Dr. Giulio Frontino and Dr. Maurizio Delvecchio discuss crafting national guidelines for the diagnosis and care of individuals with Williams Syndrome. You can listen to their presentation by following the link provided: https://youtu.be/PssLjWZgsFE
Dr. Cecile Delettre
Neuroscience Institute of Montpellier, France
Recently we have identified a family of molecules with the capacity to stimulate significantly the growth of retinal ganglion cells in vitro in a model of optic atrophy. We developed a zebrafish model with an optic atrophy and we have treated these fishes with one of these molecule. We used increasing doses of molecules to measure the toxicity and determine the most effective dose to protect the optic nerve. We have determined the dose with the best effect and confirmed that treatment with this molecule can prevent optic nerve developmental delay in vivo in our model of optic neuropathy. We are studding the mechanism of action of this molecule and using it in several model of Wolfram syndrome We look forward to a clear indication of the possibility of using this molecule in the future development of a treatment for Wolfram syndrome.
Dr. Benjamin Delprat
University of Montpellier, France
In my lab, we are developing concomitantly two therapeutic strategies: a pharmacological approach and a gene therapy. To achieve these goals, we are working with suited animal models: two transgenic mouse lines and one zebrafish line. One mouse model and the zebrafish line are deficient for Wolframin, the protein responsible for Wolfram syndrome type 1. The other mouse model has been genetically engineered to mimic a human mutation, recapitulating sensorial deficits (vision and hearing loss) and diabetes. We are hoping to treat vision and hearing, as well as central neurodegeneration.
Dr. Timothy Barrett’s Update | University of Birmingham, United Kingdom
Dear friends and colleagues,
I hope everyone is keeping OK. I have 3 items to update you on.
Firstly, the TREATWOLFRAM trial is continuing to progress well. We had an independent Data Monitoring Committee meeting in January. This is chaired by Professor Karen Morrison, an honorary consultant in adult neurology, who previously led the highly specialised service for adults with Wolfram syndrome. The Data Monitoring Committee reviewed the unblinded data. I am pleased to say that they had no safety concerns, and were happy for the trial to continue to completion. Following this meeting, our Trial Steering Committee met, chaired by Professor Marc Peschanski, Director of INSERM, a large research institute outside Paris. We discussed the trial progress so far, and plans for acting on the results at the end of the trial. The last participant will complete the trial at the end of October 2024. We will then have 2-3 months to collect any outstanding data from study sites. The Clinical Trials Unit… read in full here.
Dr. Fumihiko Urano Washington University School of Medicine, USA
Dr. Fumihiko Urano
Washington University School of Medicine, USA
Dear Friends,
I want to take a moment to express my deep gratitude for your unwavering belief in and support of our mission to find a cure for Wolfram syndrome. Your enduring encouragement has been a beacon of hope guiding us on this remarkable journey. As we embark on the year 2024, filled with hope and determination to inch closer to our goal of finding a cure, I would like to provide a summary of our progress in the battle against Wolfram syndrome.
Rare Disease Day at NIH 2024
Before I delve into our progress update, I’m excited to share some fantastic news with you. I’ve received an invitation to present our research on Wolfram Syndrome at the Rare Disease Day event held at the National Institutes of Health on February 29, 2024. This event is widely regarded as one of the most prestigious gatherings for rare diseases, offering an excellent platform for us to raise awareness about Wolfram Syndrome. Even if you can’t attend in person, you can still participate by watching my presentation remotely. Here is the link to access it: https://ncats.nih.gov/news-events/events/rdd
Dr. Vania Broccoli
San Raffaele Hospital/CNR-Institute of Neuroscience in Milan, Italy.
Eye gene therapy for restoring WFS1 gene function in Wolfram mice
AAV-based gene therapy is based on intra-vitreal injections of AAV vector expressing a therapeutic gene. This strategy is already in clinical use for treating Leber hereditary optic neuropathy (LHON) and clinical trials performed in multiple centers have reached beneficial effects without any troublesome side-effects. Strong advantages of this approach areå the ease of the surgical intervention, the efficacy of the AAV infection and the durable expression of the therapeutic genes for many years if not forever. Thus, we are developing an AAV-based replacement gene therapy to express a functional copy of the Wfs1 in retinal tissue to eb tested in Wolfram mice. However, our recent results indicate that Wolframin is significantly more expressed in glial cells where it controls MCT1 protein levels and its inactivation leads to RGC death through a non-cell autonomous mechanism of energy deprivation. These results clearly implicate that restoring Wfs1 gene expression only in RGCs might not be sufficient to protect from progressive visual loss. Our previous results indicate that both astrocytes in the retina and oligodendrocytes in the optic nerve play a crucial role in supplying energetic molecules to RGCs and this function is affected when Wolframin is inactivate in these cells. Thus, the question is in which cells the reintroduction of Wfs1 will have the best therapeutic effects in promoting RGC survival and functions. To answer to this question and to establish the most efficient strategy of gene therapy, we have been generating 4 different AAV vectors where the WFS1 gene is under the control of different promoters that combined with a specific delivery route will allow the expression of the therapeutic WFS1 gene copy in either only RGCs, optic nerve oligodendrocytes, retinal astrocytes, both glial cell types or all these type together. We will produce in our lab the AAV viral particles for intra-vitreal injections in the Wolfram mice.
This study will determine the best AAV gene therapy method considering both the ease of the administration route and its beneficial effects on visual functions. These results will pave the way to the clinical exploitation of this approach in Wolfram patients for establishing the first neuroprotective approach to arrest RGC loss in the disease.
