{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T20:42:47Z","timestamp":1789764167344,"version":"4.0.1"},"reference-count":28,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2012,2,7]],"date-time":"2012-02-07T00:00:00Z","timestamp":1328572800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2012,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Infantile neuronal ceroid lipofuscinosis (INCL) is a profoundly neurodegenerative disease of children caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase\u20101 (PPT1). There is currently no effective therapy for this invariably fatal disease. To date, preclinical experiments using single treatments have resulted in incremental clinical improvements. Therefore, we determined the efficacy of CNS\u2010directed AAV2\/5\u2010mediated gene therapy alone and in combination with the systemic delivery of the lysosomotropic PPT1 mimetic phosphocysteamine. Since CNS\u2010directed gene therapy provides relatively high levels of PPT1 activity to specific regions of the brain, we hypothesized that phosphocysteamine would complement that activity in regions expressing subtherapeutic levels of the enzyme. Results indicate that CNS\u2010directed gene therapy alone provided the greatest improvements in biochemical and histological measures as well as motor function and life span. Phosphocysteamine alone resulted in only minor improvements in motor function and no increase in lifespan. Interestingly, phosphocysteamine did not increase the biochemical and histological response when combined with AAV2\/5\u2010mediated gene therapy, but it did result in an additional improvement in motor function. These data suggest that a CNS\u2010directed gene therapy approach provides significant clinical benefit, and the addition of the small molecule PPT1 mimetic can further increase that response.<\/jats:p>","DOI":"10.1007\/s10545-011-9446-x","type":"journal-article","created":{"date-parts":[[2012,2,6]],"date-time":"2012-02-06T09:14:10Z","timestamp":1328519650000},"page":"847-857","source":"Crossref","is-referenced-by-count":48,"title":["Combination small molecule PPT1 mimetic and CNS\u2010directed gene therapy as a treatment for infantile neuronal ceroid lipofuscinosis"],"prefix":"10.1002","volume":"35","author":[{"given":"Marie S.","family":"Roberts","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Washington University School of Medicine Campus Box 8007 660 S. Euclid Ave. St. Louis MO 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon L.","family":"Macauley","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Washington University School of Medicine Campus Box 8007 660 S. Euclid Ave. St. Louis MO 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M.","family":"Wong","sequence":"additional","affiliation":[{"name":"Pediatric Storage Disorders Laboratory, Department of Neuroscience and MRC Centre for Neurodegeneration Research, Institute of Psychiatry King's College London London SE5 9NU UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Yilmas","sequence":"additional","affiliation":[{"name":"Pediatric Storage Disorders Laboratory, Department of Neuroscience and MRC Centre for Neurodegeneration Research, Institute of Psychiatry King's College London London SE5 9NU UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Hohm","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Washington University School of Medicine Campus Box 8007 660 S. Euclid Ave. St. Louis MO 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan D.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Pediatric Storage Disorders Laboratory, Department of Neuroscience and MRC Centre for Neurodegeneration Research, Institute of Psychiatry King's College London London SE5 9NU UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark S.","family":"Sands","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Washington University School of Medicine Campus Box 8007 660 S. Euclid Ave. St. Louis MO 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,2,7]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2004.02.010"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2004.05.024"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI3112"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.7.3428"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.2350\/07-03-0242.1"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2004.03.005"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2005.04.018"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2005.11.008"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.251485198"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00697751"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(73)90076-2"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1159\/000213746"},{"key":"e_1_2_6_14_1","first-page":"3877","volume-title":"The metabolic and molecular basis of inherited disease","author":"Hofmann SL","year":"2001"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1006\/mgme.1999.2803"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1053\/ejpn.2000.0465"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2006.09.001"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp355"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-006-0225-z"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2009.01.022"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.2.291"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2004.tb00502.x"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2005.01.011"},{"key":"e_1_2_6_24_1","first-page":"676","article-title":"Treatment of murine mucopolysaccharidosis type VII in newborns by syngeneic bone marrow transplantation","volume":"68","author":"Sands MS","year":"1993","journal-title":"Lab. 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