Oct 8, 2020:
The negative phycological impacts of diabetes stigma.
https://care.diabetesjournals.org/content/early/2020/09/02/dc19-2447.abstract
October 6, 2020:
A new manifestation of neovascularization in a study with mice.
October 1, 2020:
The use of OCTA (Optical coherence tomography angiography) in finding biomarkers for neurodegenerative diseases.
https://journals.sagepub.com/doi/full/10.1177/2515841420950508
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 January 2019. We currently have 12 recruits at our children’s hospital site in Birmingham, looked after by my colleague Dr Renuka Dias. We had a pause due to Coronavirus, but I am very pleased to say that Dr Ben Wright has just recruited our first adult patient at the adult site in Birmingham. With lots of help from our international colleagues, we now have all the regulatory approvals in place in each country. We spoke with Dr Gema Esteban in Spain this week, and she will recruit her first patient in October. We hope to complete recruitment in June 2021.
We now have really accurate and reproducible assessments in each site so that we can pool the results. Our independent data monitoring committee sees all the unmasked results and if there is a strong signal of effect, or signal of no effect, they will let us know without waiting for the end of the trial.
I am very grateful to everyone who is taking part or about to take part in this trial; and we are learning a lot about how to deliver clinical trials in Wolfram, for the future. Wolfram syndrome UK have been brilliant in supporting families to attend study visits; and we are very grateful to The Snow Foundation, Eye Hope Foundation, and Association Syndrome de Wolfram for support to collect research samples, which will be available to the whole Wolfram syndrome community.
Sincerely
Dr Timothy Barrett
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 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.
Neil H. White, MD (314) 286-1157
Bess A. Marshall, MD (314) 454-6051
Fumihiko Urano, MD, Ph.D.
Tamara Hershey, PhD
By Mario Plaas and Anton Terasmaa
Wfs1 KO rats. These rats were used for 5 months long Liraglutide experiment.
At University of Tartu we have created and characterized Wfs1 knock-out (Wfs1 KO) rat, which exhibits symptoms of Wolfram syndrome (WS), including diabetes mellitus, optic atrophy and degeneration of brainstem [1]. Thus, rat model mimics human condition, is well suited to study molecular mechanism of WS and to evaluate pharmacological treatment strategies. Our activities are mostly related to evaluation of pharmacological treatments in rat model of WS. While performing this work we also try to understand the molecular pathology of WS using histological and molecular biology methods.
We have evaluated effect of GLP1 receptor agonist Liraglutide in the rat model of WS. One week treatment with GLP1 receptor agonist markedly improved diabetic phenotype of these rats. We therefore have tested the effect of 5 months long treatment with GLP1 RA Liraglutide in Wfs1 KO rat, this treatment resulted in an improvement of diabetic phenotype, reduction of ER stress levels and preservation of remaining beta cell mass [2]. Our next study was aimed at evaluation of neuroprotective effects of Liraglutide in the rat model of WS. For this purpose older Wfs1 KO rats were treated with liraglutide for 6 months. Thereafter, number on neurons was evaluated in the brainstem and retina of these rats using stereology. We expect to publish the results of this study very soon.
In parallel, using similar tactics as with Liraglutide, we are evaluating also alternative pharmacological treatment options in our rat model of WS. For this purpose we treat animals with promising drug candidates and evaluate their effects on progression of symptoms of WS. This approach could be the fastest way to find and introduce new treatment options.
1. Plaas, M., et al., Wfs1- deficient rats develop primary symptoms of Wolfram syndrome: insulin-dependent diabetes, optic nerve atrophy and medullary degeneration. Sci Rep, 2017. 7(1): p. 10220.
2. Toots, M., et al., Preventive treatment with liraglutide protects against development of glucose intolerance in a rat model of Wolfram syndrome. Sci Rep, 2018. 8(1): p. 10183.
Washington University School of Medicine
Dear Wolfram Community,
As we prepare for the research clinic and the community conference with the Snow Foundation, a few other things have been going on that we want you to know about!
First, we have published a paper that describes how the size of brain regions change over time in Wolfram syndrome. This paper is based on the brain imaging that we have done over the last 8 years in the Wolfram research clinic. You can find the paper online here: Evidence for altered neurodevelopment and neurodegeneration in Wolfram syndrome using longitudinal morphometry. The findings have important implications for current and future clinical trials for treating Wolfram syndrome neurodegeneration.
Second, we have continued to interact with other groups that are working on current and future clinical trials, both here in the US, the UK and Belgium.
Finally, we have been working with investigators in Estonia on their mouse model for Wolfram syndrome to determine whether they display similar changes in the brain to people with Wolfram syndrome. If this mouse model is similar in its brain features, we then would be able to do more specific brain studies that might suggest brain-specific treatments.
If you have any questions about any of these research projects, please let me know! I am always happy to talk to you.
Sincerely,
Tamara Hershey, PhD
Professor Scientific Director and Principal Investigator WU Wolfram Research Clinic tammy@wustl.edu
Did you know? All of your wine purchases can now directly support The Snow Foundation.
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Welcome to the inner circle of wine wanderlust!
When Wolfram syndrome is caused by mutations in the WFS1 gene, it is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Some studies have shown that people who carry one copy of a WFS1 gene mutation are at increased risk of developing individual features of Wolfram syndrome or related features, such as type 2 diabetes, hearing loss, or psychiatric illness. However, other studies have found no increased risk in these individuals.
Hypogonadism is seen in some patients. Impaired fertility and erectile dysfunction in male patients and infertility, amenorrhea, and oligomenorrhea in female patients have been reported. These conditions could be treatable and managed in standard way.
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