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Combining gene therapy and ultrasounds to treat a severe neurodegenerative disease

Objectifs

The goal of this study is to test whether the combination of AAV-mediated gene therapy and low-intensity ultrasounds can provide a therapeutic effect in a mouse model of a severe neurodegenerative disease caused by a mutations in mitochondrial genes.

Résumé

Leigh syndrome (LS) is a fatal mitochondrial condition characterized by severe neurometabolic defects. No treatment is currently available for this disease because of the limited capability of drugs and viral vectors to cross the blood-brain barrier. Our team recently demonstrated that the use of a novel brain-penetrating viral vector provides a robust therapeutic benefit in a mouse model of LS (Reynaud et al. 2020, Brain). However, as this new viral vector cannot be used in humans, alternative strategies must be explored. Focused ultrasound is an emerging technology allowing to transiently et reversibly increase the permeability of the blood-brain barrier. Hence, we hypothesize that the combination of focused ultrasound and AAV vector delivery can provide a new and effective therapeutic option for LS.
We will test this hypothesis in a mouse model of LS and we will determine the possible benefit using a broad range of analyses including behavioral, histological, biochemical and molecular readouts.

Méthodes

The M2 student will perform the following techniques: mouse breeding, genotyping, ultrasound procedure, weight and temperature monitoring, behavioral tests, tissue extraction, brain sectionning, histology, immunostaining, microscopy, image analysis, protein dosage, and western blot.

Références

Reynaud-Dulaurier et al. (2020) PHP.B/eB vectors bring new successes to gene therapy for brain diseases, Front. Bioeng. Biotechnol., 8:582979

Reynaud-Dulaurier et al. (2020) Gene replacement therapy provides benefit in an adult mouse model of Leigh syndrome, Brain, 143(6):1686-1696.

Domaines d'expertise requis

No specific prior expertise is needed. The student will learn what is new for her/him.

Contacts

M. Decressac (Inserm Researcher/Group leader)
Email : Michael.Decressac@inserm.fr
Phone : 04.56.52.06.75

Téléchargement(s)

GIN_offre-stage-M2_2022-2023_MDecressac-2_20220707.pdf (PDF, 103668 Ko)

Mise à jour le 8 juillet 2022

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