WFS1 gene delivery rescues visual function in a mouse model of Wolfram syndrome

Wolfram syndrome is a rare childhood neurodegenerative disease characterized by diabetes followed by severe and rapid optic atrophy leading to blindness before the age of 20. Patients often develop other symptoms, such as deafness and neurological dysfunction. Wolfram syndrome is caused by mutations in the WFS1 gene, which encodes wolframin protein. Despite decades of intensive research, the complex mechanisms of optic neuropathy are not fully understood, and there are currently no therapies to prevent vision loss in Wolfram patients. Here, we showed that Wfs1 knockout mice generated by disruption of exon 8 of the Wfs1 gene develop progressive loss of visual acuity, optic disc pallor and severe optic nerve damage. We tested the efficiency of gene therapy using AAV2 to deliver human WFS1 to retinal ganglion cells in Wfs1 knockout mice. Our results provide the first evidence that intravitreal injection of human WFS1 has significant neuroprotective effects on retinal ganglion cells and their axons and slows the loss of visual acuity. These results demonstrate that WFS1 is able to provide both functional and structural protection to retinal ganglion cells in Wfs1 knockout mice and provide important evidence for the efficacy of WFS1 as a neuroprotective treatment for Wolfram syndrome. These results demonstrate the promising effects of gene therapy for Wolfram syndrome and encourage future research aimed at conducting clinical trials in patients.