{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T23:39:35Z","timestamp":1773013175403,"version":"3.50.1"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["U01 HD079066"],"award-info":[{"award-number":["U01 HD079066"]}]},{"name":"Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["Z01 HD008927"],"award-info":[{"award-number":["Z01 HD008927"]}]},{"name":"Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["R01 NS110349"],"award-info":[{"award-number":["R01 NS110349"]}]},{"name":"NIH Intramural Bench-to-Bedside Awards"},{"name":"Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,3,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The choroid plexuses (CP) are highly vascularized structures that project into the ventricles of the vertebrate brain. The polarized epithelia of the CP produce cerebrospinal fluid by transporting water and ions into the ventricles from the blood and normally secrete a large number of proteins. We assessed the feasibility of selective CP transduction with recombinant adeno-associated virus (rAAV) gene therapy vectors for treatment of lysosomal storage disease (LSD), a broad category of neurometabolic illness associated with significant burdens to affected patients and their families. There are no ideal or complete therapeutic options currently available, especially for the central nervous system manifestations of LSDs. Alpha-mannosidosis (AMD) is an autosomal recessive prototypical LSD caused by deficiency of lysosomal alpha-mannosidase and characterized by cerebellar ataxia, neurocognitive disability, facial and skeletal abnormalities, hearing impairment, and mild immune deficiency. In a murine model of AMD, we compared the biochemical effects of CSF-directed rAAV serotypes 1, 4, 5, 6, and 9. Recombinant AAV1 and rAAV6, two closely related serotypes whose capsid sequences differ by only six amino acids, showed the most robust transduction of CP in mouse brain, consistent with their transduction of CPE in nonhuman primates and cats, as well as in other structures. We found restoration of LAMAN enzyme activity comparable to or higher than AMD heterozygote levels in the brain globally (olfactory bulb, cortex, cerebellum, brainstem). Further IND-generating preclinical experiments will advance rAAV6-LAMAN, which appears to be the most promising choroid plexus-targeting candidate serotype for future clinical translation to treat AMD.<\/jats:p>","DOI":"10.1093\/hmg\/ddae201","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T06:30:15Z","timestamp":1737009015000},"page":"577-585","source":"Crossref","is-referenced-by-count":1,"title":["Choroid plexus-targeted viral gene therapy for alpha-mannosidosis, a prototypical neurometabolic lysosomal storage disease"],"prefix":"10.1093","volume":"34","author":[{"given":"Eun-Young","family":"Choi","sequence":"first","affiliation":[{"name":"Section on Translational Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , 9000 Rockville Pike, Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John H","family":"Wolfe","sequence":"additional","affiliation":[{"name":"Research Institute of Children's Hospital of Philadelphia, 502-G Abramson Research Center, 3615 Civic Center Boulevard , Philadelphia, PA 19104,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen G","family":"Kaler","sequence":"additional","affiliation":[{"name":"Section on Translational Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , 9000 Rockville Pike, Bethesda, MD 20892 ,","place":["USA"]},{"name":"Center for Gene Therapy, Nationwide Children\u2019s Hospital, Abigail Wexner Research Institute, and Department of Pediatrics, The Ohio State University College of Medicine , 575 Children's Crossroad, Columbus, OH 43215 ,","place":["USA"]},{"name":"Department of Pediatrics, Vagelos College of Physicians & Surgeons, Columbia University , 630 West 168th Street, Room 10-451, New York, NY 10032 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,1,16]]},"reference":[{"key":"2025032012272776200_ref1","first-page":"S118","article-title":"Delivery of recombinant proteins via the cerebrospinal fluid as a therapy option for neurodegenerative lysosomal storage diseases","volume":"47","author":"Hemsley","year":"2009","journal-title":"Int J Clin Pharmacol Ther"},{"key":"2025032012272776200_ref2","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.ymgme.2004.07.003","article-title":"Intrathecal enzyme replacement therapy reduces lysosomal storage in the brain and meninges of the canine model of MPS I","volume":"83","author":"Kakkis","year":"2004","journal-title":"Mol Genet Metab"},{"key":"2025032012272776200_ref3","doi-asserted-by":"crossref","first-page":"60ra89","DOI":"10.1126\/scitranslmed.3001380","article-title":"Replacing