AAV Vector Gene Transfer Therapy

Publication: ncbi.nlm.nih.gov | Publication Date: July 29, 2013

Authors: Shu-Jen Chen, Julie Johnston, Arbans Sandhu, Lawrence T. Bish, Ruben Hovhannisyan, Odella Jno-Charles, H. Lee Sweeney, and James M. Wilson

Abstract

The ability to regulate both the timing and specificity of gene expression mediated by viral vectors will be important in maximizing its utility. We describe the development of an adeno-associated virus (AAV)-based vector with tissue-specific gene regulation, using the ARGENT dimerizer-inducible system. Read more

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A mutant wfs1 zebrafish model of Wolfram syndrome manifesting visual dysfunction and developmental delay

Publication: nature.com | Publication Date: October 14, 2021

Authors: Cairns, G., Burté, F., Price, R. et al.

Abstract

Wolfram syndrome (WS) is an ultra-rare progressive neurodegenerative disorder defined by early-onset diabetes mellitus and optic atrophy. The majority of patients harbour recessive mutations in the WFS1 gene, which encodes for Wolframin, a transmembrane endoplasmic reticulum protein. Read more

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A mild form of Wolfram syndrome in the Ashkenazi Jewish population

Publication: wolframsyndrome.wustl.edu | Publication Date: February 1, 2022

Authors: Fumihiko Urano

Abstract

We recently identified a WFS1 gene variant associated with a mild form of Wolfram syndrome in the Ashkenazi Jewish population. This WFS1 gene variant, WFS1 c.1672C>T (p.Arg558Cys) is prevalent in the Jewish population, and 1/30 Jewish people are carriers. Read more

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Neuronal Calcium Sensor 1 (NCS1) as a Potential Drug Target for Treatment of Wolfram Syndrome

Publication: The Faseb Journal | Publication Date: April 15, 2020

Authors: Tom T. Fischer, Lien D. Nguyen, Barbara E. Ehrlich

Abstract

Wolfram syndrome (WS) is an orphan, autosomal recessive neuroendocrinological disease that affects approximately 1 in 500,000 people worldwide. Patients develop diabetes mellitus, diabetes insipidus, optical atrophy, and hearing loss and usually die in their 30s. The majority of cases are attributed to mutations in a single gene, WFS1, which encodes for the protein wolframin. Despite the known genetic cause, there is currently no direct treatment for WS. This lack of therapy is because the regular functions of wolframin, and the pathophysiological consequences following the loss of intact WFS1, remain elusive. Read more

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Gene-Edited Human Stem Cell-Derived β Cells From a Patient with Monogenic Diabetes Reverse Preexisting Diabetes in Mice

Publication: Science Translational Medicine | Publication Date: April 22, 2020

Authors: Kristina G. Maxwell, Punn Augsornworawat, Leonardo Velazco-Cruz, Michelle H. Kim, Rie Asada, Nathaniel J. Hogrebe, Shuntaro Morikawa, Fumihiko Urano, Jeffrey R. Millman

Abstract

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.
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Calpain Inhibitor and Ibudilast Rescue β cell Functions in a Cellular Model of Wolfram Syndrome

Publication: PNAS.org | Publication Date: July 21, 2020

Authors: Lien D. Nguyen, Tom T. Fischer, Damien Abreu, Alfredo Arroyo, Fumihiko Urano, and Barbara E. Ehrlich

Significance

Wolfram syndrome is a rare multisystem disease characterized by diabetes insipidus, diabetes mellitus, optic nerve atrophy, and deafness (DIDMOAD). It is primarily caused by mutations in the Wolfram syndrome 1 gene, WFS1. As a monogenetic disorder, Wolfram syndrome is a model for diabetes and neurodegeneration. There is no effective treatment for this invariably fatal disease. Here we characterize WFS1 as a regulator of calcium homeostasis and subsequently target calcium signaling to reverse deficits in a cellular model of Wolfram syndrome.
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Effect of 4-phenylbutyrate and valproate on dominant mutations of WFS1 gene in Wolfram syndrome

Publication: Springer Link | Publication Date: March 26, 2020

Authors: K. Batjargal, T. Tajima, E. F. Jimbo & T. Yamagata

Abstract

Purpose

Wolfram syndrome (WS) is a rare disorder caused by mutations in WFS1 that is characterized by diabetes mellitus, optic atrophy, sensorineural deafness, diabetes insipidus, and neurodegeneration. This disease is usually inherited as an autosomal recessive trait, but an autosomal dominant form has been reported. Read more

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Wolfram Syndrome 1 Gene Regulates Pathways Maintaining Beta-Cell Health and Survival

Publication: Nature.com | Publication Date: February 14, 2020

Authors: Damien Abreu, Rie Asada, John M. P. Revilla, Zeno Lavagnino, Kelly Kries, David W. Piston & Fumihiko Urano

Abstract

Wolfram Syndrome 1 (WFS1) protein is an endoplasmic reticulum (ER) factor whose deficiency results in juvenile-onset diabetes secondary to cellular dysfunction and apoptosis. The mechanisms guiding β-cell outcomes secondary to WFS1 function, however, remain unclear. Here, we show that WFS1 preserves normal β-cell physiology by promoting insulin biosynthesis and negatively regulating ER stress. Read more

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Liraglutide restores chronic ER stress

Publication: nature.com | Publication Date: November 23, 2017

Authors: Theodora Panagaki, Maria Michael & Christian Hölscher

Abstract

Growing evidence suggests that agonists of glucagon-like peptide (GLP-1) receptor exert neuroprotective and neurorestorative effects across a range of experimental models of neuronal degeneration, and, recently, a pilot clinical trial of Liraglutide in Alzheimer’s disease patients showed improvements in cerebral glucose consumption that signifies disease progression. Read more

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Clinical Trial Update by Dr. Barrett — January 2024

Tim Barrett update for Winter TreatWolfram newsletter

Dear friends and colleagues,

I hope everyone is keeping OK and are keeping warm enough in this cold weather. Our research teams have kept busy and I would like to use this letter to keep you updated on our progress.

The TREATWOLFRAM trial is now in its final year. It has been a long journey to get here, navigating medicine manufacture problems, BREXIT, Covid, and supply issues. Thank you to all the participants who have supported the trial with their involvement. Our trials unit team, Amy Lamb, Lewis James Victoria Homer and Darren Barton, are working hard to make sure all the information that participants have kindly supplied, will be ready to be analysed when the trial ends in October 2024. There has been an update from the UK Medicines Regulator (MHRA) to remind patients and the public about the safety precautions we all need to follow for people taking sodium valproate. Anyone female under 55 years who may be taking sodium valproate, needs to have a safety check with their doctor each year. It is important that sodium valproate should not be taken by women who may be pregnant, as there is a risk of significant harm to the baby. There is helpful information on this UK Government website: https://www.gov.uk/guidance/valproate-use-by-women-and-girls.

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