{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T09:03:10Z","timestamp":1772010190976,"version":"3.50.1"},"reference-count":49,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Izmir Institute of Technology"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Metab Brain Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Tay-Sachs disease is a lysosomal storage disorder caused by mutations in the HEXA gene, which encodes the \u03b1-subunit of \u03b2-hexosaminidase A\u2014an enzyme that breaks down GM2 ganglioside. Recently, a mouse model of Tay-Sachs, the DKO, with deficiencies in both Hexa and Neu3 genes, showed severe neurological symptoms and neuroinflammation, surviving up to 20 weeks. In this study, we evaluated the therapeutic potential of intrathecal AAVrh10-mediated delivery of mouse Hexa, in combination with istradefylline treatment, in DKO mice. Using molecular, immunohistochemical, and behavioral methods, we found that the mice\u2019s lifespan increased to 30 weeks after receiving AAV alone or with istradefylline. Molecular analyses revealed increased Hexa activity, accompanied by reduced levels of the lysosomal marker Lamp-1 and pro-inflammatory cytokines, such as CCL2 and CCL3, in the cortex, cerebellum, and various organs, including the kidney, liver, and spleen. Immunohistochemistry revealed clearance of GM2 accumulation, fewer lysosomes, decreased active astrocytes, and improvements in neurons and oligodendrocytes in the brains of DKO mice. Correspondingly, their motor activity also improved. These results suggest that AAVrh10-based intrathecal delivery combined with istradefylline provides a promising therapeutic strategy for treating Tay-Sachs disease.<\/jats:p>","DOI":"10.1007\/s11011-026-01802-2","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T08:11:22Z","timestamp":1772007082000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intrathecal delivery of AAVrh10-mHexa combined with anti-inflammatory treatment reduces neuropathological markers and extends the lifespan of mice with early-onset Tay-Sachs disease"],"prefix":"10.1007","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7935-7077","authenticated-orcid":false,"given":"Melike","family":"Can","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3059-9777","authenticated-orcid":false,"given":"Jerome","family":"Ausseil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0243-5011","authenticated-orcid":false,"given":"Volkan","family":"Seyrantepe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"issue":"3","key":"1802_CR1","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1016\/j.nbd.2004.04.012","volume":"16","author":"U Andersson","year":"2004","unstructured":"Andersson U, Smith D, Jeyakumar M, Butters TD, Borja MC, Dwek RA, Platt FM (2004) Improved outcome of N-butyldeoxygalactonojirimycin-mediated substrate reduction therapy in a mouse model of Sandhoff disease. Neurobiol Dis 16(3):506\u2013515. https:\/\/doi.org\/10.1016\/j.nbd.2004.04.012","journal-title":"Neurobiol Dis"},{"issue":"2","key":"1802_CR2","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.ymgme.2009.10.002","volume":"99","author":"D Auclair","year":"2010","unstructured":"Auclair D, Finnie J, White J, Nielsen T, Fuller M, Kakkis E, Cheng A, O\u2019Neill CA, Hopwood JJ (2010) Repeated intrathecal injections of recombinant human 4-sulphatase remove dural storage in mature mucopolysaccharidosis VI cats primed with a short-course tolerisation regimen. Mol Genet Metab 99(2):132\u2013141. https:\/\/doi.org\/10.1016\/j.ymgme.2009.10.002","journal-title":"Mol Genet Metab"},{"issue":"3","key":"1802_CR3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2024.108140","volume":"141","author":"H