Correction of duplications in the DMD gene by a CRISPR/Cas9 approach

Información del proyecto

DMD2CURE

Identificador del acuerdo de subvención: 703093

DOI

10.3030/703093

Proyecto cerrado

Fecha de la firma de la CE 14 Abril 2016

Fecha de inicio 1 Marzo 2017

Fecha de finalización 28 Febrero 2019

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 185 076,00

Aportación de la UE

€ 185 076,00

Coordinado por

ASSOCIATION GENETHON
France

Objetivo

Duchenne muscular dystrophy is an X-linked recessive muscle-wasting disease, characterized by progressive weakening of skeletal, respiratory, and cardiac muscle followed by necrosis and fibrosis. DMD affects ~1:3,500 live male births and is associated with delayed motor milestones. DMD occurs as a result of mutations within the DMD gene that lead to premature termination of translation. The most frequent type of mutations are exonic deletions and duplications that induce a frame-shift in the protein-coding sequence. To date no effective treatment exist for this disorder.
Duplications account for ~5–10% of all reported mutations in DMD in the Leiden database, although the incidence may be higher. Despite the limited number in DMD, duplications are widespread in almost all diseases and are generally neglected by therapeutic approaches.
New molecular tools, now represented by genome-editing technologies that use synthetic nucleases in order to introduce targeted alterations at specific sites in the genome, hold great promises for revolutionizing the gene therapy arena.
According to these premises, we propose a novel strategy based on the CRISPR/Cas9 system to repair tandem duplications by removing the mutation: compared to the exon deletions approach which uses two gRNA targeting two unique regions defining the sequence to be deleted, our approach will employ only one gRNA against a unique intronic sequence within the tandem duplication. This strategy will exploit the characteristic of tandem duplication (two identical contiguous sequences) and will result in the deletion or inversion of the mutation restoring the dystrophin expression. As a model we chose the exon 2 duplication which is the most frequent one in the DMD gene, but the same approach would be applicable to all tandem duplications.
This study will pave the way for the development of therapies against duplications also in pathologies in which the exon skipping approach is not feasible.

Ámbito científico (EuroSciVoc)

• ciencias médicas y de la salud › biotecnología médica › ingeniería genética › terapia génica
• ciencias médicas y de la salud › medicina básica › neurología › distrofia muscular › distrofia muscular de duchenne
• ciencias naturales › ciencias biológicas › genética › mutación
• ciencias médicas y de la salud › medicina básica › patología
• ciencias médicas y de la salud › ciencias de la salud › medicina personalizada

Programa(s)

• H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions PROGRAMA PRINCIPAL
  
• H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
  

Tema(s)

• MSCA-IF-2015-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF)
  

Régimen de financiación

MSCA-IF-EF-ST - Standard EF

Convocatoria de propuestas

H2020-MSCA-IF-2015

Coordinador

ASSOCIATION GENETHON

• Aportación neta de la UEn: € 185 076,00
• Dirección: RUE DE L INTERNATIONALE 1 BIS ; 91002 Evry ; Francia
• Tipo de actividad: Research Organisations
• Coste total: € 185 076,00