{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:27:26Z","timestamp":1782275246208,"version":"3.54.5"},"reference-count":78,"publisher":"American Society for Clinical Investigation","issue":"19","license":[{"start":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T00:00:00Z","timestamp":1728345600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,8]]},"abstract":"<jats:p>\n                    The cytoplasmic peptide:N-glycanase (NGLY1) is ubiquitously expressed and functions as a de\u2013N-glycosylating enzyme that degrades misfolded N-glycosylated proteins. NGLY1 deficiency due to biallelic loss-of-function\n                    <jats:italic>NGLY1<\/jats:italic>\n                    variants is an ultrarare autosomal recessive deglycosylation disorder with multisystemic involvement; the neurological manifestations represent the main disease burden. Currently, there is no treatment for this disease. To develop a gene therapy, we first characterized a tamoxifen-inducible\n                    <jats:italic>Ngly1<\/jats:italic>\n                    -knockout (\n                    <jats:italic>iNgly1<\/jats:italic>\n                    ) C57BL\/6J mouse model, which exhibited symptoms recapitulating human disease, including elevation of the biomarker GlcNAc-Asn, motor deficits, kyphosis, Purkinje cell loss, and gait abnormalities. We packaged a codon-optimized human\n                    <jats:italic>NGLY1<\/jats:italic>\n                    transgene cassette into 2 adeno-associated virus (AAV) capsids, AAV9 and AAV.PHPeB. Systemic administration of the AAV.PHPeB vector to symptomatic\n                    <jats:italic>iNgly1<\/jats:italic>\n                    mice corrected multiple disease features at 8 weeks after treatment. Furthermore, another cohort of AAV.PHPeB-treated\n                    <jats:italic>iNgly1<\/jats:italic>\n                    mice were monitored over a year and showed near-complete normalization of the neurological aspects of the disease phenotype, demonstrating the durability of gene therapy. Our data suggested that brain-directed\n                    <jats:italic>NGLY1<\/jats:italic>\n                    gene replacement via systemic delivery is a promising therapeutic strategy for NGLY1 deficiency. Although the superior CNS tropism of AAV.PHPeB vector does not translate to primates, emerging AAV capsids with enhanced primate CNS tropism will enable future translational studies.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.183189","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T12:00:16Z","timestamp":1723550416000},"source":"Crossref","is-referenced-by-count":7,"title":["Systemic gene therapy corrects the neurological phenotype in a mouse model of NGLY1 deficiency"],"prefix":"10.1172","volume":"9","author":[{"given":"Ailing","family":"Du","sequence":"first","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2011-7084","authenticated-orcid":true,"given":"Kun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Immunology 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