September 2020 Dear friends and colleagues, to recap, this is a trial of sodium valproate given by mouth, for 3 years, to try and slow down the progress of vision loss in Wolfram. It involves 4 countries in Europe, and is comparing the effects of sodium valproate to placebo. The trial recruited its first patient in […]
Wolfram syndrome is a rare genetic spectrum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration, and ranges from mild to severe clinical symptoms. There is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, raising the urgency for innovative therapeutics for this disease. Here, we summarize our vision for developing novel treatment strategies and achieving a cure for Wolfram-syndrome-spectrum disorder.
Wolfram syndrome is a rare genetic spectrum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration, and ranges from mild to severe clinical symptoms. There is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, raising the urgency for innovative therapeutics for this disease. Here, we summarize our vision for developing novel treatment strategies and achieving a cure for Wolfram-syndrome-spectrum disorder.
Wolfram syndrome is a rare genetic spectrum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration, and ranges from mild to severe clinical symptoms. There is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, raising the urgency for innovative therapeutics for this disease. Here, we summarize our vision for developing novel treatment strategies and achieving a cure for Wolfram-syndrome-spectrum disorder.
Dear Families: We (Drs. White, Marshall, Urano, and Hershey) are excited to announce that we are now funded to perform a clinical trial of liraglutide (Victoza®; NovoNordisk) in Wolfram Syndrome. Led by Drs. White and Marshall, this study will focus on the tolerability and safety of liraglutide and possible beneficial effects. We are inviting all […]
Endoplasmic reticulum (ER) stress-mediated cell death is an emerging target for human chronic disorders, including neurodegeneration and diabetes. However, there is currently no treatment for preventing ER stress-mediated cell death. Here, we show that mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor secreted from ER stressed cells, prevents ER stress-mediated β cell death and enhances β cell proliferation in cell and mouse models of Wolfram syndrome, a prototype of ER disorders. Our results indicate that molecular pathways regulated by MANF are promising therapeutic targets for regenerative therapy of ER stress-related disorders, including diabetes, retinal degeneration, neurodegeneration, and Wolfram syndrome.
Wolfram syndrome is a recessive genetic disease caused by mutations in WFS1 (Wolfram syndrome 1) and can present with a multitude of symptoms including diabetes, optic atrophy, and neurological problems. There is currently no cure and patients are managed with symptomatic treatment. Maxwell et al. corrected a WFS1 pathogenic variant in patient fibroblast-derived induced pluripotent stem cells (iPSCs) that they then differentiated to pancreatic β cells. The gene-corrected β cells showed improved glucose-stimulated insulin secretion and reversed hyperglycemia for 6 months after their transplantation into diabetic mice. This study may open up the possibility of autologous β cell transplants for patients with Wolfram syndrome.
We further examined the function of WFS1 in the context of glucose toxicity, to address the earliest diagnosed symptom of WS which is the onset of diabetes mellitus near age 6. Based on a recent study, we aimed to show that WFS1 interaction with a calcium binding protein, neuronal calcium sensor 1 (NCS1), is important for its normal functions.
The objective of this study was to analyze the effect of PBA and VPA on dominant WFS1 mutants in vitro.
We showed that Wolframin (WFS1) protein is enriched at mitochondrial-associated ER membranes and that in patient-derived fibroblasts WFS1 protein is completely absent. These findings support a loss-of-function pathogenic mechanism for missense mutations in WFS1, ultimately leading to defective calcium influx within mitochondria.
You must be logged in to post a comment.