Orphanet Journal of Rare Diseases | Effects of Intravenous Trehalose on Serum Metabolome in Patients with Acid Sphingomyelinase Deficiency

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This study reveals significant metabolic changes induced by trehalose therapy in patients with acid sphingomyelinase deficiency through untargeted metabolomics analysis, suggesting its therapeutic potential via modulation of glucose metabolism and promotion of sphingomyelin degradation.

 

Literature Overview

The article titled 'Metabolic improvement in patients with acid sphingomyelinase deficiency following intravenous trehalose administration: an untargeted pharmacometabolomic study', published in the Orphanet Journal of Rare Diseases, reviews and summarizes the impact of intravenous trehalose administration on the serum metabolic profiles of patients with acid sphingomyelinase deficiency (ASMD) types A/B. Using an untargeted gas chromatography-mass spectrometry (GC-MS) approach, the study analyzed serum samples from five patients before and after a 12-week treatment period, identifying significant alterations in multiple key metabolites. The results suggest that trehalose may exert protective effects by remodeling cellular metabolic pathways, promoting sphingomyelin clearance, and improving mitochondrial function. This research provides novel metabolic-level evidence for understanding the pharmacological mechanisms of trehalose and supports further exploration of its use in rare lysosomal storage disorders.

Background Knowledge

Acid sphingomyelinase deficiency (ASMD) is a rare autosomal recessive lysosomal storage disorder caused by mutations in the SMPD1 gene, leading to reduced activity of acid sphingomyelinase (ASM) and abnormal accumulation of sphingomyelin in various tissues such as liver, spleen, lungs, and bone marrow. Based on neurological involvement, ASMD is classified into the fatal neuronopathic type A (NPA) and the non-neuronopathic type B (NPB). Current treatment options include enzyme replacement therapy (e.g., olipudase alfa) and bone marrow transplantation, but these have limited efficacy, particularly for neurological symptoms. Trehalose is a natural non-reducing disaccharide with multiple biological functions, including autophagy induction, anti-inflammatory effects, antioxidant properties, and protein structure stabilization, and has demonstrated protective effects in various neurodegenerative disease models. Previous studies have shown that intravenous trehalose can reduce serum sphingomyelin levels and improve clinical symptoms in ASMD patients. However, its systemic metabolic regulatory mechanisms remain unclear. This study employs a pharmacometabolomic strategy to comprehensively analyze changes in serum metabolites following trehalose intervention, aiming to uncover its potential metabolic reprogramming mechanisms and provide a theoretical basis for developing new biomarkers and optimizing therapeutic strategies.

 

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Methods and Experiment

The study conducted a retrospective metabolomic analysis using biosamples from a previously published single-arm, open-label clinical trial. Five male ASMD patients aged 2–12 years were enrolled, each receiving weekly intravenous infusions of 15 g trehalose for 12 weeks. Serum samples were collected before and after treatment and analyzed using an untargeted metabolomics platform based on gas chromatography-mass spectrometry (GC-MS). Samples were processed with protein precipitation, methoximation, and derivatization with MSTFA prior to injection. Peak detection, alignment, and normalization were performed using MS-DIAL software, with methyl heptadecanoate as the internal standard. Multivariate statistical analysis was carried out using principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) in SIMCA software, with metabolites having a variable importance in projection (VIP) >1.5 considered significant. Univariate analysis used paired t-tests, and metabolites with p < 0.05 and FDR-corrected p < 0.05 were deemed significantly altered. Pathway enrichment analysis was performed using MetaboAnalyst to identify affected metabolic pathways.

Key Conclusions and Insights

• The OPLS-DA model showed clear separation between serum metabolic profiles before and after trehalose treatment, indicating systemic metabolic reprogramming induced by the therapy
• A total of 12 significantly altered serum metabolites were identified: phosphate, inositol, sorbitol, D-ribose, ribitol, and threitol levels significantly increased, while lactate, mannose, and 1-monopalmitoylglycerol significantly decreased
• The significant rise in phosphate levels may result from further hydrolysis of phosphocholine released during sphingomyelin degradation, suggesting enhanced sphingomyelin clearance by trehalose
• The significant decrease in lactate levels suggests that trehalose may improve mitochondrial function and reduce anaerobic glycolysis, thereby alleviating cellular energy deficits caused by oxidative stress
• Reduced levels of mannose and 1-monopalmitoylglycerol indicate that trehalose may inhibit de novo fatty acid and sphingolipid biosynthesis pathways, reducing lipid accumulation
• The accumulation of multiple sugar alcohols (e.g., sorbitol, ribitol) and D-ribose suggests glucose metabolism may be redirected toward the pentose phosphate pathway and polyol pathway, supporting redox balance and cellular antioxidant capacity
• Pathway analysis revealed that the altered metabolites were primarily enriched in galactose metabolism, branched-chain amino acid biosynthesis, fructose-mannose metabolism, and inositol phosphate metabolism, further supporting the existence of metabolic reprogramming

Research Significance and Outlook

This study is the first to systematically map the serum metabolic landscape following trehalose treatment in ASMD patients, providing important clues for understanding its pharmacological mechanisms. The observed metabolic changes reflect not only enhanced sphingomyelin degradation but also improved cellular energy metabolism and redox status. This suggests that trehalose's effects extend beyond autophagy induction to broad metabolic regulation, potentially exerting pleiotropic protective effects by mitigating lipid toxicity and preserving mitochondrial function. The findings support trehalose as a potential therapeutic strategy for ASMD and provide candidate biomarkers (e.g., lactate, phosphate, inositol) for future large-scale, long-term clinical trials.

However, the study has limitations, including small sample size, lack of a control group, and short follow-up duration. Future research should expand the cohort, include placebo controls, and integrate tissue metabolomics with functional experiments to further validate the biological significance of these metabolic changes. Additionally, exploring the metabolic effects of trehalose in other lysosomal storage disorders could help broaden its clinical applications.

 

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Conclusion

Using an untargeted pharmacometabolomic approach, this study systematically evaluated the impact of intravenous trehalose on the serum metabolic profiles of patients with acid sphingomyelinase deficiency (ASMD). The findings revealed significant changes in multiple serum metabolite levels after treatment, including increases in phosphate, inositol, and sorbitol, and decreases in lactate, mannose, and 1-monopalmitoylglycerol. These changes suggest that trehalose may exert therapeutic effects through multiple mechanisms, including promoting sphingomyelin degradation, improving mitochondrial function, redirecting glucose metabolism, and inhibiting fatty acid synthesis. The results not only deepen our understanding of trehalose's pharmacological activity but also provide new metabolic insights into the pathogenesis of ASMD. Despite limitations in sample size and study design, this work lays the foundation for future large-scale clinical studies and proposes potential biomarkers for monitoring treatment efficacy. Overall, this study supports trehalose as a safe and metabolically modulatory therapeutic strategy worthy of further exploration and validation in the field of rare lysosomal storage disorders.

 

Mahdieh Khoshakhlagh, Maede Hasanpour, Mehrdad Iranshahi, Amirhossein Sahebkar, and Milad Iranshahy. Metabolic improvement in patients with acid sphingomyelinase deficiency following intravenous trehalose administration: an untargeted pharmacometabolomic study. Orphanet Journal of Rare Diseases.