MANF Therapeutics is developing mesencephalic astrocyte-derived neurotrophic factor (MANF) as a therapeutic protein for the treatment of certain protein-misfolding and neurological disorders. MANF is currently in pre-clinical development as a disease modifying treatment for Parkinson’s disease and Wolfram’s Syndrome. In Wolfram’s, many of the key disease etiologies, including vision loss, hearing loss, diabetes and neurodegeneration have protein misfolding as a key molecular signature that MANF could potentially address. The lead application for MANF in Wolfram’s is for the treatment of vision loss. MANF has demonstrated safety and efficacy in animals for the treatment of retinal degeneration, including the increased protection and function of rods, cones and retinal ganglion cells in the retina. Leading scientists in the Wolfram’s community believe MANF could be the first disease-modifying treatment developed for the disease. MANF Therapeutics is in the process of raising capital to support preparations for clinical trials, and thereafter the initiation of human clinical trials in Wolfram’s Syndrome and Parkinson’s. Once the capital is raised, it will take approximately 12-18 months to start clinical development.
WASHINGTON 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
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
Washington 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
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/
Washington University School of Medicine
Clinical Care Update- Bess Marshall, MD
Dear Wolfram families,
As you now have heard from Samantha, I have determined that the Wolfram Research Clinic that was tentatively All of the Wolfram team is sad that we will not be able to see all of you in July. Please know that you are still a very high priority and that this bump will not derail the work at Washington University. We will not allow that to happen! You likely all saw the update from Dr. Barrett in the UK that his intervention trial is not yet underway as they also work through issues, but that it is making progress. Dr. Urano’s dantrolene study is moving along and he will be updating you on those results soon.
The Association du Syndrome de Wolfram meeting is coming up in June and Drs. Hershey and Urano and I will be going to hear updates from the other groups working on the syndrome alongside us, so we will update you in the next newsletter.
Some of the information you all have contributed by participating in the TRACK study was used to develop a paper led by Dr. Barrett’s group: Monogenic diabetes syndromes: Locus-specific databases for Alstrom, Wolfram, and Thiamine-responsive megaloblastic anemia. Human Mutation. 38(7):764-777, 2017 Jul.
This paper analyzes the specific gene changes in 309 people with WFS1 gene alterations in order to determine which changes are likely to cause a particular presentation in a person – for example, some genetic changes cause full-blown Wolfram Syndrome, which others cause diabetes mellitus without other features, others cause hearing loss without other features, etc. This will be very helpful information for patients at the time of diagnosis, getting their genetic testing results and wondering what to expect for their health.
As always, please get in touch if you need assistance with your health or with letters to insurance, etc.
All the best,
Bess Marshall, MD
Pediatric Endocrinologist
Medical Director, WU Wolfram Syndrome Research Clinic
Washington University School of Medicine
Email: Marshall@kids.wustl.edu
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
Washington University School of Medicine
Wolfram Research Clinic Update- Tamara Hershey, PhD
Dear Research Clinic Families,
As you now have heard from Samantha, I have determined that the Wolfram Research Clinic that was tentatively scheduled for July 2018 will not be able to happen. This was a very difficult decision, but ultimately, we felt it was the most ethical choice. Due to delays in NIH’s funding decision and its impact on our ability to prepare, we just could not provide the kind of experience you deserve and that the research demands. We felt that having a clinic under those circumstances would be a disservice to us all. Please know that we care deeply about you and this research and will start planning with enthusiasm once we get our funding notification. I’m assured by NIH that it will come soon, but there are many bureaucratic hurdles that they have to overcome due to their backlog. While we are very disappointed that the clinic will not happen as we had originally imagined for 2018, we already have several ideas of what we could do to make future clinics even better, such as Tasha’s work on the questionnaires, holding mini clinics throughout the year, and adding some testing of siblings without Wolfram Syndrome. We also continue to work towards analyzing and publishing the data that have already been collected, thus providing other researchers and clinicians with important information. We appreciate your understanding and apologize for the uncertainty that the funding situation has caused. We will keep you informed of any new information. Please feel free to contact me personally with any questions.
Sincerely,
Tamara Hershey, PhD
Professor, Psychiatry & Radiology Departments
Lab Chief, Neuroimaging Labs (NIL) @ MIR
Co-Director, Neuroscience PhD Program, DBBS
Washington University School of Medicine
Email: tammy@wustl.edu
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
1st teleconference meeting report
Tuesday 24 April, 2018
Report written by: Virginie Picard (Association du syndrome de Wolfram)
Report validated by: prof. Timothy Barrett, project coordinator
The first update teleconference meeting on Biomarker project led by professor Tim Barrett took place on Tuesday 24 April, six months after the official beginning of the project. Representatives of the three funding organizations were present: Stephanie Gebel (The Snow Foundation), Nolwen Le Floch & Virginie Picard (Association du syndrome de Wolfram) and Lode Carnel (Eye Hope Foundation).
The project coordinator, professor Timothy Barrett, presented the progress of the project, with the kind assistance of two members of his consortium: Drs. Dewi Astuti and Anita Slade (University of Birmingham).
