{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T06:31:19Z","timestamp":1793082679605,"version":"4.5.0"},"reference-count":66,"publisher":"American Society for Clinical Investigation","issue":"8","license":[{"start":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T00:00:00Z","timestamp":1619049600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NIH S10OD0018070"],"award-info":[{"award-number":["NIH S10OD0018070"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Swim Across America Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100013220","name":"Ultragenyx Pharmaceutical","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100013220","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NICHD\/NIH","award":["R24HD102061"],"award-info":[{"award-number":["R24HD102061"]}]},{"name":"funding sources listed below remain accurate","award":["see below"],"award-info":[{"award-number":["see below"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,22]]},"abstract":"<jats:p>\n                    Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare metabolic disorder caused by inactivating mutations in sphingosine-1-phosphate lyase 1 (\n                    <jats:italic>SGPL1<\/jats:italic>\n                    ), which is required for the final step of sphingolipid metabolism. SPLIS features include steroid-resistant nephrotic syndrome and impairment of neurological, endocrine, and hematopoietic systems. Many affected individuals die within the first 2 years. No targeted therapy for SPLIS is available. We hypothesized that\n                    <jats:italic>SGPL1<\/jats:italic>\n                    gene replacement would address the root cause of SPLIS, thereby serving as a universal treatment for the condition. As proof of concept, we evaluated the efficacy of adeno-associated virus 9\u2013mediated transfer of human\n                    <jats:italic>SGPL1<\/jats:italic>\n                    (AAV-SPL) given to newborn\n                    <jats:italic>Sgpl1<\/jats:italic>\n                    -KO mice that model SPLIS and die in the first weeks of life. Treatment dramatically prolonged survival and prevented nephrosis, neurodevelopmental delay, anemia, and hypercholesterolemia. STAT3 pathway activation and elevated proinflammatory and profibrogenic cytokines observed in KO kidneys were attenuated by treatment. Plasma and tissue sphingolipids were reduced in treated compared with untreated KO pups.\n                    <jats:italic>SGPL1<\/jats:italic>\n                    expression and activity were measurable for at least 40 weeks. In summary, early AAV-SPL treatment prevents nephrosis, lipidosis, and neurological impairment in a mouse model of SPLIS. Our results suggest that\n                    <jats:italic>SGPL1<\/jats:italic>\n                    gene replacement holds promise as a durable and universal targeted treatment for SPLIS.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.145936","type":"journal-article","created":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T12:04:35Z","timestamp":1616501075000},"source":"Crossref","is-referenced-by-count":33,"title":["Efficacy of AAV9-mediated SGPL1 gene transfer in a mouse model of S1P lyase insufficiency syndrome"],"prefix":"10.1172","volume":"6","author":[{"given":"Piming","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Pediatrics, UCSF, San Francisco, California, USA."},{"name":"Cure Genetics, Suzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gizachew B.","family":"Tassew","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, UCSF, San Francisco, California, 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