Acetyl-Leucine slows disease progression in lysosomal storage disorders

Abstract

Acetyl-DL-leucine (ADLL) is a derivative of the branched chain amino acid leucine. In observational clinical studies ADLL improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder (LSD), Niemann-Pick disease type C 1 (NPC1). Here, we investigated ADLL and its enantiomers acetyl-L-leucine (ALL) and acetyl-D-leucine (ADL) in symptomatic Npc1 -/mice and observed an improvement in ataxia with both enantiomers and ADLL. When ADLL and ALL were administered pre-symptomatically to Npc1 -/mice, both treatments delayed disease progression and extended life span, whereas ADL did not.These data are consistent with ALL being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were found to be implicated as one of the potential mechanisms of action of the L enantiomer in Npc1 -/mice. When miglustat and ADLL were used in combination significant synergy resulted. In agreement with these pre-clinical data, when NPC1 patients were evaluated after 12 months of ADLL treatment, rates of disease progression were slowed, with stabilisation or improvement in multiple neurological domains. A beneficial effect of ADLL 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 LSDs, supporting its further evaluation in clinical trials in lysosomal disorders.

N-acetyl-L-leucine improves symptoms and functioning in GM2 Gangliosidosis (Tay-Sachs & Sandhoff)

“…NALL restored aerobic (pyruvate dihydrogenase-dependent) and enhanced anaerobic (lactate dehydrogenasedependent) glycolysis, and returned the glutamate-metabolizing enzyme, glutamate dehydrogenase, to levels observed in Hexb +/+ and NPC +/+ null mice. 6,8 In normalizing altered glucose and glutamate metabolism, NALL improves energy production, as well as cellular functions and signaling. This is manifested via the drugs modulation of multiple secondary therapeutic targets, including a reduction in lipid and cholesterol accumulation and lysosomal volume, 6,18 a reduction in neuroinflammation, 19 and a normalization of neuronal membrane potential.…”

“…6,8 In normalizing altered glucose and glutamate metabolism, NALL improves energy production, as well as cellular functions and signaling. This is manifested via the drugs modulation of multiple secondary therapeutic targets, including a reduction in lipid and cholesterol accumulation and lysosomal volume, 6,18 a reduction in neuroinflammation, 19 and a normalization of neuronal membrane potential. 20 These multimodal actions lead to the restoration of neuronal function and improvement of overall brain health, including throughout the cerebellum.…”

“…Prior observational studies assessing the effect of N-acetyl-DL-leucine in patients with GM2 gangliosidosis, and other lysosomal storage disorders like Niemann-Pick disease type C (NPC) suggest a beneficial symptomatic, and long-term neuroprotective, disease-modifying treatment effect. [3][4][5][6] Recently, a parallel, multinational, Phase IIb clinical trial with NALL for NPC demonstrated a statistically significant (primary and secondary endpoints) and clinically meaningful improvement in symptoms, functioning, and quality of life for children and adults with NPC. 7 In all observational and clinical studies, NALL has been well tolerated with no serious side effects.…”

“…These studies have specifically identified the L-enantiomer as the active neuroprotective isomer of the racemate, indicating superior clinical effects when administered independently. 6,8 In addition, pharmacokinetic studies suggest that the D-enantiomer could accumulate relative to the L-enantiomer during chronic administration of the racemate, which has the potential for long-term negative effects. 9 Recently, it was reported that NALL is taken up and distributed to all tissues including the central nervous system by the monocarboxylate transporter (MCT1) and hydrolyzed to L-leucine, 10 thereby functioning as a prodrug for delivery of L-leucine, a powerful intracellular metabolic signal of pathways such as mTORC1.…”

Effects of Acetyl-DL-Leucine on Ataxia and Downbeat-Nystagmus in Six Patients With Ataxia Telangiectasia

“…[20][21][22][23] Symptomatic effects on cerebellar ataxia were shown in Niemann-Pick type C and in GM2-gangliosidoses 10,11 and an unanticipated disease-modifying, neuroprotective and anti-neuroinflammatory effect of ADLL and ALL, but not N-acetyl-D-leucine have been shown. 24 The restoration of Krebs cycle flux and the enhancement of anti-oxidation in ADLL and ALL treated mice were implicated as a potential mechanism of improved neurological function. 24…”