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A cure for Wolfram syndrome could lead to a cure for diabetes and blindness.

Wednesday, August 8, 2012

Mechanisms of ER stress-mediated cell death: Press release available

We have discovered the mechanisms of cell death under ER stress conditions. A key molecule involved in this process is called TXNIP. Expression of this molecule is increased in cells from WFS1 knockout mice, a mouse model of Wolfram syndrome. TXNIP has been shown to play a role in the initiation of inflammation. Although Wolfram syndrome is not an autoimmune disease, I think that "local" iflammation may be involved in the pathogenesis or TXNIP may activate unknown cell death pathways under ER stress conditions. Interestingly, calcium plays a role in the activation of this molecule. We recently found another enzyme which plays a role in calcium-mediated cell death in Wolfram syndrome. I feel that TXNIP or calcium homeostasis is a good drug target for Wolfram syndrome. Our article has been selected for the featured article in Cell press. So you can read it for free. You can also read a preview for our article. A press release from Washington University is informative. JDRF also did a press release for us.


Thursday, July 19, 2012

Calcium might be a key to understand Wolfram syndrome

We have recently found a critical enzyme executing cell death in Wolfram syndrome. It seems like that activity of this enzyme is regulated by calcium. Based on our preliminary data, endoplasmic dysfunction creates a shunt between the endoplasmic reticulum and the cytosol, leading to calcium leakage into the cytosol. This may be a key event that can cause cell death. We are actively looking for drugs that can prevent this event.

Sunday, July 15, 2012

www.erstress.com, updated our lab web site

I have updated our lab web site. I will start hiring new staff members and taking fellows here at Washington University to accelerate our progress.

Wednesday, July 11, 2012

My funding for Wolfram syndrome research in 2012

I have been working very hard to obtain funds supporting research and clinic for Wolfram syndrome. Here is the list of my research funds related to Wolfram syndrome in 2012.

1. 112-CT-61 (Urano, Hershey, Marshall) 1/1/12-12/31/14
American Diabetes Association
Identifying Biomarkers for an Endoplasmic Reticulum (ER) Stress Related Diabetes
     This study proposes a novel strategy that will assess patients with Wolfram syndrome (WS), a disease caused by a single mechanism that causes stress in the cells endoplasmic reticulum (ER).

2. ICTS (Urano, Hershey, Marshall)                  6/1/11-5/30/13
Support for clinic                            
Translating mechanisms for a genetic neurodegenerative diseases into new therapies

3. R01DK067493 (Urano)                          9/30/10-6/30/14
National Institutes of Health           
Endoplasmic Reticulum Stress and Diabetes
     This study proposes to study the mechanisms of ER stress-mediated cell death in Wolfram syndrome and type 1 and type 2 diabetes.

4. 40-2011-14 (Urano)                            10/01/10-9/30/12
Juvenile Diabetes Research Foundation
Targeting ER Enzymes for Enhancing Human Beta Cell Mass And Function
     This study proposes to develop a method for increasing Wolfram syndrome 1 gene function for enhancing human beta cell mass and function in patients with juvenile-onset diabetes.

5. 47-2012-760 (Urano)                            9/01/12-8/31/13
Juvenile Diabetes Research Foundation      
Identifying beta cell ER stress biomarkers for predicting type 1 diabetes
     This study proposes to identify beta cell ER stress biomarkers for predicting juvenile-onset diabetes including Wolfram syndrome using bioinformatics.

Monday, July 9, 2012

Two new ways of getting disease treatments to patients faster

Dr. Francis Collins, current Director of National Institues of Health, beautifully articulated two new ways of getting disease treatments to patients faster: repurposing existing drugs, and testing on fabricated human tissue. I agree with him and am currently using the same strategies that he mentioned in this video.


Friday, July 6, 2012

Discovery of a mechanism inducing cell death by ER dysfunction

We have discovered a critical mechanism inducing cell death by endoplasmic reticulum dysfunction. This mechanism is activated in a mouse model of Wolfram. We need to verify this mechanism is also activated in patients with Wolfram.

If we can prevent the activation of this cell death mechanism, we may be able to delay the progression of the disease. This will be published in a top journal. So Cell press, Washington University, JDRF (juvenile diabetes research foundation) and other communications media are coordinating a press release. This would be a great opportunity for us to raise awareness of Wolfram. 

Friday, June 29, 2012

Strategies for developing a treatment for Wolfram

Our current strategies for developing a treatment for Wolfram are the following.

1. Inactivate molecules that play important roles in ER stress-mediated cell death.
2. Manipulate ER redox state (maintain oxidized ER) and ER calcium homeostasis (maintain calcium levels) under ER stress conditions.

We are looking for drugs that have the ability to inactivate cell death molecule and/or maintain ER calcium levels in Wolfram syndrome.