Basirli","year":"2024","unstructured":"Basirli H, Can M, Sengul T, Seyrantepe V (2024) Lithium treatment rescues dysfunctional autophagy in the cell models of Tay-Sachs disease. Mol Genet Metab 141(3):108140. https:\/\/doi.org\/10.1016\/j.ymgme.2024.108140","journal-title":"Mol Genet Metab"},{"issue":"5","key":"1802_CR4","doi-asserted-by":"publisher","first-page":"e1233","DOI":"10.1542\/peds\/peds\/peds2011-0078","volume":"128","author":"AE Bley","year":"2011","unstructured":"Bley AE, Giannikopoulos OA, Hayden D, Kubilus K, Tifft CJ, Eichler FS (2011) Natural history of infantile GM2 gangliosidosis. Pediatr 128(5):e1233\u2013e1241. https:\/\/doi.org\/10.1542\/peds\/peds\/peds2011-0078","journal-title":"Pediatr"},{"key":"1802_CR5","doi-asserted-by":"publisher","DOI":"10.3791\/67138","volume":"219","author":"A Boitnott","year":"2025","unstructured":"Boitnott A, Rioux M, Chen X, Gray S (2025) Lumbar intrathecal injection of gene therapy vectors for central nervous system targeting in mice and rats. J Vis Exp 219:e67138. https:\/\/doi.org\/10.3791\/67138","journal-title":"J Vis Exp"},{"key":"1802_CR6","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.892248","volume":"9","author":"M Can","year":"2022","unstructured":"Can M, Seng\u00fcl T, Demir SA, \u0130nci OK, Bas\u0131rl\u0131 H, Seyrantepe V (2022) Analysis of brain lipids in the early-onset Tay-Sachs disease mouse model with the combined deficiency of \u03b2-Hexosaminidase A and Neuraminidase 3. Front Mol Biosci 9:892248. https:\/\/doi.org\/10.3389\/fmolb.2022.892248","journal-title":"Front Mol Biosci"},{"issue":"1","key":"1802_CR7","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/s12035-013-8605-5","volume":"50","author":"E Chiricozzi","year":"2014","unstructured":"Chiricozzi E, Niemir N, Aureli M, Magini A, Loberto N, Prinetti A, Bassi R, Polchi A, Emiliani C, Caillaud C, Sonnino S (2014) Chaperone therapy for GM2 gangliosidosis: effects of pyrimethamine on \u03b2-hexosaminidase activity in Sandhoff fibroblasts. Mol Neurobiol 50(1):159\u2013167. https:\/\/doi.org\/10.1007\/s12035-013-8605-5","journal-title":"Mol Neurobiol"},{"issue":"5","key":"1802_CR8","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9050446","volume":"9","author":"J Clarke","year":"2021","unstructured":"Clarke J, Kayatekin C, Viel C, Shihabuddin L, Sardi SP (2021) Murine models of lysosomal storage diseases exhibit differences in brain protein aggregation and neuroinflammation. Biomedicines 9(5):446. https:\/\/doi.org\/10.3390\/biomedicines9050446","journal-title":"Biomedicines"},{"issue":"5","key":"1802_CR9","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1517\/21678707.2015.1025746","volume":"3","author":"A d'Azzo","year":"2015","unstructured":"d\u2019Azzo A, Machado E, Annunziata I (2015) Pathogenesis, emerging therapeutic targets and treatment in sialidosis. Expert Opin Orphan D 3(5):491\u2013504. https:\/\/doi.org\/10.1517\/21678707.2015.1025746","journal-title":"Expert Opin Orphan D"},{"issue":"1","key":"1802_CR10","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-020-01947-6","volume":"17","author":"SA Demir","year":"2020","unstructured":"Demir SA, Timur ZK, Ate\u015f N, Mart\u00ednez LA, Seyrantepe V (2020) GM2 ganglioside accumulation causes neuroinflammation and behavioral alterations in a mouse model of early onset Tay-Sachs disease. J Neuroinflammation 17(1):277. https:\/\/doi.org\/10.1186\/s12974-020-01947-6","journal-title":"J Neuroinflammation"},{"issue":"12","key":"1802_CR11","doi-asserted-by":"publisher","DOI":"10.3390\/biom11121775","volume":"11","author":"C Fern\u00e1ndez-Pereira","year":"2021","unstructured":"Fern\u00e1ndez-Pereira C, San Mill\u00e1n-Tejado B, Gallardo-G\u00f3mez