Seminar: Duchenne muscular dystrophy (DMD): a developmental disease

iStem - Institute for Stem Cell Therapy and Exploration of Monogenic Diseases

Christian Pinset, Research Director (CECS) and Emmanuelle Massourides, Associate Engineer (CECS) of the Muscular Diseases team at iStem will visit Oxford from the 25th - 27th of February 2020.

If you would like to meet with them to discuss their work on human iPSCs, DMD onset mechanisms & therapies development, please get in touch with Nicole Le Grand (nicole.legrand@paedaitrics.ox.ac.uk). 

Abstract

Duchenne muscular dystrophy (DMD) is too often considered as an affection of male children. Symptoms appear in early childhood, with a diagnosis made around 4, a time where the amount of muscle damage is already significant, preventing early therapeutic interventions that could be more efficient at halting disease progression. Thus, there is a critical need to better define DMD onset as well as its first manifestations, which could help identify early disease biomarkers and novel therapeutic targets.

We have used human induced pluripotent stem cells (hiPSCs) from DMD patients to model embryonic/foetal skeletal myogenesis, and compared their differentiation dynamics to healthy control cells by a comprehensive multi-omics analysis. Transcriptome and miRnome comparisons combined with protein analyses demonstrate that hiPSC skeletal muscle differentiation 1) mimics known DMD phenotypes at the differentiation endpoint; 2) homogeneously and robustly recapitulates key developmental steps – mesoderm, somite, skeletal muscle – which offers the possibility to explore dystrophin functions and find earlier disease biomarkers; and 3) that the skeletal muscle precursors cells obtained with, are compatible with high-throughput experiments, thus increasing the capability of drug screening.

Moreover, our data strongly argue for an early developmental manifestation of DMD whose onset is triggered at the somite stage before the entry into the skeletal muscle compartment. And we describe fibrosis as an intrinsic feature of skeletal muscle cells that also starts early during myogenesis. Dystrophin functions during development need to be reconsidered.

About ISTEM

I-Stem was created in 2005, through a collaboration between Inserm -National Institute of Health and Medical Research- and AFM-Telethon -French Association against Myopathies-. I-Stem is the largest French research and development institute dedicated to human pluripotent stem cells. The specific vocation of I-Stem is to explore all the therapeutic potentials of human pluripotent stem cells for applications in patients affected by rare diseases of genetic origin. In this context, our teams are developing two major areas of research. The first one is cell therapy, which aims to replace lost or diseased cells to other cells with the same characteristics, produced in the laboratory from pluripotent stem cells. The second area is pharmacology based on automated screening of large libraries of compounds, potentially endowed with therapeutic capacity, following modelling of molecular mechanisms associated with diseases, as revealed by the study of pluripotent stem cells from affected donors. Currently, the major pathological indications studied concern diseases of the muscle, motor neurons, skin, retina and those associated with abnormalities in the development of the central nervous system.

Speaker’s Affiliations and Bios

Christian Pinset MD, Team leader of Muscle Diseases at Istem, Inserm / UEVE 861; 28, rue Henri Desbruères Corbeil Essonnes, 91100 France.

My first subject of study focused on the immunology of cancers of the digestive tract in Villejuif. Secondly, I worked for twenty years on the ontogeny of skeletal muscle cells at the Institut Pasteur. At the dawn of the 2000s, I then founded a biotechnology company (Celogos) dedicated to the treatment of urinary and fecal incontinence by cell therapy. I then joined Istem to found the Muscle Diseases team to study Duchenne muscular dystrophy using human pluripotent stem cells.