Description du projet
Un traitement de modification génétique pour la maladie d’Alexander
La maladie d’Alexander (AxD), un trouble neurodégénératif autosomique dominant, est provoquée par des mutations faux-sens des gènes portant le code de la protéine acide fibrillaire gliale (GFAP), une protéine clé du filament intermédiaire des astrocytes. Cela entraîne la formation d’agrégats de GFAP et l’activation de la réponse au stress, compromettant ainsi l’homéostasie du système nerveux central. Le projet ASTRO-EDITING, financé par l’UE, entend récupérer la fonction des astrocytes en corrigeant les points de mutation de la GFAP. À cette fin, des scientifiques adopteront une approche de modification génétique fondée sur des vecteurs viraux adéno‑associés. Le projet fournira une validation de principe de la modification in vivo des astrocytes comme possible stratégie de thérapie génique pour l’AxD, offrant en même temps une approche thérapeutique innovante pour le traitement d’autres troubles dégénératifs.
Objectif
Alexander disease (AxD) is an autosomal dominant neurodegenerative disorder caused by missense mutations in the gene encoding the glial fibrillary acidic protein (GFAP), the major intermediate filament protein in astrocytes. Accumulation of GFAP aggregates in Rosenthal fibres leads to impairment of proteasomal activity and hyperactivation of the stress response, thus compromising astrocyte functions and altering the homeostasis of the central nervous system (CNS). Currently, this orphan disease lacks a cure.
The proposed project aims at providing in vivo proof-of-concept of safety, efficiency and efficacy of a novel and definitive AAV gene therapy approach based on gene editing / base editing strategies targeting GFAP mutational hotspots to recover pathological phenotypes in astrocytes. The candidate expects to outline novel editing platforms for widespread in vivo targeting of CNS astrocytes that could be applied for the treatment of AxD, as proposed in ASTRO-EDITING, and prospectively for disease modelling studies and therapeutic treatments of other neurological and psychiatric disorders by targeting pathological pathways involved in primary astrocyte degeneration or dysfunctional/maladaptive astrogliosis.
The proposal addresses the European issue of Horizon 2020, in the social challenge “Health, Demographic Change and Wellbeing” endeavours for the call “Better health and care, economic growth and sustainable health disease”, subject SC1-BMC-04-2018 “Rare Disease European Joint Programme Cofund”.
The expertise of the host laboratory, the international environment of OSR and the personalized career development plan will significantly reinforce candidate's competences and knowledge in the gene therapy field, expand his portfolio of therapeutic areas, create a new research niche, and strengthen his organizational, management and interpersonal skills, thus favouring the progressive acquisition of independence as experienced researcher in the scientific community.
Champ scientifique
Programme(s)
Régime de financement
MSCA-IF-EF-SE - Society and Enterprise panelCoordinateur
20132 Milano
Italie