Tifft, C.J

This editorial describes the science behind a study of N-acetyl-l-leucine to treat a specific lysosomal storage disorder, Niemann–Pick disease type C. N Engl J Med 2024; 390:467-470

Tatiana Bremova-Ertl, M.D., Ph.D., Uma Ramaswami, M.D., Marion Brands, M.D., Tomas Foltan, M.D., Matthias Gautschi, M.D., Ph.D., Paul Gissen, M.D., Francesca Gowing, M.D., Andreas Hahn, M.D., Simon Jones, M.D., Richard Kay, Ph.D., Miriam Kolnikova, M.D., Ph.D., Laila Arash-Kaps, M.D., Thorsten Marquardt, M.D., Eugen Mengel, M.D., Julien H. Park, M.D., Stella Reichmannová, M.D., Ph.D., Susanne A. Schneider, M.D., Siyamini Sivananthan, M.D., Mark Walterfang, M.D., Ph.D., D.Med.Sci., Pierre Wibawa, M.D., Michael Strupp, M.D., and Kyriakos Martakis, M.D.

In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann–Pick disease type C in a 1:1 ratio to receive N-acetyl-L-leucine (NALL) for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL met its primary SARA endpoint (least-squares mean difference, −1.28 points; 95% confidence interval, −1.91 to −0.65; P<0.001) and its secondary endpoints. NALL was well-tolerated, with no serious adverse reactions. N Engl J Med 2024; 390:421-431

Fields, T., Bremova-Ertl, T., Billington, I., Churchill, G.C., Evans, W., Fields, C., Galione, A., Kay, R., Mathieson, T., Martakis, K., Patterson, M., Platt, F., Factor, M., Strupp, M.

This multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments. Trials (2023).

Kremmyda, O., Feil, K., Bardins,S., Strupp, M.

The combination of Acetyl-leucine and memantine significantly improved oscillopsia, nystagmus, stance and gait in a patient with secondary progressive Multiple Sclerosis. The patient has remained on treatment for over 5 years, with sustained benefit. No side effects have been reported.

Saberi-Karimian, M., Houra, M. Jamialahmadi, T., Sarvghadi, P., Nikbaf, M., Akhlaghi, S., Sahebkar, A.

In this placebo-controlled, crossover case study, a 12 year old patient with Multiple Sulfatase Deficiency was treated with N-acetyl-L-leucine (NALL) and placebo in two 1-month periods. Treatment with NALL was well tolerated and significantly improved symptoms (including the SARA and SCAFI scores), quality of life measure, and serum IL-6 levels, a biomarker for neuroinflammation.

Regarding quality of life assessments, the parent and child reported improved quality of life index, physical health, and emotional function after taking NALL. Moreover, total energy intake was increased with NALL treat- ment through the study period. The Cerebellum.

Saberi-Karimian, M., Beyraghi-Tousi, M., Mirzadeh, M. Gumpricht, E., Sahebkar, A.

Treatment with N-acetyl-DL-leucine for 16 weeks in a 9-year-old patient with Ataxia-Telangiectasia was well tolerated and significantly improved ataxia symptoms and quality of life measures. Cerebellum.

Brueggemann, A., Bicvic, A., Goeldlin, M., Kalla, R., Kerkeni, H., Mantokoudis, G., Abegg, M., Kolnikova, M., Mohaupt, M., Bremova-Ertl, T.

N-acetyl-leucine improved ataxia and ocular stability in 6 patients with Ataxia-Telangiectasia after 1-month treatment.


The IB1001-202 clinical trial with N-acetyl-L-leucine (IB1001) met its primary and secondary endpoints and demonstrated a statistically significant and clear clinically meaningful improvement in symptoms, functioning, and quality of life for pediatric and adult patients with GM2 Gangliosidosis (Tay-Sachs and Sandhoff). IB1001 was well-tolerated and no drug-related serious adverse events were reported, demonstrating a favorable risk-benefit profile for the treatment of GM2 Gangliosidosis. Neuro

Bremova, T., Claassen, J., Foltan, T., Gascon Bayarri, J., Gissen, P., Hahn, A., Hassan, A., Hennig, A., Jones, S. , Kolnikova, M., Martakis, K., Ramaswami, U, Sharma, R., Schneider, S. A.

The IB1001-201 clinical trial with N-acetyl-L-leucine (IB1001) met its primary and secondary endpoints and demonstrated a statistically significant and clear clinically meaningful improvement in symptoms, functioning, and quality of life for pediatric and adult patients with NPC. IB1001 was well-tolerated and no drug-related serious adverse events were reported, demonstrating a favorable risk-benefit profile for the treatment of NPC.  Journal of Neurology.

Bremova-Ertl, T., Platt, F., Strupp, M.

Observational case-series: symptomatic and disease-modifying treatment effect with Acetyl-Leucine in a Juvenile Sandhoff patient.


