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Update by Dr. Fumihiko Urano – September 14th

Fumihiko “Fumi” Urano, MDAugust 30, 2023

Dear Friends,

Thank you so much for continually believing in and supporting me. I deeply appreciate it! Your encouragement has been such a driving force in our journey. Excitingly, we’re making significant strides in our therapeutic development for Wolfram syndrome. I can’t wait to fill you in on all the details. Let’s dive right into an update about our current clinical trial.

Ongoing clinical trial

We’re genuinely excited about the positive strides being made in Wolfram syndrome treatments. In collaboration with our partners at Amylyx Pharmaceuticals, we’re actively advancing the development of AMX0035, an innovative oral medication designed to halt the progression of Wolfram syndrome. Interested in understanding how AMX0035 addresses endoplasmic reticulum stress and mitochondrial dysfunction? We invite you to explore our latest article here: https://insight.jci.org/articles/view/156549.

In 2020, the US FDA granted AMX0035 orphan drug status for Wolfram syndrome. Using previous study data, we developed a safety and effectiveness protocol for AMX0035, which has been approved by the US FDA and the Institutional Review Board at Washington University Medical Center:

We’ve started a phase 2 clinical trial for adult Wolfram syndrome patients:

https://wolframsyndrome.wustl.edu/items/a-phase-ii-study-of-safety-and-efficacy-of-amx0035-in- adult-patients-with-wolfram-syndrome/.
Our first participant was dosed in April 2023: https://www.amylyx.com/news/amylyx- pharmaceuticals-announces-first-participant-dosed-in-phase-2-study-of-amx0035-for-the- treatment-of-wolfram-syndrome.

Our trial is progressing smoothly and more patients have been dosed, and we are already mapping out our subsequent steps. Stay tuned for updates.

Gene Editing Therapy

As you are all aware, Wolfram syndrome is a medical condition caused by issues in a gene named WFS1. When this gene isn’t functioning right, it can lead to multiple health problems, including optic nerve atrophy, diabetes mellitus, and neurodegeneration. Our current focus and priority is to safeguard the retinal ganglion cells. Why? Because these cells play a crucial role in preventing damage to the optic nerve and maintaining vision.

To address this, we’ve joined hands with distinguished scientists: Dr. Catherine Verfaillie, Dr. Lies De Groef, and Dr. Lieve Moons from Katholieke Universiteit Leuven in Belgium. Together, we’re applying a pioneering technique named “Base Editing” to make corrections in the problematic gene changes. Using iPS cells derived from Wolfram syndrome patients, we’ve seen promising results with this method. Our next step is to test this approach on a mouse model that simulates the human condition of Wolfram syndrome.

Besides “Base Editing,” we’re diving deep into an even newer method called “Prime Editing.” This is cutting-edge technology in gene correction. For this endeavor, we’re collaborating with Dr. David Liu and his team from Harvard/MIT, who are at the forefront of this field.

Ultimately, our heartfelt goal is to harness these innovative techniques to bring relief to those living with Wolfram syndrome.

Regenerative Therapy for Optic Nerve Atrophy – Gene Therapy and Mesenchymal Stem Cell Transplantation
We’re looking into new ways to heal and even reverse damage to the optic nerve, which is the nerve in our eyes that helps us see. We’ve come up with two main ideas.

First, we’re trying to introduce a special regenerative factor, called MANF, into the eyes of patients with Wolfram syndrome. We use a virus (a safe one!) to help deliver this factor. MANF helps protect retinal ganglion cells and encourages them to grow.

Secondly, we’re testing the use of special cells, called mesenchymal stem cells, which we can get from fat tissues or bone marrow. In previous tests with animals, these cells have been shown to help eye nerve cells survive and grow back after damage.

Right now, we’re doing more tests using MANF in rodent models of Wolfram syndrome developed in our lab. If everything goes well, we hope to test these methods on actual patients in the next 3- 7 years.