M, P\u00e9rez-M\u00e1rquez T, Alves-Villar M, Melc\u00f3n-Crespo C, Fern\u00e1ndez-Mart\u00edn J, Ortolano S (2021) Therapeutic approaches in lysosomal storage diseases. Biomolecules 11(12):1775. https:\/\/doi.org\/10.3390\/biom11121775","journal-title":"Biomolecules"},{"key":"1802_CR12","doi-asserted-by":"publisher","unstructured":"Fripont S, Marneffe C, Marino M, Rincon MY, Holt MG (2019) Production, purification, and quality control for Adeno-associated virus-based vectors. JoVE 143. https:\/\/doi.org\/10.3791\/58960-v","DOI":"10.3791\/58960-v"},{"key":"1802_CR13","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.omtm.2022.10.004","volume":"27","author":"M Hocquemiller","year":"2022","unstructured":"Hocquemiller M, Giersch L, Mei X, Gross AL, Randle AN, Gray-Edwards HL, Hudson JA, Todeasa S, Stoica L, Martin DR, Sena-Esteves M, Aiach K, Laufer R (2022) AAVrh10 vector corrects pathology in animal models of GM1 gangliosidosis and achieves widespread distribution in the CNS of nonhuman primates. Mol Ther Methods Clin Dev 27:281\u2013292. https:\/\/doi.org\/10.1016\/j.omtm.2022.10.004","journal-title":"Mol Ther Methods Clin Dev"},{"issue":"2","key":"1802_CR14","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1016\/0005-2760(72)90104-X","volume":"280","author":"M Holm","year":"1972","unstructured":"Holm M, M\u00e5nsson JE, Vanier MT, Svennerholm L (1972) Gangliosides of human, bovine and rabbit retina. Biochim Biophys Acta 280(2):356\u2013364. https:\/\/doi.org\/10.1016\/0005-2760(72)90104-X","journal-title":"Biochim Biophys Acta"},{"key":"1802_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/mtm.2013.7","volume":"1","author":"J Homs","year":"2014","unstructured":"Homs J, Pag\u00e8s G, Ariza L, Casas C, Chill\u00f3n M, Navarro X, Bosch A (2014) Intrathecal administration of IGF-I by AAVrh10 improves sensory and motor deficits in a mouse model of diabetic neuropathy. Mol Ther Methods Clin Dev 1:7. https:\/\/doi.org\/10.1038\/mtm.2013.7","journal-title":"Mol Ther Methods Clin Dev"},{"issue":"1","key":"1802_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-46069-z","volume":"9","author":"Y Hoshino","year":"2019","unstructured":"Hoshino Y, Nishide K, Nagoshi N, Shibata S, Moritoki N, Kojima K, Tsuji O, Matsumoto M, Kohyama J, Nakamura M, Okano H (2019) The adeno-associated virus rh10 vector is an effective gene transfer system for chronic spinal cord injury. Sci Rep 9(1):9844. https:\/\/doi.org\/10.1038\/s41598-019-46069-z","journal-title":"Sci Rep"},{"issue":"4","key":"1802_CR17","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1093\/brain\/awg089","volume":"126","author":"M Jeyakumar","year":"2003","unstructured":"Jeyakumar M, Thomas R, Elliot-Smith E, Smith DA, van der Spoel AC, d\u2019Azzo A, Perry VH, Butters TD, Dwek RA, Platt FM (2003) Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain 126(4):974\u2013987. https:\/\/doi.org\/10.1093\/brain\/awg089","journal-title":"Brain"},{"issue":"1","key":"1802_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-02694-1","volume":"11","author":"A Kagiava","year":"2021","unstructured":"Kagiava A, Richter J, Tryfonos C, Leal-Juli\u00e0 M, Sargiannidou I, Christodoulou C, Bosch A, Kleopa KA (2021) Efficacy of AAV serotypes to target Schwann cells after intrathecal and intravenous delivery. Sci Rep 11(1):23358. https:\/\/doi.org\/10.1038\/s41598-021-02694-1","journal-title":"Sci Rep"},{"issue":"4","key":"1802_CR19","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1038\/s41576-019-0205-4","volume":"21","author":"C Li","year":"2020","unstructured":"Li C, Samulski RJ (2020) Engineering adeno-associated virus vectors for gene therapy. Nat Rev Genet 