Trehalose in Machado-Joseph Disease: Safety, Tolerability, and Efficacy

Zaltzman, Roy; Elyoseph, Zohar; Lev, Nirit; Gordon, Carlos R.

doi:10.1007/s12311-020-01150-6

Cited by 27 publications

(16 citation statements)

References 21 publications

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“…This study aimed to evaluate the potential efficacy of IV trehalose (at a dose of 15 mg/week) in NPA and NPB patients. The dose of 15 mg/week was selected based on recent evidence and a previous similar clinical study showing the safety and efficacy of 15 mg IV trehalose in patients with Machado–Joseph disease (MJD) [ 18 ]. We hypothesized that trehalose could slow disease progression and improve neuropathologic features by decreasing sphingolipid deposition post three months of treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Significant improvement has been observed on multiple behavioral tasks along with a marked increase in synaptophysin, doublecortin, and progranulin in the hippocampus and cortex of mice treated with oral administration of 2% trehalose for one month [ 53 , 54 , 55 ]. Moreover, a clinical study showed the effect of trehalose in patients with MJD with the optimal dose of 15 mg/week to improve disease severity and clinical symptoms [ 18 ]. Neurological involvement in NP varies in frequency and severity of disease, loss of mental abilities, and cognitive impairment more prominent in NPA, while type B patients tend to have milder symptoms with later-onset [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

“…Trehalose has been recognized as a safe additive by the Joint WHO/FOA Expert Committee on Food Additive (JECFA) and U.S. Food and Drug Administration (FDA) in 2000, and was approved for use in food in Europe in 2001 [ 10 ]. Apart from basic and experimental evidence [ 11 , 12 , 13 , 14 , 15 , 16 ], several clinical trials were performed to evaluate the safety and efficacy of trehalose in healthy subjects or patients with different diseases, both orally and intravenously [ 17 , 18 ]. At doses up to 50 g, trehalose is safe for humans, and no adverse effect has been reported in most subjects; however, gastrointestinal side effects may occur in trehalose-deficient individuals [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…Trehalose can be used by either oral or intravenous (IV) administration; however, its absorption is decreased to 0.5% in the oral route due to enzymatic metabolization with Trehalase exhibiting in the intestinal brush border, and (IV) trehalose administration is more efficient for clinical trials [ 10 , 28 ]. Nevertheless, oral administration of trehalose in both preclinical and clinical studies of oculopharyngeal muscular dystrophy (OPMD) and Machado–Joseph disease (MJD) can stabilize neurological impairment and improve the severity of clinical disease scores [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Impact of Intravenous Trehalose Administration in Patients with Niemann–Pick Disease Types A and B

Mobini

Radbakhsh

Kubaski

et al. 2022

JCM

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Background and Aims: Niemann–Pick disease (NPD) types A (NPA) and B (NPB) are caused by deficiency of the acid sphingomyelinase enzyme, which is encoded by the SMPD1 gene, resulting in progressive pathogenic accumulation of lipids in tissues. Trehalose has been suggested as an autophagy inducer with therapeutic neuroprotective effects. We performed a single-arm, open-label pilot study to assess the potential efficacy of trehalose treatment in patients with NPA and NPB patients. Methods: Five patients with NPD type A and B were enrolled in an open-label, single-arm clinical trial. Trehalose was administrated intravenously (IV) (15 g/week) for three months. The efficacy of trehalose in the management of clinical symptoms was evaluated in patients by assessing the quality of life, serum biomarkers, and high-resolution computed tomography (HRCT) of the lungs at the baseline and end of the interventional trial (day 0 and week 12). Results: The mean of TNO-AZL Preschool children Quality of Life (TAPQOL) scores increased in all patients after intervention at W12 compared to the baseline W0, although the difference was not statistically significant. The serum levels of lyso-SM-509 and lyso-SM were decreased in three and four patients out of five, respectively, compared with baseline. Elevated ALT and AST levels were decreased in all patients after 12 weeks of treatment; however, changes were not statistically significant. Pro-oxidant antioxidant balance (PAB) was also decreased and glutathione peroxidase (GPX) activity was increased in serum of patients at the end of the study. Imaging studies of spleen and lung HRCT showed improvement of symptoms in two patients. Conclusions: Positive trends in health-related quality of life (HRQoL), serum biomarkers, and organomegaly were observed after 3 months of treatment with trehalose in patients with NPA and NPB. Although not statistically significant, due to the small number of patients enrolled, these results are encouraging and should be further explored.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Impact of Intravenous Trehalose Administration in Patients with Niemann–Pick Disease Types A and B

Mobini

Radbakhsh

Kubaski

et al. 2022

JCM

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“…We report that chronic treatment with trehalose reduced NSF aggregation and ameliorated motor and cognitive phenotype in aged G2019S mice. Treatment with trehalose already demonstrated to be protective in models of Huntington disease, spinocerebellar ataxia, MAchado-Joseph disease, and Parkin-PD (Rodríguez-Navarro et al 2010;Sarkar et al 2007;Seki et al 2010;Zaltzman et al 2020). However, the pharmacokinetics properties of trehalose are poor.…”

Section: Hints Toward a Therapymentioning

confidence: 99%

LRRK2 G2019S kinase activity triggers neurotoxic NSF aggregation

Pischedda

Cirnaru

Ponzoni

et al. 2019

Preprint

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SummaryParkinson’s disease (PD) is characterized by the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta and the presence of protein aggregates in surviving neurons. LRRK2 G2019S mutation is one of the major determinants of familial PD cases and leads to late-onset PD with pleomorphic pathology, including alpha-synuclein accumulation and deposition of protein inclusions. We demonstrated that LRRK2 phosphorylates N-ethylmaleimide sensitive factor (NSF). We observed aggregates containing NSF in basal ganglia specimens from G2019S carrier PD patients and in cellular and animal models expressing the LRRK2 G2019S variant. We found that LRRK2 G2019S kinase activity induces the accumulation of NSF in toxic aggregates. Noteworthy, the induction of autophagy cleared NSF aggregation and rescued motor and cognitive impairment observed in aged hG2019S BAC mice. We suggest that LRRK2 G2019S pathological phosphorylation hampers substrate catabolism, thus causing the formation of cytotoxic protein inclusions.HighlightsLRRK2 phosphorylates NSF in vivoNSF aggregates in complementary LRRK2 G2019S modelsLRRK2 G2019S kinase activity induces NSF accumulation in toxic aggregatesAutophagy induction rescues hG2019S BAC mice motor and cognitive impairment

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