Dr. Benjamin Delprat

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.

Update March 5, 2034:

We have explored the impact of the absence of Wolframin or the presence of an abnormal protein in the neurons of our mouse models (neurons of the hippocampus and cortex) as well as in patients’ fibroblast (cells cultured from the skin). Our findings suggest considering the use of the same therapeutic targets in both cases, thus opening treatment perspectives for patients carrying a mutation leading to an abnormal protein (Wolfram-like syndrome).

Using our zebrafish model of the disease, we have validated our gene therapy strategy. Based on these encouraging results, we are now investigating the outcomes of this approach in our mouse models.

Our gene therapy approach corrected the memory deficit and locomotor coordination alteration at least one month after the injection of the virus. In addition, the virus is efficiently transducing the affected brain structure such as cerebellum, hippocampus, or cortex and lasting in time.

We are now exploring vision and hearing loss of our preclinical models, following the injection of the virus.

University of Montpellier

My projects are focused on elucidating Wolfram syndrome molecular mechanisms and more particularly to study the role of the alterations of communication between two intracellular organelles named the endoplasmic reticulum (ER) and mitochondria, one of the key pathways in the disease. Based on this impairment, we are developing two therapeutical strategies to stop the progression of Wolfram syndrome. Associated with a prompt diagnosis, we are optimistic that the manifestations of the disease can be halted in a timely-manner, decreasing the probability to develop neurological and sensorineural symptoms.

Our first strategy is a pharmacological approach. We identified a strong and potent target expressed at the ER-mitochondria junction that interacts with Wolframin, the protein responsible for WS. Its activation restored the cellular alterations in patients’ fibroblasts and the altered behaviors observed in mouse and zebrafish models. Using a phenotypic screening in zebrafish, we already identified novel chemical entities that bind to our relevant target. Following these encouraging results, we are optimizing the molecules that will be tested in cells and in our different animal models. A multi-system screening method (zebrafish and mouse models) approach will be used to screen the panel of molecules and highlight compound that can eventually be used to treat WS patients.

We are also developing an innovative gene therapy. Based on recent studies in the lab, we have envisioned a different approach from what is currently developed. We decided to express a partner protein of Wolframin but not Wolframin itself. The size of this protein allowed us to use viral transfection using a virus already proven efficient in other disorders. By developing a unique gene therapy, which will be delivered systemically, we are hoping to stop the progression of the disease, body-wise, contrarily to the currently explored strategies. Our preliminary data in both zebrafish and mouse models of the disease are very encouraging. We are currently testing the long lasting effects of the gene therapy as well as its impacts on the different symptoms of the syndrome.

Best regards,
Benjamin