GLP-1 receptor agonist liraglutide has a neuroprotective effect on an aged rat model of Wolfram syndrome

Publication: Nature.com | Publication Date: October 31, 2019

Authors: Kadri Seppa, Maarja Toots, Riin Reimets, Toomas Jagomäe, Tuuliki Koppel, Maia Pallase, Stine Hasselholt, Maiken Krogsbæk Mikkelsen, Jens Randel Nyengaard, Eero Vasar, Anton Terasmaa & Mario Plaas

Abstract

Wolfram syndrome (WS) is a rare neurodegenerative disorder that is mainly characterized by diabetes mellitus, optic nerve atrophy, deafness, and progressive brainstem degeneration. Treatment with GLP-1 receptor agonists has shown a promising anti-diabetic effect in WS treatment in both animal models and in human patients. Since previous research has tended to focus on investigation of the WS first symptom, diabetes mellitus, the aim of the present study was to examine liraglutide effect on WS-associated neurodegeneration. We took 9-month-old Wfs1 knock-out (KO) animals that already had developed glucose intolerance and treated them with liraglutide for 6 months. Our research results indicate that 6-month liraglutide treatment reduced neuroinflammation and ameliorated endoplasmic reticulum (ER) stress in the inferior olive of the aged WS rat model. Liraglutide treatment also protected retinal ganglion cells from cell death and optic nerve axons from degeneration. According to this, the results of the present study provide novel insight that GLP-1 receptor agonist liraglutide has a neuroprotective effect in the WS rat model.

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Current Landscape of Treatments for Wolfram Syndrome

Publication: ScienceDirect | Publication Date: October 2019

Authors: Damien Abreu, Fumihiko Urano

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.

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Dr. Urano’s October 2019 Update

Fumihiko “Fumi” Urano, MDOctober 13, 2019

 

Dear Friends,

 

It is wonderful to see you. I always appreciate your continued support and encouragement. I have been doing my best to develop cutting-edge treatments for Wolfram syndrome and save our patients. It has been tough, but your kind words keep me going. I feel incredibly grateful. I would like to share our progress and ideas.

 

As you know, our clinical trial of dantrolene sodium for adult and pediatric patients with Wolfram syndrome has been going well, but a mild success. To improve the efficacy of dugs targeting endoplasmic reticulum stress (ER stress: a molecular mechanism of Wolfram syndrome), I have been working on two new drugs targeting ER stress. Based on the results of dantrolene trial, I am confident that targeting ER stress is beneficial for patients with Wolfram syndrome. Preclinical data (i.e., data using cell and animal models) and safety profile of both new drugs look very good. Thus, I am planning a multi-center trial using one of these drugs. My goal is to make this happen in the next 12-24 months. I will do my best.

Another priority for me is to develop gene therapy for vision impairment in Wolfram syndrome. We have created adeno-associated virus (AAV: a safe virus utilized for gene therapy) that can deliver normal Wolfram gene (WFS1) and a regeneration factor, MANF, into retinal cells. We got an encouraging result last week showing that one of our new type of viruses can deliver MANF into retinal ganglion cells efficiently in a mouse model of Wolfram syndrome. My goal is to complete preclinical studies on gene therapy as quickly as possible. This is always on my mind. I will keep on doing my best and keep you updated. I am assembling a strong team of eye doctors.

 

As always, please feel free to contact me with any questions or concerns (urano@wustl.edu). I would like to know what you think and how you feel. Thank you again for your continued support. We will decrease human suffering and change the future of our patients together.

 

With gratitude,

Fumi Urano

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