Effect of 4-phenylbutyrate and valproate on dominant mutations of WFS1 gene in Wolfram syndrome

Batjargal, Khishigjargal; Tajima, Toshihiro; Jimbo, Eriko F.; Yamagata, Takanori

doi:10.1007/s40618-020-01228-2

Cited by 15 publications

(12 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PBA reduces ER stress in pancreatic β-cells by decreasing protein folding load and increasing insulin secretion. Valproate, widely used as an anticonvulsant and mood-stabilizing drug, has been reported to attenuate ER stress-induced apoptosis in neuronal, hepatocellular and pancreatic β-cells through an as yet unclear mechanism [ 37 ].…”

Section: Resultsmentioning

confidence: 99%

Wolfram Syndrome Type 2: A Systematic Review of a Not Easily Identifiable Clinical Spectrum

Rosanio

Candia

Occhiati

et al. 2022

IJERPH

View full text Add to dashboard Cite

Background: Wolfram syndrome (WS) is a rare autosomal recessive disorder that is characterized by the presence of diabetes mellitus, optic atrophy and hearing loss, all of which are crucial elements for the diagnosis. WS is variably associated with diabetes insipidus, neurological disorders, urinary tract anomalies, endocrine dysfunctions and many other systemic manifestations. Since Wolfram and Wagener first described WS in 1938, new phenotypic/genotypic variants of the syndrome have been observed and the clinical picture has been significantly enriched. To date, two main subtypes of WS that associated with two different mutations are known: WS type 1 (WS1), caused by the mutation of the wolframine gene (WS1; 606201), and WS type 2 (WS2), caused by the mutation of the CISD2 gene (WS2; 604928). Methods: A systematic review of the literature was describe the phenotypic characteristics of WS2 in order to highlight the key elements that differentiate it from the classic form. Conclusion: WS2 is the rarest and most recently identified subtype of WS; its clinical picture is partially overlapping with that of WS1, from which it traditionally differs by the absence of diabetes insipidus and the presence of greater bleeding tendency and peptic ulcers.

show abstract

Section: Resultsmentioning

confidence: 99%

Wolfram Syndrome Type 2: A Systematic Review of a Not Easily Identifiable Clinical Spectrum

Rosanio

Candia

Occhiati

et al. 2022

IJERPH

View full text Add to dashboard Cite

show abstract

“…Valproate [77] yes (FDA; seizures) yes (NCT03717909) Alleviating ER stress [75,76] GLP1R agonists [78,79] yes (FDA; diabetes mellitus T2) Alleviating ER stress [78,79] Stimulating proliferation ( egenerative medicine)…”

Section: Discussionmentioning

confidence: 99%

“…Valproate (VPA) is a mood stabilizer [73]. that can inhibit histone deacetylase (HDAC) [74], reduce ER stress [75], and induce WFS1 expression [76]. In a mouse model of WS, valproate improved blood glucose tolerance, potentially through enhancement of insulin sensitivity [77].…”

Section: Targeting Er Stressmentioning

confidence: 99%

Wolfram syndrome: a monogenic model for diabetes mellitus and neurodegeneration

Fischer

Ehrlich

2020

Current Opinion in Physiology

View full text Add to dashboard Cite

Wolfram syndrome (WS) is a rare, progressive disorder characterized by childhood-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus, and neurodegeneration. Currently, there is no effective treatment for WS, and patients typically die between 30 and 40 years of age. WS is primarily caused by autosomal recessive mutations in the Wolfram syndrome 1 (WFS1) gene (OMIM 222300), which encodes for wolframin (WFS1). This disorder is therefore a valuable monogenic model for prevalent diseases, particularly diabetes mellitus and neurodegeneration. Whereas reduced survival and secretion are known cellular impairments causing WS, the underlying molecular pathways and the physiological function of WFS1 remain incompletely described. Here, we characterize WFS1 as a regulator of intracellular calcium homeostasis, review our current understanding of the disease mechanism of WS, and discuss candidate treatment approaches. These insights will facilitate identification of new therapeutic strategies not only for WS but also for diabetes mellitus and neurodegeneration.

show abstract

“…Moreover, this drug was shown to enhance the dissociation of WFS1 from GRP94, suggesting that it may have ER stress-modulating effects (Kakiuchi et al, 2009). A recent study showed that sodium valproate also reduces ER stress and cell apoptosis in Wolfram syndrome 1 models caused by dominant WFS1 mutations (Batjargal et al, 2020). This drug received orphan designation for Wolfram syndrome from the EMA and the FDA.…”

Section: Approved and Non-approved Orphan-designated Repurposed Drugs For Wolfram Syndromementioning

confidence: 99%

Current Drug Repurposing Strategies for Rare Neurodegenerative Disorders

Shah

Dooms²,

Amaral-Garcia

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

Rare diseases are life-threatening or chronically debilitating low-prevalent disorders caused by pathogenic mutations or particular environmental insults. Due to their high complexity and low frequency, important gaps still exist in their prevention, diagnosis, and treatment. Since new drug discovery is a very costly and time-consuming process, leading pharmaceutical companies show relatively low interest in orphan drug research and development due to the high cost of investments compared to the low market return of the product. Drug repurposing–based approaches appear then as cost- and time-saving strategies for the development of therapeutic opportunities for rare diseases. In this article, we discuss the scientific, regulatory, and economic aspects of the development of repurposed drugs for the treatment of rare neurodegenerative disorders with a particular focus on Huntington’s disease, Friedreich’s ataxia, Wolfram syndrome, and amyotrophic lateral sclerosis. The role of academia, pharmaceutical companies, patient associations, and foundations in the identification of candidate compounds and their preclinical and clinical evaluation will also be discussed.

show abstract

Effect of 4-phenylbutyrate and valproate on dominant mutations of WFS1 gene in Wolfram syndrome

Cited by 15 publications

References 32 publications

Wolfram Syndrome Type 2: A Systematic Review of a Not Easily Identifiable Clinical Spectrum

Wolfram Syndrome Type 2: A Systematic Review of a Not Easily Identifiable Clinical Spectrum

Wolfram syndrome: a monogenic model for diabetes mellitus and neurodegeneration

Current Drug Repurposing Strategies for Rare Neurodegenerative Disorders

Contact Info

Product

Resources

About