As an introduction, professor Barrett recalled that the project is aimed at validating biomarkers relevant to underlying Wolfram syndrome mechanisms and at developing Patient-Reported Outcomes (PROs) to capture the broader experience of the patient and to define patient-relevant clinical trial endpoints for future clinical trials. The ultimate goal of the project is to hasten delivery of treatments to the patient in the clinic and to develop tools allowing to predict within the first 6 months /1 year of a clinical trial whether a candidate medicine has a chance to succeed or not.
The progress of three workpackages was then presented:
Dr. Anita Slade presented the work she is doing on the development of PROs. She has achieved initial consultations with British patients (adults or adolescents) and parents in order to define what the expected outcomes of a candidate medicine on the patient life and health can be. She has based her research on patients experience as well as on various existing clinical Quality of Life questionnaires that are relevant to Wolfram syndrome and vision loss. She has been able to establish a list of potential PROs that now need to be evaluated for their clinical meaningfulness and usefulness.
Dr. Dewi Astuti next presented her current work on the identification of biomarkers that can be used to evaluate the progress of Wolfram syndrome and more especially the neurodegenerative component of the disease. She has searched for biomarkers that can be preferentially measured in small amounts of blood and that are time and cost-effective. For this, she has made an extensive literature search, looking for candidate biomarkers already used for neurodegenerative diseases. Thanks to this, she has been able to identify 4 new candidate biomarkers that are now being tested for their relevance and sensitivity in cultures of cells depleted of WFS1 gene and in sera of patients with Wolfram syndrome. One of the biomarkers selected seems to be consistently increased in sera of Wolfram patients. Additional assays are ongoing.
Professor Barrett then presented progress being achieved with Euro-WABB, the patient registry for rare diabetes (including Wolfram syndrome). In May 2018, new European standards on data protection will be published, as well as a set of common data elements for all rare disease registries. Moreover, a common consent form for European Reference Networks is now available. The aim of all these new measures is to make all registries interoperable and linked to an EU platform for rare diseases registration. Euro-WABB is currently being modified by Richard Sinnott to comply with these new regulations and requirements. Data from past registry will be transferred to a new, user-friendly database. Hopefully, work will be completed during the summer.
Another project workpackage has not started yet. This workpackage is aimed at validating the first candidate efficacy biomarker p21cip within the frame of the European Phase II clinical trial on candidate drug Valproate. For this, biosamples need to be collected from patients treated and non-treated with the drug. The organization of the clinical trial has faced some delays, but it is now expected to start in Autumn 2018.
This work will be extensively presented at next international workshop organized by the Association du syndrome de Wolfram that will take place in June in Paris, France. The second update teleconference meeting is due in September 2018.
Mitochon Pharmaceuticals, Inc., Blue Bell, Pennsylvania, is sponsoring a Proof of Concept (POC) study in Wolfram mice using a mitochondrial target approach to attenuate diabetes, behavioral and functional decline. Mitochon has developed clinical stage (Phase I ready) pharmaceuticals that modulate mitochondrial physiology. These compounds, MP101 and MP201, have shown merit in animal models of vision loss, hearing loss, movement disorders, trauma, neuromuscular/neurodegenerative and metabolic diseases. Stephanie Gebel recommended Dr. Sulev Koks at the University of Tartu, Estonia, who generated the Wsf1 KO mice to the company. Dr. Geisler, CSO of Mitochon, said, “I was delighted to hear Dr. Koks outside the box spirit for embracing new ideas and for seeing the possible merits of our approach for Wolfram”. Dr. Saad Naseer provided Mitochon some guidance to capture critical endpoints as well.
The concept is that endoplasmic reticulum (ER) stress associated with Wolfram Syndrome has a strong detrimental effect on the mitochondria and thus cellular survival. In addition, the abundance of oxidative stress in Wolfram through reactive oxygen species (ROS) production via the mitochondria further creates a hostile environment for cells. Unlike anti-oxidants that attempt to mop up ROSs once they are made, Mitochon’s compounds, MP101/MP201, abolish overt ROS production in the mitochondria, which is a much better starting point, and reduce the burden of mitochondrial calcium overload due to ER stress. Together, these targeted approaches have been shown to prevent cell death. Dr. Geisler says “There are many diseases, such as Alzheimer’s, Parkinson, Huntington, epilepsy, Wolfram, Multiple Sclerosis, etc., that have both ER and oxidative stress issues. Our therapies work by helping the mitochondria to cope with the deleterious effects of ER stress.”
With ER stress, the mitochondria get overburdened with calcium coming from the endoplasmic reticulum. One of the main roles of the mitochondria, besides making energy (ATP), is to store calcium and to keep the cytosol calcium free. The calcium storage capacity of the mitochondria is tremendous, but there is a threshold. When that threshold is exceeded, the mitochondria will self-destruct and leak out all of the calcium into the cytoplasm. The neighboring mitochondria are obligated to take it up, but are already near their threshold, so they self-destruct. Eventually, this cascades into the death of cells such as neurons or myotubes (muscle cell). Reducing ER stress is a great approach, but lowering calcium overload at the mitochondria is critical. Since Mitochon’s compounds (MP101 and MP201) simultaneously abolish ROS production and reduce calcium overload, their targeted effects should lower the burden on mitochondria and preserve cellular health in diseases that exhibit these types of stressors. This has already been shown in models of Huntington’s disease, traumatic brain injury (TBI), and Duchenne Muscular Dystrophy DMD) and the plan is to provide evidence that this approach is useful in Wolfram Syndrome.