the enzyme alpha-Liduronidase at birth ameliorates symptoms in the brain and periphery of dogs with mucopolysaccharidosis type I","volume":"2","author":"Dierenfeld","year":"2010","journal-title":"Sci Transl Med"},{"key":"2025032012272776200_ref4","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.ymgme.2006.10.005","article-title":"Injection of recombinant human sulfamidase into the CSF via the cerebellomedullary cistern in MPS IIIA mice","volume":"90","author":"Hemsley","year":"2007","journal-title":"Mol Genet Metab"},{"key":"2025032012272776200_ref5","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.ymgme.2015.03.002","article-title":"Determination of the role of injection site on the efficacy of intra-CSF enzyme replacement therapy in MPS IIIA mice","volume":"115","author":"Beard","year":"2015","journal-title":"Mol Genet Metab"},{"key":"2025032012272776200_ref6","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.nbd.2011.04.014","article-title":"Enzyme replacement reduces neuropathology in MPS IIIA dogs","volume":"43","author":"Crawley","year":"2011","journal-title":"Neurobiol Dis"},{"key":"2025032012272776200_ref7","doi-asserted-by":"crossref","first-page":"2520","DOI":"10.1096\/fj.06-6169com","article-title":"Single dose intracerebroventricular administration of galactocerebrosidase improves survival in a mouse model of globoid cell leukodystrophy","volume":"21","author":"Lee","year":"2007","journal-title":"FASEB J"},{"key":"2025032012272776200_ref8","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/mt.2008.9","article-title":"Intraventricular enzyme replacement improves disease phenotypes in a mouse model of late infantile neuronal ceroid lipofuscinosis","volume":"16","author":"Chang","year":"2008","journal-title":"Mol Ther"},{"key":"2025032012272776200_ref9","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1002\/jnr.23423","article-title":"Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease)","volume":"92","author":"Katz","year":"2014","journal-title":"J Neurosci Res"},{"key":"2025032012272776200_ref10","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.expneurol.2008.10.021","article-title":"Intracerebroventricular infusion of acid sphingomyelinase corrects CNS manifestations in a mouse model of Niemann-pick a disease","volume":"215","author":"Dodge","year":"2009","journal-title":"Exp Neurol"},{"key":"2025032012272776200_ref11","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.ymgme.2009.10.002","article-title":"Repeated intrathecal injections of recombinant human 4-sulphatase remove dural storage in mature mucopolysaccharidosis VI cats primed with a short-course tolerisation regimen","volume":"99","author":"Auclair","year":"2010","journal-title":"Mol Genet Metab"},{"key":"2025032012272776200_ref12","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/S0140-6736(16)30374-9","article-title":"Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1\/2 trial","volume":"388","author":"Sessa","year":"2016","journal-title":"Lancet"},{"key":"2025032012272776200_ref13","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1056\/NEJMoa1700554","article-title":"Hematopoietic stem-cell gene therapy for cerebral Adrenoleukodystrophy","volume":"377","author":"Eichler","year":"2017","journal-title":"N Engl J Med"},{"key":"2025032012272776200_ref14","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1007\/s11912-018-0719-5","article-title":"Long-term effects of Myeloablative allogeneic hematopoietic stem cell transplantation in Pediatric patients with acute lymphoblastic Leukemia","volume":"20","author":"Lawitschka","year":"2018","journal-title":"Curr Oncol Rep"},{"key":"2025032012272776200_ref15","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/bmt.2011.99","article-title":"Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients","volume":"47","author":"Mynarek","year":"2012","journal-title":"Bone Marrow Transplant"},{"key":"2025032012272776200_ref16","doi-asserted-by":"crossref","first-page":"247","DOI":"10.3109\/02713688809047029","article-title":"Cell turnover in ciliary epithelium compared to other slow renewing epithelia in the adult mouse","volume":"7","author":"McDonald","year":"1988","journal-title":"Curr Eye Res"},{"key":"2025032012272776200_ref17","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1743-8454-7-16","article-title":"Development of the lateral ventricular choroid plexus in a marsupial, Monodelphis domestica","volume":"7","author":"Liddelow","year":"2010","journal-title":"Cerebrospinal Fluid Res"},{"key":"2025032012272776200_ref18","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/nrn3921","article-title":"Development and functions of the choroid