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 reported 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 reported that dantrolene, an FDA-approved drug for spasticity and malignant hyperthermia, can prevent death of ? cells and neurons in cell models of Wolfram syndrome. Dantrolene targets ryanodine receptors localized to the ER and blocks ER calcium leakage to the cytosol. Preclinical studies in my lab 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 ER calcium stabilizers might be promising therapeutics for the treatment of Wolfram syndrome. This prompted us to identify other ER calcium stabilizers under ER stress conditions using a computational algorithm and led to the discovery of JTV-519 (a.k.a., K201) as a novel candidate compound. JTV-519 acts in the ER. It binds to and stabilizes the ryanodine receptor 2 (RyR2) in its closed state and was previously evaluated for the treatment of atrial fibrillation recurrence. In this proposal, we will test the efficacy of JTV-519 in cell and mouse models of Wolfram syndrome and conduct phase 1b clinical trial of JTV-519 in patients with Wolfram syndrome.
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. Our study on Wolfram may lead to a breakthrough for treatments of such common diseases, including diabetes, neurodegeneration, and blindness.
