Academic Journal
Systemic AAV8-SIL1-TAT therapy improves motor function in a mouse model of Marinesco-Sjögren syndrome.
| Τίτλος: | Systemic AAV8-SIL1-TAT therapy improves motor function in a mouse model of Marinesco-Sjögren syndrome. |
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| Συγγραφείς: | Bellia F; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy., Ruggieri AG; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy., Amodei L; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy., Potenza F; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy., Dufrusine B; Department of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo 64100, Italy., Panella V; Department of Medicine and Aging Sciences, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy., Del Pizzo F; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy; Department of Neuroscience, Imaging, and Clinical Sciences, 'G. d'Annunzio' University, Chieti-Pescara, 66100 Chieti, Italy., Lamolinara A; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy; Department of Neuroscience, Imaging, and Clinical Sciences, 'G. d'Annunzio' University, Chieti-Pescara, 66100 Chieti, Italy., Iezzi M; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy; Department of Neuroscience, Imaging, and Clinical Sciences, 'G. d'Annunzio' University, Chieti-Pescara, 66100 Chieti, Italy., Federici L; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy., Sallese M; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy. Electronic address: michele.sallese@unich.it. |
| Πηγή: | Biochemical pharmacology [Biochem Pharmacol] 2026 Aug; Vol. 250 (Pt 2), pp. 118014. Date of Electronic Publication: 2026 May 02. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Oxford : Elsevier Science Original Publication: Oxford, New York [etc.] Paragamon Press. |
| Ιατρικοί όροι (MeSH): | Spinocerebellar Degenerations*/therapy , Spinocerebellar Degenerations*/genetics , Spinocerebellar Degenerations*/physiopathology , Dependovirus*/genetics , Genetic Therapy*/methods , Motor Activity*/physiology , Guanine Nucleotide Exchange Factors*/genetics , Guanine Nucleotide Exchange Factors*/administration & dosage , Gene Products, tat*/genetics , Gene Products, tat*/administration & dosage , Ubiquitin-Protein Ligases*/genetics , Ubiquitin-Protein Ligases*/administration & dosage , Disease Models, Animal*, Animals ; Female ; Mice ; Humans |
| Περίληψη: | Marinesco-Sjögren Syndrome (MSS) is a rare genetic disorder characterized by cerebellar ataxia, congenital cataracts, and progressive myopathy. Approximately 60% of cases result from SIL1 gene mutations, causing endoplasmic reticulum stress and neuromuscular degeneration. We investigated AAV8-mediated SIL1 gene replacement combined with TAT peptide-mediated protein delivery in the woozy (Sil1wz) mouse model. Thirty-two female Sil1wz mice received either AAV8-SIL1-TAT vector (5 × 1012 genome copies) or saline intravenously at 4 weeks of age. The construct enabled liver-produced SIL1 protein uptake by peripheral tissues. Motor performance, cognitive behaviour, and molecular changes were monitored over 20 weeks. Treated mice showed significant motor improvement versus controls. Accelerating rotarod testing revealed delayed motor deficit onset by approximately 3 weeks, with significantly higher performance from weeks 10-14 (p < 0.001). Beam walking assessment showed reduced traversal time and contralateral falls from week 9 onwards. Western blotting and immunohistochemistry confirmed intracellular SIL1 localization in hepatocytes and muscle fibres, but not cerebellum. Quadriceps SIL1 delivery peaked at 2 weeks post-treatment, then gradually declined. Treatment normalized peIF2α and LC3 expression in quadriceps, indicating reduced ER stress and autophagy in skeletal muscle. This study provides proof-of-concept evidence for liver-based protein production combined with cell-penetrating peptides as a viable approach for treating peripheral manifestations of multisystemic disorders, while highlighting the need for alternative CNS delivery strategies for comprehensive therapeutic coverage in MSS. (Copyright © 2026 The Author(s). Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Autosomal Recessive Cerebellar Ataxia; Cell-penetrating peptides; Neurodegeneration; Preclinical model; Skeletal muscle; Therapeutic approaches |
| Substance Nomenclature: | 0 (SIL1 protein, mouse) 0 (Guanine Nucleotide Exchange Factors) 0 (Gene Products, tat) EC 2.3.2.27 (Ubiquitin-Protein Ligases) 0 (SIL1 protein, human) |
| Entry Date(s): | Date Created: 20260504 Date Completed: 20260611 Latest Revision: 20260611 |
| Update Code: | 20260611 |
| DOI: | 10.1016/j.bcp.2026.118014 |
| PMID: | 42082117 |
| Βάση Δεδομένων: | MEDLINE |
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