Drug Repurpose Update #1 – Tanganil ® (Acetyl-Leucine) for potential management of SynGAP1-related disorder symptoms

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Medical Disclaimer: Exemplifying the SRF value of transparency, this article is here to make families aware of what is happening. The information provided is for general informational purposes only and is not intended as, nor should it be considered a substitute for, professional medical advice. Although it may be helpful to share with your clinicians, do not use the information on this page for diagnosing or treating any medical or health condition. If you have, or suspect you have, a medical problem, promptly contact your professional healthcare provider. See full disclaimer here.


SYNGAP1 Related Disorder and the need for effective therapies

SynGAP1-Related Disorder (SynGAP1-RD) is a rare neurodevelopmental condition caused by a pathogenic mutation in the SYNGAP1 gene. The SYNGAP1 gene encodes for a synaptic Ras-GTPase activating protein that is highly expressed in excitatory neurons. Symptoms of this disorder vary widely but generally include epilepsy involving multiple seizure types, intellectual disability, developmental delays, autistic features or autism spectrum disorder, gastrointestinal (GI) issues, sleep disturbances, and severe behavior disorders1–3. Many disease symptoms can be treatment- or drug-resistant, and there is currently no cure. Due to the severity of symptoms, heavy burden on caregivers/families, and difficulty finding effective or durable treatments, caregivers are eager to explore novel approaches to improve quality of life. 

How did SRF find NALL?

The SynGAP Research Fund supports research to find viable treatments and cures for patients with SynGAP1-RD. Drug repurposing is an approach to accelerate drug discovery by screening existing drugs against a novel indication. In 2023, SRF funded work by Dr. Clement Chow and his team at the University of Utah – Department of Human Genetics to screen 1,600 drugs using a Drosophila (fruit fly) model. Using this approach, the Chow Lab has successfully identified therapeutic targets for other monogenic deficiencies, including NGLY14, MAN1B1, and FAM177A15. For drug screening, fruit flies were engineered to eliminate SYNGAP1 gene expression in the eye. Drug efficacy was determined by restoration of normal eye appearance upon drug treatment. Within 7 months, Dr. Chow identified N-acetyl-L-leucine (NALL) as the primary potential drug candidate for treating SynGAP1-RD. He presented his results at the 2023 SYNGAP1 conference hosted by SynGAP Research Fund. SRF is currently funding Dr. Chow to validate his findings and expand his studies on NALL.

Screen shot from Dr. Chow’s presentation at the 2023 SRF Scientific Meeting
Watch his full presentation here

What is NALL?

NALL is an acetylated derivative of L-leucine, a natural essential amino acid. It is not yet pharmaceutically available. NALL mixed with N-acetyl-D-leucine forms a combination, or racemate, called N-acetyl-DL-leucine, also known as acetyl-leucine (Figure 1). Acetyl-leucine, under the trade name Tanganil® (Pierre Fabre Laboratories), has been used over-the-counter to treat vertigo in France for over 65 years6. Acetyl-leucine is being extensively studied as a potential treatment for several disorders, including cerebellar ataxia7–9, lysosomal storage disorders10–12, migraine13, restless legs syndrome14, as well as cognition and mobility in the elderly15. The therapeutic effect of acetyl-leucine is not fully understood, but it is thought to have a role in reducing neuroinflammation16,17 and normalizing neuronal function18,19. NALL within acetyl-leucine has been shown to be the therapeutic component20,21; however, neither NALL alone nor acetyl-leucine are globally available. 

Figure 1. Chemical structures of N-acetyl-D-leucine (left) and N-acetyl-L-leucine (right).

The compounds have the same chemical components but differ in the direction of a chemical bond. The carbon-nitrogen bond is shown as a dashed line for N-acetyl-D-leucine, indicating an inward orientation (heading through the page away from the reader), while the same bond for N-acetyl-L-leucine is shown as a filled triangle, indicating an outward orientation (coming out of the page toward the reader). The equal combination of both compounds constitutes acetyl-leucine. Modified from Churchill, et al21.

Photo of front and side of the brand-name and generic acetyl-leucine products available in France

One company is currently exploring NALL in clinical trials for the treatment of several neurodegenerative diseases22,23, including Niemann-Pick disease type C (phase 2 and phase 3)24, GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases; phase 2)25, and Louis-Bar syndrome (phase 2). In these completed clinical trials, NALL was safe and well-tolerated, including when treating children ages 4 and older. Treatment with NALL was associated with significant improvements in neurological outcome, functioning, and quality of life, compared to placebo recipients. These results offer the promise of a safe and effective therapeutic option for the treatment of neurological disorders. 

Since Tanganil® and the generic acetyl-leucine are available without a prescription in France and given the well-established safety and tolerability, some families have begun giving this to their children with SynGAP1-RD.

What are the risks?

While this drug is known to be safe and effective in adults with decades of use in humans, there are still unknowns that we need to acknowledge.

