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Condition: Huntington's Disease

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Total 63 results found since Jan 2013.

Current Development of siRNA Bioconjugates: From Research to the Clinic
In this study, it was shown that the main factor determining the nature of the biodistribution of conjugates is their lipophilicity. Conjugates of siRNA with lower lipophilicity; i.e., derivatives of retinoic acid, lithocholic acid, and docosahexanoic acid with greater efficiency than cholesterol conjugates accumulated in the kidneys, bladder, and lungs of the mouse after subcutaneous injection (Biscans et al., 2018). This fact is consistent with previous data that showed that more lipophilic conjugates bind more efficiently to serum components, and thus are not excreted by the kidneys (Wolfrum et al., 2007; Osborn et al.,...
Source: Frontiers in Pharmacology - April 25, 2019 Category: Drugs & Pharmacology Source Type: research

Enriched chitosan nanoparticles loaded with siRNA are effective in lowering Huntington's disease gene expression following intranasal administration
Publication date: Available online 27 October 2019Source: Nanomedicine: Nanotechnology, Biology and MedicineAuthor(s): Vasyl Sava, Oksana Fihurka, Anastasia Khvorova, Juan Sanchez-RamosAbstractTherapies to lower gene expression in brain disease currently require chronic administration into the cerebrospinal fluid (CSF) by intrathecal infusions or direct intracerebral injections. Though well-tolerated in the short-term, this approach is not tenable for a life-time of administration. Nose-to-brain delivery of enriched chitosan-based nanoparticles loaded with anti-HTT siRNA was studied in a transgenic YAC128 mouse model of Hu...
Source: Nanomedicine: Nanotechnology, Biology and Medicine - October 28, 2019 Category: Nanotechnology Source Type: research

RNAi mechanisms in Huntington ’s disease therapy: siRNA versus shRNA
AbstractHuntington ’s Disease (HD) is a genetically dominant trinucleotide repeat disorder resulting from CAG repeats within the Huntingtin (HTT) gene exceeding a normal range (>  36 CAGs). Symptoms of the disease manifest in middle age and include chorea, dystonia, and cognitive decline. Typical latency from diagnosis to death is 20 years. There are currently no disease-modifying therapies available to HD patients. RNAi is a potentially curative therapy for HD. A popular line of research employs siRNA or antisense oligonucleotides (ASO) to knock down mutant Huntingtin mRNA (mHTT). Unfortunately, this modality requ...
Source: Translational Neurodegeneration - November 27, 2017 Category: Neurology Source Type: research

Modified cyclodextrin-based nanoparticles mediated delivery of siRNA for Huntingtin gene silencing across an in vitro BBB model
In conclusion, the CD platform is a promising option for delivery of siRNA-based therapeutics for HD with wider potential to treat other diseases with a genetically validated target in the central nervous system.PMID:34793942 | DOI:10.1016/j.ejpb.2021.11.003
Source: European Journal of Pharmaceutics and Biopharmaceutics - November 18, 2021 Category: Drugs & Pharmacology Authors: Monique C P Mendon ça Michael F Cronin John F Cryan Caitriona M O'Driscoll Source Type: research

Sigma-1 receptor is involved in degradation of intranuclear inclusions in a cellular model of Huntington's disease.
Abstract The sigma-1 receptor (SIGMAR1) is one of the endoplasmic reticulum (ER) chaperones, which participate in the degradation of misfolded proteins via the ER-related degradation machinery linked to the ubiquitin-proteasome pathway. ER dysfunction in the formation of inclusion bodies in various neurodegenerative diseases has also become evident. Recently, we demonstrated that accumulation of SIGMAR1 was common to neuronal nuclear inclusions in polyglutamine diseases including Huntington's disease. Our study also indicated that SIGMAR1 might shuttle between the cytoplasm and the nucleus. In the present study, w...
Source: Neurobiology of Disease - November 14, 2014 Category: Neurology Authors: Miki Y, Tanji K, Mori F, Wakabayashi K Tags: Neurobiol Dis Source Type: research

