
[Present invention 1010]
An expression vector comprising the expression cassette of any one of the present inventions 1002 to 1009.
[Present invention 1011]
The method of any of inventions 1001 and 1004-1009, or the expression vector or expression cassette of any of inventions 1001-1009, or the vector of invention 1010, wherein said vector is a lentiviral vector.
[Invention 1012]
A lentiviral vector comprising a phosphoglycerate kinase (PGK) promoter that drives expression of a polynucleotide encoding a TREM2 polypeptide and an ApoE2 polypeptide or a fragment thereof.
[Present invention 1013]
A lentiviral vector comprising a microglia-specific promoter that drives expression of a polynucleotide encoding a TREM2 polypeptide and an ApoE2 polypeptide or a fragment thereof.
[Present invention 1014]
The lentiviral vector of the present invention 1012 or 1013, further comprising one or more copies of a polynucleotide encoding metallothionein.
[Present invention 1015]
A cell comprising the vector of any of the inventions 1002-1014 or the cassette of any of the inventions 1002-1009 and 1011.
[Invention 1016]
The cell of the invention 1015, wherein said cassette is inserted at the CX3CR1 or TSPO locus.
[Invention 1017]
The cell of the present invention 1015 or the present invention 1016, which is a microglial cell or a progenitor cell thereof, a hematopoietic stem cell, a hematopoietic stem progenitor cell (HSPC), or a progeny cell of a hematopoietic stem cell or hematopoietic stem progenitor cell.
[Invention 1018]
The cell of the invention 1017, wherein said HSPC is CD34 + and/or CD38 − and/or CD90 + .
[Invention 1019]
The cell of any of the invention 1015-1018, which is hemizygous for the CX3CR1 gene.
[Invention 1020]
A method of reducing the level of amyloid beta in a cell or tissue, the method comprising: contacting the cell with a polynucleotide encoding two or more of an ApoE2 polypeptide, a Trem2 polypeptide, and a metallothionein polypeptide, or a fragment thereof. The method includes causing.
[Present invention 1021]
A method of increasing phagocytosis of beta amyloid by a cell, the method comprising: contacting the cell with a polynucleotide encoding two or more of an ApoE2 polypeptide, a Trem2 polypeptide, and a metallothionein polypeptide, or a fragment thereof. The method, comprising:
[Invention 1022]
The method of invention 1020 or 1021, wherein said polynucleotide is included in an expression vector.
[Invention 1023]
1022. The method of the invention 1022, wherein said expression vector is a lentiviral vector.
[Invention 1024]
The method of any of inventions 1020-1023, wherein said polynucleotide comprises an expression cassette.
[Invention 1025]
The method of any of the inventions 1020-1024, wherein the polynucleotide encodes ApoE2 and TREM2, ApoE2 and metallothionein 1G, TREM2 and metallothionein 1G, or ApoE2 and TREM2 and metallothionein 1G (MT1G).
[Invention 1026]
The method of any of the inventions 1020-1025, wherein said polynucleotide encodes one or more copies of metallothionein.
[Invention 1027]
1026. The method of the invention 1026, wherein said polynucleotide encodes at least 4 copies of MT1G.
[Invention 1028]
The method of any of the inventions 1020-1027, wherein said polynucleotide comprises a promoter.
[Invention 1029]
1028. The method of the invention 1028, wherein said promoter is a phosphoglycerate kinase promoter.
[Invention 1030]
1028. The method of the invention 1028, wherein said promoter is a microglia-specific promoter.
[Present invention 1031]
1030. The method of the invention 1030, wherein the promoter is a TSPO promoter, an MHC class II promoter, or a CX3CR1 promoter.
[Invention 1032]
The method according to any of the inventions 1020 to 1031, wherein the cell is a microglial cell, hematopoietic stem cell, hematopoietic stem progenitor cell (HSPC), or a progeny cell thereof.
[Present invention 1033]
The method of any of the inventions 1020-1032, performed in vitro or in vivo.
[Present invention 1034]
A method of treating a subject having or predisposed to developing Alzheimer's disease, wherein the subject is provided with two of ApoE2 polypeptide, Trem2 polypeptide, and metallothionein polypeptide, or fragments thereof. The method comprises administering an effective amount of cells comprising a polynucleotide encoding the above.
[Invention 1035]
A method of treating a subject having or predisposed to developing neuroinflammation, the method comprising administering to the subject two of ApoE2 polypeptide, Trem2 polypeptide, and metallothionein polypeptide, or fragments thereof. The method comprises administering an effective amount of cells comprising a polynucleotide encoding the above.
[Invention 1036]
The method of the invention 1034 or 1035, wherein said polynucleotide is included in an expression vector.
[Invention 1037]
1036. The method of the invention 1036, wherein said expression vector is a lentiviral vector.
[Invention 1038]
The method of any of inventions 1034-1037, wherein said polynucleotide comprises an expression cassette.
[Invention 1039]
The method of any of the inventions 1034-1038, wherein the cells are administered intraventricularly, intravenously, or intrathecally.
[Invention 1040]
The method of any of the inventions 1034-1039, wherein the polynucleotide encodes ApoE2 and TREM2, ApoE2 and metallothionein 1G, TREM2 and metallothionein 1G, or ApoE2 and TREM2 and metallothionein 1G (MT1G).
[Present invention 1041]
The method of any of the inventions 1034-1040, wherein the polynucleotide encodes a TREM2 polypeptide and an ApoE2 polypeptide, or a fragment thereof.
