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Therefore, additional SMN-independent compounds, supporting SMN-dependent therapies, might be beneficial. Neurocalcin delta (NCALD) reduction, an SMA protective genetic modifier, ameliorates SMA across species. In a low-dose SMN-ASO-treated severe SMA mouse model, presymptomatic intracerebroventricular (i.c.v.) injection of Ncald-ASO at postnatal day 2 (PND2) significantly ameliorates histological and electrophysiological SMA hallmarks at PND21. However, contrary to SMN-ASOs, Ncald-ASOs show a shorter duration of action limiting a long-term benefit. Here, we investigated the longer-term effect of Ncald-ASOs by additional i.c.v. bolus injection at PND28. Two weeks after injection of 500 \u00b5g Ncald-ASO in wild-type mice, NCALD was significantly reduced in the brain and spinal cord and well tolerated. Next, we performed a double-blinded preclinical study combining low-dose SMN-ASO (PND1) with 2\u00d7 i.c.v. Ncald-ASO or CTRL-ASO (100 \u00b5g at PND2, 500 \u00b5g at PND28). Ncald-ASO re-injection significantly ameliorated electrophysiological defects and NMJ denervation at 2 months. Moreover, we developed and identified a non-toxic and highly efficient human NCALD-ASO that significantly reduced NCALD in hiPSC-derived MNs. This improved both neuronal activity and growth cone maturation of SMA MNs, emphasizing the additional protective effect of NCALD-ASO treatment.<\/jats:p>","DOI":"10.3390\/ijms24044198","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T05:27:01Z","timestamp":1676870821000},"page":"4198","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Long-Term SMN- and Ncald-ASO Combinatorial Therapy in SMA Mice and NCALD-ASO Treatment in hiPSC-Derived Motor Neurons Show Protective Effects"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8334-6802","authenticated-orcid":false,"given":"Anixa","family":"Mui\u00f1os-B\u00fchl","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Rombo","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen K.","family":"Ling","sequence":"additional","affiliation":[{"name":"IONIS Pharmaceuticals, Carlsbad, CA 92010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4356-7675","authenticated-orcid":false,"given":"Eleonora","family":"Zilio","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Rigo","sequence":"additional","affiliation":[{"name":"IONIS Pharmaceuticals, Carlsbad, CA 92010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Frank","family":"Bennett","sequence":"additional","affiliation":[{"name":"IONIS Pharmaceuticals, Carlsbad, CA 92010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4051-5191","authenticated-orcid":false,"given":"Brunhilde","family":"Wirth","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Rare Diseases Cologne, University Hospital of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1056\/NEJMoa1702752","article-title":"Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy","volume":"377","author":"Finkel","year":"2017","journal-title":"N. 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