plexus-cerebrospinal fluid system","volume":"16","author":"Lun","year":"2015","journal-title":"Nat Rev Neurosci"},{"key":"2025032012272776200_ref19","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/nrd.2018.110","article-title":"Gene therapy for neurological disorders: progress and prospects","volume":"17","author":"Deverman","year":"2018","journal-title":"Nat Rev Drug Discov"},{"key":"2025032012272776200_ref20","first-page":"F835","article-title":"Drainage of interstitial fluid from different regions of rat brain","volume":"246","author":"Szentistv\u00e1nyi","year":"1984","journal-title":"Am J Phys"},{"key":"2025032012272776200_ref21","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/0006-8993(85)91383-6","article-title":"Evidence for a \u2018paravascular\u2019 fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space","volume":"326","author":"Rennels","year":"1985","journal-title":"Brain Res"},{"key":"2025032012272776200_ref22","doi-asserted-by":"crossref","first-page":"147ra111","DOI":"10.1126\/scitranslmed.3003748","article-title":"A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid \u03b2","volume":"4","author":"Iliff","year":"2012","journal-title":"Sci Transl Med"},{"key":"2025032012272776200_ref23","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1126\/science.162.3853.570","article-title":"Hurler and Hunter syndromes: mutual correction of the defect in cultured fibroblasts","volume":"162","author":"Fratantoni","year":"1968","journal-title":"Science"},{"key":"2025032012272776200_ref24","first-page":"383","article-title":"Lentiviral vectors for gene transfer to the central nervous system. Applications in lysosomal storage disease animal models","volume":"76","author":"Watson","year":"2003","journal-title":"Methods Mol Med"},{"key":"2025032012272776200_ref25","doi-asserted-by":"crossref","first-page":"R65","DOI":"10.1093\/hmg\/ddv457","article-title":"Gene therapy for lysosomal storage disorders: a good start","volume":"25","author":"Biffi","year":"2016","journal-title":"Hum Mol Genet 2016"},{"key":"2025032012272776200_ref26","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.omtm.2018.07.002","article-title":"Cerebrospinal fluid- directed rAAV9-rsATP7A plus subcutaneous copper Histidinate advance survival and outcomes in a Menkes disease mouse model","volume":"10","author":"Haddad","year":"2018","journal-title":"Mol Ther Methods Clin Dev"},{"key":"2025032012272776200_ref27","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.ymthe.2006.02.012","article-title":"Genetic correction of the fetal brain increases the lifespan of mice with the severe multisystemic disease mucopolysaccharidosis type VII","volume":"14","author":"Karolewski","year":"2006","journal-title":"Mol Ther"},{"key":"2025032012272776200_ref28","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1093\/hmg\/8.8.1365","article-title":"Targeted disruption of the lysosomal alpha-mannosidase gene results in mice resembling a mild form of human alpha-mannosidosis","volume":"8","author":"Stinchi","year":"1999","journal-title":"Hum Mol Genet"},{"key":"2025032012272776200_ref29","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1038\/mt.2011.143","article-title":"ATP7A gene addition to the choroid plexus results in long-term rescue of the lethal copper transport defect in a Menkes disease mouse model","volume":"19","author":"Donsante","year":"2011","journal-title":"Mol Ther"},{"key":"2025032012272776200_ref30","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1089\/hum.2005.16.49","article-title":"Transduction of the choroid plexus and ependyma in neonatal mouse brain by vesicular stomatitis virus glycoprotein-pseudotyped lentivirus and adeno-associated virus type 5 vectors","volume":"16","author":"Watson","year":"2005","journal-title":"Hum Gene Ther"},{"key":"2025032012272776200_ref31","volume-title":"GeneReviews\u00ae[Internet]","author":"Malm","year":"1993\u20132023"},{"key":"2025032012272776200_ref32","doi-asserted-by":"crossref","first-page":"60ra89","DOI":"10.1126\/scitranslmed.3001380","article-title":"Replacing the enzyme alpha-L-iduronidase at birth ameliorates symptoms in the brain and periphery of dogs with mucopolysaccharidosis type I","volume":"2","author":"Dierenfeld","year":"2010","journal-title":"Sci Transl Med"},{"key":"2025032012272776200_ref33","doi-asserted-by":"crossref","first-page":"2538","DOI":"10.1002\/ajmg.a.32294","article-title":"Intrathecal enzyme replacement therapy in a patient with mucopolysaccharidosis type I and symptomatic spinal cord compression","volume":"146A","author":"Munoz-Rojas","year":"2008","journal-title":"Am J Med Genet A"},{"key":"2025032012272776200_ref34","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ymgme.2015.07.005","article-title":"Mucopolysaccharidosis