Dr. Geisler says, “in a nutshell, we plan to run both compounds (MP101 and MP201) in the Wfs1KO mouse starting at 2-mths of age when diabetes starts to appear. They will be orally dosed once per day for 4-mths until 6-mths of age. An oral glucose tolerance test (OGTT) will be performed each month to monitor changes in glucose flux. At the end of the study, behavior will be monitored for balance and gait. Finally, the pancreas will be removed to examine islet morphology (diameter and number), the liver will be used to measure steatosis, histology on the eyes for retinal ganglion cell (RGC) survival and the optic nerve for demyelination. We expect the study to start in July 2018 and complete in early 2019. We don’t know for sure if it will work, but it seems reasonable! We already have data on preventing hearing loss, vision loss, diabetes, neuroprotection, neuromuscular protection, and calcium overload, so Wolfram looks like a plausible target.”
About Mitochon Pharmaceuticals
Mitochon was founded in 2014 by experienced Pharma executives with the mission to develop treatments for insidious diseases through the modulation of mitochondrial physiology, with applications to neurodegeneration (Huntington’s, Parkinson’s, MS) neuromuscular (Duchenne) and developmental (Wolfram Syndrome) diseases. Mitochon’s lead programs, MP101 and MP201, specifically harnesses the power of the mitochondria to provide broad neural protection. These compounds elicit mild increases in energy expenditure that result in strengthening cellular survival – similar to the positive effects seen with fasting and exercise. These compounds also induce an important neurotrophin, Brain Derived Neurotrophic Factor (BDNF), involved in cognition and neural growth. Mitochon is supported by Ben Franklin Technology Partners Southeastern PA, an initiative of the Pennsylvania Department of Community and Economic Development funded by the Ben Franklin Technology Development Authority. Additional Information: www.mitochonpharma.com
For background information, please see [1-5]
- Feissner, R.F., et al., Crosstalk signaling between mitochondrial Ca2+ and ROS. Front Biosci (Landmark Ed), 2009. 14: p. 1197-218.
- Geisler, J.G., et al., DNP, mitochondrial uncoupling, and neuroprotection: A little dab’ll do ya. Alzheimers Dement, 2017. 13(5): p. 582-591.
- Geisler, J.G., Targeting energy expenditure via fuel switching and beyond. Diabetologia, 2011. 54(2): p. 237-44.
- Wu, B., et al., 2,4 DNP Improves Motor Function, Preserves Medium Spiny Neuronal Identity, and Reduces Oxidative Stress in a Mouse Model of Huntington’s disease. Experimental Neurology, 2017. 293(Mar 28): p. 83-90.
- Khan, R.S., et al., Mitochondrial Uncoupler Prodrug of 2,4-Dinitrophenol, MP201, Prevents Neuronal Damage and Preserves Vision in Experimental Optic Neuritis. Oxid Med Cell Longev, 2017. 2017: p. 7180632.
Washington University School of Medicine
Wolfram Research Clinic Update- Tamara Hershey, PhD
The main activity in our lab right now is the furious planning process for the 2018 Wolfram Research Clinic! However, we also have some other progress to report. First, in the past month, we have submitted two new papers on Wolfram Syndrome for review, both based on data from previous research clinics. One of the papers is on the very important topic of urological symptoms. The paper reports on the common urological issues in Wolfram Syndrome, possible explanations for these issues and makes some recommendations for interventions. The second paper is on sleep, using the overnight sleep apnea monitoring data collected during the last few years of the research clinic. This paper describes the high rate of obstructive apnea that we observed and discusses the potential importance of detecting and treating this symptom. A third paper is almost ready to be submitted; this one is on hearing impairment and how it changes over time in Wolfram Syndrome. Once these papers are peer reviewed and approved for publication we will certainly share them with all who are interested.
Second, Dr. Marshall and I are planning our trip to Paris for the International Wolfram meeting. I will be presenting on change in brain structures over time in Wolfram Syndrome, again using our Wolfram research clinic data. We are excited to learn from our Wolfram Syndrome research colleagues and see what progress the entire field has made since we last convened.
Finally, we have been talking with The Snow Foundation about submitting a grant to the NIH to fund a family/scientific conference on Wolfram Syndrome. The idea would be to bring in researchers and clinicians with relevant expertise on Wolfram Syndrome and present the latest information to other researchers, clinicians and families. As we start planning for this, we will be interested in hearing what families might be interested in learning at such a conference.
Thank you all for your interest and support.
Tamara Hershey, PhD
Professor, Psychiatry & Radiology Departments
Lab Chief, Neuroimaging Labs (NIL) @ MIR
Co-Director, Neuroscience PhD Program, DBBS
Washington University School of Medicine
Email: tammy@wustl.edu
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
You must be logged in to post a comment.