Zhifeng Xua, Changlin Liana, Lixin Pana, Wenjie Laia,e, Fen Zhanga, Lingmei Penga, Sijie Zhou b, Guanghua Zhao c, Xuezhu Yang d, Guohua Zhang a, e, Zefeng Tan a, Yukai Wanga

Orally administration of N-acetyl-L-leucine alleviated motor impairments and dopamine neuronal deficits in an animal model of Parkinson’s disease. The findings are consistent with the neuroprotective effects of N-acetyl-L-leucine in several other neurodegenerative disorders.

Naef, V., Marchese, M., Ogi, A., Fichi, G., Galatolo, D., Licitra, R., Doccini, S., Verri, T., Argenton, F., Morani, F., Santorelli, F.

The fish model of Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) (Sacs−/− larvae) was treated with Acetyl-DL-leucine. Acetyl-DL- leucine improved locomotor and biochemical phenotypes in disorder by mediating significant rescue of the molecular functions altered by sacsin loss, demonstrating the neuroprotective effect of the treatment. International Journal of Molecular Sciences. 

Churchill, C., Strupp, M., Factor, C., Bremova-Ertl, T., Factor, M., Patterson, M., Platt, F.M., Galione, A.

Small changes to molecules can have profound effects on their pharmacological activity as exemplified by the addition of the two‐carbon acetyl group to make drugs more effective by enhancing their pharmacokinetic or pharmacodynamic properties. Here we show that acetylation of leucine switches its uptake into cells from the l‐type amino acid transporter (LAT1) used by leucine to organic anion transporters (OAT1 and OAT3) and the monocarboxylate transporter type 1 (MCT1). Both the kinetics of MCT1 (lower affinity compared to LAT1) and the ubiquitous tissue expression of MCT1 make it well suited for uptake and distribution of N‐acetyl‐l‐leucine. MCT1‐mediated uptake of a N‐acetyl‐l‐leucine as a prodrug of leucine bypasses LAT1, the rate‐limiting step in activation of leucine‐mediated signalling and metabolic process inside cells such as mTOR. Nature Scientific Reports.

Churchill, C., Strupp, M., Bremova-Ertl, T., Factor, M., Patterson, M., Platt, F., Galione, A.

N-acetylation removes a charge from the nitrogen at physiological pH and N-acetyl-L-leucine is an anion that is then a substrate for the organic anion transporters. We examined N-acetyl-L-leucine uptake in human embryonic kidney cells overexpression candidate organic anion transporters (OAT) and pharmacological inhibitors. We found that N-acetyl-L-leucine is a translocated substrate for OAT1 and OAT3 with low affinity (Km ~10 mM). In contrast, L-leucine is known to be transported by the L-type Amino Acid Transporter (LAT) with high affinity (Km ~0.2 mM) and low capacity. The clinical consequence is that L-leucine uptake becomes saturated at 50-fold lower concentration than N-acetyl-L-leucine. These results demonstrate a mechanism of action that explains why N-acetyl-L-leucine is effective as a drug and L-leucine itself is not.

Kaya, E., Smith, D., Smith, C., Morris, L., Bremova-Ertl, T., Cortina-Borja, M., Fineran, P., Morten, K., Poulton, J., Boland, B., Spencer, J., Strupp, M., Platt, F.M.

Acetyl-leucine improved symptoms of ataxia in particular in mice models and patients with the lysosomal storage disorders (LSD), Niemann-Pick disease type C  and GM2 Gangliosidosis. When N-acetyl-DL-leucine and N-acetyl-L-leucine 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. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-L-leucine and underlying mechanisms of action in LSDs, supporting its therapeutic potential for lysosomal disorders.

Kaya, E., Smith, D.A, Smith, C., Boland, B. Strupp, M., Platt, F.M.

In Vivo studies with Acetyl-leucine significantly slowed disease progression and improved motor function in the GM2 gangliosidoses Sandhoff mouse model (Hexb-/-), supportive of the symptomatic and disease-modifying potential of treatment for patients with GM2 Gangliosidosis (Tay-Sachs and Sandhoff disease).

te Vrutche, D., Galione, A., Strupp, M., Mann, M.

N-Acetyl-DL-Leucine and N-Acetyl-L-Leucine reduced the relative lysosomal volume in NPC1-/- Chinese Hamster Ovary cells in a dose-dependent manner. N-Acetyl-L-Leucine was most effective at reducing relative lysosomal volumes in fibroblasts derived from NPC patients with severe disease (***p <0.001), followed by N-Acetyl-DL-Leucine (**p <0.01). Treatment with N-Acetyl-D-Leucine did not achieve statistical significance.

Hegdekar, N., Lipinski, M.M, Sarkar, C.

Scientific Reports, 2021.

Treatment with N-acetyl-L-leucine is expected to be beneficial in restricting neuronal death and hence improving neurological function after Traumatic Brain Injury (TBI) and is a promising, novel, neuroprotective drug candidate for the treatment of TBI.

Kalla, R., Teufel, J., Feil, K., Strupp, M.

Journal of Neurology 263 (2016).