Dr. Vania Broccoli San Raffaele Hospital/CNR-Institute of Neuroscience in Milan, Italy. Eye gene therapy for restoring WFS1 gene function in Wolfram mice

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.
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Dr. Vania Broccoli

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

Extending into 2026:

  1. This work will be done in conjunction with a grant from the Be a Tiger Foundation
  2. This 12-month project aims to determine which cells in the retina will need to be the target of gene editing or gene therapy vectors.
  3. Understanding which retinal cells are affected will help gene editing provide a more complete cure for visionloss in Wolfram syndrome.

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Dr. Rosemary Cater

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.

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