Clinical service

At the Washington University Medical Center’s Center for Advanced Medicine, we have established the Wolfram Syndrome and Related Disorders Clinic program, aimed at improving clinical care for patients with Wolfram syndrome and related disorders, including WFS1-related deafness and optic nerve atrophy.

Our program provides genetic evaluations, education, and counseling services to patients and family members of all ages who have either been diagnosed with Wolfram syndrome, are suspected of having it, or have WFS1-related disorders.

Our team collaborates with other specialists, including neurologists, neuro-ophthalmologists, urologists, medical geneticists, and endocrinologists at our medical center, to provide personalized management plans. We strive to see patients either on the same day or within two consecutive days. Our services are available to both pediatric and adult patients.

Patients in the US

If you’re in the US, please call Christine Manning, RN, Nurse Coordinator, at 314-747-7055 or 314-362-3500. Let her know that you or your family member has Wolfram syndrome or WFS1- related medical conditions and need to make an appointment. Once we review your medical records, Dr. Urano or his staff will contact you to discuss which specialists you may need to see.

Sending Medical Records via Fax

Please fax your medical records to 314-747-7065.

Referrals via Fax for both Missouri patients and out-of-state patients

Please fax your referral request to 314-747-7065.

International Patients

International patients are welcome to contact our international patient care office to schedule an appointment by calling +1-314-273-3780 or sending an email to Internationalpatients@wustl.edu.

Conclusion

So many things are happening in the world of Wolfram syndrome. Let’s keep the momentum going! Our team’s dedication to therapeutic development for Wolfram syndrome shines bright, and it’s deeply inspired by the resilience of patients and families facing this condition. The positive results we’re seeing are truly uplifting and fuel our hope for the future. While challenges remain, rest assured, we’re wholeheartedly committed to driving breakthroughs that could transform the lives of those with Wolfram syndrome. Stay tuned for more updates, and a huge thank you for being our rock-solid support!

With grace and gratitude, Fumi

Fumihiko Urano, MD, PhD, FACMG
Professor of Medicine and of Pathology & Immunology
Samuel E. Schechter Endowed Professor in Medicine
Director, Wolfram Syndrome/WFS1-related disorders Registry & Clinical Study and WFS1 clinic at BJC HealthCare
Washington University School of Medicine
https://wolframsyndrome.wustl.edu/

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Listen to Episode #18 Hattersley-Urano Wolfram Syndrome with Parent Tamara Blum from the Podcast “It Happened to Me”

Read more
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8th International Wolfram Symposium Presentation Liiv M1, Vaarmann A1, Kuum M1, Gupta-Blixt R1, Janickova L1, Hodurova Z1, Cagalinec M1, Zeb A1, Choubey V1, Hickey MA1, Safiulina D1, Yi-Long H2, Gogichaisvili N1, Mandel M1, Plaas M1, Vasar E1, Loncke J3, Vervliet T3, Tsai T-F2, Bultynck G3, Veksler V4, Kaasik A1.1Departments of Pharmacology and Physiology, University of Tartu, Estonia. 2Department of Life Sciences, National Yang Ming Chiao Tung University, Taiwan 3Laboratory of Molecular and Cellular Signaling, KU Leuven, Belgium. 4INSERM UMR-S 1180, University Paris-Saclay, France.

