RESEARCH UPDATE – Tamara Hershey, PhD

Washington University School of Medicine

Washington-University-Wolfram-Study-group
Washington-University-School-of-Medicine

Dear Wolfram Community, 

Since the last newsletter, we have been very busy, both looking backwards to data from previous research clinics and looking forward to our 2019 research clinic. 

Looking backwards, we submitted two papers for review based on previous research clinic data. One paper is on sleep disturbances in Wolfram syndrome, where we show that there is a high rate of sleep apnea based on the sleep monitoring we did during the 2015 and 2016 clinics. The second paper is based on our longitudinal neuroimaging data, and suggests that Wolfram syndrome affects the development of specific regions and tissue types in the brain, and ultimately degenerates others. From these data, we recommend the best measures for tracking neurodegeneration over time in clinical trials. We hope that these findings will help with clinical trial planning, with the development of more brain-targeted interventions, and will inspire other groups to investigate specific hypotheses about the mechanisms underlying these changes. 

Looking forward, planning for next summer’s research clinic is underway! Samantha has been reserving rooms, Heather has reserved the MRI scanner and collaborators are blocking off their calendars. We our also testing our new MRI sequences to better measure changes in the optic nerve and in white matter across the brain. 

Finally, the Snow Foundation is leading an effort, with which we are helping with, to obtain grant funding from the NIH to support a research and clinical symposium for families during the clinic. Stay tuned for details! Time will pass quickly, and before we know it, we will be greeting some of you in summery St. Louis! 

Sincerely, 

Tamara Hershey, PhD 

Professor
Scientific Director and Principal Investigator WU Wolfram Research Clinic tammy@wustl.edu

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Wolfram Syndrome and Genes

DID YOU KNOW?

Wolfram syndrome is inherited in an autosomal recessive manner.[1] This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

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Birmingham England, Clinic Dates

WolframSyndromeSupportUKAdult Wolfram clinics are run from the Centre for Rare Diseases in the Heritage Building at The Queen Elizabeth Hospital, Birmingham and are taking place on the following days:

January 18th

March 29th

May 24th

July 19th

September 27th

November 29th

All dates are currently provisional

For more information please contact either Andrea Mitchell , or Tracy at WSUK.  

 

The dates for the Children’s Clinics run from Waterfall House, the Rare Disease Centre at Birmingham Children’s Hospital are:

7th & 8th January

4th & 5th March

3rd & 4th June

7th & 8th October

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Types of Wolfram syndrome

DID YOU KNOW?

The two types of Wolfram syndrome (type 1 and type 2) are primarily differentiated by their genetic cause.  Variations (mutations) in the WFS1 gene are responsible for about 90% of Wolfram syndrome type 1 cases. This gene encodes wolframin, a protein that is important for the proper functioning of the endoplasmic reticulum (the part of a cell that is involved in protein production, processing, and transport). Wolframin helps regulate the amount of calcium in cells, which is important for many different cellular functions. Mutations in WFS1 result in a defective form of wolframin that is unable to perform its normal role. This causes cells to trigger their own death (apoptosis). The death of cells in various organs and other parts of the body results in the signs and symptoms of Wolfram syndrome type 1.[1]

A specific mutation in the CISD2 gene causes Wolfram syndrome type 2. Although the exact function of this gene is not known, scientists suspect that it plays an important role in the mitochondria (the part of the cell where energy is produced). Mutations in CISD2 lead to the loss of mitochondria which decreases the amount of energy available to cells. Cells that do not have enough energy die. As in Wolfram syndrome type 1, the death of cells in different parts of the body results in the many health problems associated with Wolfram syndrome type 2.[1]

 

Donate today!

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Washington University 2019 Wolfram Research Clinic Update

Washington-University-School-of-MedicineWASHINGTON UNIVERSITY’S

2019 WOLFRAM RESEARCH CLINIC UPDATE

Wait no more – the 2019 WU Wolfram Research Clinic planning is underway! We’re sure many of you have lots of questions and hopefully some of them will be answered here. If not, you can always contact Samantha directly. Her contact information is below.

