I: Experimental therapeutics – preclinical最新文献

{"title":"I12 The novel alpha-2 adrenoceptor inhibitor beditin reduces cytotoxicity and huntingtin aggregates in cell models of Huntington’s disease","authors":"Elisabeth Singer-Mikosch, L. Hunanyan, M. Melkonyan, J. Weber, L. Danielyan, H. Nguyen","doi":"10.1136/jnnp-2022-ehdn.238","DOIUrl":"https://doi.org/10.1136/jnnp-2022-ehdn.238","url":null,"abstract":"","PeriodicalId":444837,"journal":{"name":"I: Experimental therapeutics – preclinical","volume":"55 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115162797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"I15 Reduction of glutamate dehydrogenase induces autophagy via tor inhibition and AMPK activation in a drosophila model for Huntington’s disease","authors":"Stefania Santarelli, Carlotta Candelaresi, Leonardo Todeschini, Chiara Londero, P. Bellosta","doi":"10.1136/jnnp-2022-ehdn.241","DOIUrl":"https://doi.org/10.1136/jnnp-2022-ehdn.241","url":null,"abstract":"","PeriodicalId":444837,"journal":{"name":"I: Experimental therapeutics – preclinical","volume":"21 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122594084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"I23 Pridopidine exerts neuroprotective effects via activation of the sigma-1 receptor","authors":"M. Geva, C. Scaramuzzino, Sophie Lenoir, Romane A. Lahaye, Shaolin Wang, Hsiang-en Wu, Noga Gershoni-Emek, F. Saudou, T. Su, M. R. Hayden","doi":"10.1136/jnnp-2022-ehdn.249","DOIUrl":"https://doi.org/10.1136/jnnp-2022-ehdn.249","url":null,"abstract":"","PeriodicalId":444837,"journal":{"name":"I: Experimental therapeutics – preclinical","volume":"50 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134521148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"I05 CRISPR-Cas9 nickase-mediated gene editing to treat Huntington’s disease","authors":"Alvaro Murillo, M. Larin, Emma L. Randall, Alysha S. Taylor, M. Lelos, Vincent Dion","doi":"10.1136/jnnp-2022-ehdn.231","DOIUrl":"https://doi.org/10.1136/jnnp-2022-ehdn.231","url":null,"abstract":"","PeriodicalId":444837,"journal":{"name":"I: Experimental therapeutics – preclinical","volume":"86 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116745664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"I02 A CAG repeat-targeting artificial miRNA lowers the mutant huntingtin level in the YAC128 model of huntington’s disease","authors":"M. Olejniczak, Anna Kotowska-Zimmer, Lukasz Przybyl, Marianna Pewinska, Joanna Suszyńska-Zajczyk, Dorota Wronka, M. Figiel","doi":"10.1136/jnnp-2021-ehdn.116","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.116","url":null,"abstract":"Background Among many proposed therapeutic strategies for Huntington’s disease (HD), allele-selective therapies are the most desirable and the most challenging at the same time. We have previously demonstrated that RNA interference (RNAi) tools that target CAG repeats selectively reduced the mutant huntingtin level in cellular models of HD. Aim The purpose of this study was to test efficacy, selectivity and safety of two vector-based RNAi triggers in an animal model of HD. Methods/Techniques CAG repeat-targeting short hairpin RNA (shRNA) and artificial miRNA (amiRNA) were delivered to brains of YAC128 mouse model in two doses via intrastriatal injections of AAV5 vectors. Vector genome copies, protein and transcript levels in the striatum, hippocampus and cortex were analyzed four months post injection. Behavioral tests were performed every five weeks post injection. Activation of toxicity markers and protein aggregates were analyzed by immunohistochemical staining of brain tissues. Results/Outcome Molecular tests demonstrated that both shRNA and amiRNA reduced the level of mutant huntingtin to 50% without an influence on endogenous mouse huntingtin. We observed concentration-dependent reduction of HTT aggregates in the striatum and an improvement of motor performance using a static rod test. Expression of mutant huntingtin has previously been shown to increase organ weight. Interestingly, a treatment with amiRNA reduced the spleen weight to values characteristic of healthy mice (WT). In contrast to shRNA, amiRNA was well tolerated and did not reveal any signs of toxicity during the course of the experiment. Conclusions We confirmed that vector-based RNAi molecules targeting CAG tracts can be used to lower mutant huntingtin levels in vivo in an allele-selective manner. The amiRNA molecule has been shown to be effective, selective and safe. Therefore, this strategy could