8th International Wolfram Symposium Presentation Liiv M1, Vaarmann A1, Kuum M1, Gupta-Blixt R1, Janickova L1, Hodurova Z1, Cagalinec M1, Zeb A1, Choubey V1, Hickey MA1, Safiulina D1, Yi-Long H2, Gogichaisvili N1, Mandel M1, Plaas M1, Vasar E1, Loncke J3, Vervliet T3, Tsai T-F2, Bultynck G3, Veksler V4, Kaasik A1.1Departments of Pharmacology and Physiology, University of Tartu, Estonia. 2Department of Life Sciences, National Yang Ming Chiao Tung University, Taiwan 3Laboratory of Molecular and Cellular Signaling, KU Leuven, Belgium. 4INSERM UMR-S 1180, University Paris-Saclay, France.
Pharmacological targets to correct deficient ER-mitochondrial Ca2+ homeostasis in the neuronal models of Wolfram Syndrome
Abstract: Wolfram syndrome (WS) is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in WS involves poor endoplasmic reticulum (ER) Ca2+ handling, but how this disturbance leads to the disease is not known. Although the clinical symptoms of WS resemble mitochondrial diseases and WFS1 or CISD2 deficiency leads to mitochondrial abnormalities, no causal link has been established between the ER defects, mitochondrial dysfunction and cell metabolic disturbances. The current study, performed in primary isolated neurons, the most affected and disease-relevant cells, involving both WS genes explains how the disturbed ER Ca2+ handling compromises mitochondrial function and in turn affects neuronal health. Loss of ER Ca2+ content in the axons of the WFS1 or CISD2 deficient neurons is associated with lower IP3R3-mediated Ca2+ transfer from ER to mitochondria leading to decreased mitochondrial Ca2+ uptake. In turn, reduction in mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased axoplasmic NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress further compromise the neurons health. Our work also identifies pharmacological targets and compounds that potentially may restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal function.
Points noted:
•  Compounds affecting ER and mitochondrial Ca2+ could improve mitochondrial function and neuronal health.
•  WS serves as an important disease prototype for ER and mitochondrial dysfunction.
•  Hope to publish findings soon.
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8th International Wolfram Symposium Presentation Fumihiko Urano, MD, PhD, Samuel E. Schechter Professor of Medicine, Washington University School of Medicine, St. Louis, USA

8th International Wolfram Symposium Presentation Fumihiko Urano, MD, PhD, Samuel E. Schechter Professor of Medicine, Washington University School of Medicine, St. Louis, USA
 
Novel Therapies for Wolfram Syndrome
 
Abstract: Wolfram syndrome is a rare genetic spectrum disorder characterized by insulin-dependent diabetes, optic nerve atrophy, and progressive neurodegeneration, and ranges from mild to severe clinical symptoms. There is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, raising the urgency for innovative therapeutics for this disease. Here, we summarize our vision and progress on developing novel treatments and achieving a cure for Wolfram syndrome. Our approach entails utilizing oral pharmacotherapy aimed at modulating endoplasmic reticulum and mitochondrial functions to impede the progression of the disease, followed by the implementation of gene therapy to arrest its advancement, ultimately culminating in the application of regenerative therapy using a unique neurotrophic factor, MANF, and iPSC-derived tissues for the repair of any damaged tissues, especially retinal ganglion cells and brain cells. Our proposed approach has the potential to not only alleviate the symptoms of Wolfram syndrome, but it may also lead to a potential cure for medical conditions commonly seen in Wolfram syndrome, including diabetes, vision loss, and neurodegeneration. This is due to the innovative nature of our strategy, which targets the root cause of Wolfram syndrome, thereby offering a universal solution for a wide range of human chronic disorders.
 
Points noted:
•  Dr Urano is working with many collaborators. The team have medical records for +250 patients (2009-present) and long-term data for +50 patients (2011- present).
•  There is an increased understanding of this rare disease.
Look to identify patient cohorts for clinical trials and the best outcome measures.
•  Previous dantrolene clinical study showed improved beta cell function in a subset of patients. Patients with greatest increase tended to have visual acuity and less severe disease.
•  AMX-0035 – preclinical studies have confirmed that this combination therapy performs better than a single agent (e.g. reduced cell death and improved mitochondrial function). First clinical trial initiated in April 2023 with C-peptide as the primary outcome measure.
•  S1R agonist (Pridopidine) is being tested in pre-clinical models (through collaboration with Prilenia).
•  Working with an industry partner on gene therapies and gene editing with Prof Catherine Verfaillie. Willing to share protocol for iPSCs models with other researchers.
•  Shared WS mutant rodent (rat and mice) models with other researchers and is willing to share with additional researchers who would like them.
•  For entrepreneurship, need industry partners, which are also needed in Europe (current industry collaborators are US companies).
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8th International Wolfram Symposium Presentation Prof Timothy Barrett, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham UK, on behalf of the TREATWOLFRAM investigators (Dr Renuka Dias, Dr Ben Wright (UK), Dr Gema Esteban Bueno (Spain), Prof Wojciech Mlynarski (Poland), Dr Christophe Orssaud, Prof Agathe Roubertie (France)

