Early Intervention and Lifelong Treatment with GLP1 Receptor Agonist Liraglutide in a Wolfram Syndrome Rat Model with an Emphasis on Visual Neurodegeneration, Sensorineural Hearing Loss and Diabetic Phenotype

Abstract

Wolfram syndrome (WS), also known as a DIDMOAD (diabetes insipidus, early-onset diabetes mellitus, optic nerve atrophy and deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 (WFS1) gene. Previous studies have revealed that glucagon-like peptide-1 receptor agonist (GLP1 RA) are effective in delaying and restoring blood glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats. WS is an early-onset, chronic condition. Therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on the progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide up to the age of 18 months and changes in diabetes markers, visual acuity, and hearing sensitivity were monitored over the course of the treatment period. We found that treatment with liraglutide delayed the onset of diabetes and protected against vision loss in a rat model of WS. Therefore, early diagnosis and prophylactic treatment with the liraglutide may also prove to be a promising treatment option for WS patients by increasing the quality of life.

ER Calcium Depletion as a Key Driver for Impaired ER-to-Mitochondria Calcium Transfer and Mitochondrial Dysfunction in Wolfram Syndrome

“…Notably, the GLP-1 agonist liraglutide also improved Ca 2+ homeostasis and mitochondrial health in Wfs1de cient neurons. Liraglutide has demonstrated neuroprotective effects in animal experiments 40,41,58,59 and has become one of the rst-line treatments for WS. Liraglutide, being an analog of GLP-1, binds to the Gs-coupled GLP-1 receptor present in both β-cells and neurons, stimulating adenylate cyclase to generate cAMP 60,61 .…”

“…These drugs were the SERCA activator CDN1163 (0.5 µM), an inhibitor of Ca 2+ release via RYR azumolene (20 µM), an inhibitor of Ca 2+ leak through the RyR Rycal-S107 (5 µM) and a selective inhibitor of the mitochondrial Na + /Ca 2+ exchanger CGP37157 (10-20 µM). We also included liraglutide (500 nM) in our experiments as it is a rst-line treatment in WS patients and it is neuroprotective in animal experiments 7,40,41 . We examined the effects of these drugs on selected parameters of mitochondrial and axon health (mitochondrial density and length, mitophagy intensity, ATP/ADP ratio and axonal length).…”

GLP-1R agonists demonstrate potential to treat Wolfram syndrome in human preclinical models

“…GLP-1R agonists have hence been examined as a potential therapy for diabetes, neurodegeneration and vision loss in Wolfram syndrome [ 21 – 26 ]. Acute exenatide injection in Wfs1 knockout (KO) mice enhances insulin secretion [ 23 ], while prolonged exenatide and liraglutide administration in young WFS1-deficient mice and rats improves glucose-stimulated insulin secretion and protects against vision loss [ 21 , 22 , 25 ]. In older WFS1-deficient rats, liraglutide reduces neuroinflammation, delays optic nerve atrophy and improves visual acuity [ 24 , 26 ].…”

A Pair of Siblings With Wolfram Syndrome: A Review of the Literature and Treatment Options

“…For patients with WS, GLP1-RA is also a form of ER stress reducer used in animal models as a prophylactic treatment to delay the onset of diabetes and protect against vision loss. 28 Its anti-inflammatory and antioxidative properties have beneficial effects on the central and peripheral nervous systems 29 which could delay syndrome progression and potentially increase the number of healthy life years in individuals with WS. In addition to our case report, liraglutide was also reported to be safe and well tolerated in a case series of 4 pediatric patients with WS who were treated with it for 8 to 27 months.…”