[Invention 1042]
1041. The method of the invention 1041, wherein said polynucleotide further encodes one or more copies of MT1G.
[Invention 1043]
The method of any of the inventions 1034-1042, wherein said polynucleotide comprises a promoter.
[Present invention 1044]
1043. The method of the invention 1043, wherein said promoter is a human phosphoglycerate kinase promoter.
[Invention 1045]
1043. The method of the invention 1043, wherein the promoter is a microglia-specific promoter.
[Invention 1046]
1045. The method of the invention 1045, wherein the promoter is a TSPO promoter, a MHC class II promoter, or a CX3CR1 promoter.
[Invention 1047]
The method according to any one of the inventions 1034 to 1046, wherein the cell is a microglial cell or a progenitor cell thereof, a hematopoietic stem cell, a hematopoietic stem progenitor cell (HSPC), or a progeny cell thereof.
[Invention 1048]
1047. The method of the invention 1047, wherein said cells are hematopoietic stem progenitor cells (HSPCs).
[Invention 1049]
1048. The method of the invention 1048, wherein said HSPC is Lin − , CD34 + , CD38 − and/or CD90 + .
[Invention 1050]
The method of any of the inventions 1047-1049, wherein said HSPCs are functionally equivalent to microglial progenitor cells after transplantation.
[Present invention 1051]
The method according to any one of the present invention 1047 to 1050, wherein the HSPC engrafts in the brain.
[Invention 1052]
1051. The method of the invention 1051, wherein the engrafted HSPCs are functionally equivalent to microglial progenitor cells or express markers characteristic of microglial progenitor cells.
[Present invention 1053]
The method of any of the inventions 1034-1052, wherein said subject undergoes destructive conditioning prior to said method.
[Invention 1054]
1053. The method of the invention 1053, wherein destructive pretreatment comprises administering to said subject an alkylating agent.
[Present invention 1055]
The method of the invention 1054, wherein the alkylating agent is busulfan.
[Invention 1056]
1053. The method of the invention 1053, wherein said pretreatment comprises administering a CSF-1R inhibitor.
[Present invention 1057]
1056. The method of the invention 1056, wherein the inhibitor is PLX3397, PLX5622, or liposomal clodronic acid.
[Invention 1058]
The method of any of the inventions 1047-1052, wherein the HSPC is an allogeneic cell or an autologous cell.
[Invention 1059]
The method of any of the inventions 1034-1058, wherein said cell is hemizygous for the CX3CR1 gene.
[Invention 1060]
1034. The method of the invention 1034, wherein the Alzheimer's disease is familial Alzheimer's disease or early-onset Alzheimer's disease.
[Present invention 1061]
The method of any of the inventions 1034-1060, which reduces anxiety, improves cognitive function, or increases short-term working memory.
[Invention 1062]
The method of any of the invention 1034-1061, which reduces microglial activation and/or astrocyte response.
[Invention 1063]
The method of any of the invention 1034-1062, which reduces the level of Iba1 and/or GFAP.
[Invention 1064]
A pharmaceutical composition containing the HSPC of the present invention 1017 or the present invention 1018.
[Invention 1065]
A kit comprising the HSPC of the present invention 1017 or the present invention 1018 and instructions for delivering the same to a subject.
Claims (24)
載の組成物。 19. The composition of claim 18 , wherein the cell is hemizygous for the CX3CR1 gene.
composition.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962908913P | 2019-10-01 | 2019-10-01 | |
| US62/908,913 | 2019-10-01 | ||
| PCT/US2020/053824 WO2021067611A2 (en) | 2019-10-01 | 2020-10-01 | Compositions and methods for treating alzheimer's disease |
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| Publication Number | Publication Date |
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| JP2022552793A JP2022552793A (en) | 2022-12-20 |
| JPWO2021067611A5 true JPWO2021067611A5 (en) | 2024-01-30 |
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| JP2022520192A Pending JP2022552793A (en) | 2019-10-01 | 2020-10-01 | Compositions and methods for treating Alzheimer's disease |
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| Country | Link |
|---|---|
| US (1) | US20220378942A1 (en) |
| EP (1) | EP4037696A4 (en) |
| JP (1) | JP2022552793A (en) |
| CN (1) | CN114555100A (en) |
| WO (1) | WO2021067611A2 (en) |
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| US11548936B2 (en) * | 2017-01-17 | 2023-01-10 | Children's Medical Center Corporation | Compositions and methods for treating lysosomal storage diseases and disorders |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| GB9414624D0 (en) * | 1994-07-20 | 1994-09-07 | Smithkline Beecham Plc | Novel method |
| US20030077641A1 (en) * | 1998-03-11 | 2003-04-24 | Laskowitz Daniel T. | Methods of suppressing microglial activation and systemic inflammatory responses |
| CN102946907A (en) * | 2010-05-28 | 2013-02-27 | 牛津生物医学（英国）有限公司 | Delivery of lentiviral vectors to the brain |
| US11548936B2 (en) * | 2017-01-17 | 2023-01-10 | Children's Medical Center Corporation | Compositions and methods for treating lysosomal storage diseases and disorders |
-
2020
- 2020-10-01 WO PCT/US2020/053824 patent/WO2021067611A2/en unknown
- 2020-10-01 US US17/764,917 patent/US20220378942A1/en active Pending
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