8th International Wolfram Symposium Presentation Prof Timothy Barrett, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham UK, on behalf of the TREATWOLFRAM investigators (Dr Renuka Dias, Dr Ben Wright (UK), Dr Gema Esteban Bueno (Spain), Prof Wojciech Mlynarski (Poland), Dr Christophe Orssaud, Prof Agathe Roubertie (France)
 
Sodium Valproate efficacy and safety in WFS1 Spectrum Disorder (TREATWOLFRAM). Update on phase II pivotal international multicentre, double-masked, randomised controlled trial.
 
ABSTRACT: Introduction
WFS1 spectrum disorder (WFS1-SD) comprises a classic form of progressive neurodegenerative disorder, formerly known as Wolfram syndrome, and non-classic forms including low-frequency sensorineural hearing loss. This is the commonest monogenic syndrome of diabetes and vision impairment, affecting 1:500,000 in the UK. Despite this, there are no licensed pharmacological therapies for WFS1-SD. Sodium valproate (VPA) is an anti-convulsant approved for use for the treatment of epilepsy and bipolar disorder. VPA has been shown to reduce Endoplasmic Reticulum (ER) stress, is known to exert neuroprotective effects in models of neurodegeneration, and in the context of WFS1-SD, VPA is thought to mediate its effect via alteration of cell cycle kinetics, increase in p21cip1 expression levels or nuclear translocation and reduction in apoptosis, and increase in Wolfram protein expression. There is currently a lack of prospective controlled studies investigating therapeutic candidates in people with WFS1-SD.
 
Methods
TREATWOLFRAM is a phase II, pivotal, international multi-centre, double-masked, placebo-controlled, randomised clinical trial designed to investigate whether a 36 month treatment with up to 800mg/day of VPA in children aged 6-12 years, or up to 1600mg/day for those aged 12 years of over, will slow the rate of change in visual acuity as assessed by corrected visual acuity in each eye, using standardised charts, in participants with WFS1-SD. Children aged 6 years or more and adults with genetically confirmed WFS1-SD and visual acuity with LogMAR score of 1.6 or better on an EDTRS chart, were assessed for eligibility at 6 recruitment centres in Europe. Patients who satisfied the eligibility criteria were randomly assigned (2:1) to receive twice daily tablets of either VPA or VPA-placebo (control). Analysing visual acuity outcomes using longitudinal hierarchical models, and using data on a cohort of 26 patients with Wolfram syndrome kindly provided by Prof Tamara Hershey, (significance level 0.05, power 0.90), and accounting for an estimated 15% withdrawal rate, we estimated a target sample size of 70 patients, so that a minimum of 21 participants were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable participants achieving a decline in the rate of progression of vision loss between baseline and after 36 months of treatment. Visual acuity progression will be defined as the change in LogMAR units over time as measured on EDTRS charts.
 
Ethics and dissemination
The protocol was designed with assistance from the EU Committee for Medicinal Products for Human Use (CHMP) and approved by The West of Scotland Research Ethics Service (18/WS/0020) and The Medicines and Healthcare Products Regulatory Agency (EudraCT 2017-001215-37; ISRCTN 10176118). Recruitment into TREATWOLFRAM started in January 2019 and ended in October 2021, with 63 patients randomised. The treatment follow-up of TREATWOLFRAM patients is currently ongoing and due to finish in October 2024. The findings of this trial will be disseminated through peer-reviewed publications.
 
