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from mutations in the NPC1 gene encoding the lysosomal transmembrane protein NPC1. There is currently no cure for NP-C, and the only disease modifying treatment, miglustat, slows disease progression but does not significantly attenuate neurological symptoms. AAV-mediated gene therapy is an attractive option for NP-C, but due to the large size of the human NPC1 gene, there may be packaging and truncation issues during vector manufacturing. One option is to reduce the size of DNA regulatory elements that are essential for gene expression, such as the promoter sequence. Here, we describe a novel small truncated endogenous NPC1 promoter that leads to high gene expression both in vitro and in vivo and compare its efficacy to other commonly used promoters. Following neonatal intracerebroventricular (ICV) injection into the CNS, this novel promoter provided optimal therapeutic efficacy compared to all other promoters including increased survival, improved behavioural phenotypes, and attenuated neuropathology in mouse models of NP-C. Taken together, we propose that this novel promoter can be extremely efficient in designing an optimised AAV9 vector for gene therapy for NP-C.<\/jats:p>","DOI":"10.3390\/cells12121619","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T01:32:15Z","timestamp":1686706335000},"page":"1619","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["A Novel Small NPC1 Promoter Enhances AAV-Mediated Gene Therapy in Mouse Models of Niemann\u2013Pick Type C1 Disease"],"prefix":"10.3390","volume":"12","author":[{"given":"Michael Paul","family":"Hughes","sequence":"first","affiliation":[{"name":"UCL School of Pharmacy, University College London, London WC1N 1AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2407-4517","authenticated-orcid":false,"given":"Hemanth Ramesh","family":"Nelvagal","sequence":"additional","affiliation":[{"name":"UCL School of Pharmacy, University College London, London WC1N 1AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Coombe-Tennant","sequence":"additional","affiliation":[{"name":"UCL School of Pharmacy, University College London, London WC1N 1AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9845-5913","authenticated-orcid":false,"given":"Dave","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5986-6082","authenticated-orcid":false,"given":"Giulia","family":"Massaro","sequence":"additional","affiliation":[{"name":"UCL School of Pharmacy, University College London, London WC1N 1AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Poupon-Bejuit","sequence":"additional","affiliation":[{"name":"UCL School of Pharmacy, University College London, London WC1N 1AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7614-0403","authenticated-orcid":false,"given":"Frances Mary","family":"Platt","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0044-0949","authenticated-orcid":false,"given":"Ahad Abdul","family":"Rahim","sequence":"additional","affiliation":[{"name":"UCL School of Pharmacy, University College London, London WC1N 1AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1111\/j.1399-0004.1988.tb03460.x","article-title":"Niemann\u2013Pick disease group C: Clinical variability and diagnosis based on defective cholesterol esterification. A collaborative study on 70 patients","volume":"33","author":"Vanier","year":"1988","journal-title":"Clin. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1034\/j.1399-0004.2003.00147.x","article-title":"Niemann\u2013Pick disease type C","volume":"64","author":"Vanier","year":"2003","journal-title":"Clin. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1002\/ajmg.a.32642","article-title":"The clinical spectrum of fetal Niemann\u2013Pick type C","volume":"149","author":"Spiegel","year":"2009","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.cell.2019.08.038","article-title":"Structural Insight into Eukaryotic Sterol Transport through Niemann\u2013Pick Type C Proteins","volume":"179","author":"Winkler","year":"2019","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1038\/nm.1876","article-title":"Niemann\u2013Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium","volume":"14","author":"Morgan","year":"2008","journal-title":"Nat. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1111\/j.1600-0854.2010.01032.x","article-title":"Lipids on trial: The search for the offending metabolite in Niemann\u2013Pick type C disease","volume":"11","author":"Platt","year":"2010","journal-title":"Traffic"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5784","DOI":"10.1016\/S0021-9258(18)91082-3","article-title":"A genetic storage disorder in BALB\/C mice with a metabolic block in esterification of exogenous cholesterol","volume":"259","author":"Pentchev","year":"1984","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1016\/j.nbd.2011.12.027","article-title":"Early glial activation, synaptic changes and axonal pathology in the thalamocortical system of Niemann\u2013Pick type C1 mice","volume":"45","author":"Pressey","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1093\/hmg\/ddr505","article-title":"A novel mouse model of Niemann\u2013Pick type C disease carrying a D1005G-Npc1 mutation comparable to commonly observed human mutations","volume":"21","author":"Maue","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Mauhin, W., Borie, R., Dalbies, F., Douillard, C., Guffon, N., Lavigne, C., Lidove, O., and Brassier, A. (2022). Acid Sphingomyelinase Deficiency: Sharing Experience of Disease Monitoring and Severity in France. J. Clin. Med., 11.","DOI":"10.3390\/jcm11040920"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mobini, M., Radbakhsh, S., Kubaski, F., Eshraghi, P., Vakili, S., Vakili, R., Khalili, M., Varesvazirian, M., Jamialahmadi, T., and Alamdaran, S.A. (2022). Impact of Intravenous Trehalose Administration in Patients with Niemann\u2013Pick Disease Types A and B. J. Clin. Med., 11.","DOI":"10.3390\/jcm11010247"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1007\/s11011-021-00842-0","article-title":"Treatment trials in Niemann\u2013Pick type C disease","volume":"36","author":"Sitarska","year":"2021","journal-title":"Metab. Brain Dis."},{"key":"ref_13","first-page":"360","article-title":"Niemann\u2013Pick disease treatment: A systematic review of clinical trials","volume":"3","author":"Garatachea","year":"2015","journal-title":"Ann. Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1056\/NEJMoa1706198","article-title":"Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy","volume":"377","author":"Mendell","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1001\/jamaneurol.2021.1272","article-title":"Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy","volume":"78","author":"Mendell","year":"2021","journal-title":"JAMA Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3079","DOI":"10.1093\/hmg\/ddy212","article-title":"AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann\u2013Pick type C1 disease","volume":"27","author":"Hughes","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_17","first-page":"52","article-title":"Systemic AAV9 gene therapy improves the lifespan of mice with Niemann\u2013Pick disease, type C1","volume":"26","author":"Chandler","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1194\/jlr.M071274","article-title":"AAV9-NPC1 significantly ameliorates Purkinje cell death and behavioral abnormalities in mouse NPC disease","volume":"58","author":"Xie","year":"2017","journal-title":"J. Lipid Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1089\/hum.2020.175","article-title":"Gene Therapy in a Mouse Model of Niemann\u2013Pick Disease Type C1","volume":"32","author":"Kurokawa","year":"2021","journal-title":"Hum. Gene Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.ymthe.2006.01.006","article-title":"Gene therapy for lysosomal storage diseases","volume":"13","author":"Sands","year":"2006","journal-title":"Mol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.omtm.2017.11.007","article-title":"Emerging Issues in AAV-Mediated In Vivo Gene Therapy","volume":"8","author":"Colella","year":"2018","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_22","first-page":"49","article-title":"Viral expression cassette elements to enhance transgene target specificity and expression in gene therapy","volume":"19","author":"Powell","year":"2015","journal-title":"Discov. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41434-020-0169-1","article-title":"Optimization of adeno-associated viral vector-mediated transduction of the corticospinal tract: Comparison of four promoters","volume":"28","author":"Nieuwenhuis","year":"2021","journal-title":"Gene Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1093\/hmg\/ddz317","article-title":"Systemic AAV9 gene therapy using the synapsin I promoter rescues a mouse model of neuronopathic Gaucher disease but with limited cross-correction potential to astrocytes","volume":"29","author":"Massaro","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/sj.cgt.7700878","article-title":"Antitumor efficacy of AAV-mediated systemic delivery of interferon-beta","volume":"13","author":"Streck","year":"2006","journal-title":"Cancer Gene Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1056\/NEJMoa1407309","article-title":"Long-term safety and efficacy of factor IX gene therapy in hemophilia B","volume":"371","author":"Nathwani","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_27","first-page":"e51863","article-title":"Intracerebroventricular viral injection of the neonatal mouse brain for persistent and widespread neuronal transduction","volume":"91","author":"Kim","year":"2014","journal-title":"J. Vis. Exp."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1042\/BJ20101485","article-title":"AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid beta-peptide exposure","volume":"434","author":"Thornton","year":"2011","journal-title":"Biochem. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11842","DOI":"10.1038\/srep11842","article-title":"In vivo bioimaging with tissue-specific transcription factor activated luciferase reporters","volume":"5","author":"Buckley","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.nbd.2009.07.010","article-title":"Beneficial effects of anti-inflammatory therapy in a mouse model of Niemann\u2013Pick disease type C1","volume":"36","author":"Smith","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/nan.12658","article-title":"Spinal manifestations of CLN1 disease start during the early postnatal period","volume":"47","author":"Nelvagal","year":"2021","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1073\/pnas.90.4.1460","article-title":"Identification of a functional silencer element involved in neuron-specific expression of the synapsin I gene","volume":"90","author":"Li","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3317","DOI":"10.1074\/jbc.271.6.3317","article-title":"Neuron-specific gene expression of synapsin I. Major role of a negative regulatory mechanism","volume":"271","author":"Schoch","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1016\/j.ymthe.2019.06.015","article-title":"Gene Therapy Corrects Brain and Behavioral Pathologies in CLN6-Batten Disease","volume":"27","author":"Cain","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"196","DOI":"10.3389\/fnagi.2015.00196","article-title":"Neurostereology protocol for unbiased quantification of neuronal injury and neurodegeneration","volume":"7","author":"Golub","year":"2015","journal-title":"Front. Aging Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/hgtb.2015.140","article-title":"Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids","volume":"27","author":"Chamberlain","year":"2016","journal-title":"Hum. Gene Ther. Methods"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1038\/s41598-022-04892-x","article-title":"Therapeutic potential of highly functional codon-optimized microutrophin for muscle-specific expression","volume":"12","author":"Starikova","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Aschauer, D.F., Kreuz, S., and Rumpel, S. (2013). Analysis of Transduction Efficiency, Tropism and Axonal Transport of AAV Serotypes 1, 2, 5, 6, 8 and 9 in the Mouse Brain. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076310"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1007\/s00284-012-0102-y","article-title":"A novel glyceraldehyde-3-phosphate dehydrogenase (GAPDH) promoter for expressing transgenes in the halotolerant alga Dunaliella salina","volume":"64","author":"Jia","year":"2012","journal-title":"Curr. Microbiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.neulet.2014.05.044","article-title":"Widespread neuron-specific transgene expression in brain and spinal cord following synapsin promoter-driven AAV9 neonatal intracerebroventricular injection","volume":"576","author":"McLean","year":"2014","journal-title":"Neurosci. Lett."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/12\/1619\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:54:22Z","timestamp":1760126062000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/12\/1619"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,13]]},"references-count":40,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["cells12121619"],"URL":"https:\/\/doi.org\/10.3390\/cells12121619","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,13]]}}}