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Acetyl-leucine slows disease progression in lysosomal storage disorders

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Version 2 2023-06-12, 09:29
Version 1 2023-06-09, 21:37
journal contribution
posted on 2023-06-12, 09:29 authored by Ecem Kaya, David A Smith, Claire Smith, Lauren Morris, Tatiana Bremova-Ertl, Mario Cortina-Borja, Paul Fineran, Karl J Morten, Joanna Poulton, Barry Boland, John SpencerJohn Spencer, Michael Strupp, Frances M Platt
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.

Funding

LysoMod - Genetic and Small Molecule Modifiers of Lysosomal Function; G2385; EUROPEAN UNION; 734825

History

Publication status

  • Published

File Version

  • Published version

Journal

Brain Communications

ISSN

2632-1297

Publisher

Oxford University Press

Issue

1

Volume

3

Page range

1-52

Department affiliated with

  • Chemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2020-09-22

First Open Access (FOA) Date

2020-09-22

First Compliant Deposit (FCD) Date

2020-09-19

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