Due to the number of participants enrolled in the clinic and an effort to make the clinic days more manageable, we will be dividing the clinic into two sessions. The official dates for the clinic are as follows:

Group 1
 Arrival: Tuesday, 7/9/19

Clinic: Wednesday, 7/10/19 – Friday, 7/12/19

Group 2
 Arrival: Sunday, 7/14/19

Clinic: Monday, 7/15/19 – Wednesday, 7/17/19

Scientific Session (TBD) Saturday, 7/13/19

Family Dinner TBD

We are still working out the details of the Scientific Session and the Family Dinner(s) and we will share that information with you as soon as it is finalized. Until then, these are the clinic dates. It is important at this time that you let Samantha know if you have a preference to attend as part of Group 1 or Group 2. Please keep in mind that another person or family cannot communicate your preference for you. Samantha must hear from you directly as to which session you’d like to attend. If you do not have a preference, that works too. You will then be assigned to a group once all preferences are in. The deadline for reserving your slot in a particular group is Jan. 31, 2019. That being said, it is important to get your preference in as soon as possible as we are trying to split the groups evenly which means that your preferred group could reach capacity prior to you stating your preference.

 

Need Help? For questions or requests regarding the Wolfram Syndrome Research Clinic please contact the WFS Research Clinic Coord., Samantha Ranck, MSW at 314.362.6514 or rancks@npg.wustl.edu

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Dr. Urano’s October 2018 Update

October 18, 2018Fumihiko “Fumi” Urano, MD

Dear Friends,

It is wonderful to see you again. I hope you and your family are enjoying the beautiful autumn weather and nature. I love to do a nature walk especially in autumn, and I came up with the following idea during my nature walk. I’d like to share this idea with you as I know you are my friend and supporter. 

To provide a cure for Wolfram syndrome, we need to protect our eye cells, brain cells, and insulin producing cells. If they are damaged, we need to fix them and even regenerate them. I came up with the concept of “Regenerative Gene Therapy.” This is a combination of regenerative therapy and gene therapy. As you know, my team has discovered a molecule that is produced naturally in the body that can activate the proliferation of damaged beta cells and brain cells. Expression levels of this molecule, MANF, are usually low in the human body. We are developing a method to enhance the activity of MANF using a gene therapy. We are trying to produce a safe virus expressing MANF to transduce into patients’ cells with resultant creation of MANF within the cell. This treatment could then be applicable to Wolfram syndrome, as well as other forms of neurodegenerative disease.  

 

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. I always appreciate your support and encouragement. You are a wonderful person. We will decrease human suffering together.

With gratitude,

Fumi Urano

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Neuropsychiatric features of Wolfram Syndrome and other genetic disorders

As discussed in a previous newsletter, we have learned

that anxiety and depression symptoms are fairly common

in people with Wolfram Syndrome. These symptoms are

also very common in people without Wolfram Syndrome,

and may be influenced by genes, life stress, and other

factors.

In preliminary examination of our data, I have also noticed

some trends indicating that psychiatric symptoms and

certain types of neurological signs/symptoms might be

related.  I plan to further analyze the data to confirm

whether this is true. I would also like to take a closer look

at the brain imaging findings to investigate whether

specific difference in brain structure or function may be

related to specific psychiatric and/or neurological

symptoms.

I also hope to do some investigation comparing the types

of symptoms seen in Wolfram Syndrome to those

reported in other genetic disorders that affect the

functioning of ryanodine receptor calcium channels

(RYRs), which release calcium from the endoplasmic

reticulum (ER) within cells. In Wolfram Syndrome, too

much calcium is released through these channels. Studying

disorders with similar disease mechanisms could help us

understand what produces the symptoms of both

Wolfram Syndrome and other related other disorders. It is

possible that diseases with similar mechanisms may

respond to similar types of treatment.

By Angela M. Reiersen, MD, MPE

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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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