21(4):255\u2013272. https:\/\/doi.org\/10.1038\/s41576-019-0205-4","journal-title":"Nat Rev Genet"},{"issue":"12","key":"1802_CR20","doi-asserted-by":"publisher","first-page":"9150","DOI":"10.1074\/jbc.M609304200","volume":"282","author":"GH Maegawa","year":"2007","unstructured":"Maegawa GH, Tropak M, Buttner J, Stockley T, Kok F, Clarke JT, Mahuran DJ (2007) Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis. J Biol Chem 282(12):9150\u20139161. https:\/\/doi.org\/10.1074\/jbc.M609304200","journal-title":"J Biol Chem"},{"issue":"4","key":"1802_CR21","doi-asserted-by":"publisher","DOI":"10.3390\/biom11040611","volume":"11","author":"G Massaro","year":"2021","unstructured":"Massaro G, Geard AF, Liu W, Coombe-Tennant O, Waddington SN, Baruteau J, Gissen P, Rahim AA (2021) Gene therapy for lysosomal storage disorders: ongoing studies and clinical development. Biomolecules 11(4):611. https:\/\/doi.org\/10.3390\/biom11040611","journal-title":"Biomolecules"},{"issue":"8","key":"1802_CR22","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1038\/mt.2010.113","volume":"18","author":"K Matsuoka","year":"2010","unstructured":"Matsuoka K, Tsuji D, Aikawa S, Matsuzawa F, Sakuraba H, Itoh K (2010) Introduction of an N-glycan sequon into HEXA enhances human beta-hexosaminidase cellular uptake in a model of Sandhoff disease. Mol Ther 18(8):1519\u20131526. https:\/\/doi.org\/10.1038\/mt.2010.113","journal-title":"Mol Ther"},{"issue":"17\u201318","key":"1802_CR23","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1089\/hum.2022.170","volume":"33","author":"A McElroy","year":"2022","unstructured":"McElroy A, Sena-Esteves M, Arjomandnejad M, Keeler AM, Gray-Edwards HL (2022) Redosing adeno-associated virus gene therapy to the central nervous system. Hum Gene Ther 33(17\u201318):889\u2013892. https:\/\/doi.org\/10.1089\/hum.2022.170","journal-title":"Hum Gene Ther"},{"issue":"7","key":"1802_CR24","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1016\/j.gim.2022.04.002","volume":"24","author":"J Muenzer","year":"2022","unstructured":"Muenzer J, Vijayaraghavan S, Stein M, Kearney S, Wu Y, Alexanderian D (2022) Long-term open-label phase I\/II extension study of intrathecal idursulfase-IT in the treatment of neuronopathic mucopolysaccharidosis II. Genet Med 24(7):1437\u20131448. https:\/\/doi.org\/10.1016\/j.gim.2022.04.002","journal-title":"Genet Med"},{"issue":"11","key":"1802_CR25","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1093\/hmg\/11.11.1343","volume":"11","author":"R Myerowitz","year":"2002","unstructured":"Myerowitz R, Lawson D, Mizukami H, Mi Y, Tifft CJ, Proia RL (2002) Molecular pathophysiology in Tay-Sachs and Sandhoff diseases as revealed by gene expression profiling. Hum Mol Genet 11(11):1343\u20131350. https:\/\/doi.org\/10.1093\/hmg\/11.11.1343","journal-title":"Hum Mol Genet"},{"issue":"6","key":"1802_CR26","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1093\/hmg\/ddy012","volume":"27","author":"N Niemir","year":"2018","unstructured":"Niemir N, Rouvi\u00e8re L, Besse A, Vanie MT, Dmytrus J, Marais T, Astord S, Puech JP, Panasyuk G, Cooper JD, Barkats M, Caillaud C (2018) Intravenous administration of scAAV9-Hexb normalizes lifespan and prevents pathology in Sandhoff disease mice. Hum Mol Genet 27(6):954\u2013968. https:\/\/doi.org\/10.1093\/hmg\/ddy012","journal-title":"Hum Mol Genet"},{"key":"1802_CR27","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.nbd.2018.07.014","volume":"118","author":"Y Ogawa","year":"2018","unstructured":"Ogawa Y, Furusawa E, Saitoh T, Sugimoto H, Omori T, Shimizu S, Kondo H, Yamazaki M, Sakuraba H, Oishi K (2018) Inhibition of astrocytic adenosine receptor A2A attenuates microglial activation in a mouse model of Sandhoff disease. Neurobiol Dis 118:142\u2013154. https:\/\/doi.org\/10.1016\/j.nbd.2018.07.014","journal-title":"Neurobiol Dis"},{"key":"1802_CR28","doi-asserted-by":"publisher","DOI":"10.4137\/JEN.S25475","author":"RU Onyenwoke","year":"2015","unstructured":"Onyenwoke RU, Jay E (2015) Lysosomal storage diseases-regulating neurodegeneration. J Exp Neurosci. https:\/\/doi.org\/10.4137\/JEN.S25475. 