Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, diabetes insipidus, optic nerve atrophy, hearing loss, and neurodegeneration. The prognosis of this syndrome is currently poor and many patients die prematurely with severe neurological disabilities, raising the urgency for developing novel treatments for Wolfram syndrome. Endoplasmic reticulum (ER) dysfunction caused by the mutations in the WFS1 gene is the root cause of the disease. However, key molecular defects linking ER dysfunction to death of pancreatic ? cells, neurons, and retinal ganglion cells in Wolfram syndrome are not clear. Therefore, despite the underlying importance of ER dysfunction in Wolfram syndrome, no current therapies target the ER. We have recently discovered that the leakage of ER calcium to the cytosol, followed by subsequent increase in cytoplasmic calcium levels, induces death of ? cells and neurons in Wolfram syndrome. We have also discovered that dantrolene sodium, an FDA-approved drug for spasticity and malignant hyperthermia, can prevent death of ? cells and neurons in cell and patient-derived iPS models of Wolfram syndrome. Dantrolene targets ryanodine receptors localized to the ER and blocks ER calcium leakage to the cytosol. Preclinical studies revealed that dantrolene could prevent the progression of diabetes and maintain ? cell mass in a mouse model of Wolfram syndrome. These results raised the possibility that dantrolene might be a promising therapeutic agent for the treatment of Wolfram syndrome. The purpose of this phase 1b study is to evaluate safety and tolerability and determine a recommended phase 2 dose for dantrolene in pediatric and adult patients with Wolfram syndrome. ER is an emerging target for human chronic diseases including type 1 and type 2 diabetes and neurodegeneration. Its monogenic etiology makes Wolfram syndrome more amenable to discover drugs targeting ER dysfunction than other common conditions in which multiple factors typically interact to produce the disease manifestations. Our study on Wolfram may lead to a breakthrough for treatments of such common diseases.
Endoplasmic reticulum (ER) is an emerging target for human chronic diseases, especially ? cell death in type 1 and type 2 diabetes and neurodegeneration. Wolfram syndrome is a rare autosomal recessive genetic disorder characterized by juvenile-onset diabetes and neurodegeneration. Wolfram syndrome is considered as a prototype of ER disorder. Its monogenic etiology makes Wolfram syndrome more amenable to discover drugs targeting ER dysfunction than other common conditions in which multiple factors typically interact to produce the disease manifestations. Successful completion of our clinical trial for Wolfram syndrome may lead to a breakthrough for treatments of such common diseases, especially type 1 and type 2 diabetes.
