Home   >   PhD topics   >   2015


Back to search form

In vivo genome editing to cure congenital myopathies

Research unit

UMR 7104 - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
1 rue Laurent Fries 67404 ILLKIRCH


Name: Physiopathologie des maladies neuromusculaires

Group leader: LAPORTE Jocelyn - jocelyn@igbmc.fr

Group leader's phone: 0388653412

Website: Visit website

Group organization:
- Chercheurs: 5
- ITA: 3
- Doctorants: 4
- Post-Docs: 1
- Autres: 2

Publications of the team linked to the topic (3 last years):
1) Cowling BS, Chevremont T, Prokic I, Kretz C, Ferry A, Coirault C, Koutsopoulos O, Laugel V, Romero NB, Laporte J. Reducing dynamin 2 expression rescues X-linked Centronuclear Myopathy. J Clin Invest. 2014 Mar 3;124(3):1350-63.
2) Amoasii L, Bertazzi DL, Tronchère H, Hnia K, Chicanne G, Rinaldi B, Cowling BS, Ferry A, Klaholz B, Payrastre B, Laporte J, Friant S. Phosphatase-dead Myotubularin Ameliorates X-linked Centronuclear Myopathy Phenotypes in mice. PLoS Genet. 2012 Oct;8(10):e1002965.
3) Cowling BS, Toussaint A, Muller J, Laporte J. Defective membrane remodeling in neuromuscular diseases: insights from animal models. PLoS Genet. 2012 Apr;8(4):e1002595.

About PhD

PhD Director: LAPORTE Jocelyn - jocelyn@igbmc.fr

Phone: 0388653412

Junior advisor: non

Co-tutely: non

Co-Director: COWLING Belinda
University of Co-Director: Strasbourg

About PhD topic :

Title: In vivo genome editing to cure congenital myopathies

Project: Most myopathies are rare monogenic diseases posing a significant burden for patients, families and our health care system. They are associated with severe muscle weakness and there are no specific therapies to date. The simplest theoretical therapy for monogenic diseases would be to erase the mutation on the patient genome. Genome editing technologies with engineered nucleases are revolutionizing the biological research as a novel way to manipulate the genetic information. Apart from meganucleases, zinc finger nucleases and transcription activator-like effectors (TALEs) proteins, the most rapidly developing technology is the class of RNA-guided endonucleases known as Cas9 from the microbial adaptive immune system CRISPR (clustered regularly interspaced short palindromic repeats), which can be easily targeted to virtually any genomic location of choice by a short RNA guide (sgRNA). Moreover, the addition of a homologous DNA template favours homology-directed repair and the insertion of a desired sequence.

The goal of this project is to validate genome editing in vitro and in vivo as a potential therapeutic strategy for congenital myopathies. The PhD student will establish proof-of-concepts that genome editing can correct mutations and subsequently the disease in the following models:
-in cells isolated from patients with myopathies, to show the correction is possible in a human pathological context.
-in muscle cells, to establish the best conditions for genome editing in a muscular context.
-in vivo in a mouse model of myopathy, through viral delivery of the editing toolbox, to assess the efficiency of correction and the correlation with the rescue of the phenotype.
Importantly, all tools (cells and animals, and the CRISPR/Cas9 technology) are already available in the laboratory. Moreover, the host team has a long-term expertise in the genetic basis and the pathophysiology of myopathies, and in gene transfert in mice.

This strategy has the potential to treat most monogenic diseases, and has the potential to create a direct path from a rapid personalized genetic diagnosis with the next generation technologies to personalized therapies through genome editing.

Wished skills:
-basic knowledge in molecular and cellular biology
-previous training period in a research lab
-interest for human genetic disease
-ability to acquire independence
-highly motivated to learn and to work in a team

Expertises which will be acquired during the training:
-molecular biology: genome editing with nucleases
-cell culture
-viral gene transfer and pathophysiology in mouse models
-management of a research project (choice of strategies, experiments, analysis and validation)
-oral (meetings, congress) and written (publications, posters) communications
-participation to the writing of grant applications and publications