9s2","journal-title":"J Exp Neurosci"},{"issue":"21","key":"1802_CR29","doi-asserted-by":"publisher","first-page":"3610","DOI":"10.1093\/hmg\/ddz220","volume":"28","author":"G Pag\u00e8s","year":"2019","unstructured":"Pag\u00e8s G, Gim\u00e9nez-Llort L, Garc\u00eda-Lareu B, Ariza L, Navarro M, Casas C, Chill\u00f3n M, Bosch A (2019) Intrathecal AAVrh10 corrects biochemical and histological hallmarks of mucopolysaccharidosis VII mice and improves behavior and survival. Hum Mol Genet 28(21):3610\u20133624. https:\/\/doi.org\/10.1093\/hmg\/ddz220","journal-title":"Hum Mol Genet"},{"issue":"4","key":"1802_CR30","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines11041067","volume":"11","author":"MK Pandey","year":"2023","unstructured":"Pandey MK (2023) Exploring pro-inflammatory immunological mediators: unraveling the mechanisms of neuroinflammation in lysosomal storage diseases. Biomedicine 11(4):1067. https:\/\/doi.org\/10.3390\/biomedicines11041067","journal-title":"Biomedicine"},{"issue":"1","key":"1802_CR31","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17393-z","volume":"7","author":"SH Park","year":"2017","unstructured":"Park SH, Eber MR, Tsuzuki S, Booker ME, Sunil AG, Widner DB, Parker RA, Peters CM, Shiozawa Y (2017) Adeno-associated virus serotype rh10 is a useful gene transfer vector for sensory nerves that innervate bone in immunodeficient mice. Sci Rep 7(1):17428. https:\/\/doi.org\/10.1038\/s41598-017-17393-z","journal-title":"Sci Rep"},{"issue":"3","key":"1802_CR32","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1111\/imm.12163","volume":"141","author":"L Peferoen","year":"2014","unstructured":"Peferoen L, Kipp M, van der Valk P, van Noort JM, Amor S (2014) Oligodendrocyte-microglia cross-talk in the central nervous system. Immunology 141(3):302\u2013313. https:\/\/doi.org\/10.1111\/imm.12163","journal-title":"Immunology"},{"issue":"8","key":"1802_CR33","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1089\/hum.2012.015","volume":"23","author":"F Piguet","year":"2012","unstructured":"Piguet F, Sondhi D, Piraud M, Fouquet F, Hackett NR, Ahouansou O, Vanier MT, Bieche I, Aubourg P, Crystal RG, Cartier N, Sevin C (2012) Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice. Hum Gene Ther 23(8):903\u2013914. https:\/\/doi.org\/10.1089\/hum.2012.015","journal-title":"Hum Gene Ther"},{"issue":"11","key":"1802_CR34","doi-asserted-by":"publisher","first-page":"2031","DOI":"10.1038\/mt.2012.153","volume":"20","author":"MA Rafi","year":"2012","unstructured":"Rafi MA, Rao HZ, Luzi P, Curtis MT, Wenger DA (2012) Extended normal life after AAVrh10-mediated gene therapy in the mouse model of Krabbe disease. Mol Ther 20(11):2031\u20132042. https:\/\/doi.org\/10.1038\/mt.2012.153","journal-title":"Mol Ther"},{"issue":"1","key":"1802_CR35","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2023.101168","volume":"32","author":"AE Ryckman","year":"2023","unstructured":"Ryckman AE, Deschenes NM, Quinville BM, Osmon KJL, Mitchell M, Chen Z, Gray SJ, Walia JS (2023) Intrathecal delivery of a bicistronic AAV9 vector expressing \u03b2-hexosaminidase A corrects Sandhoff disease in a murine model: a dosage study. Mol Ther Methods Clin Dev 32(1):101168. https:\/\/doi.org\/10.1016\/j.omtm.2023.101168","journal-title":"Mol Ther Methods Clin