2012 Wolfram Syndrome Research Update

Compiled By: Tamara Hershey, Ph.D., Bess Marshall, M.D., Fumi Urano, M.D., Ph.D.
and the WU Wolfram Study Group members

Overview
This past year has been an exciting but also difficult one for our group and for the Wolfram community. While we have made great gains in our research efforts, we also lost our friend, colleague and leader in this field, Dr. M. Alan Permutt, M.D. on June 10th 2012. Although we mourn his death, we are comforted by the fact that his vision for Wolfram Syndrome research at Washington University is continuing, aided by Dr. Fumi Urano, M.D., Ph.D, who has newly arrived here. His exciting work in the cellular and molecular aspects of Wolfram Syndrome complements the human interdisciplinary studies that are ongoing here. Together, we hope to make great strides in the coming years towards identifying potential interventions for the degenerative processes in Wolfram Syndrome.

Human studies
For the past 3 years, our research group has conducted an annual interdisciplinary research clinic for children and young adults with Wolfram Syndrome. The goal of this research clinic is to understand the natural history of the disease process, particularly in its earliest stages. This information will help us select appropriate markers of disease progression, which will be essential for establishing the efficacy of any future interventions through clinical trials. We received funding from the American Diabetes Association and Washington University to set up our operation. More recently, the National Institutes of Health awarded us a 5 year, several million dollar grant to continue this work. To our knowledge, this is the first NIH award for the study of Wolfram Syndrome in people with the disorder. Our work is now beginning to be published; see below for a summary.

Animal studies
We have developed five different animal models of Wolfram syndrome. These are WFS1-deficient (whole body, beta cells or neurons), mutant WFS1 H313Y expressing, and WFS2 deficient mice. We have been carefully analyzing phenotypes of these animals. These animals will be used to test the efficacy of candidate drugs in the future.
Mechanisms of cell death in Wolfram syndrome
We discovered two enzymes that play important roles in cell death during the progression of Wolfram syndrome. These enzymes are promising targets for developing drugs for Wolfram syndrome.

Therapeutic Development
We have developed four screening methods for identifying drugs that have the ability to prevent cell death in Wolfram syndrome. The efficacy of candidate drug will be tested using animal models and cells from patients with Wolfram syndrome.
Recently Published Research Findings:

1) T. Hershey, H.M. Lugar, J. Shimony, J. Rutlin, J.M. Koller, D.C. Perantie, A.R. Paciorkowski, S.A. Eisenstein, M.A. Permutt and the Washington University Wolfram Study Group. Early brain vulnerability in Wolfram syndrome; PLoS One; 2012; 7(7). http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0040604
This paper uses the magnetic resonance images (MRIs) that were collected from participants. We compared these scans to scans of children/young adults with and without type 1 diabetes, using software that allows us to measure the volumes of different structures across the brain. We found that brainstem and cerebellum volumes are smaller in Wolfram Syndrome compared to other groups and that these differences can be shown at relatively early stages of the disease, something that had not been known before. We now need to compare scans across time, to understand how these volumes change over time and correlate with disease severity.

2) K.A. Pickett, R.P. Duncan, A.R. Paciorkowski, M.A. Permutt, B. Marshall, T. Hershey, G.M. Earhart and the Washington University Wolfram Study Group. Balance impairment in Wolfram syndrome. Gait and Posture; 2012
This paper analyzed data from the balance and motor tests given at the clinic. We used a standard rating scale for balance and motor skills with participants and compared results to children/young adults without any disorder. We found that balance was affected in Wolfram Syndrome, even at the relatively early stages of the disease, similar to our MRI findings. We now need to understand how these findings relate to each other, and how balance and other motor skills change over time.

3) C.M. Oslowski, T. Hara, B. O’Sullivan-Murphy, K. Kanekura, S. Lu, M. Hara, S. Ishigaki, E. Hayashi, S.T. Hui, D. Greiner, R.J. Kaufman, R. Bortell, and F. Urano. TXNIP mediates ER stress-induced beta cell death through the initiation of the inflammasome. Cell Metabolism, In press.
We have discovered a crucial cell death pathway under ER stress which is relevant to human diseases caused by ER stress including Wolfram syndrome.

Acknowledgements: We are deeply grateful to the families who have participated in studies for their dedication, time and effort, to the Snow Fund and others for their fundraising efforts, to Washington University for supporting this interdisciplinary research program, and to our funding agencies: ADA, JDRF, NIH and the Snow Fund. In addition, we are grateful to Nolwen Jaffre and the Association du syndrome de Wolfram for hosting us at the International Scientific Workshop in Paris. This annual workshop is the best way for Wolfram Syndrome researchers to find out what advances have been made, discuss what research is needed and to forge new collaborations.