SEARCHNARRATIVE_REVIEWophthalmology, neuro-ophthalmology

narrative_review·ophthalmology, neuro-ophthalmology, endocrinology, genetics, neurology·PMC10032446

Wolfram syndrome: new pathophysiological insights and therapeutic strategies

Therapeutic Advances in Rare Disease · 4 authors, 8 centres

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TL;DR

Wolfram syndrome (WS) is an ultra-rare genetic disease causing diabetes mellitus and progressive vision loss due to retinal ganglion cell degeneration. This review summarizes recent advances in understanding WS pathophysiology, including endoplasmic reticulum stress, calcium dysregulation, and mitochondrial dysfunction, and discusses emerging therapeutic strategies such as drug repurposing and gene therapy. Despite no current disease-modifying treatments, several preclinical and clinical trials are underway, offering hope for future breakthroughs.

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**Background:** Wolfram syndrome (WS) is an ultra-rare neurodegenerative disorder historically defined by diabetes insipidus, diabetes mellitus, optic atrophy, and sensorineural deafness (DIDMOAD). The prevalence varies geographically, estimated at 1 in 100,000 in North America and 1 in 770,000 in the UK, with more recent molecular-based studies reporting 1 in 54,478 in Sicily and 1 in 1,351,000 in Italy. The majority of patients harbor recessive mutations in the WFS1 gene (4p16), encoding wolframin, a transmembrane endoplasmic reticulum (ER) protein. Wolframin is highly expressed in retinal, neuronal, and muscle tissues and regulates ER homeostasis, calcium flux, and mitochondrial interactions at mitochondria-associated membranes (MAMs). The pathological hallmark is progressive degeneration of retinal ganglion cells (RGCs), leading to optic atrophy and visual loss, typically diagnosed at an average age of 10–11 years. Diabetes mellitus occurs in 98% of patients at an average age of 6 years. There is currently no effective treatment to halt disease progression; management remains supportive.

**Methods:** This is a narrative review summarizing recent pathophysiological insights and therapeutic strategies for Wolfram syndrome. The authors synthesized findings from in vitro studies (patient-derived fibroblasts, iPSC-derived neurons), in vivo animal models (Drosophila, zebrafish, mouse, rat), and clinical observations. They reviewed molecular mechanisms including ER stress, calcium dysregulation, mitochondrial dysfunction, and apoptosis, and discussed therapeutic approaches at various stages of preclinical and clinical development.

**Key Results:** The review highlights several key pathophysiological mechanisms: (1) ER stress: Wolframin negatively regulates ATF6α via the ubiquitin-proteasome pathway; WFS1 deficiency leads to increased ATF6α signaling and upregulation of the unfolded protein response (UPR), promoting apoptosis. (2) Calcium dysregulation: Wolframin deficiency reduces IP3R-mediated Ca2+ release, leading to higher cytosolic Ca2+ and altered mitochondrial dynamics. In patient-derived fibroblasts, there was an almost 50% reduction in NCS1 protein levels. (3) Mitochondrial dysfunction: WFS1 silencing in HEK cells upregulated genes related to mitochondrial dysfunction; rat neurons treated with Wfs1 shRNA showed a three-fold decrease in mitochondrial fusion events and a 20% decrease in mitochondrial length. (4) Calpain activation: Both WFS1 and CISD2 mutations increase calpain activity; calpain inhibitor XI normalized resting cytosolic calcium and rescued cell viability in wolframin-knockout insulinoma cells. Therapeutic strategies discussed include: ER calcium stabilizers (dantrolene, in a phase Ib/IIa trial NCT02829268), ER stress modulators (sodium valproate, in a phase III trial NCT03717909; 4-phenylbutyric acid; GLP-1R agonists like liraglutide), mitochondrial modulators (nicotinamide, idebenone), and gene therapy (AAV2-CMV-WFS1 vector showing stabilization of visual acuity at 3 and 6 months in a Wfs1 exon8−/− mouse model; CRISPR-Cas9 correction of WFS1 in iPSC-derived pancreatic β-cells improved glucose tolerance in diabetic mice over 6 months).

**Clinical Implications:** The review underscores the urgent need for disease-modifying therapies for WS, as current management is only supportive. The identification of druggable targets—ER stress, calcium dysregulation, and mitochondrial dysfunction—has led to several repurposed drugs entering clinical trials. Sodium valproate and dantrolene are being evaluated in phase III and phase Ib/IIa trials, respectively. Gene therapy and gene editing offer potential long-term solutions, particularly for ocular manifestations, given the eye's immune privilege and accessibility. However, challenges remain, including the rarity of WS, clinical heterogeneity, lack of universal classification, and the need for multinational collaborations. The establishment of patient registries (Wolfram Syndrome International Registry, Wolfram Syndrome Global Registry) and patient organizations (The Snow Foundation, WSRA) are critical for advancing research and clinical trials.