Trial registration: Clinicaltrials.gov NCT03717909 Points noted:
•  Visual acuity is the primary endpoint of TreatWolfram. A number of secondary endpoints are also included.
•  Sodium valproate targets the final part of the treatment pathway. This drug has decades of use, has been shown to be neuroprotective and as it is off- patent – there is freedom to operate in clinical trials and ongoing licensing.
•  TreatWolfram received 2014 orphan drug designation by EMA and FDA. Regulators may not require a gold standard double blind randomised controlled trial today.
•  The trial was delayed by a range of issues – as a result some patients were unable to participate as their vision had deteriorated while awaiting trial commencement.
•  If starting the study today, Milan would be included as a study site (this group has been developing a clinical trial centre).
•  University of Birmingham now has an established clinical trial unit for delivering pivotal trials in rare disease and a network of trial sites that would like to be included in future WS clinical trials in Europe.
•  The study clearly highlighted that Brexit has been damaging for rare disease research.
•  Better biomarkers are needed that can demonstrate efficacy in around 6 months that are relevant for patients. Researchers need to be able to identify responders to potential treatments in a much shorter timeframe.
•  With better biomarkers, new clinical trials could be designed to report in a shorter timeframe (and should therefore be less expensive). This could help attract more commercial partners into WS clinical research.
•  It was noted patient samples will be available to help assist in developing biomarkers, including placebo data from clinical trials.
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8th International Wolfram Symposium Presentation Dr Christophe Orssaud – Functional Unit of Ophthalmology, Paris, France

8th International Wolfram Symposium Presentation Dr Christophe Orssaud – Functional Unit of Ophthalmology, Paris, France
Audiowolf : Description, contribution and interest of this protocol
Alongside the Treatwolfram protocol initiated by Pr T Barrett, a second new protocol has been initiated in France, called Audiowolf. These two protocols are similar in terms of their duration (3 years), the patients for whom they are intended (patients with Wolfram syndrome) and the molecule used (sodium valproate). They nevertheless differ by several points which make them complementary.
These differences relate first to the primary judgment criterion. This primary judgment criterion is auditory in Audiowolf and not visual. It is also a non-randomized protocol without double blinding. All the patients included receive the treatment at a dose adapted to their weight. Finally, it was initially designed as being monocentric (Paris), although it is currently undergoing extension to Spain (Almeria).
However, this Audiowolf protocol is not a competitor but rather complementary to Treatwolfram. Indeed, it makes it possible to include patients who did not meet the inclusion criteria of the Treatwolfram protocol due to too low visual acuity. On the other hand, the auditory, visual, neuro-radiological and biological tests are identical. Thus, after a separate processing of both protocols, these different data can be combined for common analyses. Finally, this protocol will make it possible to better analyze the auditory impairment of Wolfram syndrome. On the other hand, all patients receiving sodium valproate, an ancillary study was initiated to understand how this molecule may affect insulin regulation.
In practice, the inclusion criteria require, among other things, a hearing impairment of at least 5 dB at 8000 Hz. And this protocol can be delivered “turnkey” to teams that would like to propose it to their patients.
Points noted:
•  Patients enrolled in this study must have some level of hearing loss (those with hearing implants can be included).
•  Study first started in Nov 2021 – after TreatWolfram (to avoid patients needing to choose which study to participate in).
•  Secondary objective of the study is to evaluate C-peptide to try to understand how sodium valproate acts on insulin secretion.
•  A rare side effect of sodium valproate is hearing loss, which is typically bilateral and reversible. This will need to be considered should any patients experience severe hearing loss during the study (patient data likely to be excluded, at least initially).
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8th International Wolfram Symposium Presentation Prof Catherine Verfaillie – Stem Cell Institute, KU Leuven, Belgium

8th International Wolfram Symposium Presentation Prof Catherine Verfaillie – Stem Cell Institute, KU Leuven, Belgium
 
iPSC-based modeling of Wolfram Syndrome and therapeutic genome editing approaches
 