Dev"},{"issue":"23","key":"1802_CR36","doi-asserted-by":"publisher","first-page":"20386","DOI":"10.1074\/jbc.M110641200","volume":"277","author":"R Sandhoff","year":"2002","unstructured":"Sandhoff R, Hepbildikler ST, Jennemann R, Geyer R, Gieselmann V, Proia RL, Wiegandt H, Gr\u00f6ne HJ (2002) Kidney sulfatides in mouse models of inherited glycosphingolipid disorders. J Biol Chem 277(23):20386\u201320398. https:\/\/doi.org\/10.1074\/jbc.M110641200","journal-title":"J Biol Chem"},{"issue":"2","key":"1802_CR37","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1038\/ng1095-170","volume":"11","author":"K Sango","year":"1995","unstructured":"Sango K, Yamanaka S, Hoffmann A, Okuda Y, Grinberg A, Westphal H, McDonald MP, Crawley JN, Sandhoff K, Suzuki K, Proia RL (1995) Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism. Nat Genet 11(2):170\u2013176. https:\/\/doi.org\/10.1038\/ng1095-170","journal-title":"Nat Genet"},{"issue":"3","key":"1802_CR38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0280650","volume":"18","author":"T Sengul","year":"2023","unstructured":"Sengul T, Can M, Ate\u015f N, Seyrantepe V (2023) Autophagic flux is impaired in the brain tissue of Tay-Sachs disease mouse model. PLoS One 18(3):e0280650. https:\/\/doi.org\/10.1371\/journal.pone.0280650","journal-title":"PLoS One"},{"key":"1802_CR39","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.expneurol.2017.09.012","volume":"299","author":"V Seyrantepe","year":"2018","unstructured":"Seyrantepe V, Demir SA, Timur ZK, Von Gerichten J, Marsching C, Erdemli E, Oztas E, Takahashi K, Yamaguchi K, Ates N, D\u00f6nmez Demir B, Dalkara T, Erich K, Hopf C, Sandhoff R, Miyagi T (2018) Murine sialidase Neu3 facilitates GM2 degradation and bypass in mouse model of Tay-Sachs disease. Exp Neurol 299:26\u201341. https:\/\/doi.org\/10.1016\/j.expneurol.2017.09.012","journal-title":"Exp Neurol"},{"key":"1802_CR40","doi-asserted-by":"publisher","unstructured":"Solovyeva VV, Alisa AS, Daria SC, Kristina VK, Lisa C, Albert AR (2018) New approaches to Tay-Sachs disease therapy. Front Physiol 9. https:\/\/doi.org\/10.3389\/fphys.2018.01663","DOI":"10.3389\/fphys.2018.01663"},{"issue":"3","key":"1802_CR41","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/sj.mt.6300049","volume":"15","author":"D Sondhi","year":"2007","unstructured":"Sondhi D, Hackett NR, Peterson DA, Stratton J, Baad M, Travis KM, Wilson JM, Crystal RG (2007) Enhanced survival of the LINCL mouse following CLN2 gene transfer using the rh.10 rhesus Macaque-derived Adeno-associated virus vector. Mol Ther 15(3):481\u2013491. https:\/\/doi.org\/10.1038\/sj.mt.6300049","journal-title":"Mol Ther"},{"key":"1802_CR42","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2015.00036","volume":"8","author":"Y Tanguy","year":"2015","unstructured":"Tanguy Y, Biferi MG, Besse A, Astord S, Cohen-Tannoudji M, Marais T, Barkats M (2015) Systemic AAVrh10 provides higher transgene expression than AAV9 in the brain and the spinal cord of neonatal mice. Front Mol Neurosci 8:36. https:\/\/doi.org\/10.3389\/fnmol.2015.00036","journal-title":"Front Mol Neurosci"},{"issue":"25","key":"1802_CR43","doi-asserted-by":"publisher","first-page":"26167","DOI":"10.1074\/jbc.M311591200","volume":"279","author":"D te Vruch","year":"2004","unstructured":"te Vruch D, Lloyd-Evans E, Veldman RJ, Neville DC, Dwek RA, Platt FM, van Blitterswijk WJ, Sillence DJ (2004) Accumulation of glycosphingolipids in Niemann-Pick C disease disrupts endosomal transport. J Biol Chem 279(25):26167\u201326175. https:\/\/doi.org\/10.1074\/jbc.M311591200","journal-title":"J Biol Chem"},{"issue":"7","key":"1802_CR44","doi-asserted-by":"publisher","first-page":"2014","DOI":"10.1093\/brain\/awy126","volume":"141","author":"J