I intrathecal research collaborative. Safety of laronidase delivered into the spinal canal for treatment of cervical stenosis in mucopolysaccharidosis I","volume":"116","author":"Dickson","year":"2015","journal-title":"Mol Genet Metab"},{"key":"2025032012272776200_ref35","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/gim.2015.36","article-title":"A phase I\/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II","volume":"18","author":"Muenzer","year":"2016","journal-title":"Genet Med"},{"key":"2025032012272776200_ref36","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ymgme.2016.05.006","article-title":"A phase 1\/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA","volume":"118","author":"Jones","year":"2016","journal-title":"Mol Genet Metab"},{"key":"2025032012272776200_ref37","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/s40478-017-0464-2","article-title":"Long-term neurologic and cardiac correction by intrathecal gene therapy in Pompe disease","volume":"5","author":"Hordeaux","year":"2017","journal-title":"Acta Neuropathol Commun"},{"key":"2025032012272776200_ref38","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1007\/s10545-013-9595-1","article-title":"Enzyme replacement therapy for alpha-mannosidosis: 12 months follow-up of a single Centre, randomised, multiple dose study","volume":"36","author":"Borgwardt","year":"2013","journal-title":"J Inherit Metab Dis"},{"key":"2025032012272776200_ref39","doi-asserted-by":"crossref","DOI":"10.3390\/ijms19051500","article-title":"Alpha-Mannosidosis: therapeutic strategies","volume":"19","author":"Ceccarini","year":"2018","journal-title":"Int J Mol Sci"},{"key":"2025032012272776200_ref40","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1007\/s10545-018-0175-2","article-title":"Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis","volume":"41","author":"Lund","year":"2018","journal-title":"J Inherit Metab Dis"},{"key":"2025032012272776200_ref41","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1007\/s10545-018-0185-0","article-title":"Efficacy and safety of Velmanase alfa in the treatment of patients with alpha- mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial","volume":"41","author":"Borgwardt","year":"2018","journal-title":"J Inherit Metab Dis"},{"key":"2025032012272776200_ref42","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.ymgme.2018.04.003","article-title":"Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): novel global treatment response model and outcomes in patients with alpha-mannosidosis","volume":"124","author":"Harmatz","year":"2018","journal-title":"Mol Genet Metab"},{"key":"2025032012272776200_ref43","doi-asserted-by":"crossref","first-page":"7034","DOI":"10.1128\/JVI.77.12.7034-7040.2003","article-title":"Intraventricular brain injection of adeno-associated virus type 1 (AAV1) in neonatal mice results in complementary patterns of neuronal transduction to AAV2 and total long-term correction of storage lesions in the brains of \u03b2-Glucuronidase-deficient mice","volume":"77","author":"Passini","year":"2003","journal-title":"J Virol"},{"key":"2025032012272776200_ref44","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.omtm.2022.07.007","article-title":"Transduction characteristics of alternative adeno-associated virus serotypes in the cat brain by intracisternal delivery","volume":"26","author":"Hunter","year":"2022","journal-title":"Mol Ther Methods Clin Dev"},{"key":"2025032012272776200_ref45","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.lfs.2015.10.025","article-title":"Men and mice: relating their ages","volume":"152","author":"Dutta","year":"2016","journal-title":"Life Sci"},{"key":"2025032012272776200_ref46","doi-asserted-by":"crossref","first-page":"5219","DOI":"10.1128\/JVI.00161-16","article-title":"Characterization of the adeno-associated virus 1 and 6 sialic acid binding site","volume":"90","author":"Huang","year":"2016","journal-title":"J Virol"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/34\/7\/577\/61455095\/ddae201.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/34\/7\/577\/61455095\/ddae201.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T23:50:39Z","timestamp":1742514639000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/34\/7\/577\/7954545"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,16]]},"references-count":46,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,1,16]]},"published-print":{"date-parts":[[2025,3,20]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddae201","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,4,1]]},"published":{"date-parts":[[2025,1,16]]}}}