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These efforts were successfully coupled with unprecedented clinical results of the trials employing the newly developed technology and with the novel establishment of academic\u2013industrial partnerships. A renewed and strengthened interest is rising in the development of gene-based approaches for inherited neurometabolic disorders with severe neurological involvement. Inherited metabolic disorders are monogenetic diseases caused by enzymatic or structural deficiencies affecting the lysosomal or peroxisomal metabolic activity. The metabolic defect can primarily affect the central nervous system, leading to neuronal death, microglial activation, inflammatory demyelination, and axonal degeneration. This review provides an overview of the GT strategies currently under clinical investigation for neurometabolic lysosomal and peroxisomal storage diseases, such as adrenoleukodystrophy and metachromatic leukodystrophy, as well as novel emerging indications such as mucopolysaccharidoses, gangliosidoses, and neuronal ceroid lipofuscinoses, with a comprehensive elucidation of the main features and mechanisms at the basis of a successful GT approach for these devastating diseases.<\/jats:p>","DOI":"10.1089\/hum.2019.190","type":"journal-article","created":{"date-parts":[[2019,8,9]],"date-time":"2019-08-09T06:57:08Z","timestamp":1565333828000},"page":"1222-1235","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":32,"title":["Gene-Based Approaches to Inherited Neurometabolic Diseases"],"prefix":"10.1177","volume":"30","author":[{"given":"Valentina","family":"Poletti","sequence":"first","affiliation":[{"name":"Gene Therapy Program, Dana-Farber\/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Biffi","sequence":"additional","affiliation":[{"name":"Gene Therapy Program, Dana-Farber\/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts"},{"name":"Pediatric Hematology, Oncology and Stem Cell Transplant, Woman's and Child Health Department, University of Padova, Padova, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,9,24]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2745"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.3233\/TRD-160005"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2015.00417"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2006.09.010"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.03.025"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-015-0313-y"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2016.2067"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr142"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1233158"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)30374-9"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2017.152"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2017.10.010"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1205858109"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1701211"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2017.10.001"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfw220"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2016.087"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1515"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2017.11.007"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2017.12.002"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2016.06.006"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2015.99"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199006283222607"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.34.11.1410"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2010.00394.x"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0306431101"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1171242"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-386509-0.00010-7"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1700554"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2018.079"},{"key":"e_1_3_3_32_2","unstructured":"The Myelin Project. 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