Differential nanotoxicological and neuroinflammatory liabilities of non-viral vectors for RNA interference in the central nervous system.
Abstract Progression of RNA interference-based gene silencing technologies for the treatment of disorders of the central nervous system (CNS) depends on the availability of efficient non-toxic nanocarriers. Despite advances in the field of nanotechnology undesired and non-specific interactions with different brain-cell types occur and are poorly investigated. To this end, we studied the cytotoxic and neuroinflammatory effects of widely-used transfection reagents and modified amphiphilic β-cyclodextrins (CDs). All non-viral vectors formed positively charged nanoparticles with distinctive physicochemical properties...
Source: Biomaterials - October 16, 2013 Category: Materials Science Authors: Godinho BM, McCarthy DJ, Torres-Fuentes C, Beltrán CJ, McCarthy J, Quinlan A, Ogier JR, Darcy R, O'Driscoll CM, Cryan JF Tags: Biomaterials Source Type: research

Abstract 4360: Validation of phosphodiesterase 10A as a cancer target
Phosphodiesterase 10A (PDE10) is a cAMP and cGMP degrading PDE isozyme that is highly expressed in the brain striatum where it plays an important role in cognition and psychomotor activity. PDE10 inhibitors are being developed for the treatment of schizophrenia and Huntington's disease and are generally well tolerated, likely because of low expression levels in peripheral tissues. We recently reported high levels of PDE10 in tumors and that genetic silencing by siRNA inhibits tumor cell growth with a high degree of selectivity over normal cells (Li et al., Oncogene 2014). These observations suggest that PDE10 may have an u...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Lee, K., Li, N., Chen, X., Zhu, B., Yet, L., Madeira da Silva, L., Russo, S., Keeton, A. B., Boyd, M. R., Piazza, G. A. Tags: Experimental and Molecular Therapeutics Source Type: research

Current Therapeutic Advances in Patients and Experimental Models of Huntington's Disease.
Abstract Huntington's disease (HD) clinical manifestations begin insidiously and are progressively incapacitating. Symptomatic therapies, in particular dopamine blockers and neuroleptics, are presently the only treatment for HD. Identification of neuropathological mechanisms that underlie the selective striatal and cortical neurodegeneration has allowed for the development of novel neuroprotective therapies that may improve HD patients' quality of life and enhance their survival. In this review we describe the symptomatic and neuroprotective therapies in HD that are currently in a pre-clinical or clinical stage. N...
Source: Current Drug Targets - November 24, 2013 Category: Drugs & Pharmacology Authors: Brett AC, Rosenstock TR, Rego AC Tags: Curr Drug Targets Source Type: research

Coenzyme Q10, Statin, and Spinocerebellar Ataxias (P6.047)
CONCLUSIONS:CoQ10 is associated with better clinical outcome in SCA1, 2, and 3 whereas statins are associated with worse clinical outcome in SCA6. These drug exposures did not appear to influence clinical progression within 2 years. CoQ10 and statins may have only symptomatic effects or require a longer period of time for disease modification.Study Supported by:American Brain Foundation Research Fellowship, Rare Disease Clinical Research Network RC1NS068897, and NINDS K08 NS083738.Disclosure: Dr. Kuo has nothing to disclose. Dr. Lo has nothing to disclose. Dr. Figueroa has nothing to disclose. Dr. Pulst has received person...
Source: Neurology - April 9, 2014 Category: Neurology Authors: Kuo, S.-H., Lo, R., Figueroa, K., Pulst, S., Perlman, S., Wilmot, G., Gomez, C., Schmahmann, J., Paulson, H., Shakkottai, V., Ying, S., Zesiewicz, T., Bushara, K., Geschwind, M., Xia, G., Subramony, S., Ashizawa, T. Tags: Movement Disorders: Spinocerebellar Ataxias Source Type: research

Coenzyme Q10, Statin, and Spinocerebellar Ataxias (I11-1.008)
CONCLUSIONS:CoQ10 is associated with better clinical outcome in SCA1, 2, and 3 whereas statins are associated with worse clinical outcome in SCA6. These drug exposures did not appear to influence clinical progression within 2 years. CoQ10 and statins may have only symptomatic effects or require a longer period of time for disease modification.Study Supported by:American Brain Foundation Research Fellowship, Rare Disease Clinical Research Network RC1NS068897, and NINDS K08 NS083738.Disclosure: Dr. Kuo has nothing to disclose. Dr. Lo has nothing to disclose. Dr. Figueroa has nothing to disclose. Dr. Pulst has received person...
Source: Neurology - April 9, 2014 Category: Neurology Authors: Kuo, S.-H., Lo, R., Figueroa, K., Pulst, S., Perlman, S., Wilmot, G., Gomez, C., Schmahmann, J., Paulson, H., Shakkottai, V., Ying, S., Zesiewicz, T., Bushara, K., Geschwind, M., Xia, G., Subramony, S., Ashizawa, T. Tags: Proteinopathy in Neurodegenerative Disease Poster Presentations Source Type: research