Points noted:
•  Developed iPSC-based models of different cell types – neural cells, ganglion, astrocytes, and blood brain barrier endothelial cells.
•  These cell lines can be shared with other WS researchers who would like to use them.
•  Further evaluate (e.g. myelination, stain for different markers) and explore changes over time. Also compare with WS-derived models to explore differences.
•  Base editing conducted using this system – look to see if / how this can be delivered in vivo.
•  Translate findings to mouse model – exchange with Fumi (Dr Urano) mouse model with current iPSC system.
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8th International Wolfram Symposium Presentation Mathias Leinders – Amylyx Pharmaceuticals 

8th International Wolfram Symposium Presentation Mathias Leinders – Amylyx Pharmaceuticals 

Helios – A Phase II Study of Safety and Efficacy of AMX0035 in Wolfram Syndrome

Summary: Update on the clinical trial design of Helios, and the rationale for using AMX0035 as potential treatment for Wolfram Syndrome. 

Points noted: 

  • AMX0035 is a combination therapy of two compounds– TUDCA (tauroursodeoxycholic acid) and sodium phenylbutyrate (PB). 
  • Approved in the US for ALS, not currently approved in the EU. 
  • Investigational drug for WS. Received orphan drug status in US. 
  • Shown to decrease neuronal death, mitigate ER stress and mitochondrial dysfunction. 
  • Excellent safety and tolerability profile shown in previous studies (Ph III in ALS). Taste issues have been reported previously (AMX0035 = sachet). 
  • Currently conducting a collaboration with Dr Urano (preclinical and clinical). 
  • As part of this collaboration, an open label Ph II study has started in US to recruit 12 patients to assess safety (using standard endpoints), tolerability, various measurements (e.g. beta cell function), and exploratory biomarkers. 
  • Study will monitor C-peptide levels (as a surrogate endpoint) over 24-week period. Patients will therefore need to be relatively healthy to be able to participate (It was noted that not many patients will meet the inclusion criteria required for C-peptide levels). Based on learnings from the dantrolene trial, the target of 12 patients should be achieved. 
  • The study aims to assess whether there is value in treating WS patients as early as possible and if data are encouraging will expand to larger and longer studies. 
  • The study protocol includes a 4-hour mixed meal tolerance test (MMTT) (which it was noted is a big ask for patients and researchers). This test was specifically requested by the FDA. If data are encouraging, the aim is to propose to reduce MMTT in a future larger trial. 
  • If data are encouraging, this will help to spur development in a juvenile programme. 
  • First patient recruited to this study April 2023 (week prior to the Symposium). 
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8th International Wolfram Symposium Presentation Dr Benjamin Delprat – University of Montpellier, France

8th International Wolfram Symposium Presentation Dr Benjamin Delprat – University of Montpellier, France
Advances on the pharmacological and gene therapies approaches
 
Abstract: Wolfram syndrome is a rare autosomal recessive disease affecting many organs with life-threatening consequences and currently no treatment is available. Therefore, the need to find a cure is imperative. The pathology is related to the deficient activity of wolframin, an endoplasmic reticulum (ER) transmembrane protein were shared from Estonia (Dr Mario Plaas). Final time point studied 7.5 months. Some changes detected very early (from 3 months). involved in contacts between ER and mitochondria termed mitochondria associated- ER membranes (MAMs). Inherited mutations usually reduce the protein’s stability, altering its homeostasis and ultimately reducing ER to mitochondria Ca2+ transfer resulting in mitochondrial dysfunction and cell death. We previously demonstrated that improving MAMs functioning by overexpressing NCS1, a wolframin partner, is efficient in correcting the cellular and behavioral alterations in our preclinical models of the pathology.
 