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narrative_review

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ophthalmology

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ORIGINAL PAPER

PMC10032446

Wolfram syndrome: new pathophysiological insights and therapeutic strategies

Therapeutic Advances in Rare Disease

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ABSTRACT

Wolfram Syndrome (WS) is an ultra-rare, progressive neurodegenerative disease characterized by early-onset diabetes mellitus and irreversible loss of vision, secondary to optic nerve degeneration. Visual loss in WS is an important cause of registrable blindness in children and young adults and the pathological hallmark is the preferential loss of retinal ganglion cells within the inner retina. In addition to optic atrophy, affected individuals frequently develop variable combinations of neurological, endocrinological, and psychiatric complications. The majority of patients carry recessive mutations in the WFS1 (4p16.1) gene that encodes for a multimeric transmembrane protein, wolframin, embedded within the endoplasmic reticulum (ER). An increasingly recognised subgroup of patients harbor dominant WFS1 mutations that usually cause a milder phenotype, which can be limited to optic atrophy. Wolframin is a ubiquitous protein with high levels of expression in retinal, neuronal, and muscle tissues. It is a multifunctional protein that regulates a host of cellular functions, in particular the dynamic interaction with mitochondria at mitochondria-associated membranes. Wolframin has been implicated in several crucial cellular signaling pathways, including insulin signaling, calcium homeostasis, and the regulation of apoptosis and the ER stress response. There is currently no cure for WS; management remains largely supportive. This review will cover the clinical, genetic, and pathophysiological features of WS, with a specific focus on disease models and the molecular pathways that could serve as potential therapeutic targets. The current landscape of therapeutic options will also be discussed in the context of the latest evidence, including the pipeline for repurposed drugs and gene therapy. Plain language summary Wolfram syndrome – disease mechanisms and treatment options Wolfram syndrome (WS) is an ultra-rare genetic disease that causes diabetes mellitus and progressive loss of vision from early childhood. Vision is affected in WS because of damage to a specialized type of cells in the retina, known as retinal ganglion cells (RGCs), which converge at the back of the eye to form the optic nerve. The optic nerve is the fast-conducting cable that transmits visual information from the eye to the vision processing centers within the brain. As RGCs are lost, the optic nerve degenerates and it becomes pale in appearance (optic atrophy). Although diabetes mellitus and optic atrophy are the main features of WS, some patients can develop more severe problems because the brain and other organs, such as the kidneys and the bladder, are also affected. The majority of patients with WS carry spelling mistakes (mutations) in the WFS1 gene, which is located on the short arm of chromosome 4 (4p16.1). This gene is highly expressed in the eye and in the brain, and it encodes for a protein located within a compartment of the cell known as the endoplasmic reticulum. For reasons that still remain unclear, WFS1 mutations preferentially affect RGCs, accounting for the prominent visual loss in this genetic disorder. There is currently no effective treatment to halt or slow disease progression and management remains supportive, including the provision of visual aids and occupational rehabilitation. Research into WS has been limited by its relative rarity and the inability to get access to eye and brain tissues from affected patients. However, major advances in our understanding of this disease have been made recently by making use of more accessible cells from patients, such as skin cells (fibroblasts), or animal models, such as mice and zebrafish. This review summarizes the mechanisms by which WFS1 mutations affect cells, impairing their function and eventually leading to their premature loss. The possible treatment strategies to block these pathways are also discussed, with a particular focus on drug repurposing (i.e., using drugs that are already approved for other diseases) and gene therapy (i.e., replacing or repairing the defective WFS1 gene).

CITATION EXPORT

Ratnakar Mishra, Benson S. Chen, Prachi Richa et al.. Wolfram syndrome: new pathophysiological insights and therapeutic
strategies. Therapeutic Advances in Rare Disease. (2021). https://doi.org/10.1177/26330040211039518

AUTHORS

4 · 8 CENTRES

Ratnakar Mishra, Benson S. Chen, Prachi Richa, Patrick Yu-Wai-Man

Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, ED Adrian Building, Robinson Way, Cambridge, CB2 0PY, UK
Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK
Moorfields Eye Hospital, London, UK
UCL Institute of Ophthalmology, University College London, London, UK