Description du projet
Intégrer des gènes thérapeutiques dans les cassures de l’ADN
Les virus tels que le virus adéno-associé (VAA) et le VIH sont utilisés depuis longtemps pour acheminer l’ADN vers des cellules cibles et ont suscité un fort intérêt pour les applications de thérapie génique. L’intégration de l’ADN viral dans le génome de l’hôte et la perte de l’expression du transgène dans les tissus en cours de réplication remettent toutefois en question l’utilisation de ces vecteurs. Financé par le Conseil européen de la recherche, le projet EXPEDITE propose une alternative plus sûre aux virus en utilisant des systèmes d’édition de l’ADN pour une intégration précise de l’ADN au niveau des cassures double-brin induites. Des essais sur des tissus et des modèles animaux pertinents devraient élargir la portée de la thérapie, et modifier le paysage de la thérapie génique.
Objectif
In vivo gene therapy based on a single administration of adeno-associated viral (AAV) vectors is emerging as an effective therapeutic option for both monogenic and complex diseases. Given the episomal nature of the AAV genome, its applications are limited to non-replicating tissues like retina or adult liver. Several AAV-based products that target these tissues are either approved or in advanced clinical development. Despite this, some limitations still remain, including: the potential for insertional mutagenesis associated with genome-wide AAV integration; the loss of transgene expression from replicating tissues like newborn liver; and the challenge to counteract toxic gain-of-function mutations, which cause dominant diseases for which canonical gene replacement is ineffective. EXPEDITE aims to integrate therapeutic DNA at desired genomic loci safely and effectively, thus overcoming the above limitations. EXPEDITE will go beyond the current state-of-the-art by implementing and comparing two parallel strategies: (i) novel Cas fusion proteins to recruit DNA repair machineries at induced double stand breaks (DSBs) to maximize on-target donor DNA integration; (ii) novel cleavage-free platforms for therapeutic DNA integration, based on transposases or bacterial single strand-DNA annealing proteins. The therapeutic relevance of these platforms will be tested in the retina and liver, two highly relevant tissues for gene therapy, using animal models of inherited retinal degenerations and lysosomal storage diseases, respectively, and, ultimately, non human primates. To reduce the risk of potential off-targets, EXPEDITE will also test non-viral vectors for transient delivery of the genome editing tools while delivering the donor DNA via AAV. The results from EXPEDITE will allow significant expansion of the patient population that can benefit from in vivo gene therapy and may represent a change of paradigm for gene therapy by replacing canonical gene addition approaches.
Champ scientifique
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
HORIZON-ERC - HORIZON ERC GrantsInstitution d’accueil
00185 Roma
Italie