Thursday, June 28, 2012

Drug repurposing

We are looking for drugs that can prevent the progression of neuronal cell death in Wolfram syndrome utilizing different strategies. The challenge we may face is that it may take a long time to get the FDA approval even if we find a drug treatment.

To overcome this challenge, we are interested in a "drug repurposing" strategy. Drug repurposing is the application of known drugs to new diseases. Current NIH director, Dr. Francis Collins, supports this concept and collaborates with the FDA director and major pharmaceutical companies to drive this idea.


Wednesday, June 27, 2012

What is Endoplasmic Reticulum Disease?

The endoplasmic reticulum (ER) is a cellular organelle found in virtually every human cell. The ER participates in many important cellular tasks, including protein and lipid biosynthesis, calcium regulation, redox regulation (regulation of oxidative stress), and cell death. Given the many vital and complex functions of the ER, it is little wonder that its failure can trigger a range of diseases. Recent genetic and clinical evidence indicates that inherited or acquired dysregulation of ER homeostasis can give rise to genetic diseases, including Wolfram syndrome characterized by juvenile-onset diabetes and neurodegeneration, as well as a number of common diseases, including diabetes, Parkinson’s disease, and Alzheimer’s disease. The primary dysfunction of ER tends to cause early-onset and inherited genetic diseases. In contrast, the secondary dysfunction of ER tends to cause diseases associated with age, such as type 2 diabetes and neurodegeneration. Wolfram syndrome is caused by the primary dysfunction of ER.

What is Wolfram syndrome?

Wolfram syndrome is a autosomal recessive disorder characterized by juvenile onset diabetes, later followed by various neurological dysfunctions and death from widespread neurodegeneration in the third or fourth decade. Dr. Permutt identified the causative gene named WFS1 in 1998. Dr. Permutt and my groups developed cell and animal models that led to the discovery that WFS1 protein resides in the endoplasmic reticulum (ER) membrane, and that mutant forms predispose β-cells and neurons to ER dysfunction-mediated cell death. A potential link between the diabetes of Wolfram syndrome and type 2 diabetes is supported by recent studies that identified WFS1 single nucleotide polymorphisms (i.e., genetic variations among people) associated with an increased risk for type 2 diabetes. Based on the data accumulated in the past 10 years, we believe that Wolfram syndrome is an endoplasmic reticulum disease. So what is endoplasmic reticulum?

Sunday, June 24, 2012

Three step formula for developing a novel therapy for Wolfram syndrome.

Here is the three step formula for developing a novel therapy for Wolfram syndrome.
1. Understand the disease
2. Identify drug targets and biomarkers
3. Develop drugs and treat patients

Our patient registry and Wolfram clinic help us understand the disease. The second step depends on research using biotechnology in our lab. For the third step, we need to choose clinical endpoints. We also need help from the patient organization for the third step (i.e., clinical trial). My goal is to start a trial in 2014.

Sunday, June 17, 2012

Dr. M. Alan Permutt

I attended Dr. M. Aaln Permutt's funeral last Wednesday. Dr. Permutt made a number of contributions to the field of medicine and diabetes. He will be missed. I always respected Alan as a physician scientist, mentor, and friend. I feel honored to take over his projects on Wolfram syndrome and carry on his legacy.

From Dream to Action

Last year, I attended the Wolfram syndrome clinic and workshop. Patients with Wolfram syndrome develop juvenile-onset diabetes and neurodegenaration. I gave a lecture and could connect with people with the same cause. I was inspired and encouraged by all the participants because of the following reasons.

1. From Dream to Action
All the patients, their families and doctors share the same cause, which is to find a cure for the disease. All of us have the same dream. More importantly, all of us are actively taking action to make the dream come true. I have been impressed by Stephanie and Beth who are mothers of Wolfram patients. I was also encouraged by Kip Branch, a head of the Wolfram syndrome patients' association.

2. Strong supporting team
We have great supporters who work very hard to raise awareness of the disease and money for our research.

3. Strong leadership
We have a strong leader, Dr. Alan Permutt.

Thank you everyone! 

Combating Wolfram syndrome

I am a physician scientist who is studying diseases in children. My major focus is to find a treatment for Wolfram syndrome characterized by juvenile-onset diabetes, optic atrophy, and neurodegeneration.

The first milestone for this task was to create an international registry of patients with Wolfram syndrome. The driving force was a mother who had a son with this disorder. She emailed me, Dr. Barrett in England, Dr. Tanizawa in Japan, and my long-term collaborator, Dr. Permutt. She asked us if she could do anything to help her son and other patients. She raised money and hosted a small workshop in Paris, France. 

The workshop was a big success. We exchanged our vision there and made a road map. The registry started in October, 2009. It was a wonderful accomplishment. I felt gratified and thanked all the people who helped us. We then moved to the next level.