Acetyl-leucine slows disease progression in lysosomal storage disorders
- Kaya, Ecem Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
- Smith, David A Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
- Smith, Claire Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
- Morris, Lauren Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
- Bremova-Ertl, Tatiana Department of Chemistry, School of Life Sciences, University of Sussex, Brighton, UK
- Cortina-Borja, Mario Population, Policy and Practice Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London
- Fineran, Paul Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
- Morten, Karl J Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK
- Poulton, Joanna Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK
- Boland, Barry Dept. of Pharmacology and Therapeutics, Western Gateway Building, College of Medicine and Health, University College Cork, Ireland
- Spencer, John Department of Chemistry, School of Life Sciences, University of Sussex, Brighton, UK
- Strupp, Michael Department of Neurology and German Center for Vertigo and Balance Disorders, Ludwig Maximilians University, Munich, Germany
- Platt, Frances M Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
- 2020-9-15
Published in:
- Brain Communications. - Oxford University Press (OUP). - 2020
English
Abstract
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-/- 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-/- 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-/- 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 stabilisation 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.
- Language
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- English
- Open access status
- gold
- Identifiers
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- DOI 10.1093/braincomms/fcaa148
- ISSN 2632-1297
- Persistent URL
- https://sonar.ch/global/documents/429
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