Based on these data, we focused our research on another crucial protein of the MAMs physiology, the sigma-1 receptor (S1R), an endoplasmic reticulum resident protein involved in Ca2+ transfer. Very interestingly, S1R could be activated by small active molecules to foster the Ca2+ transfer between ER and mitochondria. Therefore, we demonstrated that activation of S1R with the prototypic agonist PRE-084, restored Ca2+ transfer and mitochondrial respiration in vitro, corrected the associated increased autophagy and mitophagy, and was able to alleviate the behavioral symptoms observed in the genetic animal models of the disease, i.e. hyperlocomotion in wfs1abKO zebrafish and memory deficits and anxiety in Wfs1∆Exon8 mice. Our findings provide a new therapeutic strategy for Wolfram syndrome patients, by efficiently boosting MAM function using the ligand operated S1R chaperone.
 
Points noted:
•  NCS-1 (neuronal calcium sensor -1) represents a relevant target for treating WS.
•  Activation of S1R is beneficial in WS – (e.g. improved memory and increased Ca2+ in WS models).
•  S1R targeting is therefore relevant for WS patients.
•  NCS-1 modulators / stabilizers were not investigated.
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8th International Wolfram Symposium Presentation Karan Ahuja, Marjan Vandenabeele, Arefe Nami, Catherine Verfaillie, Lieve Moons, Lies De Groef

8th International Wolfram Symposium Presentation Karan Ahuja1, Marjan Vandenabeele2,3, Arefe Nami1, Catherine Verfaillie1, Lieve Moons2, Lies De Groef3
 
Oligodendrocytes in Wolfram syndrome: bystanders or partners in crime?
 
1Development and Regeneration Department, KU Leuven Stem Cell Institute, Leuven, Belgium 2Neural Circuit Development and Regeneration Research Group, Biology Department, KU Leuven Brain Institute, Leuven, Belgium
 3Cellular Communication and Neurodegeneration Research Group, Biology Department, KU Leuven Brain Institute, Leuven, Belgium
 
Abstract: Up till today, the neurodegenerative pathology associated with Wolfram syndrome (WS) is unstoppable. This treatment gap is at least in part due to the limited understanding of the underlying cellular mechanisms. In particular, it is becoming increasingly clear that –although neurons eventually die– there is a central role for glial cell types in most neurodegenerative disorders and it is essential to determine which of these cell types is the catalyst of the disease processes leading to WS, so that future therapies can be targeted to this cell type. In this study, based on recent evidence suggesting that the neurodegenerative component of WS could be driven by an oligodendrocyte rather than a neuronal pathology, we aimed to investigate what the effect of these ‘diseased’ oligodendrocytes is on the function of ‘healthy’ neurons, focusing on ER stress, mitochondria and cell metabolism as potential underlying mechanisms.
Our studies in iPSC-derived oligodendrocytes from WS patients reveal that these may be more vulnerable to ER stress and display signs of mitochondrial dysfunction. This, together with their seemingly reduced capacity to transfer metabolites and thereby support axons, suggests that oligodendrocyte dysfunction may, at least partially, be underlying the neurodegenerative component of WS. Next, we validated these findings in vivo, by investigating the retina and optic nerve of the Wfs1 KO mouse. We found that functional and glial cell alterations precede structural neuronal changes, and that these animals have problems with the oligodendrocyte cell lineage, leading to a decreased oligodendrocyte precursor cell number, a thinner myelin sheet and more signs of axonal degeneration in the Wfs1 KO animals. Finally, MRI studies of the brain of these Wfs1 KO mice showed a reduction in the volume of several brain regions, including the cerebellum, brainstem and corpus callosum which are also affected in WS patients– as well as changes in the apparent diffusion coefficient, pointing towards neurodegeneration and changes in myelination. Based on these data, it is tempting to speculate that the white matter changes and neuronal loss observed in WS patients is at least partly caused by problems with the supportive functions of oligodendrocytes: signal transduction via myelination and metabolic support of axons. This suggests that future WS therapies may need to target oligodendrocytes, rather than or in addition to neurons. All in all, our findings indicate that the eye is a window to the brain, with the retina reflecting the pathological processes ongoing in the brain.
 
Points noted:
•  Wfs1 KO mice
•  Also shared preliminary in vitro data where ER stress, mitochondrial dysfunction and cell death were observed in WS patient derived cell lines.
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