Trehalose

Trehalose is a natural disaccharide sugar, commonly used in the food industry for its ability to preserve the freshness and texture of food products. Known for its safety, trehalose has been widely consumed for many years without significant adverse effects (link). In recent years, there has been growing interest in trehalose as a therapeutic agent, particularly in the context of neurodegenerative and neuromuscular disorders (summarized here). Since 2004, studies have explored its potential benefits in various diseases and models, including Alzheimer's, Parkinson's, and Huntington's diseases, where it has shown promise in alleviating symptoms and slowing progression.  

HSPB8 myopathy is characterized by a gain of function mutation in one of the two copies of the HSPB8 gene (first described here). The wild type HSPB8 protein is protein is an important player in cellular autophagy machinery – a part the CASA complex. The mutation results in one healthy and one dysfunctional copy of the HSPB8 protein. The healthy copy exerts its physiological role in autophagy regulation, but at reduced capacity, leading to impaired autophagy. The dysfunctional HSPB8 protein forms insoluble aggregates, which accumulate in the cell, are harmful, and lead to cell death.  

Key Facts about Trehalose

  • Trehalose has been identified as a potential therapeutic agent for this HSPB8 myopathy because of its extremely safe profile and therapeutic effects stemming from at least two mechanisms:

    Upregulation of autophagy

    Trehalose helps in clearing harmful protein aggregates formed by the dysfunctional HSPB8 protein by boosting autophagy, which is impaired in HSPB8 myopathy.

    Upregulation of healthy HSPB8 Protein

    Trehalose can upregulate the expression of the wild-type (healthy) HSPB8 protein and boosts autophagy indirectly.

  • Trehalose is a sugar consisting of two glucose molecules (a disaccharide), known for high water retention capabilities and is used in various industries, including pharmaceuticals and food production. Trehalose was recently found to enhance the autophagic removal of neurotoxic protein aggregates. Because trehalose is degraded in the gut, for neurodegenerative disorders it is administered via injection.

  • Trehalose boosts autophagy, a process which is impaired in several neurodegenerative diseases and HSPB8 myopathy alike. Autophagy is a cellular process where cells break down and recycle their own components, a process crucial for maintaining cellular health. When autophagy is impaired, damaged components of the cells accumulate, eventually leading to cell death. This dysfunction is particularly harmful in neuronal and muscle cell. Trehalose induces autophagy and has been shown to have positive effects in models of AD, HD and PD.

  • Dozens of animal studies in neurodegenerative diseases report increased autophagic flux and amelioration of phenotype upon trehalose administration, as summarized by a systematic review

    Protective capacity of trehalose has been evaluated in several animal models for various neurodegenerative disorders, including tau pathology, synucleinopathies, polyglutamine tract diseases, and amyotrophic lateral sclerosis (ALS).

    A recent systematic review (Yap et al, 2023) concludes: Most studies primarily supported the purported role that trehalose plays in the autophagic flux and protein refolding necessary for the removal of protein aggregates in neurodegenerative diseases.

  • Trehalose's mechanism of action, particularly in the context of neuroprotection and autophagy, is multifaceted and has been a subject of ongoing research and debate:

    Autophagy Induction and Protein Aggregation Clearance

    The primary hypothesis for trehalose's mechanism of neuroprotection is its ability to induce autophagy. Autophagy is a cellular process for clearing out protein aggregates, which is essential in counteracting aggregate-prone misfolded protein toxicity in neurodegenerative diseases. Animal studies have supported this hypothesis, showing activation of autophagy and reduced protein aggregates after trehalose administration in models of neurodegenerative diseases like Parkinson's and Huntington's.

    Trehalose and TFEB Activation

    Trehalose promotes autophagy via the activation of TFEB (transcription factor EB), which is important in ameliorating disease phenotypes in multiple neurodegenerative disease models. It regulates autophagy by inducing lysosomal enlargement and membrane permeabilization, which correlates with calcium-dependent phosphatase activation, TFEB dephosphorylation, and nuclear translocation. This process leads to the upregulation of genes related to lysosomal hydrolases, membrane proteins, and several autophagy-related components in a TFEB-dependent manner.

    Systemic Effects and Modulation of Autophagy

    Trehalose may exert its neuroprotective effects through indirect mechanisms at systemic levels, such as influencing the gut microbiota.

  • Trehalose is currently under investigation in clinical trials for its potential therapeutic effects in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Spinocerebellar Ataxia (SCA), sponsored by Seelos Therapeutics.

    Spinocerebellar Ataxia (SCA) 

    STRIDES, a randomized, double-blind, placebo-controlled trial, known as SLS-005, is assessing the safety and efficacy of trehalose in treating adults with SCA, currently in its phase 2/3 stage. 

    Amyotrophic Lateral Sclerosis (ALS) 

    The HEALEY ALS Platform Trial is a perpetual, multi-center clinical trial assessing the safety and efficacy of various investigational treatments for ALS, operating under a single Master Protocol (NCT04297683). Regimen E of this trial specifically evaluates the safety and efficacy of SLS-005 (Trehalose injection), with participants randomized in a 3:1 ratio to receive either the active treatment or a placebo.

Key Publications

Yap et al, 2023

This systemic review summarizes the animal studies of trehalose in neurodegenerative disorders. In the majority of reviewed studies, trehalose upregulates autophagy and improves physiological and behavioral symptoms in rodent models of neurodegeneration.

Zaltzman et al, 2020

Trehalose was well tolerated, and no serious drug-related adverse events were recorder in patients with Machado-Jospeh Disease. Functional scores for all patients remained stable at 6 months. Six patients received treatment for as long as 12 months and continued to remain stable on all the above tests.

Rusmini et al, 2019

Trehalose promotes autophagy via the activation of TFEB (transcription factor EB), which is important in ameliorating disease phenotypes in multiple neurodegenerative disease models. It regulates autophagy by inducing lysosomal enlargement and membrane permeabilization, which correlates with calcium-dependent phosphatase activation, TFEB dephosphorylation, and nuclear translocation. This process leads to the upregulation of genes related to lysosomal hydrolases, membrane proteins, and several autophagy-related components in a TFEB-dependent manner.

Noorasyikin et al, 2020

This study shows that oral trehalose is safe and was able to improve disease severity scores (SARA), 8-min walking test scores, and quality of life scores, in approximately 61% of SCA 3 patients at 6 months.

Cicardi et al, 2019

The study finds that the heat shock protein B8 (HspB8) aids in the autophagic removal of misfolded ARpolyQ, suggesting that treatments boosting autophagic flux and ARpolyQ clearance could be beneficial for SBMA patients. This publication shows that trehalose elevates Hspb8 mRNA levels.