Novel use of exon skipping technology to study structure-function relationship of dystrophin

Información del proyecto

DYS_FUNCTION

Identificador del acuerdo de subvención: 658560

DOI

10.3030/658560

Proyecto cerrado

Fecha de la firma de la CE 13 Marzo 2015

Fecha de inicio 1 Enero 2016

Fecha de finalización 31 Diciembre 2017

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 195 454,80

Aportación de la UE

€ 195 454,80

Coordinado por

UNIVERSITY COLLEGE LONDON
United Kingdom

Objetivo

Duchenne muscular dystrophy (DMD) stems from loss of dystrophin in skeletal and cardiac muscles, which leads to loss of ambulation and cardio-respiratory failure. The most promising treatment that could be applicable to 83% of DMD patients is exon skipping, a technology where the EU is a world leader. Antisense oligonucleotide mediated exon skipping targets DMD pre-mRNA to induce skipping of specific exons and restore the open reading frame. This allows expression of shorter dystrophin proteins that lack domains encoded by the skipped exon(s). A crucial question is how to predict which short dystrophins will be stable and functional. This knowledge is fundamental to select DMD patients that would most benefit from this treatment and identify exons worth targeting via exon skipping.
The goal of this proposal is to develop a new use of exon skipping technology to rapidly generate mouse models to screen short dystrophins for in vivo stability and functionality in both skeletal and cardiac muscles. This is made possible by a new exon skipping chemistry developed in the UK with unparalleled skipping efficiency in vivo and capable of targeting the heart. I will use this technology to create mouse models for two short dystrophins generated in DMD patients undergoing exon 51 skipping in the current UK clinical trial. I will then biochemically assess their stability and functionality in limb, cardiac and respiratory muscles. Parallel histological studies will assess the presence of muscle pathology with a focus on heart and diaphragm that cannot be sampled in DMD patients. This project will serve as a trampoline for future studies to identify dystrophin exons that when skipped will produce functional proteins with clinical benefits. In addition, this research will generate new fundamental knowledge on dystrophin domains critical for muscle function and may help in the prognosis of DMD patients currently undergoing exon 51 skipping.

Ámbito científico (EuroSciVoc)

• ciencias médicas y de la salud › biotecnología médica › ingeniería genética › terapia génica
• ciencias médicas y de la salud › medicina básica › farmacología y farmacia › medicamento
• ciencias médicas y de la salud › medicina básica › neurología › distrofia muscular › distrofia muscular de duchenne
• ciencias médicas y de la salud › medicina básica › patología
• ciencias médicas y de la salud › medicina clínica › cardiología

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-2014-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF)
  

Régimen de financiación

MSCA-IF-EF-RI - RI – Reintegration panel

Convocatoria de propuestas

H2020-MSCA-IF-2014

Coordinador

UNIVERSITY COLLEGE LONDON

• Aportación neta de la UEn: € 195 454,80
• Dirección: GOWER STREET ; WC1E 6BT LONDON ; Reino Unido
• Región: London › Inner London — West › Camden and City of London
• Tipo de actividad: Higher or Secondary Education Establishments
• Coste total: € 195 454,80