{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:17:41Z","timestamp":1789993061687,"version":"4.0.1"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,9,15]],"date-time":"2020-09-15T00:00:00Z","timestamp":1600128000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Niemann-Pick UK"},{"name":"NPSuisse"},{"name":"Horizon 2020 - Marie Sk\u0142odowska-Curie Research and Innovation Staff Exchange (RISE)"},{"DOI":"10.13039\/501100008165","name":"Niemann-Pick Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008165","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UK Department of Health\u2019s NIHR Biomedical Research Centres"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Acetyl-dl-leucine is a derivative of the branched chain amino acid leucine. In observational clinical studies, acetyl-dl-leucine improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder, Niemann-Pick disease type C1. Here, we investigated acetyl-dl-leucine and its enantiomers acetyl-l-leucine and acetyl-d-leucine in symptomatic Npc1\u2212\/\u2212 mice and observed improvement in ataxia with both individual enantiomers and acetyl-dl-leucine. When acetyl-dl-leucine and acetyl-l-leucine were administered pre-symptomatically to Npc1\u2212\/\u2212 mice, both treatments delayed disease progression and extended life span, whereas acetyl-d-leucine did not. These data are consistent with acetyl-l-leucine being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were implicated as one of the potential mechanisms of action of the l-enantiomer in Npc1\u2212\/\u2212 mice. When the standard of care drug miglustat and acetyl-dl-leucine were used in combination significant synergy resulted. In agreement with these pre-clinical data, when Niemann-Pick disease type C1 patients were evaluated after 12 months of acetyl-dl-leucine treatment, rates of disease progression were slowed, with stabilization or improvement in multiple neurological domains. A beneficial effect of acetyl-dl-leucine on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual-cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-l-leucine and underlying mechanisms of action in lysosomal storage diseases, supporting its further evaluation in clinical trials in lysosomal disorders.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaa148","type":"journal-article","created":{"date-parts":[[2020,9,15]],"date-time":"2020-09-15T14:38:56Z","timestamp":1600180736000},"source":"Crossref","is-referenced-by-count":83,"title":["Acetyl-leucine slows disease progression in lysosomal storage disorders"],"prefix":"10.1093","volume":"3","author":[{"given":"Ecem","family":"Kaya","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Oxford OX1 3QT, 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