Contract Research Offering

Transcription

1 Contract Research Offering Helping you understand the therapeutic in vivo effects of your Alzheimer drug candidates

2 the partner you can trust to help you understand as fast as possible the therapeutic in vivo effects of all your experimental Alzheimer treatments Spin-off from Leuven University with more than 10 years experience in AD transgenics Unique and validated transgenic mouse models, with several compounds in clinic Clients in US, Europe and Japan, incl. leading biotechs and 6 of the top 10 pharmacos Extensive expertise to help you with study design and results interpretation Extensive experience with all types of treatments; small molecules, immunization as well as nutraceuticals Short response time allowing rapid study start both with young and aged mice Highly specialized research partner for preclinical in vivo testing in AD 1

3 A long-term research partner rather than an ad hoc conductor of in vivo studies: thinking along with you on your strategy to assess the in vivo PoC for your pipeline collaborating for a series of studies, extending beyond the scope of a given study sharing our expertise in drug testing of a wealth of compounds in a series of highly validated transgenics 2

4 Overview of remynd s Contract Research Offering Animal models APP[V717I] London mutation progressive amyloidosis model APP[V717I] x PS1[A246E] more aggressive, early-onset model than APP[V717I] TAU[P301L] progressive tauopathy model UPCOMING: TAU[P301L] x APP[V717I] TAU[P301S] Manipulations All types of treatments - small molecules - immunization - nutraceuticals All routes of administration - ip, iv, ic, sc, im - intranasal - osmotic pumps - stereotactic injections - oral (gavage, food, water) Sample collection brain blood CSF organs Tissue preparation - total brain excision - (micro)dissection of brain - differential extraction - free-floating brain sections Read-outs Immunohistochemistry Plaque load: - Total: anti-a Nanobody - Dense: ThioS Inflammation: - GFAP, CD45/CD11b CAA, µbleeds: - ThioS, Perl s Iron ptau, NFT s: - AT8, AT100 Biochemistry sol & insol ha 40/42 APP processing sol & insol (p)tau [PAGE/WB, ELISA] Behaviour - Open field - Morris Water Maze - Beam walk 3

5 Contract Research Offering remynd s APP[V717I] and APP[V717I] x PS1[A246E] transgenic Alzheimer mouse models 4

6 remynd s APP and APPxPS1 models Summary Model Key characteristics APP[V717I] London mutation Moechars et al.,jbc, Van Dorpe et al., AJP, Terwel et al., AJP, APP[V717I] x PS1[A246E] Dewachter et al., J. Neurosci., Expression of happ under control of mthy-1 gene promotor More gentle AD phenotype Later-onset amyloidosis with plaque development in subiculum and cortex as of 10.5 months Cognitive impairment; deficit in spatial reference memory (MWM) Early Aβ-induced GSK3β-activation and mtau phosphorylation Dystrophic neurites containing hyperphosphorylated mtau (no tanglepathology) CAA pathology (as of months) Micro-bleedings (as of months) Expression of happ and hps1 under control of mthy-1 gene promotor More aggressive AD phenotype Earlier-onset amyloidosis with plaque development in subiculum and cortex as of 4.5 months Cognitive impairment; deficit in spatial reference memory (MWM) Early Aβ-induced GSK3β-activation and mtau phosphorylation Dystrophic neurites containing hyperphosphorylated mtau (no tanglepathology) CAA pathology (as of 8 months) Micro-bleedings (as of months) 5

7 Contract Research Offering remynd s htau[p301l] transgenic tauopathy mouse model 6

8 remynd s htau[p301l] transgenic mouse model Summary Expression of htau driven by the neuron-specific mouse Thy-1 promoter Age-dependent hyperphosphorylation and confirmational change of parenchymal Tau o o o Onset around 8 months of age Pathology is mainly observed in brain stem (and spinal cord) and to a decreasing extent in midbrain and cerebral cortex Strong correlation with motoric impairment (clasping phenotype, motoric testing deficit) and impaired survival Increases or decreases in normal and pathological phosphorylation can be measured through our routine biochemical PAGE/WB procedures with monoclonal antibodies AT8 and AT100 in different fractions of different brain structures. Additionally or alternatively we use immunohistochemistry with the same antibodies to assess changes in Tau in circumscribed brain nuclei. Age-dependent increase of CSF pan-tau PDF-copy of original research paper available on request: Terwel D, Lasrado R, Snauwaert J, Vandeweert E, Van Haesendonck C, Borghgraef P, Van Leuven F. Change conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, non-lethal axonopathy of Tau-4R/2N transgenic mice, J. Biol. Chem. 280 (2005)

9 Contact information remynd nv Bio-Incubator (Wetenschapspark) Gaston Geenslaan Leuven-Heverlee Belgium Tel: Fax: cro@remynd.com No part of this presentation may be circulated, quoted, or reproduced for distribution outside the client's organisation without prior written approval from remynd. 8