The Power of Wolfram: The weapon to combat type 1 diabetes

I am often asked, "Why do you study such a rare disease, Wolfram?" My answer is, "It is the weapon to combat common diseases." My secret answer is, "I want to help Wolfram patients and their families."

Why it is so important to study Wolfram syndrome, a rare condition characterized by juvenile-onset diabetes, optic atrophy, and neurodegeneration? It is a frightening condition. Wolfram syndrome is always on my mind just like pediatric cancer was always on my mind when I was a young doctor (some people still think that I am a young doctor...thank you). I just want to help them. That's all I want. This is my last research project.

From a scientific standpoint, I always believe that there is a tremendous benefit for us to study Wolfram syndrome. Increasing evidence now indicates that endoplasmic reticulum (ER) dysfunction is involved in more common diseases, especially type 1 diabetes. I propose that Wolfram syndrome is the "weapon to combat type 1 diabetes."

Despite its rarity, Wolfram syndrome probably represents the best model currently available for identifying treatments for diseases associated with ER dysfunction. Wolfram syndrome arises from mutation of a single gene (WFS1), a gene shown to be also involved in β cell dysfunction and death in other forms of diabetes mellitus. Its monogenic etiology makes Wolfram syndrome more amenable to dissecting out the mechanisms underpinning cellular responses to ER dysfunction than other diabetic conditions, such as type 1 diabetes mellitus, in which multiple factors typically interact to produce the disease manifestations.

A common molecular process altered in Wolfram syndrome and type 1 diabetes

We have revealed the mechanisms of cell death in Wolfram syndrome and type 1 diabetes, and our findings will be published in Endocrinology soon. In short, calcium leakage from the endoplasmic reticulum is a common molecular process altered in Wolfram syndrome and type 1 diabetes. We are trying to control this process to develop a novel treatment for Wolfram syndrome. Two more research articles related to this topic are under review.

Endocrinology. 2014. [In press]
Calcium efflux from the endoplasmic reticulum leads to β cell death.
Hara T, Mahadevan J, Kanekura K, Hara M, Lu S, Urano F.
Abstract
It has been established that intracellular calcium homeostasis is critical for survival and function of pancreatic β cells. However, the role of endoplasmic calcium (ER) calcium homeostasis in β cell survival and death is not clear. Here we show that ER calcium depletion plays a critical role in β cell death. Various pathological conditions associated with β cell death, including ER stress, oxidative stress, palmitate, and chronic high glucose, decreased ER calcium levels and SERCA2b expression, leading to β cell death. Ectopic expression of mutant insulin and genetic ablation of WFS1, a causative gene for Wolfram syndrome, also decreased ER calcium levels and induced β cell death. Hyperactivation of calpain-2, a calcium dependent proapoptotic protease, was detected in β cells undergoing ER calcium depletion. Ectopic expression of SERCA2b, as well as pioglitazone and rapamycin treatment, could prevent calcium efflux from the ER and mitigate β cell death under various stress conditions. Our results reveal a critical role of ER calcium depletion in β cell death and indicate that identification of pathways and chemical compounds restoring ER calcium levels will lead to novel therapeutic modalities and pharmacologic interventions for type 1 and type 2 diabetes and other ER-related diseases including Wolfram syndrome.

Patient-based therapeutics part 3

Instead of introducing my research activities,  I would like to introduce my colleagues today. I have a lot of colleagues who have been helping me develop diagnostics and therapeutics for Wolfram at the Washington University Medical Center. Without their help, I cannot accomplish anything. I give many lectures and talks on Wolfram syndrome, but I feel that I am just a spokesperson or a salesman of our team.

Today I would like to introduce Dr. Bess Marshall and Dr. Tamara Hershey. Dr. Marshall is a pediatric endocrinologist and serves as a medical director of our annual Wolfram clinic. Dr. Marshall is an experienced, smart, and caring physician scientist. Dr. Hershey is a neuropsychologist and serves as a scientific director of our Wolfram clinic. Dr. Hershey is thoughtful, smart, and extremely good at getting things done. They are powerful driving force of our Wolfram project! I always appreciate their continuous support and advice. Here is their picture! (From left to right: Dr. Marshall, Fumi, and Dr. Hershey)

Patient-based therapeutics part 2

We are taking an unconventional approach to develop therapeutics for Wolfram syndrome. I would call it "patient-based therapeutics." This implies a few things. One of these is the  "mechanism-based treatment." How can we achieve this component of "patient-based therapeutics" for Wolfram syndrome? Here are our current efforts.

1. Looking for FDA-approved drugs that can potentially halt progression of Wolfram syndrome (drug repurposing).
We looked for drugs that can protect cell death mediated by the leakage of calcium from the endoplasmic reticulum (ER) to the cytosol. We found four FDA approved drugs and one supplement so far. We are testing these drugs in Wolfram iPSC-derived neural progenitor cells and mouse models of Wolfram syndrome.

2. Looking for a new class of drugs that can protect cell death mediated by endoplasmic reticulum dysfunction.
We have developed a drug screening method to identify drugs that can protect cell death mediated by ER dysfunction. In collaboration with a non-profit organization, we are actively looking for a new class of drugs that can potentially halt the progression of Wolfram. 

3. Testing if MANF (mesencephalic astrocyte-derived neurotrophic factor) can suppress the ER calcium leakage-mediated neuronal cell dysfunction in Wolfram iPSC-derived neural progenitor cells.

I will talk about more on MANF some other time. I thought that this was a good biomarker for Wolfram syndrome because expression of this molecule is increased by ER dysfunction. However, the increase of MANF might be an adaptive mechanism of our cells to cope with abnormal ER function.

A novel way to monitor blood sugar levels has been developed. How about electrolyte levels?

It has been announced that Google has invented a novel way to monitor blood glucose levels for patients with diabetes. This is wonderful news. We also need a new device by which we can monitor electrolyte levels in blood easily. Some patients with Wolfram experience low sodium levels. This is probably due to the combined effects of diabetes mellitus, diabetes insipidus, and DDAVP treatment. Low sodium is life-threatening. We need a small device that a patient can carry to monitor blood sodium levels.
http://abcnews.go.com/Health/google-contact-lens-monitor-diabetes-holds-promise/story?id=21577373