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.

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.

http://www.tedmed.com/videos-info?name=Francis_S._Collins_at_TEDMED_2012&q=updated&year=all

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?

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.

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.
https://news.wustl.edu/news/Pages/23961.aspx

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.

http://www.snowmanfund.com/

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.