make an original and valuable contribution to currently used therapeutic approaches for HD.","PeriodicalId":444837,"journal":{"name":"I: Experimental therapeutics – preclinical","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130698315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"I11 Pharmacologic inhibition of the classical complement pathway enhances neuronal function and HD R6/2 mouse survival","authors":"A. Tassoni, Vidhu K. Mathur, Joseph Vereen, E. Cahir-McFarland, S. Sankaranarayanan, T. Yednock, Y. Andrews-Zwilling","doi":"10.1136/jnnp-2021-ehdn.125","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.125","url":null,"abstract":"Background Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by expansion of CAG repeats in the Huntingtin (HTT) gene. Aim There is human evidence of increased complement biosynthesis and activation in HD, with increased immunoreactivity for C1q, C4, C3 and C3b observed in striatal neurons, astrocyte, and microglia cells. However, the role of the classical pathway in HD pathogenesis is unclear. Methods Using the R6/2 mouse model of HD with ~ 120 CAG expansion, we investigated alteration of classical complement cascade in plasma and cerebral spinal fluid (CSF), we evaluated correlation of classical complement C1q levels with the neurodegenerative biomarker Neurofilament Light Chain (NFL) levels and assessed efficacy of anti C1q mAb therapy in preventing neurodegeneration and ameliorating disease progression. Results We found evidence of perturbations in the complement pathway, such as significant increase in plasma levels of C1q, C1s, C4, C3 and C3d during disease progression. Positive correlation of plasma C1q with CSF NFL levels was observed, suggesting a role of the classical complement cascade in neurodegeneration and disease progression. To test this hypothesis, we pharmacologically inhibited the classical pathway via systemic administration of anti-C1q mAb (ANX-M1, Annexon Biosciences). We observed that reduction of free C1q by anti C1q mAb therapy resulted in normalized complement pathway activity, reduced levels of CSF NFL, improved motor behavior measured with the open field assay and improved R6/2 mouse survival. Conclusions Altogether this study suggests that inhibiting C1q restores synaptic and neuronal health in mice with expanded CAG repeats in the HTT gene and C1q is a potential pharmacological target in HD. A Phase 2 study of ANX005 anti-C1q therapy in HD patients (clinical trials.gov NCT04514367) is ongoing.","PeriodicalId":444837,"journal":{"name":"I: Experimental therapeutics – preclinical","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133424795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"I09 In vivo mtHTT protein reduction in the CNS and periphery by passive immunization with the monoclonal antibody C6–17","authors":"S. Bartl, Y. Xie, N. Potluri, Benjamin Gordon, A. Willenberg, K. Balash, Abid Oueslati, Michela Parth, Nina Salhat, Alberto Siddu, O. Smrzka, F. Cicchetti, Günther Straffler, M. R. Hayden, A. Southwell","doi":"10.1136/jnnp-2021-ehdn.123","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.123","url":null,"abstract":"","PeriodicalId":444837,"journal":{"name":"I: Experimental therapeutics – preclinical","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130648773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"I03 CPEB alteration and aberrant transcriptome-polyadenylation unveil a treatable vitamin B1 deficiency in huntington’s disease","authors":"S. Picó, A. Parras, M. Santos-Galindo, Julia Pose-Utrilla, M. Castro, Enrique Fraga, Ivó H Hernández, Ainara Elorza, Héctor Anta, Nan Wang, L. Martí-Sánchez, Eulàlia Belloc, Paula Garcia-Esparcia, J. J. Garrido, I. Ferrer, D. Macías-García, P. Mir, R. Artuch, Belén Pérez, F. Hernández, P. Navarro, J. López-Sendón, T. Iglesias, X. W. Yang, Raúl Méndez, J. Lucas","doi":"10.1136/jnnp-2021-ehdn.117","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.117","url":null,"abstract":"Background Although promising gene-silencing therapies are being tested for Huntington’s disease (HD), no disease-modifying treatments are available. Thus, study of molecular mechanisms underneath Htt-mutation must continue to identify easily druggable targets. Cytoplasmic polyadenylation element binding proteins 1–4 (CPEB1–4) are RNA-binding proteins that repress or activate translation of CPE-containing transcripts by shortening or elongating their poly(A) tail. Alteration of CPEB-dependent transcriptome polyadenylation has been associated