{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T01:52:08Z","timestamp":1783734728682,"version":"3.55.0"},"reference-count":77,"publisher":"SAGE Publications","issue":"5-6","license":[{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:p>\n                    Beta-propeller protein-associated neurodegeneration (BPAN) is an ultra-rare, X-linked dominant, neurodevelopmental, and neurodegenerative disease caused by loss-of-function mutations in the\n                    <jats:italic toggle=\"yes\">WDR45<\/jats:italic>\n                    gene. It manifests in neurodevelopmental delay and seizures followed by secondary neurological decline with dystonia\/parkinsonism and dementia in adolescence and early adulthood and is characterized by progressive accumulation of iron in the basal ganglia.\n                    <jats:italic toggle=\"yes\">WDR45<\/jats:italic>\n                    encodes \u03b2-propeller-shaped scaffold protein, or WD repeat domain phosphoinositide-interacting protein 4 (WIPI4), which plays an important role in autophagosome formation. While the mechanisms of how WIPI4 loss of function results in neurological decline and brain pathology have not yet been established, findings of lower autophagic activity provide a direct link between impaired autophagy and neurological disease in BPAN. Here we performed phenotypical characterization of a novel mouse model of BPAN, Wdr45_ex9+1g&gt;a mouse. We identified hyperactive behavior and reduction of autophagy markers in brain tissue in Wdr45_ex9+1g&gt;a hemizygous males as early as at 2 months of age. Given the early onset and spectrum of neurological symptoms such as hyper-arousal and attention deficits in human patients, this model presents a disease-relevant phenotype and can be used in preclinical studies. We used this mouse model for a proof-of-concept study to evaluate whether adeno-associated virus (AAV)-mediated central nervous system (CNS)-targeted gene transfer of\n                    <jats:italic toggle=\"yes\">WDR45<\/jats:italic>\n                    can provide therapeutic benefit and be considered a therapeutic paradigm for BPAN. We observed successful expression of human\n                    <jats:italic toggle=\"yes\">WDR45<\/jats:italic>\n                    transcripts and WIPI4 protein in the brain tissue, rescue of hyperactive behavior, and correction of autophagy markers. These data demonstrate that\n                    <jats:italic toggle=\"yes\">WDR45<\/jats:italic>\n                    gene transfer can be a promising therapeutic strategy for BPAN.\n                  <\/jats:p>","DOI":"10.1089\/hum.2024.224","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T19:31:57Z","timestamp":1740079917000},"page":"637-652","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["AAV-Mediated Gene Transfer of WDR45 Corrects Neurological Deficits in the Mouse Model of Beta-Propeller Protein-Associated Neurodegeneration"],"prefix":"10.1177","volume":"36","author":[{"given":"Maria Carla","family":"Carisi","sequence":"first","affiliation":[{"name":"Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Shamber","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Bishop","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison","family":"Sangster","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uma","family":"Chandrachud","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Meyerink","sequence":"additional","affiliation":[{"name":"Pediatrics and Rare Diseases Group, Sanford Research Institute, University of South Dakota, Sioux Falls, South Dakota, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis Jean","family":"Pilaz","sequence":"additional","affiliation":[{"name":"Pediatrics and Rare Diseases Group, Sanford Research Institute, University of South Dakota, Sioux Falls, South Dakota, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4684-4159","authenticated-orcid":false,"given":"Yulia","family":"Grishchuk","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,3,6]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.10.019"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2562"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2021.1899669"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/ccr3.1358"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2022.07.009"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awt095"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2015.01.020"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2020.03.005"},{"key":"e_1_3_6_10_2","volume-title":"GeneReviews. 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