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

BackgroundWolfram 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 revealed that glucagonlike peptide-1 receptor agonist (GLP1 RA) anti-diabetic drugs are effective in delaying and restoring glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats, reducing neuroinflammation, retinal ganglion cell death and optic nerve degeneration. WS is an early-onset, chronical condition and, therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression in WS patients. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide (0.4mg/kg/day) up to the age of 18 months and changes in diabetes markers, visual acuity, hearing sensitivity were monitored in vivo over the course of the 16-month treatment period. ResultsEarly and chronic (16-month) intervention with the GLP-1 RA liraglutide delayed the development of glucose intolerance in WS rats. At the end of the experiment, 91% of saline- and 55% of liraglutide-treated WS rats needed daily insulin supplementation. Liraglutide administration was effective in maintaining visual acuity in WS rats by stalling the progression of cataract, degeneration of retinal ganglion cells and of optic nerve atrophy. Prolonged liraglutide therapy could not prevent sensorineural hearing loss at low frequencies. ConclusionThe rat model of WS used in this study is an excellent predictive model for preclinical trials as it closely recapitulates the relative onset and severity of the main symptoms of WS observed in human patients. We found that a 16-month treatment with GLP1 receptor agonist liraglutide delays or prevents the onset of diabetes and protects against vision loss in a rat model of Wolfram syndrome. Therefore, early diagnosis and prophylactic treatment with the GLP-1R agonist liraglutide may also prove to be a promising treatment option for Wolfram syndrome patients by increasing the quality of life of WS patients.

Wfs1E864K knock-in mice illuminate the fundamental role of Wfs1 in endocochlear potential production

“…The four studies reporting affected carriers of the disease-causing variant demonstrated a high variability in the severity of the hearing impairment, the age of onset and the affected frequencies, as well as the associated symptoms 4,5,30,31 . Contrary to other Wfs1 null models discussed previously (Wfs1 ΔExon8 , Wfs1-KO rat 25 ), Wfs1 E864K have early onset (P23) and rapidly progressing hearing loss. By P31, the mice are profoundly deaf for all tested frequencies.…”

“…Responsible for WS, variants of WFS1 were also associated with different forms of inherited deafness and Wolfram-like syndrome 42 . Despite the emergence of multiple animal models, none of them present with an early onset hearing loss, hampering the understanding of WFS1 role in the auditory pathway [25][26][27]43 .…”

“…ΔExon8 model resembled the one of the Wfs1-KO rat model, with late onset and slowly progressive hearing loss 24,25 . However, all tested frequencies were affected for the mouse model while only low frequencies showed alterations in the Wfs1 de cient rat.…”

“…So far, among Wolfram syndrome established animal models, hearing impairment has only been reported in the rat 24,25 , but not in zebra sh 26,27 nor the mouse 28,29 . Wfs1 KO rats developed progressive, lowfrequency, neurosensory HL.…”

Morphological, behavioral and cellular analyses revealed different phenotypes in Wolfram syndrome wfs1a and wfs1b zebrafish mutant lines

“…In humans, hearing loss appears in 46% of the patients ( 43 ) in the second decade of life. In addition, in a recent study on a rat model of WS, null for WFS1, hearing loss was observed starting at 6.5 months old, in the higher frequencies, and worsened with age ( 44 ). Despite being a prominent feature of WS, none of the characterization studies of the several mouse models of the pathology report any hearing deficit, suggesting either a mild or non-existent hearing loss, or a late onset of the phenotype.…”