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前臨床薬物評価試験

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QPS社の神経変性疾患に関する前臨床試験

前臨床薬物評価試験

高齢化社会を迎え、パーキンソン病、アルツハイマー症などの中枢神経系に障害を生じる神経変性疾患の患者数はますます増大する傾向にあり、これらの神経変性疾患に対する治療薬研究・開発が激化しています。トランスジェニック社では日本における神経変性疾患の研究・開発をサポートするために、世界的に評価の高いオーストリアのQPS社 (QPS Austria GmbH) のサービスをご提供しています。

QPS社では様々な神経変性疾患の創薬において、in vitro, in vivoの非臨床試験から、臨床試験までの受託・コンサルタントサービスを行っております。特に非臨床薬理試験においては、病態モデルとなる遺伝子改変動物を用いたユニークな薬物評価系を保有しています。表はその評価系の一部を示したものです。

in vivo 評価系

Indication Strain Name Species Mutation
Construct Promoter
AD
human APP/Aβ
APPSL tg Mouse human APP751SL-h London (717) & Swedish (670/671) mutation murine Thy-1
Tg2576 human APP695 with double mutations at KM670/671NL hamster prion protein gene
5xFAD human APPSwFlLon, PSEN1 * M146L * L286V 6799Vas/J murine Thy-1
TBA2.1 truncated mutated human Aβ(Q3-42) murine Thy-1
TBA83 N-truncated human Aβ(4-42) murine Thy-1
APP homo Rat human APP751 with Swedish and Indiana mutation murine Thy-1
AD
human TAU
TMHT10 hTau (V337M, R406W) Mouse human TAU441 bearing the missense mutations V337M and R406W murine Thy-1
TAU (P301L) human TAU with the P301L mutation murine prion
genomic Tau 6 human Tau isoforms, no endogenous Tau human Tau
TAU (P301L) Rat human TAU40 with P301L mutation murine prion
AD
crossbreds
APPSL x ApoB100 Mouse human APP751SL-h London (717) & Swedish (670/671) mutation & human ApoB100 m Thy-1, h ApoB100
APPSL x hQC human APP751SL-h London (717) & Swedish (670/671) mutations & hQC murine Thy-1
5xFAD x hQC human APPSwFlLon, PSEN1 * M146L * L286V 6799Vas/J & hQC murine Thy-1
PD D-Line Mouse wildtype human α-synuclein human PDGF-β
Line-61 wildtype human α-synuclein murine Thy-1
A53T human α-synuclein with mutation A53T human PDGF-β
HD R6/2 Mouse human Huntington with 110-125 CAG repeat expansions -
BAC HD Rat human Huntington with CAG repeat expansions Rat HD
ALS (SOD1-G93A)1Gur/J Mouse human SOD1 with G93A mutations murine Thy-1
ALS-FTLD TDP43 Mouse human wildtype Tar DNA Binding Protein-43 murine Thy-1
Hyperlipidemia/ AD ApoB100 Mouse human ApoB-100 human ApoB100
Niemann-Pick disease type C1 NPC1-/- Mouse knockout -