to diseases like cancer, autism and epilepsy. Aims Analyze CPEBs and polyadenylation in HD. Identify easily druggable targets among genes mis-expressed due to altered CPEB-dependent polyadenylation, to assay them in HD mice. Methods a) Western blot and immunostaining of CPEBs in brains of HD patients and mouse models. b) Genome-wide poly(A)-tail analysis through poly(U) chromatography+gene chip. c) status of CPEB targets and related metabolites by western blot and HPLC. d) radiological, neuropathological and behavioural analysis of HD mice receiving target-related treatment. Results There is a CPEB1/4 imbalance in HD striatum with concomitant altered transcriptome polyadenylation affecting many neurodegeneration-linked genes like PSEN1, MAPT, SNCA, LRRK2, PINK1, DJ1, SOD1, TARDBP, FUS and HTT. Among top deadenylated genes was SLC19A3 (ThTr2 thiamine transporter) whose mutation causes biotin+thiamine responsive basal ganglia disease (BTBGD). Decreased ThTr2 in HD and HD mice led us to discover that HD is in part a BTBG-like thiamine deficiency. Remarkably, high dose biotin+thiamine treatment prevented the thiamine deficiency of HD mice and attenuated their radiological, neuropathological and motor phenotypes. Conclusions This study unveils altered polyadenylation as a new molecular mechanism in neurodegeneration uncovering HD as a thiamine deficiency and, therefore, an easy to implement therapy.","PeriodicalId":444837,"journal":{"name":"I: Experimental therapeutics – preclinical","volume":"8 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131320196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"I07 A new generation of brain-targeted nanoparticles for cholesterol delivery in huntington’s disease: kinetics, drug release and behavioral effects in mouse models","authors":"M. Valenza, Giulia Birolini, I. Ottonelli, A. Passoni, Monica Favagrossa, J. Duskey, M. Bombaci, B. Ruozi, M. Salmona, G. Tosi, E. Cattaneo","doi":"10.1136/jnnp-2021-ehdn.121","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.121","url":null,"abstract":"","PeriodicalId":444837,"journal":{"name":"I: Experimental therapeutics – preclinical","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130686675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"I10 Acute innate immune responses to simulated transplantation surgery in two HD mouse models","authors":"F. Sharouf, M. Lelos, A. Rosser, W. Gray","doi":"10.1136/jnnp-2021-ehdn.124","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.124","url":null,"abstract":"Multiple studies provide proof-of-concept for the benefits of cell replacement therapy (CRT) in Huntington’s disease (HD), however attaining a high survival rate of the cells post-transplantation has remained a significant challenge. Neuroinflammation is crucial in the onset and progression of HD. We hypothesise that inflammatory response to CRT surgery might be exacerbated due to a primed intrinsic inflammatory environment, partly explaining cell death and graft failure. This study aims to define innate immune responses to simulated transplantation surgery in two HD mouse models (HDQ175 & HDR6/1). Mice (96 in total: 24 HDQ175, 24 HDR6/1 and 48 wild-type control) were either kept as Control (no surgery, time 0), or underwent bilateral stereotactic needle insertion to the striatum simulating CRT surgery and culled at 1hr, 24hrs or 72hrs post-surgery. A 3mm3 cube of tissue surrounding and including the injury site was collected for RNA sequencing and multiplex cytokine analysis. The introduction of a needle into mouse brain produced an amplified pro-inflammatory response in both HD models, compared with background controls. Cytokines including IL-1β, IL-6, TNF-α were raised at 1hr and 24hrs post-needle insertion ‘p The amplified pro-inflammatory response to needle injury in HD brain compared to wild-type, reveals a state of enhanced basal pro-inflammatory activation. Thus the HD brain appears to be ‘primed’ to produce an enhanced immune response. The inflammatory reaction to surgical trauma post-CRT is likely to contribute to neural graft site hostility. Simultaneous modulation of these pro-inflammatory pathways during graft delivery may improve graft survival in CRT and advance the translation of direct intraparenchymal delivery of cells into clinical practice.","PeriodicalId":444837,"journal":{"name":"I: Experimental therapeutics – preclinical","volume":"10 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134065163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}