  1. The current label for Tanganil® does not have a pediatric dose, but it has been used substantially in the GM1 and GM2 communities. Also, there has been pediatric dosing in recent trials.
  2. There is very little publicly available data on long-term use, besides a case study in France15.  We are reaching out to Pierre Fabre to see if they have more information.
  3. We don’t know what N-acetyl-D-leucine does and by using Tanganil® we are giving patients a mixture of both N-acetyl-D-leucine and N-acetyl-L-leucine. 

Current Case Study 

In the SRF community, an 8-year-old boy with SynGAP1-RD was treated orally with 1 gram of acetyl-leucine (Tanganil®) twice daily (2 grams per day). No adjustments were made to his existing medications before initiation of treatment. Parents recorded changes in the patient’s seizures, sleep, behaviors, communication, sensory, and GI issues before and during the use of acetyl-leucine.

Parent notes on the impact of acetyl-leucine during the first five weeks of treatment are summarized in Table 1. The medication was well-tolerated and no safety concerns were noted. Significant improvements in seizure frequency, sleep, and problematic behaviors were observed within the first month of treatment. Within 2 weeks of treatment, the patient had no identifiable seizures during the day. Within 3 weeks of treatment, the patient began sleeping through the night. Within 4 weeks, marked improvements in behaviors were observed by multiple caregivers at home, at school, and during group activities. Improvements in communication and sensory issues were also observed. Minimal improvements were observed for GI issues; an upset stomach was reported at week 5, but this may have been unrelated.

Weeks after initiation of acetyl-leucine
SymptomsPre-initiationWeek 1Week 2Week 3Week 4Week 5
EpilepsyAverage of 5 absence seizures per day.Average of 5 absence seizures per day.No seizures during the day.No seizures during the day.No seizures during the day.No seizures during the day.
SleepDifficulty falling asleep. Restless at night. Up at 4am.Difficulty falling asleep. Restless at night. Up at 4am.Difficulty falling asleep. More restful during night. Up at 4am.Fell asleep quickly. Slept all night.Fell asleep quickly. Slept all night.Fell asleep quickly. Slept all night.
Behaviorsno changeMore centered. Easier transitions. Followed directions.Improvements following instructions, staying on task, and initiating activities. Increased patience and independence. Reduced obsessions. Noted improvements by teachers, therapists and coach.Improvements completing school work. More focused non-electronic toys. No issues with lunchtime or transitions. Increased independence. Reduced elopements.Improvements using the toilet independently, following directions and completing school work. Did not have tantrum during challenging event.Improvements following directions and completing school work. Increased engagement with siblings. Report of significantly improved behaviors at school.
Communicationno changeno changeIncreased focus on communication.Improved labeling, both verbally and with AAC device. Increased focus and participation during speech therapy.Increased focus and participation during speech therapy.Improvements communicating emotions and needs. Attempting to use new words.
Sensoryno changeno changeno changeShowed appropriate satiation response; stopped eating when normally wouldn’t.no changeRemained clothed when normally would prefer to be naked.
GIno changeno changeno changeno changeno changeUpset stomach.

Quality of life impact
Undesired ChangeDesired Change
SignificantModerateMildNo changeMildModerateSignificant
Table 1. Parent record of quality of life impact of acetyl-leucine treatment on SynGAP1-RD symptoms 5 weeks.

Changing symptoms are highlighted in shades of green if the desired outcomes were observed or shades of red if undesired were observed. Changes were scored as mild, moderate, or significant, relative to how the change impacted the patient and family life overall.

Conclusions

In this patient-driven single case study, acetyl-leucine appeared to be safe, well-tolerated, and effective at controlling seizures, as well as SynGAP1-RD symptoms. We do not know if seizure reduction and sleep improvement will endure with continued dosing or continue to present over time. After 5 weeks, however, the parents were highly satisfied with their child’s improvements and continued to include acetyl-leucine in their medication regimen.

What is the difference between N-acetyl-L-leucine, L-leucine or other L-amino acids?

Amino acids, like leucine or serine, are building blocks your body uses to make proteins. Your body can make certain amino acids; other essential amino acids are obtained through your diet. Your body uses amino acids for many functions, including building muscle, repairing tissue, creating energy, and making hormones and neurotransmitters. Having a ready supply of amino acids is, therefore, important to maintaining a healthy body. A healthy, balanced diet should provide all of the essential amino acids your body needs to function properly. If your body is under excessive stress or prolonged illness, amino acid supplements could be beneficial. For example, L-leucine is an FDA-approved supplement advertised to bodybuilders to help develop muscle mass. Such amino acid supplements can be found at most health food stores or online. While these supplements may have a positive health impact on the body, their role does not extend beyond proper nutrition.

While N-acetyl-L-leucine is similar to the essential amino acid leucine, the modifications make it unique6. Acetylation changes the chemical properties of leucine, creating a compound that has a pharmacological impact on the body. Importantly, acetylated leucine can enter cells by a different route than leucine alone. This change in compound transport increases tissue distribution, rate of absorption, and concentrations achieved inside the cell. Once inside the cell, it can exert its therapeutic effects. Due to these unique features of NALL, it is considered to function as a pharmaceutical compound that may have therapeutic benefits.

What is the difference between pharmaceutical-grade and laboratory-grade NALL?