Abstract 1762: Phosphodiesterase 10, a novel target for colorectal cancer therapeutics
Phosphodiesterase 10 (PDE10) is a newly characterized PDE isozyme that is expressed in regions of the brain affecting cognition and psychomotor activity. Inhibitors are currently being developed for the treatment of schizophrenia and Huntington's disease, one of which, Pf-2545920 (MP-10), is in clinical trials. Although PDE10 is not expressed in most peripheral tissues, we recently found high levels in colon tumor cells compared with normal colonocytes and that genetic silencing by siRNA selectively suppressed colon tumor cell growth. These observations suggest that PDE10 may represent a novel anticancer target. Pf-2545920...
Source: Cancer Research - September 30, 2014 Category: Cancer & Oncology Authors: Lee, K. J., Li, N., Chen, X., Zhu, B., Yet, L., Piazza, G. Tags: Experimental and Molecular Therapeutics Source Type: research

Polyglutamine Disease Modeling: Epitope Based Screen for Homologous Recombination using CRISPR/Cas9 System
Discussion We show that CRISPR/Cas9 system can be utilized to perform homologous recombination in human cells to generate a HD isogenic allelic series (21, 72, 97 CAG). In our study, we compared the Cas9 vs. Cas9 D10A enzymes for their ability to mediate this event using two distinct endpoints. The use of Cas9 D10A is likely to be more selective with less off target effects. When we compared CRISPR-assisted HR using methylene blue stained clonal colonies it appeared that the wildtype Cas9 was much more effective at mediating HR. However, when we analyzed the same experiment in our 1C2 western blot assay which only detects ...
Source: PLOS Currents Huntington Disease - April 15, 2014 Category: Neurology Authors: mahrucan Source Type: research

siRNA screen identifies QPCT as a druggable target for Huntington's disease
Nature Chemical Biology 11, 347 (2015). doi:10.1038/nchembio.1790 Authors: Maria Jimenez-Sanchez, Wun Lam, Michael Hannus, Birte Sönnichsen, Sara Imarisio, Angeleen Fleming, Alessia Tarditi, Fiona Menzies, Teresa Ed Dami, Catherine Xu, Eduardo Gonzalez-Couto, Giulia Lazzeroni, Freddy Heitz, Daniela Diamanti, Luisa Massai, Venkata P Satagopam, Guido Marconi, Chiara Caramelli, Arianna Nencini, Matteo Andreini, Gian Luca Sardone, Nicola P Caradonna, Valentina Porcari, Carla Scali, Reinhard Schneider, Giuseppe Pollio, Cahir J O'Kane, Andrea Caricasole & David C Rubinsztein
Source: Nature Chemical Biology - April 6, 2015 Category: Biology Authors: Maria Jimenez-SanchezWun LamMichael HannusBirte SönnichsenSara ImarisioAngeleen FlemingAlessia TarditiFiona MenziesTeresa Ed DamiCatherine XuEduardo Gonzalez-CoutoGiulia LazzeroniFreddy HeitzDaniela DiamantiLuisa MassaiVenkata P SatagopamGuido MarconiChi Tags: Article Source Type: research

Neurodegenerative disorders: New Huntington disease target identified
Nature Reviews Drug Discovery 14, 386 (2015). doi:10.1038/nrd4652 Author: Sarah Crunkhorn Huntington disease (HD) is caused by the expansion of a CAG repeat tract in the gene encoding huntingtin (HTT), resulting in aggregation of a toxic mutant HTT protein (mHTT). Using an siRNA-based screen in human cultured cells, followed by hit validation in Drosophila melanogaster,
Source: Nature Reviews Drug Discovery - May 15, 2015 Category: Drugs & Pharmacology Authors: Sarah Crunkhorn Tags: Research Highlight Source Type: research