Acetyl-leucine slows disease progression in lysosomal storage disorders

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 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.