Acetyl-leucine slows disease progression in lysosomal storage disorders

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.

Acetyl-L-leucine for Niemann-Pick type C – a multi-national, rater-blinded phase II trial

“…This is in line with the previous observational studies that indicated the additive effect of NALL with Miglustat (Bremova et al, 2015;Cortina-Borja et al, 2018), and studies demonstrating synergistic effects of NALL and Miglustat (Kaya et al, 2020a). NALL's positive treatment effects directly correlate to its pharmacological action: Animal studies in an Npc1 -/mouse model show NALL significantly reduces ataxia when treatment is initiated either symptomatically (from 8-weeks of age) or pre-symptomatically (from 3-weeks of age) (Kaya et al, 2020a). These in vivo studies further show NALL can restore neuronal function and protect against/delay disease progression in multiple neurological brain circuits.…”

“…In a case series, short-term treatment with N-acetyl-DL-leucine was found to improve ataxia, cognition, and quality of life in 12 patients with NPC (Bremova et al, 2015). Subsequent long-term case series and pre-clinical studies demonstrated the neuroprotective, disease modifying effect of treatment in NPC (Cortina-Borja et al, 2018; Kaya et al, 2020a). In all, the compound was well tolerated with no serious side effects.…”

“…One mechanism of action of NALL is the activation of cerebral glucose metabolism in the cerebellum, correlated with enhanced cerebellar activity (Günther et al, 2015; Tighilet et al, 2015). In an animal model of NPC, N-acetyl-DL-leucine and its enantiomers significantly reduced ataxia in Npc1 -/- mice, when commenced symptomatically (from 8-9-weeks of age) and pre-symptomatically (from 3-weeks of age) (Kaya et al, 2020a). These studies specifically identify the L-enantiomer as the neuroprotective isomer, observed to significantly delay the onset of functional decline (gait abnormalities, motor dysfunction), the decline in general health and condition, as well as to slow disease progression and prolong survival (whereas the D-enantiomer did not).…”

Rapid Identification of New Biomarkers for the Classification of GM1 Type 2 Gangliosidosis Using an Unbiased 1H NMR-Linked Metabolomics Strategy

“…Very recently, Kaya et al [ 48 ] reported that orally-administered N-acetyl-DL-leucine (ADLL) to NPC1 patients significantly retarded its rate of clinical disease progression, with improvements in or stabilization of a range of neurological domains. This agent also exerted beneficial effects on gait in patients afflicted with Tay-Sachs and Sandhoff diseases (GM2 gangliosidoses), and also in a mouse model of the latter.…”

Acetylation of L-leucine switches its carrier from the L-amino acid transporter (LAT) to organic anion transporters (OAT)

“…At the molecular level, several mechanisms of action have been suggested including physicochemical partitioning into the phopspholipid bilayer to decrease its fluidity (Neuzil et al, 2002), direct action on glycine recptors and AMPA receptors (Neuzil et al, 2002), effects on branched chain aminotransferaes affecting glutamate neurotransmission (Kalla and Strupp, 2019), an increase in glucose metabolism (Kalla and Strupp, 2019). For the lysosomal storage disorder Niemann-Pick type C (NPC), N-acetyl-L-leucine mediates a shift in global cellular metabolism from glycolysis to oxidative phosphorylation for ATP production (Kaya et al, 2020), and in another lysosomal storage disorder Sandoff disease, it normalizes the aberant metabolism that results in oxidative stress (Kaya et al, 2020). All of the above mechanisms could contrribute to the observed effect of normalizing membrane potential and excitability leading to activation of the vestibulo-cerebellum and a deactivation of the posterolateral thalamus (Ferber-Viart et al, 2009; Kalla and Strupp, 2019; Vibert and Vidal, 2001).…”