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.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00The Snow Foundationhttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgThe Snow Foundation2020-07-21 06:53:102024-02-16 18:23:57ZOLD Calpain inhibitor and ibudilast rescue β cell functions in a cellular model of Wolfram syndrome
Wolfram Syndrome is a rare, autosomal recessive genetic disorder with clinical symptoms appearing in early childhood. Here, we report a generation of iPSCs from fibroblasts of a patient affected by this disease. Read more
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00The Snow Foundationhttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgThe Snow Foundation2020-07-20 06:56:592024-02-16 18:01:29Characterization of an induced pluripotent stem cell line (IMBPASi001-A) derived from fibroblasts of a patient affected by Wolfram Syndrome
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 participants over 10 years old in the Wolfram Research Clinic to participate in this study.
Liraglutide is a compound that is a glucagon-like peptide-1 (GLP-1) receptor agonist; that is, it acts like the natural hormone GLP-1. GLP-1 increases the release of insulin from the pancreas after a meal and slows down the digestion of the meal; this lowers blood sugars in people with type 2 diabetes. Liraglutide is approved by the Food and Drug Administration (FDA) for use in adults and children older than 10 years old with type 2 diabetes. In animal models of Wolfram syndrome, liraglutide has also been shown to slow the progression of diabetes, and possibly neurodegeneration. It is not known if this is also true in people with Wolfram Syndrome.
Participation in this study would require injecting liraglutide once a day for 12 months. Being on liraglutide will likely lower blood sugars and insulin doses, but it is unlikely to eliminate the need for insulin completely. In addition, evaluations of insulin secretion, vision, and an MRI would be conducted at the annual research clinic, and data would be shared between those two studies. Participation in this study is voluntary, and you will be free not to participate or to stop participating at any time, and you will still be able to keep participating in the research clinic.
If you are interested in learning more about this study we will discuss it with you during your visit to the Wolfram Syndrome Research Clinic, or you can contact Dr. Neil White at (314) 286-1157 or Dr. Bess Marshall at (314) 454-6051, and we can discuss it with you further.
Publication: Nature.com | Publication Date: May 4, 2020
Authors: Jana Mahadevan, Shuntaro Morikawa, Takuya Yagi, Damien Abreu, Simin Lu, Kohsuke Kanekura, Cris M. Brown & Fumihiko Urano
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. Read more
I hope you and your family are safe and well during this COVID-19 pandemic. Three things are always on my mind: Improve clinical care, Raise awareness, and Provide a cutting-edge treatment for Wolfram syndrome. As I mentioned on January 1st, I am determined to make 2020 the game-changing year for us despite this challenging time. Today, I would like to share the good news with you.
We have been testing if gene editing by CRISPR-Cas9, in combination with patient-derived induced pluripotent stem cells (iPSCs), can be utilized for the treatment of Wolfram Syndrome.I am glad to inform you thatgene editing worked in Wolfram patient iPSC-derived beta cells. We were able to use these cells to cure one of the problems, making normal beta cells by correcting WFS1 gene mutation. We could cure diabetes in cells and mice. This is a proof of concept demonstrating that correcting gene defects that cause or contribute to medical problems— in this case, in the Wolfram syndrome gene — we can cure the problems.This is a major discovery in the gene therapy field, and it has been just published in a high-profile medical research journal, Science Translational Medicine.https://medicine.wustl.edu/news/diabetes-reversed-in-mice-with-genetically-edited-patient-derived-stem-cells/
Based on this discovery, it is now possible that by correcting the genetic defects in these cells, we may correct other problems Wolfram Syndrome patients experience, such as visual impairment and neurodegeneration.So, we are currently working on eye and brain cells derived from iPSCs of patients with Wolfram Syndrome to replicate this success for other problems. Many, many thanks to my patients, colleagues at Washington University and supporters in the world. Thank you, Stephanie Snow Gebel and the Snow Foundation.
As always, please feel free to contact me with any questions (urano@wustl.edu). I would like to know what you think and how you feel.Thank you again for your continued support and encouragement, especially in this very trying time, not only for our country, but the world.We will work as one team and change history together.
“That’s one small step for us today, leading to one giant leap toward a cure for Wolfram Syndrome.”
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
Repaired β cells for replacement therapy
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.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00The Snow Foundationhttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgThe Snow Foundation2020-04-22 07:05:212024-02-16 18:25:23ZOLD Gene-edited human stem cell–derived β cells from a patient with monogenic diabetes reverse preexisting diabetes in mice
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. Here, 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. NCS1 is known to regulate exocytosis, promote cell survival, and maintain calcium homeostasis. We showed that knocking out WFS1 in rat insulinoma (INS1) cells resulted in increased baseline calcium, reduced ATP‐evoked inositol‐trisphosphate receptor (InsP3R)‐dependent calcium response, reduced phospho‐Akt (Ser473), and increased vulnerability to high glucose treatment. Furthermore, both INS1 control (CTRL) and WFS1 knockout (KO) cells showed increased NCS1 mRNA following high glucose treatment. However, only the CTRL cells showed increased NCS1 protein expression, whereas WFS1 KO cells showed decreased NCS1 expression. These results suggest that NCS1‐WFS1 interaction protects NCS1 from degradation, potentially by the calcium‐dependent protease calpain. Lastly, we showed that overexpression of NCS1, or treatment with a putative NCS1‐binding drug, rescued the deficits observed in WFS1 KO cells. Overall, we demonstrated a physiological function of the WFS1‐NCS1 interaction and that protecting NCS1 levels can ameliorate the deficits caused by loss of WFS1. These findings will facilitate the discovery of drugs that can prevent or reduce the symptoms of WS.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00The Snow Foundationhttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgThe Snow Foundation2020-04-15 07:09:412024-02-16 18:26:24ZOLD Neuronal Calcium Sensor 1 (NCS1) as a Potential Drug Target for Treatment of 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. WFS1 encodes a transmembrane protein, which is a maintenance component of endoplasmic homeostasis. These dominant mutations were thought to increase endoplasmic reticulum (ER) stress. Recent studies suggest that 4-phenylbutyrate (PBA) and valproate (VPA) reduce ER stress. The objective of this study was to analyze the effect of PBA and VPA on dominant WFS1 mutants in vitro.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00The Snow Foundationhttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgThe Snow Foundation2020-03-26 07:12:262024-02-16 18:27:20ZOLD Effect of 4-phenylbutyrate and valproate on dominant mutations of WFS1 gene in Wolfram syndrome
Publication: Nature.com | Publication Date: March 16, 2020
Authors: Chiara La Morgia, Alessandra Maresca, Giulia Amore, Laura Ludovica Gramegna, Michele Carbonelli, Emanuela Scimonelli, Alberto Danese, Simone Patergnani, Leonardo Caporali, Francesca Tagliavini, Valentina Del Dotto, Mariantonietta Capristo, Federico Sadun, Piero Barboni, Giacomo Savini, Stefania Evangelisti, Claudio Bianchini, Maria Lucia Valentino, Rocco Liguori, Caterina Tonon, Carlotta Giorgi, Paolo Pinton, Raffaele Lodi & Valerio Carelli
Abstract
Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent of mitochondrial diseases. The role played by mitochondria remains elusive, with contradictory results on the occurrence of mitochondrial dysfunction. Read more
Background: Wolfram syndrome is a rare genetic disease characterized by insulin-dependent diabetes, optic nerve atrophy, sensorineural hearing loss and neurodegeneration. Read more
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00The Snow Foundationhttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgThe Snow Foundation2020-02-22 07:21:342024-02-16 18:14:13Taste and smell function in Wolfram syndrome
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