GNAO1 (G protein alpha subunit O1) gene mutations are considered one of the primary causes of severe pediatric encephalopathy. This encephalopathy typically manifests as epilepsy, movement disorders, developmental delay, and intellectual disability, with limited effectiveness of current treatments. The GαO protein encoded by the GNAO1 gene is a key component in neuronal signaling, and its mutations lead to abnormal signal transduction, thereby triggering a series of neurological diseases. Although studies have shown that zinc salts can partially correct the functional abnormalities of GNAO1 mutant proteins, the specific mechanisms of action and clinical safety of this treatment have not been fully verified.

This article aims to verify the efficacy and safety of zinc salts in treating GNAO1-related encephalopathies through systematic preclinical studies and the first human trial, exploring the differential responsiveness of different mutation types to zinc salts, providing scientific evidence for future large-scale clinical trials.

Source of the Paper

This paper was co-authored by Yonika A. Larasati, Moritz Thiel, Alexey Koval, Denis N. Silachev, Anne Koy, and Vladimir L. Katanaev, from institutions including the University of Geneva in Switzerland, Cologne University Hospital in Germany, and Moscow State University in Russia. It was published on January 10, 2025, in the journal Med, titled “Zinc for GNAO1 Encephalopathy: Preclinical Profiling and a Clinical Case.”

Research Process and Results

1. Classification of GNAO1 Mutants’ Response to Zinc Salts

The research team first conducted biochemical analyses on 16 GNAO1 mutants, testing their GTP binding and hydrolysis capabilities under the influence of zinc salts. Based on the results, the mutants were categorized into three classes: - Class I: Such as L23P, C215Y, and I344del, where zinc salts had no significant effect on GTP binding or hydrolysis. - Class II: Including G203R, R209C, and E246K, where zinc salts significantly restored GTP hydrolysis ability. - Class III: Such as K46N, H57P, and T182I, where zinc salts significantly reduced the mutants’ affinity for GTP.

This classification provides crucial evidence for stratified treatment of patients in the future.

2. Safety Study of Zinc Salts in Mouse Models

To assess the safety of zinc salts in neonatal and juvenile mice, the research team added different concentrations (4-8 g/L) of zinc sulfate (ZnSO4) to drinking water, feeding the mice until adulthood. The results showed that zinc salt treatment only briefly affected weight gain from postnatal day 7 to day 17 but did not result in significant health issues in adulthood. Additionally, zinc salt treatment improved motor coordination and exploratory behavior in mice.

3. First Human Trial

The research team administered zinc salts to a 3.4-year-old child with GNAO1 encephalopathy carrying the G203R mutation. The initial dose was 40 mg of zinc daily (in the form of zinc gluconate), later increased to 50 mg of zinc daily (in the form of zinc acetate). After 11 months of treatment, the patient showed significant improvement in motor function, a reduction in seizure frequency, enhanced quality of life, and no notable side effects.

Research Conclusions

This study systematically verified the efficacy and safety of zinc salts in treating GNAO1-related encephalopathies for the first time. Through multi-level research from biochemistry, animal models, and the first human trial, the team revealed the differential responses of various GNAO1 mutants to zinc salts and demonstrated the potential of zinc salts in improving clinical symptoms. This discovery lays the foundation for future large-scale clinical trials and may provide a new standard of care for GNAO1-related encephalopathies.

Highlights of the Research

1. Mutation Classification: First-time classification of GNAO1 mutants based on their response to zinc salts, providing a scientific basis for personalized treatment.
2. Safety Verification: Verified the safety of zinc salts in neonatal and juvenile mice, providing important support for clinical applications.
3. First Human Trial: First verification of the therapeutic effect of zinc salts on GNAO1 encephalopathy in humans, demonstrating its clinical application potential.
4. Multi-Level Validation: Provided comprehensive scientific evidence from molecular mechanisms to animal models and then to human trials.

Significance of the Research

This article not only deepens the theoretical understanding of the functional abnormalities of GNAO1 mutants but also provides practical solutions for treating GNAO1-related encephalopathies. Zinc salts, approved for treating multiple diseases, have further uncovered their potential value. Future large-scale clinical trials will aim to validate the broad applicability of this therapy and provide reference for the treatment of more rare diseases.

Additional Valuable Information

The research team plans to launch a clinical trial named “ZincGNAO1” in July 2024 to further evaluate the efficacy and safety of zinc salts in GNAO1-related encephalopathies. Additionally, the European Joint Program on Rare Diseases “GNAO1-EU” will start in 2025, aiming to deeply study the natural history and biomarkers of GNAO1-related diseases.