{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T20:42:55Z","timestamp":1789764175518,"version":"4.0.1"},"reference-count":30,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2012,2,24]],"date-time":"2012-02-24T00:00:00Z","timestamp":1330041600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2012,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective:<\/jats:title><jats:p>Infantile neuronal ceroid lipofuscinosis (INCL) is an inherited childhood neurodegenerative disorder caused by the loss of palmitoyl protein thioesterase\u20101 (PPT1) activity. Affected children suffer from blindness, epilepsy, motor dysfunction, cognitive decline, and premature death. The <jats:italic>Ppt1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse shares the histological and clinical features of INCL. Previous single\u2010therapy approaches using small molecule drugs, gene therapy, or neuronal stem cells resulted in partial histological correction, with minimal improvements in motor function or lifespan. Here, we combined central nervous system (CNS)\u2010directed adeno\u2010associated virus (AAV)2\/5\u2010mediated gene therapy with bone marrow transplantation (BMT) in the INCL mouse.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>At birth, <jats:italic>Ppt1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and wild\u2010type mice were given either intracranial injections of AAV2\/5\u2010PPT1 or bone marrow transplantation, separately as well as in combination. To assess function, we measured rotorod performance monthly as well as lifespan. At terminal time points, we evaluated the therapeutic effects on several INCL\u2010specific parameters, such as cortical thickness, autofluorescent accumulation, and glial activation. Finally, we determined levels of PPT1 enzyme activity and bone marrow engraftment in treated mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>AAV2\/5\u2010mediated gene therapy alone resulted in significant histological correction, improved motor function, and increased lifespan. Interestingly, the addition of BMT further increased the lifespan of treated mice and led to dramatic, sustained improvements in motor function. These data are truly striking, given that BMT alone is ineffective, yet it synergizes with CNS\u2010directed gene therapy to dramatically increase efficacy and lifespan.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation:<\/jats:title><jats:p>AAV2\/5\u2010mediated gene therapy in combination with BMT provides an unprecedented increase in lifespan as well as dramatic improvement on functional and histological parameters. ANN NEUROL 2012;<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.23545","type":"journal-article","created":{"date-parts":[[2012,2,1]],"date-time":"2012-02-01T15:29:46Z","timestamp":1328110186000},"page":"797-804","source":"Crossref","is-referenced-by-count":75,"title":["Synergistic effects of central nervous system\u2010directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis"],"prefix":"10.1002","volume":"71","author":[{"given":"Shannon L.","family":"Macauley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie S.","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew 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