in vitro 評価系

Indication Cell system Assay Read out
Parkinson’s Disease Primary TH neurons Survival and Apoptosis determined by Image based analysis using TH, MAP2 and Annexin V (or cleavedcaspase 3) % TH neurons of total or MAP2 positive neurons % apoptotic cells of TH % apoptotic cells of MAP2
Primary TH neurons Image based analysis using synapsin, MAP2 and TH Synapses in TH positive and MAP2 positive neurons
Primary TH neurons Image based analysis using TH and tubulin Dendritic networkof TH neurons outgrowth determined as immunoreactive area)
Primary TH neurons PD relevant lesions (e.g. MPP+, 6-OHDA) in combination with image based analysis % Survival of TH and MAP2 neurons % Apoptosis of TH and MAP2 neurons Synapses in TH and MAP2 positive neurons Effects on mitochondrial activity or distribution
Hippocampal neurons BrdU Incorporation (Image basedanalysis) Neurogenesis
SH-SY5Y and RN cells overexpressing wildtype α-synuclein or A53T Compound effects on synuclein levels (ELISA) alpha synucleinaggregate induction(image based analysis) Synucleinand autophagy Synucleinand synapses (image based analysis) Mitochondrial profile (image based analysis) Synucleinlevels Synucleinaggregate induction (image based analysis) Synapses in synucleinoverexpressing cells Mitochondrial profile (activity and distribution)
Primary cortexand hippocampal neurons PD relevant lesions (MMP+, 6-OHDA, BSO) and 96-well-plate readout Survival (MTT), Toxicity(LDH), Apoptosis (caspase 3, YOPRO) or mitochondrial activity (mitotracker)
Primary human fibroblasts from PD patients MMP+ / 6-OHDA Survival (MTT), Toxicity(LDH), Apoptosis (caspase 3, YOPRO) or mitochondrial activity (mitotracker)
SH-SY5Y or PC12 Colorimetric assay Acetylcholinesterase activity
Microglial cell lines (Bv-2, C6, HMO6) Inflammation Cytokines, oxidative stress
Amyotrophic Lateral Sclerosis Motor neurons Glutamate lesion Viability (MTT), Toxicity (LDH), Apoptosis (caspase 3, YOPRO), Mitochondrial profile (activity, membrane potential, shape)
Primary neurons Glutamate lesion Viability (MTT), Toxicity (LDH), Apoptosis (caspase 3, YOPRO), Mitochondrial profile (activity, membrane potential, shape)
SH-SY5Y cells overexpressing TDP43 MTT or LDH YOPRO or caspase 3 Nuclear/Cytoplasmfractionation Viability Apoptosis Translocation of TDP43
Huntington’s Disease Primary neurons Glutamate lesion Viability (MTT), Toxicity (LDH), Apoptosis (caspase 3, YOPRO), Mitochondrial profile (activity, membrane potential, shape)
Stroke Primary neurons Glutamate or NMDA lesion Survival (MTT), Toxicity(LDH), Apoptosis (caspase 3, YOPRO), Mitochondrial profile (activity, membrane potential, shape)
Alzheimer’s Disease SH-SY5Y Hippocampal neurons Chicken neurons Aβ toxicity assay Survival (MTT), Toxicity(LDH), Apoptosis (caspase 3, YOPRO)
SH-SY5Y-hTau441 Immunosorbent assay Total Tau and phospho Tau sites (Ser202, 231, 262, 396, 181)
Hippocampal neurons Aβ oligomers and Image based analysis using Tau and actin Missorting of Tau (soma & dendrites versus axon)
Hippocampal neurons Aβ oligomers and Image based analysis using tubulin Scatteredneurites Neurite outgrowth
Hippocampal neurons Aβ oligomers and Image based analysis using synapsin and MAP2 Synapses in Aβ positive MAP2
Hippocampal neurons BrdU Incorporation (Image based analysis) Neurogenesis
Hippocampal neurons orcell line (exceptsynapses) MTT or LDH assay YOPRO, caspase 3 activation Synapsin, MAP2 (image based) Tubulin (image based) Mitotracker(image based or fluorometric read out) Viability Apoptosis Synapses Neurite outgrowth (tubulin) Mitochondrial activity
Cells overexpressing APP Primary neurons APP processing, gamma-secretase inhibitor APP, Aβ peptides
Microglial cell lines (Bv-2, C6, HMO6) Inflammation Cytokines, oxidative stress
Microglial cell lines (Bv-2, C6, HMO6) Amyloid clearance assay Determinationof amyloid oligomers (modified A4 assay) inside
SH-SY5Y-hTau441 Screening for kinase inhibitors (Immunosorbentassay) Total Tau and phospho Tau sites (202, 231, 262, 396, 181)
SH-SY5Y-hTau441, SH-SY5Y Hypothermia Total Tau and phospho Tau sites (202, 231, 262, 396, Tau181)
No cells Tau aggregation and dis-aggregation assay Fluorescent based detection Transmission Electron Microscopy
No cells Inhibition of Amyloidoligomer formation Determinationof amyloid oligomers (modified A4 assay)
SH-SY5Y or PC12 cells, or primary neurons Acetylcholinesterase activity

価格

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QPS Austria GmbH概要

QPS Austria GmbH

QPS社の神経薬理学部門は、神経変性疾患に特化したCRO、JSW Life Sciences社としてオーストリアのグラーツに1999年に設立され、その後QPS社に統合されました。パーキンソン病、アルツハイマー症など神経変性疾患の分野において、その科学レベル、技術レベルは高く評価され、世界の大手製薬企業から多くの試験の受託実績があります。トランスジェニック社はQPS社の日本代理店となっております。
http://qpsneuro.com/

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