RESEARCH UPDATE-Tamara Hershey, PhD

 Washington-University-Wolfram-Study-groupWashington-University-School-of-MedicineWashington University School of Medicine

Dear Wolfram Community:

I am very pleased to announce that we have received

notification from the NIH that our Wolfram natural

history study has been OFFICIALLY FUNDED! This means

that we can start having our Wolfram Research Clinics

again, probably starting next summer and continuing for

5 more years! Samantha, Dr. Marshall and I will begin

planning for the research clinic and will keep you all informed as things move along.

We are excited to continue working with Dr. Bess

Marshall as our caring and dedicated Medical Director!

We will also continue to collaborate with Dr. Fumi Urano

by collecting samples for his lab and coordinating with

the Dantrolene trial. In addition, Dr. Tim Barrett in

Birmingham, UK will share MRIs from his clinical trial, so

that we can learn about individual differences in

neurological progression. Finally, Dr. Gordon Xu, at Mt

Sinai in New York, is helping us measure the optic nerve

with MRI. We are excited to work with all of the

incredible scientists and clinicians on our team.

Thank you for your support and patience during this

time of being in limbo. Please know that we never

stopped caring and we never stopped working on

understanding Wolfram syndrome and its effect on the

brain and its functions. We have high hopes that the

information we gain from this study will have a positive

and lasting impact on all people affected by Wolfram

syndrome! Please call me or Samantha with any questions

about the research clinic.

Sincerely,

Tamara Hershey, PhD

Professor

Scientific Director and Principal Investigator

WU Wolfram Research Clinic

tammy@wustl.edu; 314-362-5593

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Update from the Institute of Neurosciences, Montpellier

Our team’s goal is to discover, test and develop treatments in order to prevent or limit visual impairment and to improve the autonomy and the quality of life of patients. Our efforts focus on a very severe form of syndromic Inherited Optic Neuropathy: Wolfram Syndrome (WS). WS is characterized by a rapid degeneration of retinal ganglion cells (RGC) resulting to severe visual impairment before the age of 20 years. To date, there is no treatment to stop the progression of the disease.

The analysis of biological samples from patients with the recessive WS revealed that the WFS1 protein is absent, or less stable, compared to the normal protein. This reduced quantity of WFS1 suggests that the re- expression of WFS1 through gene augmentation therapy could restore the protein function and thus possibly protect the cells from degeneration.

It is important to say that the eye is a perfect model for applying gene therapy approach. It is small, transparent, allowing for very precise visual monitoring. It is also a closed organ, relatively isolated from the rest of the body. RGC are easily accessed by the ocular surgeon who targets them through intravitreal injection, a current routine procedure used to inject medications in various retinal pathologies. In this regard, gene complementation for Wolfram patients is an ideal therapeutic approach to treat visual impairment. Consequently, micro-injection of a vector expressing the human WFS1 cDNA, directly in the vitreous close to the retinal ganglion cell layer should allow to prevent RGC dysfunction and degeneration.

We have studied mice models of WS. Our results indicate that mice reproduced the optic atrophy of WS patients with loss of visual acuity starting at 1 month. We designed a therapeutic vector expressing human WFS1 that we microinjected into the vitreous of Wfs1 mutant mice. We showed that the animals injected with the therapeutic vector have a stabilization of their visual acuity between 3 and 6 months post-injection, a decrease of optic disc pallor and axonal damages. A parallel approach is applied on wild type animals using the same vector in order to assess the innocuousness of the treatment and the transgene expression and distribution. These promising results lead us to continue these therapeutic approach.

Our project consists in demonstrating the validity of the pre-clinical approach to treat Wolfram Syndrome by gene therapy. Obtaining this proof of concept will allow to transfer the protocol to patients assess the therapeutic benefits in the short and medium.

Dr. Cécile Delettre, PhD
cecile.delettre@inserm.fr
http://www.inmfrance.com/inm/en/

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Dr. Urano’s September Update

September 24th, 2018

Dear Friends,

Thank you so much for your support. I hope you had a nice summer season with your family. I feel that autumn is coming, and it is time for me to update you about our progress. Today, I’d like to talk about one of the new drugs we are developing as we have made significant progress on this drug in the past few months. I call it “Molecular Prosthetics.”

To provide a cure for Wolfram syndrome, we need to stop the disease progression. A common problem in patients with Wolfram syndrome is a particular type of cell stress, endoplasmic reticulum stress (ER stress), caused by the expression of mutant Wolfram protein (WFS1 protein) produced in patients’ cells. ER stress can ultimately result in dysfunction and death of insulin producing cells, retinal cells, and brain cells.  To resolve this issue, we have been developing molecular prostheses that can optimize the structure and conformation of mutant Wolfram protein. If we can restore the structure of mutant Wolfram protein, it should result in resolution of ER stress and reduction of cell death.

I have been working with Amylyx Pharmaceuticals in Cambridge, MA, and NIH/NCATS to evaluate a novel molecular prosthesis in brain cells derived from induced-pluripotent stem cells (iPSCs) of patients with Wolfram syndrome to determine whether this therapeutic has potential to act as a molecular prosthetic/ER stress reducer to treat the disease. We have been getting encouraging results using cells from patients. My goal is to confirm the results in our humanized mouse and rat models of Wolfram syndrome for conducting a clinical trial. This drug seems to be especially beneficial for brain cells. So it is important for us to know if this drug can improve visual acuity and motor function in our rodent models of Wolfram syndrome.

As always, please feel free to contact me with any questions or concerns (urano@wustl.edu). I would like to know what you think and how you feel. Thank you again for your support. Your encouragement keeps me going. I think about our patients every single day. We will decrease human suffering together.

With passion, hope, and gratitude,

Fumi Urano

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