National Research Council of Italy: Project application
Title: Novel experimental therapies to treat blindness in Wolfram syndrome
Applicant: Dr. Vania Broccoli
San Raffaele Hospital/CNR-Institute of Neuroscience, Milan Italy
Eye gene therapy for restoring WFS1 gene function in Wolfram mice
AAV-based gene therapy is based on intra-vitreal injections of AAV vector expressing a therapeutic gene. This strategy is already in clinical use for treating Leber hereditary optic neuropathy (LHON) and clinical trials performed in multiple centres have reaches beneficial effects without any troublesome side-effects. Strong advantages of this approach areå the ease of the surgical intervention, the efficacy of the AAV infection and the durable expression of the therapeutic genes for many years if not forever. Thus, we are developing an AAV-based replacement gene therapy to express a functional copy of the Wfs1 in retinal tissue to eb tested in Wolfram mice. However, our recent results indicate that Wolframin is significantly more expressed in glial cells where it controls MCT1 protein levels and its inactivation leads to RGC death through a non-cell autonomous mechanism of energy deprivation. These results clearly implicate that restoring Wfs1 gene expression only in RGCs might not be sufficient to protect from progressive visual loss. Our previous results indicate that both astrocytes in the retina and oligodendrocytes in the optic nerve play a crucial role in supplying energetic molecules to RGCs and this function is affected when Wolframin is inactivate in these cells. Thus, the question is in which cells the reintroduction of Wfs1 will have the best therapeutic effects in promoting RGC survival and functions. To answer to this question and to establish the most efficient strategy of gene therapy, we have been generating 4 different AAV vectors where the WFS1 gene is under the control of different promoters that combined with a specific delivery route will allow the expression of the therapeutic WFS1 gene copy in either only RGCs, optic nerve oligodendrocytes, retinal astrocytes, both glial cell types or all these type together. We will produce in our lab the AAV viral particles for intra-vitreal injections in the Wolfram mice. Six groups of mice will be prepared (4 animals for each group) to be treated each group with a different AAV vector at 2 months of age. Then, treated mice will be subjected to the visual acuity test (Optodrum machine) every 2 months. After 10 months from the treatment, the eyes will be isolated and analyzed for retinal morphology, RGC numbers and optic nerve anatomy by electron microscopy. This analysis will define in which cell type is most relevant to express the WFS1 functional gene copy to obtain the best protection of visual functions in Wolfram mice.
Although we expect that the AAV supporting the expression of WFS1 in both RGC and glial cells will provide the most beneficial effects, it is possible that WFS1 expression only in retinal astrocytes will trigger significant improvements. In that case, this last option might be preferable given that it might be easier to transduce glial cells respect to RGCs in the retina with AAV particles. This study will determine the best AAV gene therapy method considering both the ease of the administration route and its beneficial effects on visual functions. These results will pave the way to the clinical exploitation of this approach in Wolfram patients for establishing the first neuroprotective approach to arrest RGC loss in the disease.
Timeline
Understanding the molecular role of WFS1 and how mutations in this protein cause Wolfram syndrome.
Wolfram syndrome manifests as a genetic disorder marked by early-onset diabetes, progressive optic atrophy, and hearing loss. In addition to these defining symptoms, some individuals may also experience neurological complications, including motor impairments, neurological disorders, and deficits in memory and learning. Tragically, Wolfram syndrome carries a high mortality rate, and currently, there are no therapeutic interventions available to halt or slow its progression. This lack of effective treatment stems, in part, from our incomplete understanding of the disease’s underlying mechanisms.
While it is known that Wolfram syndrome is caused by mutations in the WFS1 gene, the precise role of the WFS1 protein in healthy individuals remains elusive, as does the link between its various mutations and Wolfram Syndrome. Our research is focused on understanding the molecular function of the protein encoded by WFS1, and what this protein looks like on an atomic level. By gaining these molecular insights into the normal WFS1 protein, we will be able to understand how mutations in this protein disrupt its activity and cause Wolfram syndrome.
Through a collaborative effort with Prof Vania Broccoli (San Raffaele Hospital and CNR-Institute of Neuroscience in Milan) and Prof Filippo Mancia (Columbia University, USA), we have preliminary results that are already helping us understand what this protein looks like and are enthusiastic about furthering this research to fill this gap in knowledge within the field, and ultimately contribute to the development of effective treatments for Wolfram syndrome.
The Neural Circuit Development and Regeneration research group at the University of Leuven (Biology Department, KU Leuven, Belgium), led by Prof. L. Moons and Dr. Lies De Groef, aims to define the cellular and molecular mechanisms underlying neurodegeneration, -inflammation and -regeneration in the injured, diseased or aged central nervous system. Within their research, they focus on the inter-relatedness of neurobiology and ophthalmology research, and position the eye ‘as a window to the brain’. Besides glaucoma, Alzheimer’s and Parkinson’s disease, they have a major interest in Wolfram syndrome. Via ocular and MRI imaging, electrophysiology and visual function testing in laboratory animals, they try to unravel the impact of Wolfram syndrome on the retina and visual system and understand the underlying disease mechanisms. Their studies in a Wolfram mouse model (Wfs1Δexon8) revealed progressive vision loss, neuronal dysfunction and neuroinflammation in the retina, and axonal conduction defects in the optic nerve. Based on these findings and their special interest in the role of glial cells (oligodendrocytes, micro- and astroglia) in the pathogenesis of Wolfram syndrome, they are further complementing this work with mechanistic studies in patient iPSC-derived cells (in collaboration with Prof. C. Verfaillie and G. Bultynck, KU Leuven). Furthermore, building on their expertise in visual system phenotyping, the Neural Circuit Development and Regeneration research group is also evaluating the effect of novel therapeutics to prevent blindness, including preclinical studies with GLP-1 analogues (in collaboration with M. Igoillo Esteve, Université Libre de Bruxelles) and gene editing approaches (in collaboration with C. Verfaillie).
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