Additionally, N-acetyl-L-leucine is available in bulk from online chemical distributors. This type of product is meant for use in the laboratory and not for patient treatment. Laboratory-grade and pharmaceutical-grade compounds differ in their purity, quality, and intended use. Pharmaceutical-grade compounds are subject to strict manufacturing and quality control regulations to ensure patient safety. Only pharmaceutical-grade compounds, obtained from a pharmacy or via prescription, should be given to patients.

Next Steps

The SRF team is helping families get the most out of their observational trials by offering data tracking sheets that can be compared to the results that other families see. If you are trying this or another untested treatment, please reach out and let us know. To have widespread access to NALL, there needs to be a clinical trial, and data gathered in these initial family-driven trials will help inform the design of these trials.

References

  1. Wright, D., Kenny, A., Eley, S., McKechanie, A. G. & Stanfield, A. C. Clinical and behavioural features of SYNGAP1-related intellectual disability: a parent and caregiver description. J. Neurodev. Disord. 14, 34 (2022).
  2. Wiltrout, K., Brimble, E. & Poduri, A. Comprehensive phenotypes of patients with SYNGAP1-related disorder reveals high rates of epilepsy and autism. Epilepsia (2024) doi:10.1111/epi.17913.
  3. Vlaskamp, D. R. M. et al. SYNGAP1 encephalopathy. Neurology 92, e96–e107 (2019).
  4. Hope, K. A., Berman, A. R., Peterson, R. T. & Chow, C. Y. An in vivo drug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency. PLoS Genet. 18, e1010228 (2022).
  5. Kiefer, J. Rare but not forgotten. University of Utah Health https://attheu.utah.edu/health-medicine/rare-but-not-forgotten/.
  6. Churchill, G. C. et al. Acetylation turns leucine into a drug by membrane transporter switching. Sci. Rep. 11, 15812 (2021).
  7. Kalla, R. & Strupp, M. Aminopyridines and Acetyl-DL-leucine: New Therapies in Cerebellar Disorders. Curr. Neuropharmacol. 17, 7–13 (2019).
  8. Schniepp, R. et al. Acetyl-DL-leucine improves gait variability in patients with cerebellar ataxia-a case series. Cerebellum Ataxias 3, 8 (2016).
  9. Strupp, M. et al. Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series. J. Neurol. 260, 2556–2561 (2013).
  10. Kaya, E. et al. Acetyl-leucine slows disease progression in lysosomal storage disorders. Brain Commun. 3, fcaa148 (2021).
  11. Kaya, E. et al. Beneficial Effects of Acetyl-DL-Leucine (ADLL) in a Mouse Model of Sandhoff Disease. J. Clin. Med. 9, 1050 (2020).
  12. Bremova, T. et al. Acetyl-dl-leucine in Niemann-Pick type C: A case series. Neurology 85, 1368–1375 (2015).
  13. Strupp, M., Bayer, O., Feil, K. & Straube, A. Prophylactic treatment of migraine with and without aura with acetyl-DL-leucine: a case series. J. Neurol. 266, 525–529 (2019).
  14. Fields, T., Schoser, B., Oertel, W. & Strupp, M. Acetyl-DL-leucine improves restless legs syndrome: a case report. J. Neurol. 268, 2595–2596 (2021).
  15. Platt, F. & Strupp, M. An anecdotal report by an Oxford basic neuroscientist: effects of acetyl-DL-leucine on cognitive function and mobility in the elderly. J. Neurol. 263, 1239–1240 (2016).
  16. Hegdekar, N., Lipinski, M. M. & Sarkar, C. N-Acetyl-L-leucine improves functional recovery and attenuates cortical cell death and neuroinflammation after traumatic brain injury in mice. Sci. Rep. 11, 9249 (2021).
  17. Xu, Z. et al. N-acetyl-L-leucine protects MPTP-treated Parkinson’s disease mouse models by suppressing Desulfobacterota via the gut-brain axis. Brain Res. Bull. 202, 110729 (2023).
  18. Ferber-Viart, C., Dubreuil, C. & Vidal, P. P. Effects of acetyl-DL-leucine in vestibular patients: a clinical study following neurotomy and labyrinthectomy. Audiol. Neurootol. 14, 17–25 (2009).
  19. Vibert, N. & Vidal, P. P. In vitro effects of acetyl-DL-leucine (tanganil) on central vestibular neurons and vestibulo-ocular networks of the guinea-pig. Eur. J. Neurosci. 13, 735–748 (2001).
  20. Tighilet, B., Leonard, J., Bernard-Demanze, L. & Lacour, M. Comparative analysis of pharmacological treatments with N-acetyl-DL-leucine (Tanganil) and its two isomers (N-acetyl-L-leucine and N-acetyl-D-leucine) on vestibular compensation: Behavioral investigation in the cat. Eur. J. Pharmacol. 769, 342–349 (2015).
  21. Churchill, G. C., Strupp, M., Galione, A. & Platt, F. M. Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance. PloS One 15, e0229585 (2020).
  22. Tifft, C. J. N-Acetyl-l-Leucine and Neurodegenerative Disease. N. Engl. J. Med. 390, 467–470 (2024).
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