Tordo","year":"2018","unstructured":"Tordo J, O\u2019Leary C, Antunes ASLM, Palomar N, Aldrin-Kirk P, Basche M, Bennett A, D\u2019Souza Z, Gleitz H, Godwin A, Holley RJ, Parker H, Liao AY, Rouse P, Youshani AS, Dridi L, Martins C, Levade T, Stacey KB, Davis DM, Henckaerts E (2018) A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency. Brain 141(7):2014\u20132031. https:\/\/doi.org\/10.1093\/brain\/awy126","journal-title":"Brain"},{"key":"1802_CR45","doi-asserted-by":"publisher","DOI":"10.1038\/mtm.2015.57","volume":"3","author":"MB Tropak","year":"2016","unstructured":"Tropak MB, Yonekawa S, Karumuthil-Melethil S, Thompson P, Wakarchuk W, Gray SJ, Walia JS, Mark BL, Mahuran D (2016) Construction of a hybrid \u03b2-hexosaminidase subunit capable of forming stable homodimers that hydrolyze GM2 ganglioside in vivo. Mol Ther Methods Clin Dev 3:15057. https:\/\/doi.org\/10.1038\/mtm.2015.57","journal-title":"Mol Ther Methods Clin Dev"},{"issue":"4","key":"1802_CR46","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1002\/ana.22262","volume":"69","author":"D Tsuji","year":"2011","unstructured":"Tsuji D, Akeboshi H, Matsuoka K, Yasuoka H, Miyasaki E, Kasahara Y, Kawashima I, Chiba Y, Jigami Y, Taki T, Sakuraba H, Itoh K (2011) Highly phosphomannosylated enzyme replacement therapy for GM2 gangliosidosis. Ann Neurol 69(4):691\u2013701. https:\/\/doi.org\/10.1002\/ana.22262","journal-title":"Ann Neurol"},{"issue":"3","key":"1802_CR47","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1093\/hmg\/ddt454","volume":"23","author":"H Wang","year":"2014","unstructured":"Wang H, Yang B, Qiu L, Yang C, Kramer J, Su Q, Guo Y, Brown RH, Gao G, Xu Z (2014) Widespread spinal cord transduction by intrathecal injection of rAAV delivers efficacious RNAi therapy for amyotrophic lateral sclerosis. Hum Mol Genet 23(3):668\u2013681. https:\/\/doi.org\/10.1093\/hmg\/ddt454","journal-title":"Hum Mol Genet"},{"key":"1802_CR48","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.omtm.2018.10.011","volume":"12","author":"E Woodley","year":"2019","unstructured":"Woodley E, Osmon KJ, Thompson P, Richmond C, Chen Z, Gray SJ, Walia JS (2019) Efficacy of a bicistronic vector for correction of Sandhoff disease in a mouse model. Mol Ther Methods Clin Dev 12:47\u201357","journal-title":"Mol Ther Methods Clin Dev"},{"issue":"21","key":"1802_CR49","doi-asserted-by":"publisher","first-page":"9975","DOI":"10.1073\/pnas.91.21.9975","volume":"91","author":"S Yamanaka","year":"1994","unstructured":"Yamanaka S, Johnson MD, Grinberg A, Westphal H, Crawley JN, Taniike M, Suzuki K, Proia RL (1994) Targeted disruption of the hexa gene results in mice with biochemical and pathologic features of Tay-Sachs disease. PNAS 91(21):9975\u20139979. https:\/\/doi.org\/10.1073\/pnas.91.21.9975","journal-title":"PNAS"}],"container-title":["Metabolic Brain Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11011-026-01802-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11011-026-01802-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11011-026-01802-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T08:11:23Z","timestamp":1772007083000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11011-026-01802-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,25]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1802"],"URL":"https:\/\/doi.org\/10.1007\/s11011-026-01802-2","relation":{},"ISSN":["1573-7365"],"issn-type":[{"value":"1573-7365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,25]]},"assertion":[{"value":"26 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 February 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"39"}}